Upregulated CDKN2A expression may be an independent protective factor in Luminal-like breast cancer

Upregulated CDKN2A expression may be an independent protective factor in Luminal-like breast cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Upregulated CDKN2A expression may be an independent protective factor in Luminal-like breast cancer Yier Qiu, Guowen Lu, Yingjie Wu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-29971/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Previous studies revealed that CDKN2A (cyclin-dependent kinase inhibitor 2A) functioned as a tumour suppressor in various types of malignant tumours. The aim of the study was to clarify the value of CDKN2A expression in the prognosis of breast cancer. Method Using the Cancer Genome Atlas (TCGA) database, we compared CDKN2A mRNA levels between breast cancer tissues and normal tissues and analyzed the relationship between clinical features and CDKN2A expression with the Wilcox test and the Kruskal-Wallis test. Kaplan-Meier and Cox analyses were performed to determine the correlation between CDKN2A expression and breast cancer prognosis. Gene set enrichment analysis (GSEA) was performed using the TCGA data set. Results We first found that CDKN2A expression was markedly higher in breast cancer tissues than in normal tissues using the TCGA database (P=0.000). In addition, CDKN2A mRNA expression in breast cancer was positively correlated with age (P=0.018), histological types (P=0.028), ER status (P=0.000), PR status (P=0.000) and molecular subtypes (P=0.000). Kaplan-Meier analysis showed that increased CDKN2A expression was associated with increased survival time in breast cancer patients (P=0.000), especially in Luminal-like subtype. Univariate and multivariate Cox analyses indicated that CDKN2A expression was an independent prognostic biomarker for breast cancer (P=0.037). GSEA suggested that pathways involving cell adhesion molecules (CAMs), cytokine-receptor interactions, cytosolic DNA sensing, the cell cycle, and killer cell-mediated cytotoxicity were differentially enriched in the CDKN2A-high expression group. Conclusion Our research demonstrated that high CDKN2A mRNA expression was an independent protective factor for improved prognosis in Luminal-like breast cancer. Additionally, the signaling pathways related to CAMs, cytokine-receptor interactions, cytosolic DNA sensing, the cell cycle, and killer cell-mediated cytotoxicity regulated by CDKN2A mRNA expression should be further studied. Cancer Biology Oncology CDKN2A breast cancer Prognosis TCGA GSEA Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Breast cancer (BC) has the highest incidence of any cancer not only in China (38.9% of total cases) but also worldwide (30% of total cases) and is also second most common female malignancy worldwide[1,2]. Based on the expression of different molecular biomarkers, breast cancer patients are grouped into four molecular subtypes: luminal A, luminal B, HER‐2 enriched, and triple‐negative BC(TNBC)[3-5]. Accordingly, dependent on molecular subtypes, there are numerous standard protocols and emerging treatments for breast cancer patients in the last few years[6,7]. However, treatment resistance, tumour metastasis and recurrence in breast cancer seriously influence patient survival and quality of life[8]. Therefore, it remains important to detect effective prognostic biomarkers and therapeutic targets for breast cancer patients. Indeed, recent studies focus on an ideal target for breast cancer molecular targeting therapy. CDKN2A, which was situated on chromosome 9p21 and encoded the tumour suppressor protein p16[9], played a vital role in the occurrence of melanoma in the earliest stage[10]. The function and importance of CDKN2A in different types of cancer have been frequently inferred. Steven et al. demonstrated that CDKN2A served as a tumour suppressor in mice and prevented plexiform neurofibroma progression[11]. Moreover, another study showed that increased CDKN2A immunostaining indicated increased survival time in cats with oral squamous cell carcinomas[12]. In addition, Ganjoo’s study noted that CDKN2A deletion was associated with poor prognosis in histological subtypes of sarcoma[13]. Similarly, by inhibiting CDKN2A/p16, C-terminal binding protein-2 promoted proliferation and migration, as well as lower p16 expression was predictive of lower survival rate in BC patients[14]. In contrast, Lee et al. suggested that elevated CDKN2A expression in breast cancer predicted poor survival outcomes[15]. Given the controversy surrounding CDKN2A, we used TCGA data to identify the role of CDKN2A expression in breast cancer. Furthermore, GSEA was in order to recognize signalling pathways activated in breast cancer about the mechanism of CDKN2A. In our present study, we revealed that increased CDKN2A expression correlated with increased survival time in breast cancer. GSEA showed that signalling pathways associated with cell adhesion molecules (CAMs), the cell cycle, cytokine-receptor interactions, DNA replication, killer cell-mediated cytotoxicity and P53 were enriched in breast cancer patients with high CDKN2A expression. Methods Data mining We downloaded CDKN2A expression data and corresponding clinical information from TCGA database (https://portal.gdc.cancer.gov/)[16]. GSEA GSEA is a powerful processor that catches on several cancer-related datasets and reveals many common biological pathways[17]. In our study, GSEA was implemented to distinguish signalling pathways activated in breast cancer between high and low CDKN2A groups. Gene sets with a normal P-value <0.05 and a false discovery rate (FDR) <0.25 were considered to be significantly enriched. Statistical analysis Most statistical analyses were conducted using R (v.3.6.0). Differential expression of CDKN2A between normal tissues and tumour tissues in breast cancer patients was evaluated by Wilcox test. The relationship between clinicopathological parameters and CDKN2A mRNA expression was analysed with Wilcox test and Kruskal-Wallis test. Patients were assigned into two groups (high and low CDKN2A level) according to median value. Chi-square test was used to analyze associations of CDKN2A expression with clinicopathological data clinicopathological characteristics through IBM SPSS 24.0 (SPSS Inc, Chicago, USA) software. Survival analysis was displayed by Kaplan-Meier method and log-rank test. Univariate and multivariate analysis was implemented to distinguish prognostic factors with the Cox proportional hazard regression test. P-values of < 0.05 were regarded as statistically significant. Results Differential expression of CDKN2A in breast cancer patients based on TGCA data First, the CDKN2A expression data of 122 normal tissues and 1,066 tumor tissues from breast cancer patients were downloaded from TCGA in March 2019. We detected that CDKN2A levels were markedly higher in tumor tissues (P= 0.000) (Figure 1A). Besides, we compared CDKN2A mRNA levels in normal tissues and matched tumor tissues in breast cancer patients. Similarly, CDKN2A levels were higher in the tumor tissues (P= 0.000) (Figure 1B), which implies that CDKN2A may play a relevant role in breast cancer. Clinicopathological parameters As displayed in Table 1, we analysed Clinicopathological parameters of 832 female breast cancer patients according to clinical data downloaded from TCGA after excluding incomplete clinical prognostic information . The median age of confirmed diagnosis was 58 years old. Most of pathologic types (73.9%, n= 615) were of infiltrating ductal carcinoma , 19.6% (n= 163) were infiltrating lobular carcinoma , least were mixed histology (n= 25) and another specific carcinoma (n= 29). Moreover, clinical stage I of breast cancer was found in 143 patients ( 17.19% ), stage II was found in 482 patients (57.93%), stage III was found in 193 patients ( 23.20% ), and stage IV was found in 14 patients ( 1.68% ). Besides, there were four different subtypes of breast cancer, including Luminal A (73.6%, n= 613) , Luminal B (7.7%, n= 64) , HER2-enriched (17.1%, n= 142) and Triple negative (1.6%, n= 13) . The mean and median follow-up times after surgery were 3.2 and 2.3 years respectively. During the 23 years of follow-up in this survey, 109 (13.1%) patients died. Table 1. Clinicopathological parameters of the breast cancer patients. Clinicopathological parameters N Age ≤58 416 >58 416 Histological type N Infiltrating ductal carcinoma 615 Infiltrating lobular carcinoma 163 Mixed histology 25 Another specific carcinoma 29 Tumor classification T1 220 T2 486 T3 104 T4 22 Lymphatic classification N0 396 N1 281 N2 105 N3 50 Distant classification M0 818 M1 14 Clinical stage I 143 II 482 III 193 IV 14 Estrogen receptor Positive 666 Negative 166 Progesterone receptor Positive 583 Negative 249 HER2 Positive 77 Negative 755 Molecular subtypes Luminal A 613 Luminal B 64 Triple negative 142 HER2-enriched 13 Survival status Death 109 Survival 723 CDKN2A expression in breast cancer tissues according to clinical characteristics We further investigated CDKN2A expression between tumour tissues and normal tissues in breast cancer patients based on clinical characteristics (Figure 2). Our results revealed that there were differences in CDKN2A expression among four molecular subtypes ( P= 0.000 ). In addition , we found that as the clinical stage increased, CDKN2A expression decreased inversely (P= 0.491). However, no differences were observed according to TNM stage, distant metastasis and HER2 status (P= 0.917, P= 0.458, P= 0.5 and P= 0.579 respectively). CDKN2A expression is associated with clinicopathological features To evaluate the clinical significance of CDKN2A, we analysed the associations between CDKN2A expression and the clinicopathological characteristics by chi-square test. CDKN2A expression was correlated with age (P= 0.018), histological types (P= 0.028), ER status (P= 0.000) , PR status (P= 0.000) and molecular subtypes (P= 0.000) , respectively. However, no significant correlation was detected in TNM stage and HER2 status (Table 2). Table 2. Relationships of CDKN2A expression with clinical features based on TGCA data. Variable CDKN2A (n) low high P 1 n=416 n=416 Age(years) ≤58 191 225 0.018 >58 225 191 Histological types Infiltrating ductal carcinoma 315 300 0.028 Infiltrating lobular carcinoma 69 94 Mixed histology 18 7 Other specific carcinoma 14 15 T classification T1 113 107 0.924 T2 239 247 T3 52 52 T4 12 10 Lymphatic metastasis N0 195 201 0.051 N1 135 146 N2 65 40 N3 21 29 Distant metastasis M0 409 409 1.000 M1 7 7 Clinical stage I 69 74 0.831 II 238 244 III 102 91 Ⅳ 7 7 ER Positive 364 302 0.000 Negative 52 114 HR Positive 316 267 0.000 Negative 100 149 HER2 Positive 41 36 0.550 Negative 375 380 Molecular subtypes Luminal A 334 279 0.000 Luminal B 35 29 Triple negative 41 101 HER2-enriched 6 7 The bold number is on behalf of the P-values with significant differences. 