L1CAM Expression in Recurrent Estrogen Positive/HER2 Negative Breast Cancer

L1CAM Expression in Recurrent Estrogen Positive/HER2 Negative 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 L1CAM Expression in Recurrent Estrogen Positive/HER2 Negative Breast Cancer Ioana Moisini, Huina Zhang, Marcus D’Aguiar, David G. Hicks, Bradley M. Turner This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-56325/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: We investigate L1CAM expression in ER positive/HER2 negative breast carcinomas. The finding of a potential correlation between high L1CAM expression and recurrent/metastatic disease in luminal A and B breast carcinomas may be helpful for risk stratification and open opportunities for targeted therapies. Methods: 304 cases comprising 152 cases of ER positive, PR positive/negative and HER2 negative recurrent/metastatic breast carcinomas and 152 non-recurrent controls were included. ER, PR, HER-2, Ki-67 status, Nottingham grade, tumor size, tumor stage, number of foci, lymph node status, lymphovascular invasion, phenotype, laterality, age at diagnosis and first distant or local recurrence were recorded. Results: L1CAM positive cases showed increased specificity for recurrence and these patients were significantly younger than L1CAM negative ones. Compared to L1CAM negative recurrent cases, L1CAM positive ones had a noticeably higher Ki-67, tended to be larger and recurred sooner. All L1CAM positive recurrent/metastatic cases were of the luminal B subtype compared to 67.3% of the L1CAM negative cases. Conclusions: L1CAM is highly specific for recurrence in a subset of breast cancer patients and may be associated with more aggressive behavior, particularly in luminal B breast cancers with higher Ki-67 expression. Further investigation about the prognostic value of L1CAM is warranted. Cancer Biology Oncology L1CAM estrogen receptor progesterone receptor recurrence breast cancer Figures Figure 1 Background Breast cancer is the most common cancer in women worldwide and the second leading cause of cancer death, surpassed only by lung cancer. The American Cancer Society estimates that there will be approximately 276,480 new cases of breast cancer in women and about 2,620 new cases in men in 2020 and although the death rates have been decreasing since 1989 – especially in women over 50 years of age – they still remain steady in those under 50 and roughly 42,170 women in the United States are expected to die from breast cancer in 2020 alone [ 1 ]. Classification of breast carcinoma is based on expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2) and is pivotal in helping determine therapy and predict survival. Using RNA expression profiling, four significant groups of breast cancer have been reported, based on the expression ER, PR and HER2 [ 2 , 3 ]. The ER positive group is the most diverse subtype with the best prognosis, comprising two categories: luminal A breast carcinomas – ER positive and/or PR positive with a Ki-67 < 14% and luminal B type – ER positive and/or PR positive with a Ki-67 ≥ 14% or ER positive and/or PR positive with positive HER2 expression. The ER negative groups include the HER2-enriched – ER/PR negative and HER2 positive and basal- breast carcinomas – typically (but not always) negative for ER, PR, and HER2, the so-called “triple negative breast carcinomas” (TNBC), EGFR or CK5/6 positive. like In addition, TNBC that are negative for both EGFR and CK5/6 are defined as TNBC-non basal [ 4 ]. These four breast cancer subtypes have significantly different treatment options and differences between subtypes have been shown to have relevance for locoregional relapse [ 4 ]. HER2-enriched tumors have a 5-year-locoregional recurrence rate of 15% compared to 1% for luminal A ones [ 5 ], while HER2-enriched and TNBC are both associated with higher risk of local recurrence than the luminal A subtype [ 6 ]. Local and distant recurrence for luminal A tumors at 10-years was 8% and 3%, respectively, after partial or total mastectomy, results that confirm the excellent survival outcome for this subtype of tumors [ 7 ]. Compared to the luminal A subtype, women with HER-2 enriched breast carcinoma have roughly a two-fold increased adjusted risk of breast cancer mortality [ 8 ] and patients with TNBC have a poorer short-term prognosis than all the other subtypes [ 9 , 10 ]. Although expected to have similar outcomes due to the similar hormonal profile, luminal A and B type tumors can paradoxically have a significantly different prognosis. The latter group accounts for approximately 35% of ER/PR positive HER2 negative cases and have a higher risk of locoregional recurrences, which is in part attributable to a higher proliferation index, as a Ki-67 ≥ 14% has been shown to predict recurrence in small node-negative hormone positive tumors [ 11 ]. This difference is also reflected in relapses at 15 years (27.8% of luminal A tumors versus 42.9% for luminal B), in median survival from the time of first distant metastasis (2.2 years for luminal A versus 1.6 years for luminal B subtype), as well as in the overall survival (OS) at 10 years (70% luminal A versus 54.4% for luminal B tumors) [ 12 ]. Hormonal therapy only is the primary established treatment for patients with luminal A phenotype, while hormonal plus anti-HER2 target therapies is the strategy appropriate for treatment of luminal B HER2-enriched subtype [ 13 ]. Challenges remain in accurately identifying which subsets of luminal subtype patients will benefit from systemic chemotherapy, as 20–30% of patients with early stage luminal subtype breast carcinoma will relapse and have an unexpectedly poor outcome. These challenges have led to the proliferation of multigene assays to aid in clinical decision making around the suitability of chemotherapy as part of adjuvant treatment regimens [ 14 ]. L1CAM (L1 cell adhesion molecule) is a 200–220 kDa transmembrane glycoprotein of the immunoglobulin (Ig) superfamily, involved in neurogenesis, cell-cell interaction, synaptogenesis, myelination and neuron survival. The molecule is composed of six Ig-like domains and five fibronectin type III, followed by a transmembrane region that connects them to a highly conserved cytoplasmic tail [ 15 ]. A large multicenter evaluation of L1CAM expression in early-stage type I endometrial carcinoma – expected to have excellent prognosis, with more than 80% 10-year OS – showed that despite appropriate treatment, a number of patients exhibited recurrence and poor survival and this trend was associated with L1CAM expression [ 16 , 17 ]. L1CAM has subsequently been proposed to be a strong prognostic factor in endometrial carcinoma and it has been suggested that the classical “low-risk” disease should potentially be further risk stratified [ 18 ]. Despite increasing evidence showing involvement of L1CAM in multiple different types of neoplasia [ 19 – 22 ], little is known about its expression and prognostic value in breast cancer. To-date, only two studies have provided most of the information, both with findings associated primarily with hormone negative breast carcinomas [ 23 , 24 ]. L1CAM is overexpressed in TNBC and is correlated with high tumor grade, propensity for lymph node involvement, negative ER status, HER2 overexpression, and most concerning, with shorter disease-free and OS; it has only been sporadically detected in other non-TNBC (HER2 positive tumors). This prompted our efforts to investigate L1CAM in ER positive/HER2 negative