Nomograms to Predict Individual Potential Benefit from Targeted Therapy for patients with lymph node positive  Luminal B (HER2-) breast cancer

Nomograms to Predict Individual Potential Benefit from Targeted Therapy for patients with lymph node positive Luminal B (HER2-) 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 Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Nomograms to Predict Individual Potential Benefit from Targeted Therapy for patients with lymph node positive Luminal B (HER2-) breast cancer Yuhan Yue, Ran Meng, Dan Li, Haiyan Ma, Yuruo Wu, Pengcheng Li, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3862639/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 Purpose To construct nomograms combining clinicopathological characteristics, bone metastases (BM), viscera metastases (VM) and cancer-related deaths (CRD) to predict the higher-risk patients with lymph node positive (N+) Luminal B (HER2-) breast cancer (BC). Method Kaplan-Meier survival analysis, Venn diagram, Bar charts were used to describe the data for subsequent metastasis and CRD. Thirty-six clinicopathological characteristics were extracted in univariate and multivariate Cox regression analyses to develop nomogram to predict potential risk of BM, VM and CRD among patients with N+ Luminal B (HER2-) BC. The calibration plots, concordance index and receiver operating characteristics (ROC) analysis were applied to determine the nomogram accuracy. Result The median age of 8139 patients was 51 years, with a median follow-up of 124 months (4–216 months). There was no statistical difference between the metachronous primary bilateral BC and synchronous primary bilateral BC. The number-peak period of patients with subsequent BM was the third year, VM was the 4th year and CRD was the 6th year (range second–6th year, 4th–6th year and third–8th year, respectively). BM, VM and CRD nomograms showed outstanding performance and discriminative ability (C-index 0.69, 0.68 and 0.71, respectively). The calibration curves and ROC curves analysis demonstrated the considerable clinical usefulness of the combined nomogram. Three clinical examples showed results differences in optimal period who had similar pathological stage. Conclusion The developed nomogram model consisting of time-event-dependent clinicopathological characteristics could reliable in predicting BM, VM and CRD probability of patients with N+ Luminal B (HER2-) BC. clinicopathological characteristics lymph node positive Luminal B (HER2-) breast cancer targeted therapy nomogram Chinese female patient Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Breast cancer (BC) is the most common cancer among women worldwide (in 2023). 1 Luminal B-like human epidermal growth factor receptor 2 negative (Luminal B [HER2−]) accounts for more than half of molecular subtypes of BC, moreover, lymph node positive (N + Luminal B [HER2−]) is a high risk for metastasis. 2 Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have shown superiority in patients with HR + HER2- BC bone or visceral metastases. 3 , 4 Moreover, the lighting points of oral targeted therapies are the targeted point and the smaller treatment-related adverse events which is allowed out-hospitalization. 5 , 6 Due to more patients with Luminal B (HER2-) BC are prone to chemotherapy-resistance, 7 according to the most influential guidelines by the National Comprehensive Cancer Network (NCCN, breast cancer version[4.2023] is available), 8 patients with N + Luminal B (HER2-) BC (Ki-67 index ≥ 20%) were undergone chemotherapy-free and offered CDK 4/6 inhibitors, but the long-term outcomes are unknown. 9 In fact, several early-stage patients showed ineffective in clinic. 10 Patients with HR + BC have a higher proportion of contralateral BC than HR- or HER2+, whether synchronous bilateral breast cancer (BBC) or metachronous BBC. 11 , 12 Currently, patient with BBC whom is considered to have a poorer prognosis and is frighted to physicians and patients, moreover, the number of metachronous BBC is increasing with the prolongation of overall survival of patients with BC, 13 especially in patients with N + Luminal B (HER2-) BC. Eventually, the most beneficial and recommended regimen in this setting is still controversial, as a result of recent interest in CDK4/6 inhibitors the eligibility for patients with HR+/HER2- early-stage BC, physicians believe that well selected high-risk patients should not be excluded a priori, as good short- and long-term results could likely be achieved. Based on clinicopathological data and follow-up results, we designed a retrospective study to develop an easy-to-use risk prediction model for more accurately predict the high-risk patients with N + Luminal B (HER2-) BC to maximize clinical benefit while minimizing toxicity, and reduce the risk of future metastasis who are more suitable for targeted therapies that include BBC for the clinic. Patients and Methods Patients Between May 2005 and April 2015, 8139 patients with N + Luminal B (HER2-) BC at XXX Medical University Cancer Hospital (XXX) that were reviewed for clinicopathological characteristics at first diagnosis of BC. Follow-up informed consent was provided by all women whose data was analyzed indicating the site of metastasis, alive or died, and event-free survival time. The follow-up cutoff date of current analysis was May 2023. Figure 1 shows the flowchart of how the study population was obtained. The inclusion criteria were as follows: (a) age > 22 years, (b) pathological diagnosis of Luminal B (HER2-) invasive breast cancer, (c) ipsilateral axillary metastasis, and (d) breast cancer as the first malignant tumor. The exclusion criteria were as follows: (a) pathological subtypes with better prognosis and metastasis relatively rare, (b) subsequent other site malignant tumor with different differentiation, (c) male patients with BC, and (d) follow-up information was unknown. Demographic and clinicopathological variables at baseline, laboratory values and preoperative examination data was retrieved from the medical records which within 2 weeks of the initial BC diagnosis. Three endpoints were considered for the analysis clinicopathological characteristics, the BM was chosen as an endpoint because it is a commonly metastatic site in patients with N + Luminal B (HER2-) BC, the VM was chosen as an endpoint because the CDK 4/6 inhibitors were effectively used in the patients with HR + HER2- metastatic BC and targeted therapies in patients with early-stage HR + BC in recent years. CRD was defined as the time interval from surgery to death from any site metastasis or last follow-up, while bone metastasis-free survival and visceral metastasis-free survival were defined as the time interval from surgery to metastasis in the bone and viscera, or the date of the last follow-up. The pathological features of the first cancer in patients with synchronous BBC were N + Luminal B (HER2-), with larger tumor size if the molecular subtype and stage were the same, and more lymph nodes if the tumor size was similar. Patients with metachronous BBC were initial diagnosed with N + Luminal B (HER2-) BC, and a second BC was diagnosed 6 months later. The present study was conducted in accordance with the Declaration of Helsinki, was prospectively approved by the ethics committee of XXX Medical University Cancer Institute and Hospital (approval number XXX). All patients gave written informed consent prior to treatment in this study. Statistical analysis The Kaplan-Meier method was used to evaluate the special survival of synchronous BBC, metachronous BBC and first-site-locoregional recurrence, and comparisons were performed with the log-rank tests. A bar chart was generated with Prism 10.0 software, to show the annual incidence of the BM, the VM and the CRD. To predict the probability risk of BM, VM, and CRD, multivariate Cox regression models were performed, including correlate predictive factors (p < 0.05) at the univariate analysis and clinically relevant variables. Cox proportional-hazard models were used to estimate the hazard ratios. Significant risk factors with p < 0.10 in multivariate Cox regression model were used into the final prediction model for the statistical efficiency, which can minimize the loss of potential predict factors. All reported P-values were based on two-sided tests. Basing on the multivariable Cox regression model, nomogram was built and internally validated using bootstrap resampling. For each group of 1000 bootstrap samples. The predictive accuracy of various Cox models was quantified by calculating the concordance index (C-index), which is a probability of concordance between predicted and observed survival, equal to the area under the receiver operating characteristics (ROC) curve for censored data. The calibration curves and the ROC curve were plotted to evaluate the nomogram’s accuracy. Cox analyses were performed using SPSS software (IBM SPSS Statistics 26). The Kaplan-Meier curves, nomogram, calibration plots, ROC curves and Harrell’s C-index were obtained using the survival, rms, pROC and timeROC packages of R software version (version 4.3.2; http//.r-project.org). This study was designed to comply with the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) diagnosis. 