1 P Value was calculated by χ2 test. ER: estrogen receptor ; PR: progesterone receptor ; HER2: human epidermal growth factor receptor 2. High CDKN2A expression is an independent protective factor for OS Survival analysis showed that high CDKN2A expression was positively associated with overall survival (OS) (P=0.000, Figure 3A). We also found that increased CDKN2A expression was related to superior overall survival, in spite of age, lymphatic metastasis and HER2 status. Beyond that, high CDKN2A expression was correlated with superior OS, especially in breast cancer patients with T2-T3 classification, clinical stage II-III and luminal-like subtype but without distant metastasis (Figure 3B-P). Univariate Cox regression analysis showed that CDKN2A expression, age, TNM stage and HER2 status were significantly associated with OS (Table 3). Moreover, multivariate analysis confirmed that CDKN2A expression and age were independent predictors of OS in breast cancer patients (Table 3). Table 3. Univariate and multivariate analyses in breast cancer patients Variable Univariate analysis Multivariate analysis HR 95% CI P value HR 95% CI P value CDKN2A 0.701 0.584-0.842 0.000 0.976 0.953-0.998 0.037 Age 1.033 1.018-1.049 0.000 1.030 1.014-1.046 0.000 T 1.624 1.280-2.059 0.000 1.260 0.964-1.645 0.091 N 1.624 1.334-1.978 0.000 1.267 0.999-1.607 0.051 M 3.251 1.961-5.391 0.000 1.885 0.925-3.842 0.081 STAGE 0.571 0.419-1.049 0.000 0.704 0.482-1.028 0.069 ER 1.067 0.697-1.632 0.765 PR 1.225 0.831-1.806 0.304 HER-2 0.501 0.312-0.811 0.004 0.743 0.441-1.253 0.265 Molecular types 1.143 0.939-1.391 0.182 HR: Hazard ratio; CI: Confidence interval. The bold number is on behalf of P-values with significant differences. CDKN2A -related signaling pathway We implemented GSEA to recognize the signalling pathways activated in breast cancer by comparing the low and high CDKN2A expression datasets. GSEA showed significant differences (FDR<0.25, NOM P-value <0.05) in the enrichment of the MSigDB Collection pathways. As shown in Table 4, we chose the signalling pathways that were most significantly enriched in breast cancer patients with high CDKN2A expression, including pathways related to bladder cancer, CAMs, the cell cycle, cytokine-receptor interactions, cytosolic DNA sensing, DNA replication, killer cell-mediated cytotoxicity and P53 (Figure 4). Table 4. Gene sets enriched in the high CDKN2A expression. Gene set name NES NOM p-val FDR q-val BLADDER_CANCER 1.857 0.006 0.108 DNA_REPLICATION 1.853 0.013 0.094 CELL_ADHESION_MOLECULES_CAMS 1.763 0.032 0.062 CELL_CYCLE 1.780 0.040 0.058 CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION 1.656 0.042 0.086 NATURAL_KILLER_CELL_MEDIATED_CYTOTOXICITY 1.634 0.043 0.085 P53_SIGNALING_PATHWAY 1.602 0.047 0.093 CYTOSOLIC_DNA_SENSING_PATHWAY 1.556 0.048 0.114 NES: normalized enrichment score; NOM: nominal; FDR: false discovery rate. Gene sets with NOM p-val ＜ 0.05 and FDR q-val ＜ 0.25 are regarded as significant. Discussion Breast cancer (BC) accounts for approximately 2.1 million new cases and 62,000 deaths per year, with high mortality and morbidity rates in women worldwide[1]. Meanwhile, owing to gene expression profiles of breast cancer, there were four molecular subtypes as well as each requires different treatment[18]. Despite substantial research efforts devoted to exploring effective biomarkers for breast cancer, few basic research results have been applied in the clinical field. As a consequence, it is badly in need of recognizing truly effective biomarkers and therapeutic targets for breast cancer. Recent studies have reported that CDKN2A functions as a tumour suppressor in different types of carcinoma, such as melanoma[10], ovarian cancer[19], lung cancer[20], atypical neurofibroma[11], malignant mesothelioma[21] and bladder cancer[22]. Several studies also showed that decreased CDKN2A expression correlated to poor prognosis in osteosarcoma[23], soft tissue sarcoma[13], and oral squamous cell carcinoma[24]. With respect to the roles of CDKN2A expression in breast cancer, Feng et al found that KDM2B promoted triple-negative breast cancer cell proliferation by suppressing CDKN2A/p16 expression[25]. Fu et al. also showed that C-terminal binding protein-2 motivated proliferation and migration in breast cancer via the inhibition of CDKN2A/p16[14]. The above results suggest that reduced CDKN2A expression contributes to poor outcomes in breast cancer. However, contrasting results showed that increased expression of CDKN2A/p16 was associated with poor prognosis in breast cancer [15]. Therefore, there still exists controversy regarding the prognostic value of CDKN2A in BC, and signalling pathways related to the regulatory mechanism have not yet been determined. In our study, we first found that CDKN2A expression was markedly elevated in BC tissues than in normal tissues using TCGA database, which implied that CDKN2A may play its part in the tumorigenesis of BC. Thus, we further analysed the relationship between CDKN2A expression and clinical features of BC patients. The results showed that the CDKN2A expression was positively related to age, ER status, PR status and molecular subtypes in breast cancer. Then, the Kaplan-Meier curves for OS also showed that reduced CDKN2A expression correlated to decreased survival time, especially in Luminal-like subtype, a finding that was in contrast to the findings of Lee’s study[15] but was consistent with the previously identified roles of CDKN2A in breast cancer[14,25,23]. Then Univariate and multivariate Cox analyses indicated CDKN2A expression and age were prognostic biomarkers for BC patients. Additionally, to identify the potential signalling pathways, we implemented GSEA comparing the low and high CDKN2A expression datasets and observed that pathways related to bladder cancer, CAMs, the cell cycle, cytokine-receptor interactions, cytosolic DNA sensing, DNA replication, killer cell-mediated cytotoxicity and P53 were enriched in breast cancer. A previous study showed that loss of CDKN2A negatively regulated with the cell cycle and CDK4/6/RB pathway in Luminal-like breast cancer patients[26]. Meanwhile, another study pointed out that cancer gene therapy mediated by CDKN2A was beneficial for the induction of cell death in non-small-cell lung carcinoma[20]. In addition, we found CDKN2A mRNA expression was associated with bladder cancer, the cell cycle and DNA replication[27-29]. However, it is the first time that the results in this paper showing correlations between CDKN2A expression and signalling pathways involving CAMs, cytokine-receptor interactions, cytosolic DNA sensing and killer cell-mediated cytotoxicity are reported, as well as biological mechanism needs to be further clarified. Conclusions In conclusion, upregulated CDKN2A expression may be an effective prognostic biomarker in luminal-like breast cancer suggesting longer survival times. However, we should focus on the association between luminal-like subtypes and CDKN2A to inform the current controversial results. Additionally, signalling pathways related to CAMs, cytokine-receptor interactions, cytosolic DNA sensing and killer cell-mediated cytotoxicity may be pivotal pathways regulated by CDKN2A in breast cancer, and these relationships should be further clarified. Abbreviations CDKN2A: cyclin dependent kinase inhibitor 2A; TGCA: The Cancer Genome Atlas; GSEA: Gene Set Enrichment Analysis; OS: overall survival; HR: Hazard ratio; CI: Confidence interval; NES: normalized enrichment score; NOM: nominal; FDR: false discovery rate Declarations Acknowledgements None. Authors’ contributions YEQ and YJW participated in the study design. WJX and GWL contributed to data collection and analysis. All authors were involved in the writing of the article. YEQ critically reviewed the manuscript. All authors have read and approved the final manuscript. Funding None. Availability of data and materials The datasets analyzed during the current study are available in the TGCA (https://portal.gdc.cancer.gov/). Ethics approval and consent to participate None. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. References Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. 