breast carcinomas. The invasive potential of a tumor is mediated by cell adhesion molecules which break and form cell-cell bonds. Since L1CAM promotes adhesion to the endothelium – the first step toward extravasation – the hypothesis that recurrent ER positive HER2 negative breast cancers might be L1CAM positive seems feasible. The finding of a potential correlation between high L1CAM expression and recurrent/metastatic disease in luminal A and B subtypes may be helpful for risk stratification and open new opportunities for targeted therapies. Methods Patients and data retrieval A retrospective search of the pathology information system database between January 2008 and December 2015 after Institutional Review Board (IRB) approval was performed to identify patients with recurrent or metastatic ER positive, PR positive/negative and HER2 negative breast carcinomas. A total of 304 cases (303 patients) were included in this study (Table 1 ). A total of 165 cases of recurrent or metastatic breast carcinomas were identified and hematoxylin-eosin (H&E) slides and paraffin blocks for 152 cases (151 patients) were available and retrieved. One patient had bilateral disease and accounted for two separate cases. 152 cases (152 patients) of non-recurrent/non-metastatic ER positive, PR positive/negative and HER2 negative breast carcinomas from the same time period were identified and included for comparison analysis (Table 1 ). Table 1 Population clinicopathologic characteristics Total population (n = 304) Recurrent (n = 152) Non-Recurrent (n = 152) p-value Years of age (mean/range) 60.0 (21–92) 61.2 (21–90) 58.7 (32–92) NS PR positive 255 122 133 NS PR negative 49 30 19 Nottingham grade 1 87 24 64 < 0.0001 2 141 81 59 3 76 47 29 Ki-67 (mean/range) 21.9 (1–95) 27.8 (1–85) 17.4 (1–95) < 0.0001 Ki-67 < 14 121 35 85 < 0.0001 Ki- 67 ≥ 14 142 79 64 Excision and biopsy 289 137 152 NA Biopsy only 15 15 0 Tumor size (mean/range) 3.1 (0.4–22) 3.8 (0.6–22) 2.4 (0.4–15) < 0.001 Stage pT1a 2 0 2 pT1b 35 15 20 < 0.001 pT1c 101 29 72 pT2 106 60 46 pT3 38 26 12 pT4 5 5 0 Not evaluated 17 17 0 NA Lymphovascular invasion Positive 86 61 25 < 0.001 Negative 201 74 127 Unknown 17 17 0 NA Lymph node involvement Positive 170 52 118 < 0.001 Negative 88 60 28 Unknown 46 40 6 NA Histological type Ductal 247 123 124 NS Lobular 45 24 21 Mixed (ductal and lobular) 11 4 7 Other 1 1 0 Years to recurrence (mean/range) 4 (0–21) NA NA Metastatic disease at time of diagnosis 26 26 NA NA L1CAM positive 7 7 0 0.015 L1CAM negative 297 145 152 Information on ER, PR, HER2, Ki-67, Nottingham grade, tumor size, tumor stage, number of foci, lymph node status, lymphovascular invasion, phenotype, and laterality were extracted from the pathology report. The Nottingham grade was calculated using the Nottingham modification of the Bloom-Richardson system [ 25 , 26 ]. Information on age at diagnosis and first distant or local recurrence were extracted from the medical record. Immunohistochemistry (IHC) All tumor H&E and IHC slides were reviewed by at least two board-certified breast pathologists, with manual interpretation of ER, PR, HER2, and Ki-67, using standard histological criteria [ 27 ]. IHC was performed on whole sections from the surgical excision if available; otherwise, IHC was performed on the biopsy specimen. For cases with multiple foci of tumor, IHC was performed on the largest focus and for recurrent/metastatic cases positive for L1CAM, IHC was also performed on the metastatic focus. ER, PR, and HER2 were evaluated using FDA-approved test kits - [DAKO] - ERα [clones ID5 and ER-2-123], PR [clone PgR1294] pharmDxTM), and HER2 IHC scores (Rabbit anti-human HER-2 HercepTestTM). HER2 FISH was performed (FDA-approved test kit [DAKO] - HER2 IQFISH pharmDxTM) on all equivocal HER2 IHC results. Ki-67 was evaluated by calculating the percentage of positive staining tumor cells on a single slide (Monoclonal mouse anti-human Ki-67 antigens [clone MIB-1, code M7240]). L1CAM analysis was performed using the L1 mAb clone 14.10 (BioLegend, San Diego, CA). Formalin-fixed paraffin-embedded tissues were sectioned at 4 microns, placed on glass slides, and baked for 60 minutes at 60 °C. The slides were placed on the Dako Omnis Automated Staining Platform. The protocol uses Envision Flex TRS Low pH retrieval buffer for 30 minutes at 95 °C in which the antibody is diluted to 1:400 in Dako Antibody Diluent and incubated for 20 minutes, then visualized by Envision Flex HRP using DAB as the Chromogen. The slides were counterstained with hematoxylin, dehydrated through graded alcohols and cover slipped. High L1CAM-expressing normal kidney and brain tissue was used as positive control. L1CAM expression of ≥ 10% is considered positive [ 17 ]. Statistical evaluation Available clinical and pathologic data were summarized using percentages, descriptive statistics (mean, range) and inferential statistics (chi-square (X 2 ) test of independence, relative-risk, and t-test). All data analyses were performed using the statistical Analysis ToolPak (Microsoft Excel Office 2010 version 14.0.7015.100) except for the inferential statistics, which were performed using JavaStat 2-way Contingency Table Analysis (revised version 7/23/2013 http://statpages.org/ctab2x2.html ). For all results, a p-value of < 0.05 was considered significant. This study received IRB approval from the University of Rochester (IRB# 00003173). Results A summary of clinicopathologic features in the patient population is detailed in Tables 1 and 2 . Table 2 Clinicopathologic characteristics of L1CAM positive and L1CAM negative recurrent cases L1CAM positive (n = 7) L1CAM negative (n = 145) p-value Years of age (mean/range) 41.0 (21–59) 62.2 (29–90) < 0.001 PR positive 6 116 NS PR negative 1 29 Nottingham grade 1 1 23 NS 2 3 78 3 3 44 Ki-67 (mean/range) 41.4 (20–60) 26.9 (1–85) NS Ki-67 < 14 0 35 NS Ki- 67 ≥ 14 6 72 Excision and biopsy 5 132 NS Biopsy only 2 13 Tumor size (mean/range) 4.9 (1.4–7) 3.7 (0.6–22) NS Stage pT1a 0 0 NS pT1b 0 15 pT1c 1 28 pT2 1 59 pT3 3 23 pT4 0 5 Not evaluated (biopsy only) 2 15 NA Lymphovascular invasion Positive 3 58 NS Negative 3 72 Unknown 1 15 NA Lymph node involvement Positive 3 49 NS Negative 2 59 Unknown 2 37 Histological type Ductal 6 117 NS Lobular 0 24 Mixed (ductal and lobular) 1 3 Other 0 1 Years to recurrence (mean/range) 3.2 (1–6) 4.0 (0–21) NS Metastatic disease at diagnosis 2 24 NS The vast majority of cases were ductal carcinomas (n = 247), 216 ductal carcinoma not otherwise specified (NOS), 16 with micropapillary features, 9 with mucinous features, 3 with tubular features, 2 with papillary features, and one with cribriform features. 45 lobular carcinomas were identified (41 lobular carcinoma NOS, 3 pleomorphic subtypes, and 1 signet ring cell subtype). 