14 Results Eight thousand one hundred thirty-nine female patients with N+ Luminal B (HER2-) BC had initial age 22-75, median age was 51 years, with 59.1 % patients of follow-up for beyond 10 years. There were 7688 patients with unilateral BC and 451 patients with BBC, with median age of 451 patients with BBC was 50 years (range 24-75). 196 patients (2.4%) with synchronous BBC, 255 (3.1%) metachronous BBC. Survival outcomes according to BBC 84 patients with N+ Luminal B (HER2-) BC had the second BC when the distant metastases occurred prior, simultaneity or within subsequent 3 months, with a very high mortality (94.0%, 79/84), to some extent, contralateral breast cancer was another metastatic organ in some ways. As shown in Fig. 2a, Kaplan-Meier curves and univariate Cox regressive analysis showed difference from synchronous primary BBC and metachronous primary BBC, which was not significant (HR 1.29, 95%CI 0.83-2.07, p -value=0.292), and significant difference in first-site-locoregional recurrence (HR 3.09, 95%CI 1.97-4.87, p -value<0.001). Metastatic sites and annual endpoint events As shown in Fig. 2b, Venn diagram shows the distribution of the metastatic sites, with the largest number of BM (1165, 60.2%), followed by lung metastasis (896, 46.3%). 73.6% of patients with N+ Luminal B (HER2-) metastatic BC died (1425/1935). Fig. 2c presented the number of patients with the BM, the VM and the CRD according to the year at diagnosis. The number of the BM, the VM, and the CRD showed a different-peak pattern, with the BM peak at year 3 (the highest number range year 2-6), the VM peak at year 4 (the largest number range year 4-6) and the CRD peak at year 6 (the largest number range year 3-8) after diagnosis of BC. The patients with synchronous BBC showed a relative security time at the 9th year after surgery, who had earlier metastasis than unilateral BC. 35.0% of BM and 42.6% of VM from N+ Luminal B (HER2-) BC later than 5 years after initial diagnosis. Endpoints in Cox analysis To consider differences in therapeutic regimen, risk analysis was conducted separately for the BM, the VM and the CRD. Median follow-up time was 124 months (rang 4 - 216 months). Selected patient and 36 clinicopathological characteristics stratified by metastatic status are presented in Table 1 and Supplementary Table S1. The ratio of BM was 14.3%, VM was 17.5%, and CRD was 18.0%, respectively. 45.6% of the patients had 4 or more positive lymph nodes and the proportion of high Ki-67 expression was 93.4% in our study. Only 3.9 % patients with grade Ⅰ cancers, whereas the risk of histological grade was quite similar between the grade Ⅲ and “unknown” (considerable specific pathological subtypes), the effect of the PR expression is so strong that risk factors such as Ki-67 expression have a lowered impact on outcome. Thirty-six parameters of clinicopathological characteristics for risk have been analyzed in Table 2 and Supplementary Table S2. In the multivariate Cox regression analysis of high risk clinicopathological characteristics of BM, VM and CRD, the same high risks were TS, LN, clavicular lymph node, PR status, skin infiltration, age at initial diagnosis, unilateral oophorectomy, delivery, and region of residence. The distribution of high-risk clinicopathological characteristics between the VM and CRD were similar, however, lymphatic vessel infiltration, menstrual status, anti-HBAg and ALT were also related to VM and CRD. Prediction models for bone metastasis and visceral metastasis One thousand one hundred and sixty-five patients experienced BM after a median time of 45 months (3-171). According to the multivariable Cox regression, addition of PR status and unilateral oophorectomy were considered to improve concordance of the model, the results of this model were mapped by a nomogram to predict 12-, 36- and 60-month metastasize to bone (Fig.3a). The model had a slightly good prediction capability with C-index of 0.69 (95% CI 0.68-0.71). The calibration plot showed a good calibration (Fig.4a), the discriminative power of the nomogram-based screening model was quantified by the ROC curves, showing that the area under curve (AUC) of the effective applicability of BM at 12-month, 36-month, and 60-month were 0.751, 0.741 and 0.728, respectively, which confirm the good discrimination of this screening model (Fig.4d). The median time of 1425 patients with BC metastasize to viscera was 54 months (3-195). Age at initial diagnosis, menstrual status, unilateral oophorectomy, region of residence, TS, LN, clavicular lymph node, lesions, histological grade, stage, PR status, lymphatic vessel infiltration, skin infiltration, delivery, anti-HBAg, and ALT increased the hazard of VM at multivariable Cox regression analyses. These results were used to developed a nomogram to predict 24-, 48- and 60-month VM (Fig.3b), which had a C-index of 0.68 (95% CI 0.67-0.69). The calibration plots for probability of VM showed a good agreement (Fig.4b). The ROC curves showed the AUC of the effective applicability of 24-month, 48-month, and 60-month were 0.755, 0.737 and 0.715, respectively, which confirm the good predicted probability of this screening model (Fig.4e). Prediction models for cancer-related death One thousand four hundred and sixty-seven patients died because of metastasis during follow-up, with median follow-up 76 months (4-205). According to univariable Cox regression analysis age at initial diagnosis, menstrual status, unilateral oophorectomy, pregnancy period, HBAg, region of residence, TS, LN, clavicular lymph node, lesions, histological grade, stage, PR status, laterality, nipple areola infiltration, pectorales infiltration, lymphatic vessel infiltration, skin infiltration, delivery, anti-HBAg, ALT, GGT, and synchronous BBC increased the odds of CRD while family history of cancer decreased the odds. These variables were included in a multivariable Cox model and based on the results of this model a nomogram was displayed showing the probability of the CRD (Fig.3c). The model had a good prediction capability with a C-index of 0.71(95% 0.69-0.73), and the calibration plots showed good calibration fitted with the reference line, indicating predictive validity (Fig.4c). Moreover, the discriminative power of the nomogram-based screening model was quantified by the ROC curves, showing that the AUC of the effective applicability of 36-month, 60-month, 72-month, 120-month, and 180-month were 0.784, 0.743, 0.741, 0.715 and 0.706, respectively, which indicate the better discrimination of this screening model (Fig.4f). Example nomograms Three nomograms were developed using the statistically significant variables. In predicting the likelihood of BM, 3 clinical examples had similar total scores (235, 228 and 217, respectively). As shown in Fig. 5a, BM risk was similarity, patient 1 showed slightly higher risk among 3 patients. In predicting the likelihood of VM, the total scores of 3 clinical examples were calculated to be 241, 363 and 302, respectively. As shown in Fig. 5b, there were significant difference in prognostic hazard risk of VM, patient 2 had higher hazard risk than patient 3, and patient 1with the lowest risk. Fig. 5c showed there were difference in prognostic risk of CRD. The total scores of 3 clinical examples were calculated to be 253, 299 and 286, respectively. Although the pathological stage of patient 1 and patient 3 was same (stage Ⅲ C), patient 2 (stage Ⅲ A) with a very high risk of CRD. Discussion There is significant heterogeneity among N + Luminal B (HER2-) BC, moreover, there is no one method can accurately predict contralateral BC because the more complex heterogeneity. 