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Cancer Res 78 (3):781-797. doi:10.1158/0008-5472.CAN-17-2802 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-29971","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":605856,"identity":"037fdcbf-ffb0-462b-b976-26f9998d03a1","order_by":0,"name":"Yier Qiu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYDACZiBOACF25gaGDwY2diRoYWZsYJxRkJZMtGVgLcw8Hw4xNhBSynecx0ziQcW9PH5mxsbHNgYHmBnYDx/dgE+L5GGgloQzxcWSzYzNxjkGd/gYeNLSbuDTYgDSktiWkLjhMGObdI7BM2YGCR4zIrT8S0jcD9JiYXCYsYE4LQ1AW5iBWhiI0SJ5mK3YIuFYQuKMw4zNhj0GaclshPzCd/7wxps/ahIS+9ubDz748cfGjp/98DG8WhgOMLBIoAiw4VUO0cL8gaCiUTAKRsEoGNkAAJgcSZzLL39JAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-3721-6644","institution":"Yinzhou People's Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yier","middleName":"","lastName":"Qiu","suffix":""},{"id":605857,"identity":"7e05ed98-b2b8-4447-80a1-a3d834756877","order_by":1,"name":"Guowen Lu","email":"","orcid":"","institution":"Yinzhou People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Guowen","middleName":"","lastName":"Lu","suffix":""},{"id":605858,"identity":"db74d15e-a3dd-43cb-8e91-cd7c87c95087","order_by":2,"name":"Yingjie Wu","email":"","orcid":"","institution":"Yinzhou People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yingjie","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2020-05-19 05:29:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-29971/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-29971/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":1206790,"identity":"bd30e1d5-761b-4810-9c83-5f76501cf77c","added_by":"auto","created_at":"2020-05-29 14:03:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":43845,"visible":true,"origin":"","legend":"CDKN2A expression in breast cancer patients based on TGCA data. A: Scatter gram represents CDKN2A expressions from normal to tumor tissues, respectively; B: A dot plot with connecting lines represents CDKN2A expressions from normal to matched tumor tissues. P-values of \u003c 0.05 were considered significant.","description":"","filename":"1.PNG","url":"https://assets-eu.researchsquare.com/files/rs-29971/v1/1.PNG"},{"id":1206791,"identity":"095d7b6e-a933-4cae-a609-3daf38038d5a","added_by":"auto","created_at":"2020-05-29 14:03:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":54341,"visible":true,"origin":"","legend":"CDKN2A expression on the basis of TGCA data. A-F: CDKN2A expression was compared according to patient age, T classification, lymph node, distant metastasis and clinical stage, respectively.","description":"","filename":"2.PNG","url":"https://assets-eu.researchsquare.com/files/rs-29971/v1/2.PNG"},{"id":1206792,"identity":"77190ed5-982e-4212-9d54-7df39df58a04","added_by":"auto","created_at":"2020-05-29 14:03:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":88433,"visible":true,"origin":"","legend":"Survival curves on TCGA data. (A): Comparisons of the overall survival duration between the low and high CDKN2A expression; (B-C): Independent of patient age; (D-E): Independent of T classifications;( F-G): Independent of lymphatic metastasis; (H): Independent of distant metastasis; (I-J): Independent of clinical stage; (K-P): Independent of ER status, PR status, HER2 and molecular subtypes.","description":"","filename":"3.PNG","url":"https://assets-eu.researchsquare.com/files/rs-29971/v1/3.PNG"},{"id":1206793,"identity":"78d652d2-3e17-4632-85c6-ae6935490261","added_by":"auto","created_at":"2020-05-29 14:03:24","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":161671,"visible":true,"origin":"","legend":"Enrichment plots from GSEA. Different pathways including bladder cancer (A), cell adhesion molecules cams (B), cell cycle (C), cytokine receptor interaction (D), cytosolic DNA sensing cell cycle (E), DNA replication (F), killer cell mediated cytotoxicity (G) and P53 signaling (H) are enriched in breast cancer patients with high CDKN2A expression according to GSEA. (I): Sum of 8 enriched pathways in breast cancer patients with high CDKN2A expression.","description":"","filename":"4.PNG","url":"https://assets-eu.researchsquare.com/files/rs-29971/v1/4.PNG"},{"id":13533491,"identity":"530a530e-48f9-4db2-8161-1140ee8afaf9","added_by":"auto","created_at":"2021-09-17 01:21:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":691794,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-29971/v1/6c4ff6f3-15de-49a6-909f-e4ddb3a3a444.pdf"}],"financialInterests":"","formattedTitle":"Upregulated CDKN2A expression may be an independent protective factor in Luminal-like breast cancer","fulltext":[{"header":"Background","content":"\u003cp\u003eBreast cancer (BC) has the highest incidence of any cancer not only in China (38.9% of total cases) but also worldwide (30% of total cases) and is also second most common female malignancy worldwide[1,2]. Based on the expression of different molecular biomarkers, breast cancer patients are grouped into four molecular subtypes: luminal A, luminal B, HER‐2 enriched, and triple‐negative BC(TNBC)[3-5]. Accordingly, dependent on molecular subtypes, there are numerous standard protocols and emerging treatments for breast cancer patients in the last few years[6,7]. However, treatment resistance, tumour metastasis and recurrence in breast cancer seriously influence patient survival and quality of life[8]. Therefore, it remains important to detect effective prognostic biomarkers and therapeutic targets for breast cancer patients.\u003c/p\u003e\n\u003cp\u003eIndeed, recent studies focus on an ideal target for breast cancer molecular targeting therapy. CDKN2A, which was situated on chromosome 9p21 and encoded the tumour suppressor protein p16[9], played a vital role in the occurrence of melanoma in the earliest stage[10]. The function and importance of CDKN2A in different types of cancer have been frequently inferred. Steven et al. demonstrated that CDKN2A served as a tumour suppressor in mice and prevented plexiform neurofibroma progression[11]. Moreover, another study showed that increased CDKN2A immunostaining indicated increased survival time in cats with oral squamous cell carcinomas[12]. In addition, Ganjoo\u0026rsquo;s study noted that CDKN2A deletion was associated with poor prognosis in histological subtypes of sarcoma[13]. Similarly, by inhibiting CDKN2A/p16, C-terminal binding protein-2 promoted proliferation and migration, as well as lower p16 expression was predictive of lower survival rate in BC patients[14]. In contrast, Lee et al. suggested that elevated CDKN2A expression in breast cancer predicted poor survival outcomes[15].\u003c/p\u003e\n\u003cp\u003eGiven the controversy surrounding CDKN2A, we used TCGA data to identify the role of CDKN2A expression in breast cancer. Furthermore, GSEA was in order to recognize signalling pathways activated in breast cancer about the mechanism of CDKN2A. In our present study, we revealed that increased CDKN2A expression correlated with increased survival time in breast cancer. GSEA showed that signalling pathways associated with cell adhesion molecules (CAMs), the cell cycle, cytokine-receptor interactions, DNA replication, killer cell-mediated cytotoxicity and P53 were enriched in breast cancer patients with high CDKN2A expression.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eData mining\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe downloaded CDKN2A expression data and corresponding clinical information from TCGA database (https://portal.gdc.cancer.gov/)[16].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGSEA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGSEA is a powerful processor that catches on several cancer-related datasets and reveals many common biological pathways[17]. In our study, GSEA was implemented to distinguish signalling pathways activated in breast cancer between high and low CDKN2A groups. Gene sets with a normal P-value \u0026lt;0.05 and a false discovery rate (FDR) \u0026lt;0.25 were considered to be significantly enriched.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMost statistical analyses were conducted using R (v.3.6.0). Differential expression of CDKN2A between normal tissues and tumour tissues in breast cancer patients was evaluated by Wilcox test. The relationship between clinicopathological parameters and CDKN2A mRNA expression was analysed with Wilcox test and Kruskal-Wallis test. Patients were assigned into two groups (high and low CDKN2A level) according to median value. Chi-square test was used to analyze associations of CDKN2A expression with clinicopathological data clinicopathological characteristics through IBM SPSS 24.0 (SPSS Inc, Chicago, USA) software. Survival analysis was displayed by Kaplan-Meier method and log-rank test. Univariate and multivariate analysis was implemented to distinguish prognostic factors with the Cox proportional hazard regression test. P-values of \u0026lt; 0.05 were regarded as statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eDifferential expression of CDKN2A in breast cancer patients based on TGCA data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFirst, the CDKN2A expression data of 122 normal tissues and 1,066 tumor tissues from breast cancer patients were downloaded from TCGA in March 2019. We detected that CDKN2A levels were markedly higher in tumor tissues (P= 0.000) (Figure 1A). Besides, we compared CDKN2A mRNA levels in normal tissues and matched tumor tissues in breast cancer patients. Similarly, CDKN2A levels were higher in the tumor tissues (P= 0.000) (Figure 1B), which implies that CDKN2A may play a relevant role in breast cancer.