11 cases with mixed ductal and lobular features and one with neuroendocrine features were identified. Ki-67 proliferation marker was available in 263 of the 304 cases. Time of recurrence/metastasis ranged from 1–21 years, with the predominant sites including ipsilateral or contralateral breast, chest wall, liver, lung, and bone, with sporadic involvement of orbital soft tissue, colon, and stomach; two cases presented as angiosarcoma at 6 and 8-years post initial diagnosis. Compared to patients with non-recurrent/non-metastatic tumors, patients with recurrences showed similar age, PR expression, and histological types. As would be expected, recurrent cases had significantly higher grade, higher Ki-67, higher percentage of luminal B type tumors, larger tumor size, higher tumor stage, more frequent lymphovascular invasion and lymph node involvement (Table 1 ). Patients with recurrent/metastatic breast cancer were significantly associated with positive L1CAM staining compared to patients without recurrences (Table 1 , Fig. 1: L1CAM pattern of staining: (a) L1CAM negative tumor; (b) L1CAM positive tumor). L1CAM positive cases showed increased specificity for recurrence (p = 0.015, RR = 2.048, Table 1 and Table 3 ) and L1CAM recurrent/metastatic patients were significantly younger than L1CAM negative recurrent ones (p < 0.001, Table 2 ). Although not quite reaching statistical significance (p = 0.08), L1CAM positive recurrent cases had a trend towards a noticeably higher Ki-67 than L1CAM negative ones and 100% of the L1CAM positive recurrent cases were of the luminal B subtype versus 67.3% L1CAM negative recurrences. Compared to L1CAM negative recurrent/metastatic tumors, L1CAM positive cases tended to be larger and recur sooner (Table 2 ). Interestingly, metastatic tumors in four of the seven L1CAM positive recurrent cases were also positive, while two were negative and one case – a patient with lung metastasis for which endoscopic ultrasound-guided fine needle aspiration was performed resulting in a cytology specimen – could not be processed due to exhaustion of the cell block. Table 3 Recurrent and non-recurrent case and L1CAM expression L1CAM positive L1CAM negative Recurrent 7 145 Non-recurrent 0 152 Sensitivity: 0.046 Specificity: 1.000 Positive Predictive Value: 1.000 Negative Predictive Value: 0.512 Relative Risk: 2.048 (p = 0.015) Discussion L1CAM has lately garnered considerable interest due to its association with several malignancies portending poor prognosis – most notably ovarian and endometrial carcinoma and malignant melanoma, but also colon and pancreatic carcinoma [ 16 , 17 , 19 , 20 , 21 ], as well as its role in cell motility, invasion, chemoresistance and metastatic potential [ 28 – 30 ]. These findings have led to attempts to develop new targeted therapies, such as knockdown of L1CAM, which significantly reduces metastasis in a xenograft model of melanoma [ 31 ] and the use of circulating autoantibodies to anti-L1CAM that can be used as a potential diagnostic biomarker in esophageal squamous cell carcinoma [ 22 ]. A large international study focused on endometrial carcinoma FIGO grade 1 stage 1 - expected to have more than 80% 10-year OS – revealed that L1CAM-positive tumors are associated with a considerable increase in the likelihood of recurrence and unexpectedly poor overall survival. This finding raised questions regarding the particular management for these patients – until recently considered being “low-risk” – and adjuvant chemotherapy was proposed as a treatment option for patients with L1CAM-positive FIGO grade 1 stage 1 endometrial carcinoma [ 17 ]. Ongoing trials have established L1CAM as being important in tumor invasion as well as tumor recurrence and old paradigms regarding treatment of “low-risk” endometrial carcinoma patients are being questioned [ 18 , 21 , 32 , 33 ]. In addition, L1CAM has also been detected in benign conditions, such as inflammatory bowel disease and endometriosis [ 34 , 35 ]. Given these findings, examination of expression and prognostic value of L1CAM in breast carcinoma was expected. Upon evaluation of 15 benign and 25 malignant breast tumors (fibroadenoma and invasive ductal carcinoma, respectively) by one of the early studies, no expression of L1CAM was detected [ 36 ]. A subsequent study using a larger number of cases, different IHC protocols and microarray analysis identified L1CAM staining and overexpression in 15% of breast tumors [ 23 ], associated with shortened disease free survival (DFS). These emerging data regarding the role of L1CAM in breast carcinoma subsequently led to an extensive analysis of TNBC, a particularly aggressive breast cancer subtype [ 24 ]. L1CAM expression was found to be more abundant in TNBC and expression of L1CAM was inversely correlated with androgen receptor (AR) expression, suggesting a possible correlation between L1CAM expression and an unfavorable prognosis in both OS and DFS in this patient population. This is of particular significance, as AR is a prognostic marker in TNBC. Expression of AR is associated with improved OS and DFS regardless of ER status, while loss of AR expression is associated with early recurrence in basal-like breast cancer and TNBC [ 37 ]. Overall, the literature to date suggests that L1CAM expression is associated with a particularly aggressive subtype of breast carcinomas. Our study results support this conclusion and suggest that L1CAM expression in a subset of ER-positive HER2 negative breast carcinomas is associated with a more aggressive clinical course and a significantly increased likelihood of recurrence, compared to L1CAM negative ER-positive HER2 negative cases. Recurrent tumors with L1CAM expression occurred in significantly younger women with luminal B phenotype (100% of cases) compared to L1CAM negative recurrent tumors (67.3%) and had a trend toward higher Ki-67 expression. These patients also tended to have larger tumors and earlier recurrences compared to patients whose tumors showed no evidence of L1CAM expression. We believe that, with a larger patient population, these findings would also be statistically significant. L1CAM expression and recurrence was independent of age, phenotype, PR expression, tumor stage, and Nottingham grade. Unlike prior publications, we did not find an association with lymph node status or pathologic stage, at least not in this particular subset of breast cancer patients. Our study is limited because of its retrospective nature, the lack of uniform treatment as well as the fact that we only identified seven cases of L1CAM positive carcinomas; however, all of these patients had recurrent/metastatic breast cancer, while none of the 152 patients without recurrence demonstrated L1CAM expression. Given these limitations, we feel that our results are intriguing, hypothesis generating and warrant further examination of the role of L1CAM expression and its biologic significance in the luminal-B subtype of ER-positive breast cancers. While it is generally accepted that expression of hormone receptors and absence of HER2 amplification is associated with better outcome in women with breast cancer, recurrence and/or metastases still occur in this patient population. This study, although limited in numbers, is an indication that L1CAM may play a deleterious role for DFS not only in patients with TNBC, but also in patients with ER-positive HER2 negative breast tumors. Additional investigations in larger populations are needed to further evaluate these findings, as well as the mechanisms of action and prognostic value of L1CAM. Potential therapies focused on down-regulation of this molecule may be warranted in breast cancers that show evidence of L1CAM expression. Conclusion Our findings suggest that L1CAM expression may be associated with more aggressive behavior, particularly in luminal B subtype breast carcinomas with higher Ki-67 expression. Additional studies with larger populations are needed to further validate these results. List of Abbreviations Estrogen receptor (ER) Progesterone receptor (PR) Human epidermal growth factor receptor (HER2) Triple negative breast carcinomas (TNBC) Overall survival (OS) L1CAM (L1 cell adhesion molecule) Immunoglobulin (Ig) Hematoxylin-eosin (H&E) Immunohistochemistry (IHC) Institutional Review Board (IRB) Chi-square (X2) Not otherwise specified (NOS) Disease free survival (DFS) Androgen receptor (AR) Declarations Ethics approval and consent to participate : All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent for this research was waived according to Institutional Review Board (IRB) approval from the University of Rochester Medical Center (IRB# 00003173). Consent for publication : Not applicable. Availability of data and materials : The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Competing interests : All authors declare that they have no conflict of interest. Funding : This work was supported by the University of Rochester Medical Center Pathology Department. This included funding for the L1CAM antibody, retrieval of histology slides and paraffin blocks, histology sections, and immunohistochemistry. We extend special thanks to our chairman, Dr. Bruce Smoller for his unyielding support. Authors’ contributions : Dr. IM and HZ conducted the project in its entirety, analyzed the data and drew conclusions. Mr. MDA and Drs. IM and HZ pulled all the data. Dr. DH provided input on data analysis and edited the manuscript. Dr. BT analyzed the data along with Drs. IM and HZ and had a pivotal contribution to statistics and manuscript editing. All authors have read and approved the manuscript. 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Overexpression of the cell adhesion molecule L1 is associated with metastasis in cutaneous malignant melanoma. Eur J Cancer. 2002;38(13):1708-1716. Dellinger TH , Smith DD , Ouyang C et al. L1CAM is an independent predictor of poor survival in endometrial cancer - An analysis of The Cancer Genome Atlas (TCGA). Gynecol Oncol. 2016;141(2):336-340. Schäfer H, Struck B, Feldmann E et al.TGF-β1-dependent L1CAM expression has an essential role in macrophage-induced apoptosis resistance and cell migration of human intestinal epithelial cells. Oncogene2013;32:180–189. Finas D , Huszar M , Agic A et al. L1 cell adhesion molecule (L1CAM) as a pathogenetic factor in endometriosis. Hum Reprod. 2008;23(5):1053-1062. Huszar M , Moldenhauer G , Gschwend V et al. Expression profile analysis in multiple human tumors identifies L1 (CD171) as a molecular marker for differential diagnosis and targeted therapy. Hum Pathol. 2006;37(8):1000-1008. Thike AA , Yong-Zheng Chong L et al. Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer. Mod Pathol. 2014;27(3):352-360. 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-56325","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":1696148,"identity":"7f602b86-ac94-4632-a411-83f0a9142a86","order_by":0,"name":"Ioana Moisini","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIiWNgGAWjYBACNgSDsYEhoQLIYmZuIEXLGZAWRvxaUAFjG5jEr4WPvfnZgx8M2+T4+A+3PXg4rzaavx2o5UfFNtwO4zlmbtjDcNuYTSKx3SBx2/HcGYcZGxh7ztzGrUUiwUyCh+F2YpsEY5tE4rZjuQ1ALcyMbfi0pH+T/APSwn8QqGXOsdz5hLXkmEmDbWEAWpTYUJO7gaAWnjNl0jIGYL+0SSQcO5C7EajlID6/yLe3b5N8U3FbTr7/+DPJHzV1ufPOHz744EcFbi0QYABnHQaTBwioRwF1pCgeBaNgFIyCEQIAAOhVAixFf8sAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0856-1246","institution":"University of Rochester Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Ioana","middleName":"","lastName":"Moisini","suffix":""},{"id":1696149,"identity":"bc25b91f-3470-4bbd-9819-7ec96a34d179","order_by":1,"name":"Huina Zhang","email":"","orcid":"","institution":"University of Rochester Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Huina","middleName":"","lastName":"Zhang","suffix":""},{"id":1696150,"identity":"0d22f534-444e-4bac-bebe-c0297cc200e7","order_by":2,"name":"Marcus D’Aguiar","email":"","orcid":"","institution":"University of Rochester Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Marcus","middleName":"","lastName":"D’Aguiar","suffix":""},{"id":1696151,"identity":"7408556c-4bee-4eec-86e4-d78b18947f4b","order_by":3,"name":"David G. Hicks","email":"","orcid":"","institution":"University of Rochester Medical Center","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"G.","lastName":"Hicks","suffix":""},{"id":1696152,"identity":"633a6968-86b9-4c91-acc9-ec08bb439c94","order_by":4,"name":"Bradley M. Turner","email":"","orcid":"","institution":"University of Rochester Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Bradley","middleName":"M.","lastName":"Turner","suffix":""}],"badges":[],"createdAt":"2020-08-09 11:19:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-56325/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-56325/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":2087685,"identity":"afec4136-dabe-4fd5-ac26-620ababc5db8","added_by":"auto","created_at":"2020-08-26 15:32:17","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":104349,"visible":true,"origin":"","legend":"Figure 1","description":"","filename":"Fig1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-56325/v1/Fig1.JPG"},{"id":13585365,"identity":"d4c53908-8118-48b4-abc2-ff11bd468ac5","added_by":"auto","created_at":"2021-09-17 04:43:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":599939,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-56325/v1/c3fd79ac-736c-4549-bfb4-888568e75d35.pdf"}],"financialInterests":"","formattedTitle":"L1CAM Expression in Recurrent Estrogen Positive/HER2 Negative Breast Cancer","fulltext":[{"header":"Background","content":" \u003cp\u003eBreast cancer is the most common cancer in women worldwide and the second leading cause of cancer death, surpassed only by lung cancer. The American Cancer Society estimates that there will be approximately 276,480 new cases of breast cancer in women and about 2,620 new cases in men in 2020 and although the death rates have been decreasing since 1989 \u0026ndash; especially in women over 50\u0026nbsp;years of age \u0026ndash; they still remain steady in those under 50 and roughly 42,170 women in the United States are expected to die from breast cancer in 2020 alone [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClassification of breast carcinoma is based on expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2) and is pivotal in helping determine therapy and predict survival. Using RNA expression profiling, four significant groups of breast cancer have been reported, based on the expression ER, PR and HER2 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The ER positive group is the most diverse subtype with the best prognosis, comprising two categories: luminal A breast carcinomas \u0026ndash; ER positive and/or PR positive with a Ki-67\u0026thinsp;\u0026lt;\u0026thinsp;14% and luminal B type \u0026ndash; ER positive and/or PR positive with a Ki-67\u0026thinsp;\u0026ge;\u0026thinsp;14% or ER positive and/or PR positive with positive HER2 expression. The ER negative groups include the HER2-enriched \u0026ndash; ER/PR negative and HER2 positive and basal- breast carcinomas \u0026ndash; typically (but not always) negative for ER, PR, and HER2, the so-called \u0026ldquo;triple negative breast carcinomas\u0026rdquo; (TNBC), EGFR or CK5/6 positive. like In addition, TNBC that are negative for both EGFR and CK5/6 are defined as TNBC-non basal [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These four breast cancer subtypes have significantly different treatment options and differences between subtypes have been shown to have relevance for locoregional relapse [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. HER2-enriched tumors have a 5-year-locoregional recurrence rate of 15% compared to 1% for luminal A ones [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], while HER2-enriched and TNBC are both associated with higher risk of local recurrence than the luminal A subtype [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Local and distant recurrence for luminal A tumors at 10-years was 8% and 3%, respectively, after partial or total mastectomy, results that confirm the excellent survival outcome for this subtype of tumors [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Compared to the luminal A subtype, women with HER-2 enriched breast carcinoma have roughly a two-fold increased adjusted risk of breast cancer mortality [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and patients with TNBC have a poorer short-term prognosis than all the other subtypes [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough expected to have similar outcomes due to the similar hormonal profile, luminal A and B type tumors can paradoxically have a significantly different prognosis. The latter group accounts for approximately 35% of ER/PR positive HER2 negative cases and have a higher risk of locoregional recurrences, which is in part attributable to a higher proliferation index, as a Ki-67\u0026thinsp;\u0026ge;\u0026thinsp;14% has been shown to predict recurrence in small node-negative hormone positive tumors [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This difference is also reflected in relapses at 15\u0026nbsp;years (27.8% of luminal A tumors versus 42.9% for luminal B), in median survival from the time of first distant metastasis (2.2\u0026nbsp;years for luminal A versus 1.6\u0026nbsp;years for luminal B subtype), as well as in the overall survival (OS) at 10\u0026nbsp;years (70% luminal A versus 54.4% for luminal B tumors) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHormonal therapy only is the primary established treatment for patients with luminal A phenotype, while hormonal plus anti-HER2 target therapies is the strategy appropriate for treatment of luminal B HER2-enriched subtype [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Challenges remain in accurately identifying which subsets of luminal subtype patients will benefit from systemic chemotherapy, as 20\u0026ndash;30% of patients with early stage luminal subtype breast carcinoma will relapse and have an unexpectedly poor outcome. These challenges have led to the proliferation of multigene assays to aid in clinical decision making around the suitability of chemotherapy as part of adjuvant treatment regimens [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eL1CAM (L1 cell adhesion molecule) is a 200\u0026ndash;220\u0026nbsp;kDa transmembrane glycoprotein of the immunoglobulin (Ig) superfamily, involved in neurogenesis, cell-cell interaction, synaptogenesis, myelination and neuron survival. The molecule is composed of six Ig-like domains and five fibronectin type III, followed by a transmembrane region that connects them to a highly conserved cytoplasmic tail [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A large multicenter evaluation of L1CAM expression in early-stage type I endometrial carcinoma \u0026ndash; expected to have excellent prognosis, with more than 80% 10-year OS \u0026ndash; showed that despite appropriate treatment, a number of patients exhibited recurrence and poor survival and this trend was associated with L1CAM expression [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. L1CAM has subsequently been proposed to be a strong prognostic factor in endometrial carcinoma and it has been suggested that the classical \u0026ldquo;low-risk\u0026rdquo; disease should potentially be further risk stratified [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite increasing evidence showing involvement of L1CAM in multiple different types of neoplasia [\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], little is known about its expression and prognostic value in breast cancer. To-date, only two studies have provided most of the information, both with findings associated primarily with hormone negative breast carcinomas [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. L1CAM is overexpressed in TNBC and is correlated with high tumor grade, propensity for lymph node involvement, negative ER status, HER2 overexpression, and most concerning, with shorter disease-free and OS; it has only been sporadically detected in other non-TNBC (HER2 positive tumors). This prompted our efforts to investigate L1CAM in ER positive/HER2 negative breast carcinomas. The invasive potential of a tumor is mediated by cell adhesion molecules which break and form cell-cell bonds. Since L1CAM promotes adhesion to the endothelium \u0026ndash; the first step toward extravasation \u0026ndash; the hypothesis that recurrent ER positive HER2 negative breast cancers might be L1CAM positive seems feasible. The finding of a potential correlation between high L1CAM expression and recurrent/metastatic disease in luminal A and B subtypes may be helpful for risk stratification and open new opportunities for targeted therapies.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003ePatients and data retrieval\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eA retrospective search of the pathology information system database between January 2008 and December 2015 after Institutional Review Board (IRB) approval was performed to identify patients with recurrent or metastatic ER positive, PR positive/negative and HER2 negative breast carcinomas. A total of 304 cases (303 patients) were included in this study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). A total of 165 cases of recurrent or metastatic breast carcinomas were identified and hematoxylin-eosin (H\u0026amp;E) slides and paraffin blocks for 152 cases (151 patients) were available and retrieved. One patient had bilateral disease and accounted for two separate cases. 152 cases (152 patients) of non-recurrent/non-metastatic ER positive, PR positive/negative and HER2 negative breast carcinomas from the same time period were identified and included for comparison analysis (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePopulation clinicopathologic characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal population (n\u0026thinsp;=\u0026thinsp;304)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRecurrent (n\u0026thinsp;=\u0026thinsp;152)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-Recurrent (n\u0026thinsp;=\u0026thinsp;152)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYears of age (mean/range)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.0 (21\u0026ndash;92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61.2 (21\u0026ndash;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58.7 (32\u0026ndash;92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePR positive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e255\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePR negative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNottingham grade\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKi-67 (mean/range)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.9 (1\u0026ndash;95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.8 (1\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.4 (1\u0026ndash;95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKi-67\u0026thinsp;\u0026lt;\u0026thinsp;14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKi- 67\u0026thinsp;\u0026ge;\u0026thinsp;14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExcision and biopsy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBiopsy only\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor size (mean/range)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.1 (0.4\u0026ndash;22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.8 (0.6\u0026ndash;22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.4 (0.4\u0026ndash;15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot evaluated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLymphovascular invasion\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLymph node involvement\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistological type\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuctal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e247\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLobular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed (ductal and lobular)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYears to recurrence (mean/range)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (0\u0026ndash;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMetastatic disease at time of diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eL1CAM positive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eL1CAM negative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e297\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e152\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eInformation on ER, PR, HER2, Ki-67, Nottingham grade, tumor size, tumor stage, number of foci, lymph node status, lymphovascular invasion, phenotype, and laterality were extracted from the pathology report. The Nottingham grade was calculated using the Nottingham modification of the Bloom-Richardson system [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Information on age at diagnosis and first distant or local recurrence were extracted from the medical record.\u003c/p\u003e \u003c/div\u003e \u003cp\u003e\u003cstrong\u003eImmunohistochemistry (IHC)\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eAll tumor H\u0026amp;E and IHC slides were reviewed by at least two board-certified breast pathologists, with manual interpretation of ER, PR, HER2, and Ki-67, using standard histological criteria [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. IHC was performed on whole sections from the surgical excision if available; otherwise, IHC was performed on the biopsy specimen. For cases with multiple foci of tumor, IHC was performed on the largest focus and for recurrent/metastatic cases positive for L1CAM, IHC was also performed on the metastatic focus.\u003c/p\u003e \u003cp\u003eER, PR, and HER2 were evaluated using FDA-approved test kits - [DAKO] - ERα [clones ID5 and ER-2-123], PR [clone PgR1294] pharmDxTM), and HER2 IHC scores (Rabbit anti-human HER-2 HercepTestTM). HER2 FISH was performed (FDA-approved test kit [DAKO] - HER2 IQFISH pharmDxTM) on all equivocal HER2 IHC results. Ki-67 was evaluated by calculating the percentage of positive staining tumor cells on a single slide (Monoclonal mouse anti-human Ki-67 antigens [clone MIB-1, code M7240]). L1CAM analysis was performed using the L1 mAb clone 14.10 (BioLegend, San Diego, CA). Formalin-fixed paraffin-embedded tissues were sectioned at 4 microns, placed on glass slides, and baked for 60 minutes at 60\u0026nbsp;\u0026deg;C. The slides were placed on the Dako Omnis Automated Staining Platform. The protocol uses Envision Flex TRS Low pH retrieval buffer for 30 minutes at 95\u0026nbsp;\u0026deg;C in which the antibody is diluted to 1:400 in Dako Antibody Diluent and incubated for 20 minutes, then visualized by Envision Flex HRP using DAB as the Chromogen. The slides were counterstained with hematoxylin, dehydrated through graded alcohols and cover slipped. High L1CAM-expressing normal kidney and brain tissue was used as positive control. L1CAM expression of \u0026ge;\u0026thinsp;10% is considered positive [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cp\u003e\u003cstrong\u003eStatistical evaluation\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eAvailable clinical and pathologic data were summarized using percentages, descriptive statistics (mean, range) and inferential statistics (chi-square (X\u003csup\u003e2\u003c/sup\u003e) test of independence, relative-risk, and t-test). All data analyses were performed using the statistical Analysis ToolPak (Microsoft Excel Office 2010 version 14.0.7015.100) except for the inferential statistics, which were performed using JavaStat 2-way Contingency Table Analysis (revised version 7/23/2013 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://statpages.org/ctab2x2.html\u003c/span\u003e\u003c/span\u003e). For all results, a p-value of \u0026lt;\u0026thinsp;0.05 was considered significant. This study received IRB approval from the University of Rochester (IRB# 00003173).\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cp\u003eA summary of clinicopathologic features in the patient population is detailed in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eClinicopathologic characteristics of L1CAM positive and L1CAM negative recurrent cases\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eL1CAM positive (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eL1CAM negative (n\u0026thinsp;=\u0026thinsp;145)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYears of age (mean/range)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41.0 (21\u0026ndash;59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.2 (29\u0026ndash;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePR positive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e116\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePR negative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNottingham grade\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKi-67 (mean/range)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41.4 (20\u0026ndash;60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.9 (1\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKi-67\u0026thinsp;\u0026lt;\u0026thinsp;14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKi- 67\u0026thinsp;\u0026ge;\u0026thinsp;14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExcision and biopsy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBiopsy only\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor size (mean/range)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.9 (1.4\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.7 (0.6\u0026ndash;22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot evaluated (biopsy only)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLymphovascular invasion\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLymph node involvement\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistological type\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuctal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLobular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed (ductal and lobular)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYears to recurrence (mean/range)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.2 (1\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0 (0\u0026ndash;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMetastatic disease at diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe vast majority of cases were ductal carcinomas (n\u0026thinsp;=\u0026thinsp;247), 216 ductal carcinoma not otherwise specified (NOS), 16 with micropapillary features, 9 with mucinous features, 3 with tubular features, 2 with papillary features, and one with cribriform features. 