15 Cancer metastasis is targeted and not random, which also had been reflected by the clinicopathological characteristics. If according the NCCN guidelines, 8 94.3% of the patients should be mainly offered to CDK4/6 inhibitors in our study. However, 23.4% of the patients experienced recurrence and metastasis and every patient with a unique condition that varies from case to case. 16 In this reappraised of high for patients with N + Luminal B (HER2-) BC, targeted therapies were hampered by non-negligible target-loss and treatment related advent events, nonetheless, we showed that strict selection of the high risk and minimization of the treatment delay could lower the rate of adverse events, 5 offering good long-term outcomes. In addition, targeted therapies need to be individualized and the process cannot be omitted, importance of definite the high-risk patient consider to reduce the risk of future metastasis. 17 Current, targeted points among patients with N + Luminal B (HER2-) BC were not exactly accurate. The clinical values of these BBC were not well established but might be a missing to evaluate and predict the risk and survival, 18 particularly in patients with metachronous BBC when the first BC was diagnosed. 19 Consider unpredictable metachronous BBC has higher mortality than synchronous BBC, 12 , 15 and recent study has displayed metachronous primary BBC has better prognosis than synchronous BBC. 15 , 20 We evaluated the risks for metachronous primary BBC and synchronous BBC after the second breast surgery for patients with non-metastatic BC, so the first-site-locoregional recurrence was compared concerning special survival and CRD risks. 21 Furthermore, we found differences in annual pattern of incidence according to metastatic sites and cancer-related deaths, which is largely consistent with the research. 22 Knowledge of the metastasis pattern may identify the periods of prevalent BC metastasis and optimize the treatment regimen. For example, physicians should consider dual-targeting therapy was offered to the high-risk BM patient at years 1 to 3 after BC diagnosis, while targeted therapy for the potential VM risk patients with N + Luminal B (HER2-) BC according to the risk score. 23 This analysis comprises 8139 patients with N + Luminal B (HER2-) BC with a median follow-up of 124 months and is one of the largest Chinese female patients analyzed so far. In addition, data from national clinical research center for cancer with the patients with BC from whole country was used, therefore the patients collective highly representative for clinical practice. Because of the nature of retrospective data, the observed risk difference between the BM, the VM, and the CRD could theoretically be due to random differences in the distribution of prognostic factors. There are risk variables difference between BM and VM that may conclude the different outcomes. Therefore, one could assume that there is a mechanism of internal environment and homeostasis differentiation between the BM and the VM. 24 To summary, our study suggests a high-risk prediction model characterized by clinically used clinicopathological characteristics of patients with N + Luminal B (HER2-) BC. Importantly, the high risk differs from the HR + HER2- subtypes. 7 Also, an altered Ki-67 status in high-risk patients is suggested, including lower expression levels of PR, which less known about. Overall, we found that models trained to predict including patients with synchronous BBC had better discriminative predictions than those trained to predict initial diagnosis unilateral BC. Since patients with VM have significantly worse survival, these models can help identify patients who would benefit most from targeted therapies. In our model, age at initial diagnosis, TS, LN, clavicular LN, PR status, skin invasion, unilateral oophorectomy, delivery, and region of residence were ranked the most important features, furthermore, Koch et al. demonstrated that non-natural-change of hormone level could increase the risk of cancer. 25 This study highlights more readily available clinicopathological characteristics to assess a patient's risk of metastasis and inform the choice of targeted therapies. 17 By identifying patients with the highest risk of distant metastases, predictive models can minimize overtreatment and optimize adjuvant therapy benefits. Patients often describe the possibility of metastases as psychological and economic burden, potentially leading to anxiety and delay diagnosis , 26 as rapid disease progression can occur after metastasis. Management consideration, including prognosis, potential adverse events, treatment burden, and costs to the healthcare system and the individual, are complex. Although the occurrence of HR loss or HER2 mutation related events is relatively uncommon, 27 some patients experience toxicities or side effects that require long-term therapy, 28 such as CDK4/6 inhibitors ineffective in some metastatic patients. 17 , 29 As our study illustrates, time-to-event nomograms demonstrate the improved ability to capture the complexities of patients with metastatic BC that are underrepresented in the current study and likely hold the promise of future advancements in personalized medicine. “How long and what do I have the probability of metastasis? Doctor?” is an important question for patients with N + BC that physicians often difficulty to address. Therefore, individualized treatment depends mainly on the patient of precise selection, as a consequence, limiting the extent of targeted therapies, as well as patient selection, could eventually reduce medical insurance stress and improve outcomes. However, by delaying chemotherapy, CDK4/6 inhibitor may increase the risk the risk of metastasis, especially for non-targeted points tumors. Another key issue is the optimal timing question of targeted therapies, it is possible that starting targeted therapy later might be reasonable. In our prediction model, a calculated likelihood of metastatic risk is displayed by selecting the patients’ clinicopathological characteristics, the largest number of the BM, the VM and the CRD occurred according the duration at diagnosis, while the clinical characteristics of the patients themselves are added to estimate risk. These prediction models were constructed entirely with clinicopathological characteristics, prolong predict the CRD to 15 years, in order to reduce or delay breast cancer metastasis and to identify the best treatment regimen and eventually discuss risks, benefits, and individualization with the patient, we believe that this represents a useful tool in the clinical setting for both the patient and the physician. We use these results to provide therapeutic option to physician, on how best to screen high-risk patients, and what regimen to give, when, and in what order, based on the information the nomograms provide. Limitations There are several limitations to our study. First, metastasis events were conducted mainly during the period of severe acute respiratory syndrome coronavirus 2 pandemic, therefore, the coronavirus disease pandemic cause delays in the diagnosis, treatment and fear also lead to an uptick in metastatic BC and mortality. However, the diagnosed of distant metastases were evaluated at tertiary hospitals by dedicated breast cancer specialists. Second, as with most long-term follow-up studies, lost to follow-up was possible for approximately half of the patients with CRD whose sites and time of metastases were unclear. Third, patients with axillary accessory BC occurring with unilateral or BBC were included in BBC. Another clear strength of our study includes the performance and annotation of clinicopathological characteristics of BBC analyses. However, the number of patients with BBC in this study was relatively small, and there are currently no other studies supporting this association, further preclinical and clinical research is warranted. Conclusion We found that the metastasis risk of patients with N + Luminal B (HER2-) BC wasn’t very high during long follow-up considering CRD around discussing metastasis. 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Bilateral oophorectomy and rate of colorectal cancer: A prospective cohort study. International journal of cancer 2022; 150: 38-46. 2021/08/28. DOI: 10.1002/ijc.33776. Cardoso F, Fallowfield L, Costa A, et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22 Suppl 6: vi25-30. 