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eClinicopathological parameters \u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eAs displayed in Table 1, we analysed\u003c/span\u003e \u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eClinicopathological parameters of 832 female breast cancer patients according to clinical data downloaded from TCGA after excluding incomplete clinical prognostic information\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e. The median age of confirmed diagnosis was 58 years old. Most of pathologic types (73.9%, n= 615) were of \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003einfiltrating ductal carcinoma\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e, 19.6% (n= 163) were \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003einfiltrating lobular carcinoma\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e, least were \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003emixed histology \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e(n= 25)\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e and another specific carcinoma \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e(n= 29). Moreover, clinical stage I of breast cancer was found in 143 patients (\u003cspan style=\"color: black;\"\u003e17.19%\u003c/span\u003e), stage II was found in 482 patients (57.93%), stage III was found in 193 patients (\u003cspan style=\"color: black;\"\u003e23.20%\u003c/span\u003e), and stage IV was found in 14 patients (\u003cspan style=\"color: black;\"\u003e1.68%\u003c/span\u003e). Besides, there were four different subtypes of breast cancer, including \u003cspan style=\"color: black;\"\u003eLuminal A \u003c/span\u003e(73.6%, n= 613)\u003cspan style=\"color: black;\"\u003e, Luminal B\u003c/span\u003e (7.7%, n= 64)\u003cspan style=\"color: black;\"\u003e, HER2-enriched \u003c/span\u003e(17.1%, n= 142) \u003cspan style=\"color: black;\"\u003eand Triple negative\u003c/span\u003e (1.6%, n= 13)\u003cspan style=\"color: black;\"\u003e.\u003c/span\u003e The mean and median follow-up times after surgery were 3.2 and 2.3 years respectively. During the 23 years of follow-up in this survey, 109 (13.1%) patients died.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eTable 1. \u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eClinicopathological parameters of the breast cancer patients.\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse; border: none;\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eClinicopathological parameters\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eN\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eAge\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026le;58\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e416\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026gt;58\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e416\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eHistological type\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eN\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eInfiltrating ductal carcinoma\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e615\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eInfiltrating lobular carcinoma\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e163\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eMixed histology\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e25\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eAnother specific carcinoma\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e29\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eTumor classification\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eT1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e220\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eT2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e486 \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eT3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e104 \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eT4\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e22\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eLymphatic classification\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eN0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e396\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eN1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e281\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eN2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e105 \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eN3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e50\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eDistant classification\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eM0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e818 \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eM1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e14\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eClinical stage\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eI\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e143 \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eII\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e482\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eIII\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e193\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eIV\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e14 \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eEstrogen receptor\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003ePositive\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e666\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eNegative\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e166\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eProgesterone receptor\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003ePositive\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e583\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eNegative\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e249\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eHER2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003ePositive\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e77\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eNegative\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e755\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eMolecular subtypes\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eLuminal A\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e613\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eLuminal B\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e64\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eTriple negative\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e142\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eHER2-enriched\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e13\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eSurvival status\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eDeath\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e109 \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eSurvival\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 207.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"277\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e723\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eCDKN2A\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e expression in breast cancer tissues according to clinical characteristics\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eWe further \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003einvestigated \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eCDKN2A expression between tumour tissues and normal tissues in breast cancer patients based on clinical characteristics (Figure 2). Our results revealed that \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003ethere were differences in CDKN2A expression among four molecular subtypes (\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eP= 0.000\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e). In addition\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e, we found that as the clinical stage increased, CDKN2A expression decreased inversely (P= 0.491). However, no differences were observed according to TNM stage, distant metastasis and HER2 status (P= 0.917, P= 0.458, P= 0.5 and P= 0.579 respectively).\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eCDKN2A expression is associated with clinicopathological features\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eTo evaluate the clinical significance of CDKN2A, we analysed the associations between CDKN2A expression and the clinicopathological characteristics by chi-square test. CDKN2A expression was correlated with age (P= 0.018), histological types (P= 0.028), \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eER status \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e(P= 0.000)\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e, PR status \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e(P= 0.000)\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e and molecular subtypes\u003c/span\u003e \u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e(P= 0.000)\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e, respectively. However, no significant correlation was detected in TNM stage and HER2 status (Table 2). \u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eTable 2. \u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eRelationships of CDKN2A expression with clinical features \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003ebased on TGCA data. \u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse; border: none;\" width=\"570\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 3.15in; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" rowspan=\"3\" width=\"302\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eVariable\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 200.9pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"3\" width=\"268\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eCDKN2A (n)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003elow\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003ehigh\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"79\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cem\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eP\u003c/span\u003e\u003c/em\u003e\u003csup\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003en=416\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003en=416\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"79\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 120.