45 lobular carcinomas were identified (41 lobular carcinoma NOS, 3 pleomorphic subtypes, and 1 signet ring cell subtype). 11 cases with mixed ductal and lobular features and one with neuroendocrine features were identified. Ki-67 proliferation marker was available in 263 of the 304 cases. Time of recurrence/metastasis ranged from 1\u0026ndash;21 years, with the predominant sites including ipsilateral or contralateral breast, chest wall, liver, lung, and bone, with sporadic involvement of orbital soft tissue, colon, and stomach; two cases presented as angiosarcoma at 6 and 8-years post initial diagnosis. Compared to patients with non-recurrent/non-metastatic tumors, patients with recurrences showed similar age, PR expression, and histological types. As would be expected, recurrent cases had significantly higher grade, higher Ki-67, higher percentage of luminal B type tumors, larger tumor size, higher tumor stage, more frequent lymphovascular invasion and lymph node involvement (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePatients with recurrent/metastatic breast cancer were significantly associated with positive L1CAM staining compared to patients without recurrences (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;1: L1CAM pattern of staining: (a) L1CAM negative tumor; (b) L1CAM positive tumor). L1CAM positive cases showed increased specificity for recurrence (p\u0026thinsp;=\u0026thinsp;0.015, RR\u0026thinsp;=\u0026thinsp;2.048, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) and L1CAM recurrent/metastatic patients were significantly younger than L1CAM negative recurrent ones (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Although not quite reaching statistical significance (p\u0026thinsp;=\u0026thinsp;0.08), L1CAM positive recurrent cases had a trend towards a noticeably higher Ki-67 than L1CAM negative ones and 100% of the L1CAM positive recurrent cases were of the luminal B subtype versus 67.3% L1CAM negative recurrences. Compared to L1CAM negative recurrent/metastatic tumors, L1CAM positive cases tended to be larger and recur sooner (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Interestingly, metastatic tumors in four of the seven L1CAM positive recurrent cases were also positive, while two were negative and one case \u0026ndash; a patient with lung metastasis for which endoscopic ultrasound-guided fine needle aspiration was performed resulting in a cytology specimen \u0026ndash; could not be processed due to exhaustion of the cell block.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRecurrent and non-recurrent case and L1CAM expression\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eL1CAM positive\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eL1CAM negative\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-recurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e152\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eSensitivity: 0.046\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eSpecificity: 1.000\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003ePositive Predictive Value: 1.000\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eNegative Predictive Value: 0.512\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eRelative Risk: 2.048 (p\u0026thinsp;=\u0026thinsp;0.015)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eL1CAM has lately garnered considerable interest due to its association with several malignancies portending poor prognosis \u0026ndash; most notably ovarian and endometrial carcinoma and malignant melanoma, but also colon and pancreatic carcinoma [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], as well as its role in cell motility, invasion, chemoresistance and metastatic potential [\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. These findings have led to attempts to develop new targeted therapies, such as knockdown of L1CAM, which significantly reduces metastasis in a xenograft model of melanoma [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and the use of circulating autoantibodies to anti-L1CAM that can be used as a potential diagnostic biomarker in esophageal squamous cell carcinoma [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A large international study focused on endometrial carcinoma FIGO grade 1 stage 1 - expected to have more than 80% 10-year OS \u0026ndash; revealed that L1CAM-positive tumors are associated with a considerable increase in the likelihood of recurrence and unexpectedly poor overall survival. This finding raised questions regarding the particular management for these patients \u0026ndash; until recently considered being \u0026ldquo;low-risk\u0026rdquo; \u0026ndash; and adjuvant chemotherapy was proposed as a treatment option for patients with L1CAM-positive FIGO grade 1 stage 1 endometrial carcinoma [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Ongoing trials have established L1CAM as being important in tumor invasion as well as tumor recurrence and old paradigms regarding treatment of \u0026ldquo;low-risk\u0026rdquo; endometrial carcinoma patients are being questioned [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In addition, L1CAM has also been detected in benign conditions, such as inflammatory bowel disease and endometriosis [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven these findings, examination of expression and prognostic value of L1CAM in breast carcinoma was expected. Upon evaluation of 15 benign and 25 malignant breast tumors (fibroadenoma and invasive ductal carcinoma, respectively) by one of the early studies, no expression of L1CAM was detected [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. A subsequent study using a larger number of cases, different IHC protocols and microarray analysis identified L1CAM staining and overexpression in 15% of breast tumors [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], associated with shortened disease free survival (DFS). These emerging data regarding the role of L1CAM in breast carcinoma subsequently led to an extensive analysis of TNBC, a particularly aggressive breast cancer subtype [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. L1CAM expression was found to be more abundant in TNBC and expression of L1CAM was inversely correlated with androgen receptor (AR) expression, suggesting a possible correlation between L1CAM expression and an unfavorable prognosis in both OS and DFS in this patient population. This is of particular significance, as AR is a prognostic marker in TNBC. Expression of AR is associated with improved OS and DFS regardless of ER status, while loss of AR expression is associated with early recurrence in basal-like breast cancer and TNBC [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOverall, the literature to date suggests that L1CAM expression is associated with a particularly aggressive subtype of breast carcinomas. Our study results support this conclusion and suggest that L1CAM expression in a subset of ER-positive HER2 negative breast carcinomas is associated with a more aggressive clinical course and a significantly increased likelihood of recurrence, compared to L1CAM negative ER-positive HER2 negative cases. Recurrent tumors with L1CAM expression occurred in significantly younger women with luminal B phenotype (100% of cases) compared to L1CAM negative recurrent tumors (67.3%) and had a trend toward higher Ki-67 expression. These patients also tended to have larger tumors and earlier recurrences compared to patients whose tumors showed no evidence of L1CAM expression. We believe that, with a larger patient population, these findings would also be statistically significant.