2011/10/20. DOI: 10.1093/annonc/mdr372. Morganti S, Marra A, Gandini S, et al. Clinicopathological features and survival outcomes of luminal-like breast tumors with estrogen receptor loss at metastatic recurrence: A case-control study. European journal of cancer (Oxford, England : 1990) 2023; 195: 113397. 2023/10/28. DOI: 10.1016/j.ejca.2023.113397. Kuukasjärvi T, Kononen J, Helin H, et al. Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 1996; 14: 2584-2589. 1996/09/01. DOI: 10.1200/jco.1996.14.9.2584. Morrison L, Loibl S and Turner NC. The CDK4/6 inhibitor revolution - a game-changing era for breast cancer treatment. Nat Rev Clin Oncol 2023 2023/12/12. DOI: 10.1038/s41571-023-00840-4. Tables Tables 1 to 2 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable.doc Table1.doc Table2.doc 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 Advisory Board 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-3862639","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":267407879,"identity":"c73c0e00-d485-411f-9d2b-55d8e766fd32","order_by":0,"name":"Yuhan Yue","email":"","orcid":"","institution":"Peking University Cancer Hospital (Inner Mongolia Campus)/Affiliated Cancer Hospital of Inner Mongolia Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuhan","middleName":"","lastName":"Yue","suffix":""},{"id":267407880,"identity":"71729bf2-33a1-4253-a3cd-ed209bd0880d","order_by":1,"name":"Ran Meng","email":"","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ran","middleName":"","lastName":"Meng","suffix":""},{"id":267407881,"identity":"c9d0e1aa-360a-4f51-824a-7182dc4bb18e","order_by":2,"name":"Dan Li","email":"","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Dan","middleName":"","lastName":"Li","suffix":""},{"id":267407882,"identity":"d6d375ab-dcaa-4203-8d23-f8908d5b6bb2","order_by":3,"name":"Haiyan Ma","email":"","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Haiyan","middleName":"","lastName":"Ma","suffix":""},{"id":267407883,"identity":"74666f72-bc90-4d9d-8b90-e836081fd7af","order_by":4,"name":"Yuruo Wu","email":"","orcid":"","institution":"Peking University Cancer Hospital (Inner Mongolia Campus)/Affiliated Cancer Hospital of Inner Mongolia Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuruo","middleName":"","lastName":"Wu","suffix":""},{"id":267407884,"identity":"ce158da2-ff47-4983-acd4-cc8b60ef8116","order_by":5,"name":"Pengcheng Li","email":"","orcid":"","institution":"Peking University Cancer Hospital (Inner Mongolia Campus)/Affiliated Cancer Hospital of Inner Mongolia Medical University","correspondingAuthor":false,"prefix":"","firstName":"Pengcheng","middleName":"","lastName":"Li","suffix":""},{"id":267407885,"identity":"f11e64e7-f680-4b8c-b306-0d9e9a2d837b","order_by":6,"name":"Junqing Liang","email":"","orcid":"","institution":"Peking University Cancer Hospital (Inner Mongolia Campus)/Affiliated Cancer Hospital of Inner Mongolia Medical University","correspondingAuthor":false,"prefix":"","firstName":"Junqing","middleName":"","lastName":"Liang","suffix":""},{"id":267407886,"identity":"17f6c47b-9137-4e37-a809-198f6d06862a","order_by":7,"name":"Xin Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYNACAwY5BoYDDAyMDSRoMeYhUQsDQ2IPiCRKi8Hxs4df8xTcSd/PeDpN4ucOBnl+sQMEtJzJS7OcYfAst4fh7DbJ3jMMhjNnJ+DXYnYgx8zgg8FhsBZpxjaGBIPbhLScf2NmkGBwOJ2HeC03cowfAG1JIF6L/Y03ZowzDA4b9hw4u9myt02CsF8k+3OMP/P8OSzPPuPsxhs/22zk+aUJaAECNgkwJXEATBJUDgLMH8AUfwNRqkfBKBgFo2AEAgBaCUdscRWIUgAAAABJRU5ErkJggg==","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Medical University","correspondingAuthor":true,"prefix":"","firstName":"Xin","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-01-14 08:14:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3862639/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3862639/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49762345,"identity":"dec17cb1-b880-45bd-bbc0-5747f8ef3ae4","added_by":"auto","created_at":"2024-01-17 16:07:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":395816,"visible":true,"origin":"","legend":"\u003cp\u003ePatients selection process flowchart.\u003c/p\u003e\n\u003cp\u003eBBC, bilateral breast cancer; BC, breast cancer; Luminal B (HER2 -), Luminal B-like human epidermal growth factor receptor 2 negative; LRR, locoregional recurrence; mBBC, metachronous bilateral breast cancer; mPBBC, metachronous primary biliteral breast cancer; N+, lymph node positive; sBBC, synchronous biliteral breast cancer; sPBBC, synchronous primary bilateral breast cancer; uBC, unilateral breast cancer.\u003c/p\u003e\n\u003cp\u003e※, the patient developed brain metastasis at followed the 3th month after surgery, was excluded temporarily; ▲, 54 patients with distant metastases between the first and the second BC; ★, 29 patients with distant metastasis occurred simultaneity or after the second BC within subsequent 3 months; LRR\u003csup\u003e#\u003c/sup\u003e, locoregional recurrence was defined as the first local/regional recurrence without other site metastasis in the following 3 months.\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3862639/v1/97fbe91b4b801066e4408d8b.png"},{"id":49762928,"identity":"b907339e-0e78-48cc-a349-7959273aad76","added_by":"auto","created_at":"2024-01-17 16:15:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2496977,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves of special survival comparing the mPBBC, sPBBC, and LRR (a); The distribution of metastatic sites (b). The annual number of patients with difference endpoints (c).\u003c/p\u003e\n\u003cp\u003eBBC, bilateral breast cancer; BC, breast cancer; Luminal B (HER2 -), BM, bone metastasis; CI, confidence interval; CRD, cancer related death; Luminal B-like human epidermal growth factor receptor 2 negative; LRR, locoregional recurrence; mBBC, metachronous bilateral breast cancer; mPBBC, metachronous primary biliteral breast cancer; No., number; N+, lymph node positive; sBBC, synchronous biliteral breast cancer; sPBBC, synchronous primary bilateral breast cancer; uBC, unilateral breast cancer; VM, visceral metastasis.\u003c/p\u003e\n\u003cp\u003eLRR\u003csup\u003e#\u003c/sup\u003e, locoregional recurrence was referred to the first local/regional recurrence, which didn’t metastasis to other site within subsequent 3 months; LN\u003csup\u003e*\u003c/sup\u003e, distant lymph node metastasis excluding ipsilateral axillary, supraclavicular, infraclavicular or internal mammary lymph node.\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3862639/v1/9748f417704d077eb4fbdc06.png"},{"id":49762927,"identity":"bc868b37-4da6-4c40-9644-3a98e33b6721","added_by":"auto","created_at":"2024-01-17 16:15:02","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1059545,"visible":true,"origin":"","legend":"\u003cp\u003eNomograms for predicting BM, VM and CRD of patients with N+ Luminal B (HER2 -) BC. Nomogram to estimate the 12-, 36-, and 60-month BM probabilities (a); Nomogram to estimate the 24-, 48-, and 60-month VM probabilities (b); Nomogram to estimate the 36-, 60-, 72-, 120-, and 180-month CRD probabilities (c).\u003c/p\u003e\n\u003cp\u003eALT, alanine aminotransferase; Anti-HBAg, hepatitis B antibody; BC, breast cancer; BM, bone metastasis; CRD, cancer related death; GGT, γ-glutamyl transferase; HBAg, hepatitis B antigen; Luminal B (HER2 -), Luminal B-like human epidermal growth factor receptor 2 negative; N+, lymph node positive; NW, northwest China; PR, progesterone receptor; sBBC, synchronous biliteral breast cancer; SE, southeast China; TS, tumor size; VM, visceral metastasis.\u003c/p\u003e","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3862639/v1/8a3294fcd91a68adc1caca43.png"},{"id":49762339,"identity":"ec77c6ff-706c-49fe-bbc7-88e20c133ce6","added_by":"auto","created_at":"2024-01-17 16:07:02","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1739038,"visible":true,"origin":"","legend":"\u003cp\u003eCalibration curves and receiver operating characteristic (ROC) curves of nomograms for bone metastasis, visceral metastasis and cancer related deaths. Calibration curves for predicting BM (a), VM (b) and CRD (c) at different interval time. ROC curves for evaluating the performance of prediction BM (d), VM (e) and CRD (f) at different interval time.\u003c/p\u003e\n\u003cp\u003eAUC, area under the curve; BM, bone metastasis; CRD, cancer related deaths; ROC, receiver operating characteristic; VM, visceral metastasis.