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"2\" width=\"161\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eAge(years)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026le;58\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e191\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e225\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"2\" width=\"79\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.018\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026gt;58\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e225\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e191\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 29.5pt;\"\u003e\n\u003ctd style=\"width: 120.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" rowspan=\"4\" width=\"161\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eHistological types\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eInfiltrating ductal carcinoma\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e315\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e300\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" rowspan=\"4\" width=\"79\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.028\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 29.5pt;\"\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eInfiltrating lobular carcinoma\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e69\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e94\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 29.5pt;\"\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eMixed histology\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e18\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e7\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 29.5pt;\"\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eOther specific carcinoma\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e14\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e15\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 29.5pt;\"\u003e\n\u003ctd style=\"width: 120.5pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" rowspan=\"4\" width=\"161\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eT classification\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; border-top: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eT1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-top: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e113\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-top: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e107\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.1pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 29.5pt;\" rowspan=\"4\" width=\"79\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.924\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eT2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e239\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; 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line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eN0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e195\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e201\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.1pt; border: none; 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line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e135\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e146\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eN2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e65\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e40\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eN3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e21\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e29\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 120.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"2\" width=\"161\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eDistant metastasis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eM0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e409\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e409\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"2\" width=\"79\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.000\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eM1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e7\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e7 \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 120.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"4\" width=\"161\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eClinical stage\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eI\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e69\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e74\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"4\" width=\"79\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.831\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eII\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e238\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e244\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 30.25pt;\"\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 30.25pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eIII\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 30.25pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e102\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 30.25pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e91\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eⅣ\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e7\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e7\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 120.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"2\" width=\"161\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eER\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003ePositive\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e364\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e302\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"2\" width=\"79\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.000\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eNegative\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e52\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e114\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 120.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"2\" width=\"161\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eHR\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003ePositive\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e316\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e267\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"2\" width=\"79\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.000\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eNegative\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e100\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e149\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 120.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"2\" width=\"161\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eHER2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003ePositive\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e41\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e36\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"2\" width=\"79\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.550\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eNegative\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e375\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e380\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 120.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"4\" width=\"161\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eMolecular subtypes\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eLuminal A\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e334\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e279\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" rowspan=\"4\" width=\"79\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.000\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eLuminal B\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e35\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e29\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eTriple negative\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e41\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e101\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.3pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eHER2-enriched\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 78.0pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 63.