\u003c/p\u003e","description":"","filename":"OnlineFigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-3862639/v1/e9f7fbe4dca7d3cedbb1451a.png"},{"id":49762934,"identity":"af51cff7-fad4-4ba0-9289-998093942cfd","added_by":"auto","created_at":"2024-01-17 16:15:02","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1307206,"visible":true,"origin":"","legend":"\u003cp\u003eClinical examples of nomogram use. Examples nomogram for predicting 12-, 36-, and 60-month BM (a), examples nomogram for predicting 24-, 48-, and 60-month VM (b), examples nomogram for predicting 36-, 60-, 72-, 120-, and 180-month CRD (c).\u003c/p\u003e\n\u003cp\u003eALT, alanine aminotransferase; Anti-HBAg, hepatitis B antibody; BM, bone metastasis; CRD, cancer related death; GGT, γ-glutamyl transferase; HBAg, hepatitis B antigen; NW, northwest China; PR, progesterone receptor; sBBC, synchronous biliteral breast cancer; SE, southeast China; TS, tumor size; VM, visceral metastasis.\u003c/p\u003e\n\u003cp\u003ePatient 1 was a 57-year-old post-menopausal woman who was confirmed sBBC, with grade 3 invasive breast cancer of ER+, PR+, HER2- and Ki-67 high (labeling index was 50%), the stage was T2N3 (Ⅲ C) in the right breast, concurrently, another tumor with grade 2 invasive breast cancer of ER+, PR+, HER2- and Ki-67 high (30%), was classified as T2N0 in the left breast, who had delivered 1 child. The region of residence was in the southeast China.\u003c/p\u003e\n\u003cp\u003ePatient 2 was a 30-year-old pre-menopausal female patient with grade 2 invasive breast cancer of ER+, PR-, HER2- and Ki-67 high (40%), the pathological stage was T2N2 (stage Ⅲ A) in the left breast, married but nulliparous, with anti-HBAg +, and living in the southeast China.\u003c/p\u003e\n\u003cp\u003ePatient 3 was a 46-year-old peri-menopausal woman with grade 2 invasive breast cancer of ER+, PR+, HER2- and Ki-67 high (80%), with pathological staging - pT2N3 (stage Ⅲ C) in the right breast, with clavicular lymph-node positive, with anti-HBAg +, gave birth to 2 children. In the past, she was admitted to other hospital with adenoma of left ovary, which had had unilateral oophorectomy. Her father died of colorectal cancer. The region of residence was in the northwest China.\u003c/p\u003e","description":"","filename":"OnlineFigure5.png","url":"https://assets-eu.researchsquare.com/files/rs-3862639/v1/065e1b69c8b0f86e81b44f91.png"},{"id":50007534,"identity":"0da21702-897a-4a41-8d39-15f6b5f6cb50","added_by":"auto","created_at":"2024-01-23 03:37:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1494115,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3862639/v1/ba6fdd6a-4718-4783-a414-f8c44c40c7e1.pdf"},{"id":49762338,"identity":"d7e51754-aa46-41cb-947e-6f41acca74a5","added_by":"auto","created_at":"2024-01-17 16:07:02","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":87040,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable.doc","url":"https://assets-eu.researchsquare.com/files/rs-3862639/v1/8ff47e4e93a2e1a7c25d92f8.doc"},{"id":49762341,"identity":"c4d8c7bf-cdb3-4ee6-a927-0a135fbefb04","added_by":"auto","created_at":"2024-01-17 16:07:02","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":177152,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.doc","url":"https://assets-eu.researchsquare.com/files/rs-3862639/v1/7a1f72f9fb99beb85ab049e3.doc"},{"id":49762343,"identity":"82132a90-c74b-430d-9547-eedc5b2f519e","added_by":"auto","created_at":"2024-01-17 16:07:02","extension":"doc","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":237568,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.doc","url":"https://assets-eu.researchsquare.com/files/rs-3862639/v1/a006d5ba633da4734667325a.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Nomograms to Predict Individual Potential Benefit from Targeted Therapy for patients with lymph node positive Luminal B (HER2-) breast cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer (BC) is the most common cancer among women worldwide (in 2023).\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Luminal B-like human epidermal growth factor receptor 2 negative (Luminal B [HER2\u0026minus;]) accounts for more than half of molecular subtypes of BC, moreover, lymph node positive (N\u0026thinsp;+\u0026thinsp;Luminal B [HER2\u0026minus;]) is a high risk for metastasis.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have shown superiority in patients with HR\u0026thinsp;+\u0026thinsp;HER2- BC bone or visceral metastases.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Moreover, the lighting points of oral targeted therapies are the targeted point and the smaller treatment-related adverse events which is allowed out-hospitalization.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Due to more patients with Luminal B (HER2-) BC are prone to chemotherapy-resistance,\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e according to the most influential guidelines by the National Comprehensive Cancer Network (NCCN, breast cancer version[4.2023] is available),\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e patients with N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC (Ki-67 index\u0026thinsp;\u0026ge;\u0026thinsp;20%) were undergone chemotherapy-free and offered CDK 4/6 inhibitors, but the long-term outcomes are unknown.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e In fact, several early-stage patients showed ineffective in clinic.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePatients with HR\u0026thinsp;+\u0026thinsp;BC have a higher proportion of contralateral BC than HR- or HER2+, whether synchronous bilateral breast cancer (BBC) or metachronous BBC.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Currently, patient with BBC whom is considered to have a poorer prognosis and is frighted to physicians and patients, moreover, the number of metachronous BBC is increasing with the prolongation of overall survival of patients with BC,\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e especially in patients with N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC.\u003c/p\u003e \u003cp\u003eEventually, the most beneficial and recommended regimen in this setting is still controversial, as a result of recent interest in CDK4/6 inhibitors the eligibility for patients with HR+/HER2- early-stage BC, physicians believe that well selected high-risk patients should not be excluded a priori, as good short- and long-term results could likely be achieved. Based on clinicopathological data and follow-up results, we designed a retrospective study to develop an easy-to-use risk prediction model for more accurately predict the high-risk patients with N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC to maximize clinical benefit while minimizing toxicity, and reduce the risk of future metastasis who are more suitable for targeted therapies that include BBC for the clinic.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eBetween May 2005 and April 2015, 8139 patients with N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC at XXX Medical University Cancer Hospital (XXX) that were reviewed for clinicopathological characteristics at first diagnosis of BC. Follow-up informed consent was provided by all women whose data was analyzed indicating the site of metastasis, alive or died, and event-free survival time. The follow-up cutoff date of current analysis was May 2023. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the flowchart of how the study population was obtained.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe inclusion criteria were as follows: (a) age\u0026thinsp;\u0026gt;\u0026thinsp;22 years, (b) pathological diagnosis of Luminal B (HER2-) invasive breast cancer, (c) ipsilateral axillary metastasis, and (d) breast cancer as the first malignant tumor. The exclusion criteria were as follows: (a) pathological subtypes with better prognosis and metastasis relatively rare, (b) subsequent other site malignant tumor with different differentiation, (c) male patients with BC, and (d) follow-up information was unknown. Demographic and clinicopathological variables at baseline, laboratory values and preoperative examination data was retrieved from the medical records which within 2 weeks of the initial BC diagnosis.\u003c/p\u003e \u003cp\u003eThree endpoints were considered for the analysis clinicopathological characteristics, the BM was chosen as an endpoint because it is a commonly metastatic site in patients with N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC, the VM was chosen as an endpoint because the CDK 4/6 inhibitors were effectively used in the patients with HR\u0026thinsp;+\u0026thinsp;HER2- metastatic BC and targeted therapies in patients with early-stage HR\u0026thinsp;+\u0026thinsp;BC in recent years. CRD was defined as the time interval from surgery to death from any site metastasis or last follow-up, while bone metastasis-free survival and visceral metastasis-free survival were defined as the time interval from surgery to metastasis in the bone and viscera, or the date of the last follow-up.\u003c/p\u003e \u003cp\u003eThe pathological features of the first cancer in patients with synchronous BBC were N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-), with larger tumor size if the molecular subtype and stage were the same, and more lymph nodes if the tumor size was similar. Patients with metachronous BBC were initial diagnosed with N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC, and a second BC was diagnosed 6 months later.\u003c/p\u003e \u003cp\u003e The present study was conducted in accordance with the Declaration of Helsinki, was prospectively approved by the ethics committee of XXX Medical University Cancer Institute and Hospital (approval number XXX). All patients gave written informed consent prior to treatment in this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe Kaplan-Meier method was used to evaluate the special survival of synchronous BBC, metachronous BBC and first-site-locoregional recurrence, and comparisons were performed with the log-rank tests. A bar chart was generated with Prism 10.0 software, to show the annual incidence of the BM, the VM and the CRD. To predict the probability risk of BM, VM, and CRD, multivariate Cox regression models were performed, including correlate predictive factors (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) at the univariate analysis and clinically relevant variables. Cox proportional-hazard models were used to estimate the hazard ratios. Significant risk factors with \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.10 in multivariate Cox regression model were used into the final prediction model for the statistical efficiency, which can minimize the loss of potential predict factors. All reported P-values were based on two-sided tests.\u003c/p\u003e \u003cp\u003eBasing on the multivariable Cox regression model, nomogram was built and internally validated using bootstrap resampling. For each group of 1000 bootstrap samples. The predictive accuracy of various Cox models was quantified by calculating the concordance index (C-index), which is a probability of concordance between predicted and observed survival, equal to the area under the receiver operating characteristics (ROC) curve for censored data. The calibration curves and the ROC curve were plotted to evaluate the nomogram\u0026rsquo;s accuracy.\u003c/p\u003e \u003cp\u003eCox analyses were performed using SPSS software (IBM SPSS Statistics 26). The Kaplan-Meier curves, nomogram, calibration plots, ROC curves and Harrell\u0026rsquo;s C-index were obtained using the survival, rms, pROC and timeROC packages of R software version (version 4.3.2; http//.r-project.org). This study was designed to comply with the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) diagnosis.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eEight thousand one hundred thirty-nine\u0026nbsp;female patients with N+ Luminal B (HER2-) BC\u0026nbsp;had initial\u0026nbsp;age 22-75, median age was 51 years, with\u0026nbsp;59.1 % patients of follow-up for beyond 10 years. There were 7688 patients with unilateral BC and 451 patients with BBC, with\u0026nbsp;median age of 451 patients with BBC was 50 years (range 24-75). 196 patients (2.4%) with synchronous BBC, 255 (3.1%) metachronous BBC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurvival outcomes according to BBC\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e84 patients with N+ Luminal B (HER2-) BC had the second BC when the distant metastases occurred prior, simultaneity or within subsequent 3 months, with a very high mortality (94.0%, 79/84), to some extent, contralateral breast cancer was another metastatic organ in some ways. As shown in Fig. 2a, Kaplan-Meier curves and univariate Cox regressive analysis showed difference from synchronous primary BBC and metachronous primary BBC, which was not significant (HR 1.29, 95%CI 0.83-2.07, \u003cem\u003ep\u003c/em\u003e-value=0.292), and significant difference in first-site-locoregional recurrence (HR 3.09, 95%CI 1.97-4.87, \u003cem\u003ep\u003c/em\u003e-value\u0026lt;0.001).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMetastatic sites and annual endpoint events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in\u0026nbsp;Fig. 2b,\u0026nbsp;Venn diagram shows the distribution of the metastatic sites, with the largest number of BM (1165, 60.2%), followed by lung metastasis (896, 46.3%). 73.6% of patients with N+ Luminal B (HER2-) metastatic BC died (1425/1935).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFig. 2c presented the number of patients with\u0026nbsp;the\u0026nbsp;BM, the VM and the CRD according to the year at diagnosis. The number of the BM, the VM, and the CRD showed a different-peak pattern, with the BM peak at year 3 (the highest number range year 2-6), the VM peak at year 4 (the largest number range year 4-6) and the CRD peak at year 6 (the largest number range year 3-8) after diagnosis of BC. The patients with synchronous BBC showed a relative security time at the 9th year after surgery, who had earlier metastasis than unilateral BC. 35.0% of BM and 42.6% of VM from N+ Luminal B (HER2-) BC later than 5 years after initial diagnosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEndpoints in Cox analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo consider differences in therapeutic regimen, risk analysis was conducted separately for the BM, the VM and the CRD. Median follow-up time was 124 months (rang 4 - 216 months). Selected patient and 36 clinicopathological characteristics stratified by metastatic status are presented in Table 1 and Supplementary Table S1. The ratio of BM was 14.3%, VM was 17.5%, and CRD was 18.0%, respectively. 45.6% of the patients had 4 or more positive lymph nodes and the proportion of high Ki-67 expression was 93.4% in our study. Only 3.9 % patients with grade Ⅰ cancers, whereas the risk of histological grade was quite similar between the grade Ⅲ and “unknown” (considerable specific pathological subtypes), the effect of the PR expression is so strong that risk factors such as Ki-67 expression have a lowered impact on outcome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThirty-six parameters of clinicopathological characteristics for risk have been analyzed in Table 2 and Supplementary Table S2. In the multivariate Cox regression analysis of high risk clinicopathological characteristics of BM, VM and CRD, the same high risks were TS, LN, clavicular lymph node, PR status, skin infiltration, age at initial diagnosis, unilateral oophorectomy, delivery, and region of residence. The distribution of high-risk clinicopathological characteristics between the VM and CRD were similar, however, lymphatic vessel infiltration, menstrual status, anti-HBAg and ALT were also related to VM and CRD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrediction models for bone metastasis and visceral metastasis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOne thousand one hundred and sixty-five patients experienced BM after a median time of 45 months (3-171). According to the multivariable Cox regression, addition of PR status and unilateral oophorectomy were considered to improve concordance of the model, the results of this model were mapped by a nomogram to predict 12-, 36- and 60-month metastasize to bone (Fig.3a). The model had a slightly good prediction capability with C-index of 0.69 (95% CI 0.68-0.71). The calibration plot showed a good calibration (Fig.4a), the discriminative power of the nomogram-based screening model was quantified by the ROC curves, showing that the area under curve (AUC) of the effective applicability of BM at 12-month, 36-month, and 60-month were 0.751, 0.741 and 0.728, respectively, which confirm the good discrimination of this screening model (Fig.4d).