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"85\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e7\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eThe bold number is on behalf of the P-values with significant differences. \u003csup\u003e1\u003c/sup\u003e\u003cem\u003eP \u003c/em\u003eValue was calculated by \u0026chi;2 test. ER: \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eestrogen receptor\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e; PR: \u003cspan style=\"color: black;\"\u003eprogesterone receptor\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e; HER2: human epidermal growth factor receptor 2. \u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eHigh CDKN2A expression is an independent protective factor for OS \u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eSurvival analysis showed that high CDKN2A expression was positively associated with overall survival (OS) (P=0.000, Figure 3A). We also found that increased CDKN2A expression was related \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eto\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e superior overall survival, in spite of age, lymphatic metastasis and HER2 status. Beyond that, high CDKN2A expression was correlated \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003ewith\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e superior OS, especially in breast cancer patients with T2-T3 classification, clinical stage II-III and luminal-like subtype but without distant metastasis (Figure 3B-P).\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eUnivariate Cox regression analysis showed that\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e \u003cspan style=\"color: black;\"\u003eCDKN2A expression, age, TNM stage and HER2 status were significantly associated with OS (Table 3). Moreover, multivariate analysis confirmed that CDKN2A expression and age were independent predictors of OS in breast cancer patients (Table 3). \u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eTable 3. \u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eUnivariate and multivariate analyses in breast cancer patients \u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width: 420.8pt; border-collapse: collapse; border: none;\" width=\"561\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 19.75pt;\"\u003e\n\u003ctd style=\"width: 60.8pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.75pt;\" rowspan=\"2\" width=\"81\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eVariable\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 202.05pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.75pt;\" colspan=\"3\" width=\"269\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eUnivariate analysis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 119.9pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.75pt;\" colspan=\"3\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eMultivariate analysis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.7pt;\"\u003e\n\u003ctd style=\"width: 59.7pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"80\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eHR\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"113\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e95% CI\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 57.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"77\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cem\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eP\u003c/span\u003e\u003c/em\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e value\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.2pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"66\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eHR\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 56.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"75\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e95% CI\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 52.25pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" colspan=\"2\" width=\"70\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cem\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eP\u003c/span\u003e\u003c/em\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e value\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.7pt;\"\u003e\n\u003ctd style=\"width: 60.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"81\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eCDKN2A\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"80\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.701\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"113\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.584-0.842\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 57.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"77\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.000\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"66\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.976\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" colspan=\"2\" width=\"94\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.953-0.998\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 38.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"51\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.037\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.7pt;\"\u003e\n\u003ctd style=\"width: 60.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"81\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eAge\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"80\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.033\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"113\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.018-1.049\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 57.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"77\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.000\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"66\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.030\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" colspan=\"2\" width=\"94\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.014-1.046\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 38.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"51\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.000\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.7pt;\"\u003e\n\u003ctd style=\"width: 60.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"81\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eT\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"80\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.624\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"113\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.280-2.059\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 57.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"77\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.000\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"66\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.260\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" colspan=\"2\" width=\"94\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.964-1.645\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 38.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"51\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.091\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.7pt;\"\u003e\n\u003ctd style=\"width: 60.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"81\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eN\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"80\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.624\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"113\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.334-1.978\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 57.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"77\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.000\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"66\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.267\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" colspan=\"2\" width=\"94\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.999-1.607\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 38.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"51\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.051\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.7pt;\"\u003e\n\u003ctd style=\"width: 60.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"81\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eM\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"80\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e3.251\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"113\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.961-5.391\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 57.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"77\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.000\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"66\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.885\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" colspan=\"2\" width=\"94\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.925-3.842\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 38.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"51\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.081\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.7pt;\"\u003e\n\u003ctd style=\"width: 60.