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe median time of 1425 patients with BC metastasize to viscera was 54 months (3-195). Age at initial diagnosis, menstrual status, unilateral oophorectomy, region of residence, TS, LN, clavicular lymph node, lesions, histological grade, stage, PR status, lymphatic vessel infiltration, skin infiltration, delivery, anti-HBAg, and ALT increased the hazard of VM at multivariable Cox regression analyses. These results were used to developed a nomogram to predict 24-, 48- and 60-month VM (Fig.3b), which had a C-index of 0.68 (95% CI 0.67-0.69). The calibration plots for probability of VM showed a good agreement (Fig.4b). The ROC curves showed the AUC of the effective applicability of 24-month, 48-month, and 60-month were 0.755, 0.737 and 0.715, respectively, which confirm the good predicted probability of this screening model (Fig.4e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrediction models for cancer-related death\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOne thousand four hundred and sixty-seven patients died because of metastasis during follow-up, with median follow-up 76 months (4-205). According to univariable Cox regression analysis age at initial diagnosis, menstrual status, unilateral oophorectomy, pregnancy period, HBAg, region of residence, TS, LN, clavicular lymph node, lesions, histological grade, stage, PR status, laterality, nipple areola infiltration,\u0026nbsp;pectorales infiltration, lymphatic vessel infiltration, skin infiltration, delivery, anti-HBAg, ALT, GGT,\u0026nbsp;and synchronous BBC increased the odds of CRD while family history of cancer decreased the odds. These variables were included in a multivariable Cox model and based on the results of this model a nomogram was displayed showing the probability of the CRD (Fig.3c). The model had a good prediction capability with a C-index of 0.71(95% 0.69-0.73), and the calibration plots showed good calibration fitted with the reference line, indicating predictive validity (Fig.4c). Moreover, the discriminative power of the nomogram-based screening model was quantified by the ROC curves, showing that the AUC of the effective applicability of 36-month, 60-month, 72-month, 120-month, and 180-month were 0.784, 0.743, 0.741, 0.715 and 0.706, respectively, which indicate the better discrimination of this screening model (Fig.4f). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExample nomograms\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree nomograms were developed using the statistically significant variables. In predicting the likelihood of BM, 3 clinical examples had similar total scores (235, 228 and 217, respectively). As shown in Fig. 5a, BM risk was similarity, patient 1 showed slightly higher risk among 3 patients. In predicting the likelihood of VM, the total scores of 3 clinical examples were calculated to be 241, 363 and 302, respectively. As shown in Fig. 5b, there were significant difference in prognostic hazard risk of VM, patient 2 had higher hazard risk than patient 3, and patient 1with the lowest risk. Fig. 5c showed there were difference in prognostic risk of CRD. The total scores of 3 clinical examples were calculated to be 253, 299 and 286, respectively. Although the pathological stage of patient 1 and patient 3 was same (stage Ⅲ C), patient 2 (stage Ⅲ A) with a very high risk of CRD.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere is significant heterogeneity among N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC, moreover, there is no one method can accurately predict contralateral BC because the more complex heterogeneity.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Cancer metastasis is targeted and not random, which also had been reflected by the clinicopathological characteristics. If according the NCCN guidelines,\u003csup\u003e8\u003c/sup\u003e 94.3% of the patients should be mainly offered to CDK4/6 inhibitors in our study. However, 23.4% of the patients experienced recurrence and metastasis and every patient with a unique condition that varies from case to case.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e In this reappraised of high for patients with N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC, targeted therapies were hampered by non-negligible target-loss and treatment related advent events, nonetheless, we showed that strict selection of the high risk and minimization of the treatment delay could lower the rate of adverse events,\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e offering good long-term outcomes. In addition, targeted therapies need to be individualized and the process cannot be omitted, importance of definite the high-risk patient consider to reduce the risk of future metastasis.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Current, targeted points among patients with N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC were not exactly accurate.\u003c/p\u003e \u003cp\u003eThe clinical values of these BBC were not well established but might be a missing to evaluate and predict the risk and survival,\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e particularly in patients with metachronous BBC when the first BC was diagnosed.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Consider unpredictable metachronous BBC has higher mortality than synchronous BBC,\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e and recent study has displayed metachronous primary BBC has better prognosis than synchronous BBC.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e We evaluated the risks for metachronous primary BBC and synchronous BBC after the second breast surgery for patients with non-metastatic BC, so the first-site-locoregional recurrence was compared concerning special survival and CRD risks.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e Furthermore, we found differences in annual pattern of incidence according to metastatic sites and cancer-related deaths, which is largely consistent with the research.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Knowledge of the metastasis pattern may identify the periods of prevalent BC metastasis and optimize the treatment regimen. For example, physicians should consider dual-targeting therapy was offered to the high-risk BM patient at years 1 to 3 after BC diagnosis, while targeted therapy for the potential VM risk patients with N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC according to the risk score.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis analysis comprises 8139 patients with N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC with a median follow-up of 124 months and is one of the largest Chinese female patients analyzed so far. In addition, data from national clinical research center for cancer with the patients with BC from whole country was used, therefore the patients collective highly representative for clinical practice. Because of the nature of retrospective data, the observed risk difference between the BM, the VM, and the CRD could theoretically be due to random differences in the distribution of prognostic factors. There are risk variables difference between BM and VM that may conclude the different outcomes. Therefore, one could assume that there is a mechanism of internal environment and homeostasis differentiation between the BM and the VM.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e To summary, our study suggests a high-risk prediction model characterized by clinically used clinicopathological characteristics of patients with N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC. Importantly, the high risk differs from the HR\u0026thinsp;+\u0026thinsp;HER2- subtypes.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Also, an altered Ki-67 status in high-risk patients is suggested, including lower expression levels of PR, which less known about.\u003c/p\u003e \u003cp\u003eOverall, we found that models trained to predict including patients with synchronous BBC had better discriminative predictions than those trained to predict initial diagnosis unilateral BC. Since patients with VM have significantly worse survival, these models can help identify patients who would benefit most from targeted therapies. In our model, age at initial diagnosis, TS, LN, clavicular LN, PR status, skin invasion, unilateral oophorectomy, delivery, and region of residence were ranked the most important features, furthermore, Koch et al. demonstrated that non-natural-change of hormone level could increase the risk of cancer.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis study highlights more readily available clinicopathological characteristics to assess a patient's risk of metastasis and inform the choice of targeted therapies.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e By identifying patients with the highest risk of distant metastases, predictive models can minimize overtreatment and optimize adjuvant therapy benefits. Patients often describe the possibility of metastases as psychological and economic burden, potentially leading to anxiety and delay diagnosis ,\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e as rapid disease progression can occur after metastasis. Management consideration, including prognosis, potential adverse events, treatment burden, and costs to the healthcare system and the individual, are complex. Although the occurrence of HR loss or HER2 mutation related events is relatively uncommon,\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e some patients experience toxicities or side effects that require long-term therapy,\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e such as CDK4/6 inhibitors ineffective in some metastatic patients.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e As our study illustrates, time-to-event nomograms demonstrate the improved ability to capture the complexities of patients with metastatic BC that are underrepresented in the current study and likely hold the promise of future advancements in personalized medicine.\u003c/p\u003e \u003cp\u003e\u0026ldquo;How long and what do I have the probability of metastasis? Doctor?\u0026rdquo; is an important question for patients with N\u0026thinsp;+\u0026thinsp;BC that physicians often difficulty to address. Therefore, individualized treatment depends mainly on the patient of precise selection, as a consequence, limiting the extent of targeted therapies, as well as patient selection, could eventually reduce medical insurance stress and improve outcomes. However, by delaying chemotherapy, CDK4/6 inhibitor may increase the risk the risk of metastasis, especially for non-targeted points tumors. Another key issue is the optimal timing question of targeted therapies, it is possible that starting targeted therapy later might be reasonable. In our prediction model, a calculated likelihood of metastatic risk is displayed by selecting the patients\u0026rsquo; clinicopathological characteristics, the largest number of the BM, the VM and the CRD occurred according the duration at diagnosis, while the clinical characteristics of the patients themselves are added to estimate risk. These prediction models were constructed entirely with clinicopathological characteristics, prolong predict the CRD to 15 years, in order to reduce or delay breast cancer metastasis and to identify the best treatment regimen and eventually discuss risks, benefits, and individualization with the patient, we believe that this represents a useful tool in the clinical setting for both the patient and the physician. We use these results to provide therapeutic option to physician, on how best to screen high-risk patients, and what regimen to give, when, and in what order, based on the information the nomograms provide.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThere are several limitations to our study. First, metastasis events were conducted mainly during the period of severe acute respiratory syndrome coronavirus 2 pandemic, therefore, the coronavirus disease pandemic cause delays in the diagnosis, treatment and fear also lead to an uptick in metastatic BC and mortality. However, the diagnosed of distant metastases were evaluated at tertiary hospitals by dedicated breast cancer specialists. Second, as with most long-term follow-up studies, lost to follow-up was possible for approximately half of the patients with CRD whose sites and time of metastases were unclear. Third, patients with axillary accessory BC occurring with unilateral or BBC were included in BBC. Another clear strength of our study includes the performance and annotation of clinicopathological characteristics of BBC analyses. However, the number of patients with BBC in this study was relatively small, and there are currently no other studies supporting this association, further preclinical and clinical research is warranted.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe found that the metastasis risk of patients with N\u0026thinsp;+\u0026thinsp;Luminal B (HER2-) BC wasn\u0026rsquo;t very high during long follow-up considering CRD around discussing metastasis. Based on easy-to-obtain clinicopathological characteristics, the easy-useful-tool nomogram was used to more accurately predict the chemotherapy-ineffective and standard endocrine-useless patient, who was offered the best treatment regimen at the optimal period.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eXin Wang and YHY conceived and designed the study. RM and YHY collected the data. HYM, DL, YRW and PCL performed the follow-up. YHY wrote the first draft of the manuscript. XW and JQL contributed to the editing and critical revision of the manuscript. XW, JQL and YHY reviewed and revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBizuayehu HM, Dadi AF, Hassen TA, et al. 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DOI: 10.1038/s41571-023-00840-4.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 2 are available in the Supplementary Files section\u003c/p\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":"clinicopathological characteristics, lymph node positive Luminal B (HER2-) breast cancer, targeted therapy, nomogram, Chinese female patient","lastPublishedDoi":"10.21203/rs.3.rs-3862639/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3862639/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose \u003c/strong\u003eTo construct nomograms combining clinicopathological characteristics, bone metastases (BM), viscera metastases (VM) and cancer-related deaths (CRD) to predict the higher-risk patients with lymph node positive (N+) Luminal B (HER2-) breast cancer (BC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod \u003c/strong\u003eKaplan-Meier survival analysis, Venn diagram, Bar charts were used to describe the data for subsequent metastasis and CRD. Thirty-six clinicopathological characteristics were extracted in univariate and multivariate Cox regression analyses to develop nomogram to predict potential risk of BM, VM and CRD among patients with N+ Luminal B (HER2-) BC. The calibration plots, concordance index and receiver operating characteristics (ROC) analysis were applied to determine the nomogram accuracy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResult \u003c/strong\u003eThe median age of 8139 patients was 51 years, with a median follow-up of 124 months (4–216 months). There was no statistical difference between the metachronous primary bilateral BC and synchronous primary bilateral BC. The number-peak period of patients with subsequent BM was the third year, VM was the 4th year and CRD was the 6th\u003csup\u003e \u003c/sup\u003eyear (range second–6th year, 4th–6th year and third–8th year, respectively). BM, VM and CRD nomograms showed outstanding performance and discriminative ability (C-index 0.69, 0.68 and 0.71, respectively). The calibration curves and ROC curves analysis demonstrated the considerable clinical usefulness of the combined nomogram. Three clinical examples showed results differences in optimal period who had similar pathological stage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003eThe developed nomogram model consisting of time-event-dependent clinicopathological characteristics could reliable in predicting BM, VM and CRD probability of patients with N+ Luminal B (HER2-) BC.\u003c/p\u003e","manuscriptTitle":"Nomograms to Predict Individual Potential Benefit from Targeted Therapy for patients with lymph node positive Luminal B (HER2-) breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-17 16:06:57","doi":"10.21203/rs.3.rs-3862639/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":"aa3815c1-2eb1-4d4b-8eda-4b55f23eb712","owner":[],"postedDate":"January 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-01-23T03:29:16+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-17 16:06:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3862639","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3862639","identity":"rs-3862639","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}