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"81\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eSTAGE\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"80\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.571\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"113\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.419-1.049\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 57.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"77\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.000\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"66\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.704\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" colspan=\"2\" width=\"94\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.482-1.028\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 38.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"51\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.069\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.7pt;\"\u003e\n\u003ctd style=\"width: 60.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"81\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eER\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"80\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.067\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"113\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.697-1.632\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 57.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"77\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.765\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"66\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" colspan=\"2\" width=\"94\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 38.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"51\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.7pt;\"\u003e\n\u003ctd style=\"width: 60.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"81\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003ePR\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"80\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.225\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"113\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.831-1.806\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 57.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"77\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.304\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"66\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" colspan=\"2\" width=\"94\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 38.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"51\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.7pt;\"\u003e\n\u003ctd style=\"width: 60.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"81\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eHER-2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"80\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.501\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"113\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.312-0.811\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 57.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"77\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.004\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"66\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.743\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" colspan=\"2\" width=\"94\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.441-1.253\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 38.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"51\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.265\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 20.7pt;\"\u003e\n\u003ctd style=\"width: 60.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"81\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eMolecular types\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 59.7pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"80\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e1.143\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 84.8pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"113\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.939-1.391\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 57.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"77\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e0.182\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.2pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"66\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 70.7pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" colspan=\"2\" width=\"94\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 38.05pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 20.7pt;\" width=\"51\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: none;\" width=\"81\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"80\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"113\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"77\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"66\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"19\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: none;\" width=\"51\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"margin-bottom: 12.0pt; text-align: left; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003eHR: Hazard ratio; CI: Confidence interval. The bold number is on behalf of P-values with significant differences.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 200%; text-autospace: none;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif; color: black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eCDKN2A\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e-related signaling pathway\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eWe implemented GSEA\u003c/span\u003e \u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eto recognize the signalling pathways activated in breast cancer by comparing the low and high CDKN2A expression datasets. GSEA showed significant differences (FDR\u0026lt;0.25, NOM P-value \u0026lt;0.05) in the enrichment of the MSigDB Collection pathways. As shown in Table 4, we chose the signalling pathways that were most significantly enriched in breast cancer patients with high CDKN2A expression, including pathways related to bladder cancer, CAMs, the cell cycle, cytokine-receptor interactions, cytosolic DNA sensing, DNA replication, killer cell-mediated cytotoxicity and P53 (Figure 4).\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eTable 4.\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e Gene sets enriched in the high CDKN2A expression.\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse; border: none;\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 290.35pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"387\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eGene set name\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eNES\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eNOM p-val \u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.4pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eFDR q-val\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 290.35pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"387\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eBLADDER_CANCER\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e1.857\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.006\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.108\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 290.35pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"387\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eDNA_REPLICATION\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e1.853\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.013\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.094\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 290.35pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"387\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eCELL_ADHESION_MOLECULES_CAMS\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e1.763\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.032\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.062\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 290.35pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"387\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eCELL_CYCLE\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e1.780\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.040\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.058\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 290.35pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"387\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eCYTOKINE_CYTOKINE_RECEPTOR_INTERACTION\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e1.656\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.042\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.086\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 290.35pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"387\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eNATURAL_KILLER_CELL_MEDIATED_CYTOTOXICITY\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e1.634\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; 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border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"387\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eCYTOSOLIC_DNA_SENSING_PATHWAY\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e1.556\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.048\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.4pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.114\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003eNES: normalized enrichment score; NOM: nominal; FDR: false discovery rate. Gene sets with NOM p-val\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%;\"\u003e＜\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.05 and FDR q-val\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%;\"\u003e＜\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%; font-family: 'Times New Roman',serif;\"\u003e0.25 are regarded as significant.\u003c/span\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eBreast cancer (BC) accounts for approximately 2.1 million new cases and 62,000 deaths per year, with high mortality and morbidity rates in women worldwide[1]. Meanwhile, owing to gene expression profiles of breast cancer, there were four molecular subtypes as well as each requires different treatment[18]. Despite substantial research efforts devoted to exploring effective biomarkers for breast cancer, few basic research results have been applied in the clinical field. As a consequence, it is badly in need of recognizing truly effective biomarkers and therapeutic targets for breast cancer. Recent studies have reported that CDKN2A functions as a tumour suppressor in different types of carcinoma, such as melanoma[10], ovarian cancer[19], lung cancer[20], atypical neurofibroma[11], malignant mesothelioma[21] and bladder cancer[22]. Several studies also showed that decreased CDKN2A expression correlated to poor prognosis in osteosarcoma[23], soft tissue sarcoma[13], and oral squamous cell carcinoma[24].\u003c/p\u003e\n\u003cp\u003eWith respect to the roles of CDKN2A expression in breast cancer, Feng et al found that KDM2B promoted triple-negative breast cancer cell proliferation by suppressing CDKN2A/p16 expression[25]. Fu et al. also showed that C-terminal binding protein-2 motivated proliferation and migration in breast cancer via the inhibition of CDKN2A/p16[14]. The above results suggest that reduced CDKN2A expression contributes to poor outcomes in breast cancer. However, contrasting results showed that increased expression of CDKN2A/p16 was associated with poor prognosis in breast cancer [15].\u003c/p\u003e\n\u003cp\u003eTherefore, there still exists controversy regarding the prognostic value of CDKN2A in BC, and signalling pathways related to the regulatory mechanism have not yet been determined. In our study, we first found that CDKN2A expression was markedly elevated in BC tissues than in normal tissues using TCGA database, which implied that CDKN2A may play its part in the tumorigenesis of BC. Thus, we further analysed the relationship between CDKN2A expression and clinical features of BC patients. The results showed that the CDKN2A expression was positively related to age, ER status, PR status and molecular subtypes in breast cancer. Then, the Kaplan-Meier curves for OS also showed that reduced CDKN2A expression correlated to decreased survival time, especially in Luminal-like subtype, a finding that was in contrast to the findings of Lee\u0026rsquo;s study[15] but was consistent with the previously identified roles of CDKN2A in breast cancer[14,25,23]. Then Univariate and multivariate Cox analyses indicated CDKN2A expression and age were prognostic biomarkers for BC patients. Additionally, to identify the potential signalling pathways, we implemented GSEA comparing the low and high CDKN2A expression datasets and observed that pathways related to bladder cancer, CAMs, the cell cycle, cytokine-receptor interactions, cytosolic DNA sensing, DNA replication, killer cell-mediated cytotoxicity and P53 were enriched in breast cancer. A previous study showed that loss of CDKN2A negatively regulated with the cell cycle and CDK4/6/RB pathway in Luminal-like breast cancer patients[26]. Meanwhile, another study pointed out that cancer gene therapy mediated by CDKN2A was beneficial for the induction of cell death in non-small-cell lung carcinoma[20]. In addition, we found CDKN2A mRNA expression was associated with bladder cancer, the cell cycle and DNA replication[27-29]. However, it is the first time that the results in this paper showing correlations between CDKN2A expression and signalling pathways involving CAMs, cytokine-receptor interactions, cytosolic DNA sensing and killer cell-mediated cytotoxicity are reported, as well as biological mechanism needs to be further clarified.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, upregulated CDKN2A expression may be an effective prognostic biomarker in luminal-like breast cancer suggesting longer survival times. However, we should focus on the association between luminal-like subtypes and CDKN2A to inform the current controversial results. Additionally, signalling pathways related to CAMs, cytokine-receptor interactions, cytosolic DNA sensing and killer cell-mediated cytotoxicity may be pivotal pathways regulated by CDKN2A in breast cancer, and these relationships should be further clarified.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCDKN2A: cyclin dependent kinase inhibitor 2A; TGCA: The Cancer Genome Atlas; GSEA: Gene Set Enrichment Analysis; OS: overall survival; HR: Hazard ratio; CI: Confidence interval; NES: normalized enrichment score; NOM: nominal; FDR: false discovery rate\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYEQ and YJW participated in the study design. WJX and GWL contributed to data collection and analysis. All authors were involved in the writing of the article. YEQ critically reviewed the manuscript. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets analyzed during the current study are available in the TGCA (https://portal.gdc.cancer.gov/).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. 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Diabetes 65 (2):527-533. doi:10.2337/db15-0602\u003c/li\u003e\n\u003cli\u003eGadhikar MA, Zhang J, Shen L, Rao X, Wang J, Zhao M, Kalu NN, Johnson FM, Byers LA, Heymach J, Hittelman WN, Udayakumar D, Pandita RK, Pandita TK, Pickering CR, Redwood AB, Piwnica-Worms H, Schlacher K, Frederick MJ, Myers JN (2018) CDKN2A/p16 Deletion in Head and Neck Cancer Cells Is Associated with CDK2 Activation, Replication Stress, and Vulnerability to CHK1 Inhibition. Cancer Res 78 (3):781-797. doi:10.1158/0008-5472.CAN-17-2802\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"CDKN2A, breast cancer, Prognosis, TCGA, GSEA","lastPublishedDoi":"10.21203/rs.3.rs-29971/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-29971/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground Previous studies revealed that CDKN2A (cyclin-dependent kinase inhibitor 2A) functioned as a tumour suppressor in various types of malignant tumours. The aim of the study was to clarify the value of CDKN2A expression in the prognosis of breast cancer. \u003c/p\u003e\u003cp\u003eMethod Using the Cancer Genome Atlas (TCGA) database, we compared CDKN2A mRNA levels between breast cancer tissues and normal tissues and analyzed the relationship between clinical features and CDKN2A expression with the Wilcox test and the Kruskal-Wallis test. Kaplan-Meier and Cox analyses were performed to determine the correlation between CDKN2A expression and breast cancer prognosis. Gene set enrichment analysis (GSEA) was performed using the TCGA data set. \u003c/p\u003e\u003cp\u003eResults We first found that CDKN2A expression was markedly higher in breast cancer tissues than in normal tissues using the TCGA database (P=0.000). In addition, CDKN2A mRNA expression in breast cancer was positively correlated with age (P=0.018), histological types (P=0.028), ER status (P=0.000), PR status (P=0.000) and molecular subtypes (P=0.000). Kaplan-Meier analysis showed that increased CDKN2A expression was associated with increased survival time in breast cancer patients (P=0.000), especially in Luminal-like subtype. Univariate and multivariate Cox analyses indicated that CDKN2A expression was an independent prognostic biomarker for breast cancer (P=0.037). GSEA suggested that pathways involving cell adhesion molecules (CAMs), cytokine-receptor interactions, cytosolic DNA sensing, the cell cycle, and killer cell-mediated cytotoxicity were differentially enriched in the CDKN2A-high expression group. \u003c/p\u003e\u003cp\u003eConclusion Our research demonstrated that high CDKN2A mRNA expression was an independent protective factor for improved prognosis in Luminal-like breast cancer. Additionally, the signaling pathways related to CAMs, cytokine-receptor interactions, cytosolic DNA sensing, the cell cycle, and killer cell-mediated cytotoxicity regulated by CDKN2A mRNA expression should be further studied.\u003c/p\u003e","manuscriptTitle":"Upregulated CDKN2A expression may be an independent protective factor in Luminal-like breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-05-29 14:03:14","doi":"10.21203/rs.3.rs-29971/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"70ff5cd3-9a69-493f-8414-ea27e2fd00ad","owner":[],"postedDate":"May 29th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":108730,"name":"Cancer Biology"},{"id":108731,"name":"Oncology"}],"tags":[],"updatedAt":"2020-10-12T19:38:20+00:00","versionOfRecord":[],"versionCreatedAt":"2020-05-29 14:03:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-29971","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-29971","identity":"rs-29971","version":["v1"]},"buildId":"GqpaHPwrfC8PjnIFayRh5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}