\u003c/p\u003e \u003cp\u003eL1CAM expression and recurrence was independent of age, phenotype, PR expression, tumor stage, and Nottingham grade. Unlike prior publications, we did not find an association with lymph node status or pathologic stage, at least not in this particular subset of breast cancer patients. Our study is limited because of its retrospective nature, the lack of uniform treatment as well as the fact that we only identified seven cases of L1CAM positive carcinomas; however, all of these patients had recurrent/metastatic breast cancer, while none of the 152 patients without recurrence demonstrated L1CAM expression. Given these limitations, we feel that our results are intriguing, hypothesis generating and warrant further examination of the role of L1CAM expression and its biologic significance in the luminal-B subtype of ER-positive breast cancers.\u003c/p\u003e \u003cp\u003eWhile it is generally accepted that expression of hormone receptors and absence of HER2 amplification is associated with better outcome in women with breast cancer, recurrence and/or metastases still occur in this patient population. This study, although limited in numbers, is an indication that L1CAM may play a deleterious role for DFS not only in patients with TNBC, but also in patients with ER-positive HER2 negative breast tumors. Additional investigations in larger populations are needed to further evaluate these findings, as well as the mechanisms of action and prognostic value of L1CAM. Potential therapies focused on down-regulation of this molecule may be warranted in breast cancers that show evidence of L1CAM expression.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eOur findings suggest that L1CAM expression may be associated with more aggressive behavior, particularly in luminal B subtype breast carcinomas with higher Ki-67 expression. Additional studies with larger populations are needed to further validate these results.\u003c/p\u003e"},{"header":"List of Abbreviations","content":" \u003cp\u003eEstrogen receptor (ER)\u003c/p\u003e \u003cp\u003eProgesterone receptor (PR)\u003c/p\u003e \u003cp\u003eHuman epidermal growth factor receptor (HER2)\u003c/p\u003e \u003cp\u003eTriple negative breast carcinomas (TNBC)\u003c/p\u003e \u003cp\u003eOverall survival (OS)\u003c/p\u003e \u003cp\u003eL1CAM (L1 cell adhesion molecule)\u003c/p\u003e \u003cp\u003eImmunoglobulin (Ig)\u003c/p\u003e \u003cp\u003eHematoxylin-eosin (H\u0026amp;E)\u003c/p\u003e \u003cp\u003eImmunohistochemistry (IHC)\u003c/p\u003e \u003cp\u003eInstitutional Review Board (IRB)\u003c/p\u003e \u003cp\u003eChi-square (X2)\u003c/p\u003e \u003cp\u003eNot otherwise specified (NOS)\u003c/p\u003e \u003cp\u003eDisease free survival (DFS)\u003c/p\u003e \u003cp\u003eAndrogen receptor (AR)\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent for this research was waived according to Institutional Review Board (IRB) approval from the University of Rochester Medical Center (IRB# 00003173).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: All authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This work was supported by the University of Rochester Medical Center Pathology Department. This included funding for the L1CAM antibody, retrieval of histology slides and paraffin blocks, histology sections, and immunohistochemistry. We extend special thanks to our chairman, Dr. Bruce Smoller for his unyielding support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e: Dr. IM and HZ conducted the project in its entirety, analyzed the data and drew conclusions. Mr. MDA and Drs. IM and HZ pulled all the data. Dr. DH provided input on data analysis and edited the manuscript. Dr. BT analyzed the data along with Drs. IM and HZ and had a pivotal contribution to statistics and manuscript editing. All authors have read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: We thank the immunohistochemistry laboratory (Sierra Kovar, Qi Yang, Dalton Smith) and our breast-gynecologic fellow, Dr. Hasan Khatib for their hard work and unyielding dedication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; information\u003c/strong\u003e: Drs. Moisini and Zhang contributed equally to this work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAmerican Cancer Society. How Common Is Breast Cancer? Jan. 2020. Available at:\u0026nbsp;\u003ca href=\"https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html\"\u003ehttps://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eWeigelt B, Horlings HM, Kreike B et al. Refinement of breast cancer classification by molecular characterization of histological special types. J Pathol. 2008;216:141-150.\u003c/li\u003e\n\u003cli\u003e\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=S%C3%B8rlie%20T%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=11553815\"\u003eS\u0026oslash;rlie T\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Perou%20CM%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=11553815\"\u003ePerou CM\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Tibshirani%20R%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=11553815\"\u003eTibshirani R\u003c/a\u003e et al. 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L1CAM is an independent predictor of poor survival in endometrial cancer - An analysis of The Cancer Genome Atlas (TCGA). \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/26861585\"\u003eGynecol Oncol.\u003c/a\u003e2016;141(2):336-340.\u0026nbsp;\u003c/li\u003e\n\u003cli\u003eSch\u0026auml;fer H, Struck B, Feldmann E\u0026nbsp;et al.TGF-\u0026beta;1-dependent L1CAM expression has an essential role in macrophage-induced apoptosis resistance and cell migration of human intestinal epithelial cells.\u0026nbsp;Oncogene2013;32:180\u0026ndash;189.\u003c/li\u003e\n\u003cli\u003e\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Finas%20D%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=18332088\"\u003eFinas D\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Huszar%20M%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=18332088\"\u003eHuszar M\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Agic%20A%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=18332088\"\u003eAgic A\u003c/a\u003e et al. 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Expression profile analysis in multiple human tumors identifies L1 (CD171) as a molecular marker for differential diagnosis and targeted therapy. \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/16867862\"\u003eHum Pathol.\u003c/a\u003e2006;37(8):1000-1008.\u003c/li\u003e\n\u003cli\u003e\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Thike%20AA%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=23929266\"\u003eThike AA\u003c/a\u003e,\u0026nbsp;\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Yong-Zheng%20Chong%20L%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=23929266\"\u003eYong-Zheng Chong L\u003c/a\u003e et al. Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer. \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/23929266\"\u003eMod Pathol.\u003c/a\u003e2014;27(3):352-360.\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":"L1CAM, estrogen receptor, progesterone receptor, recurrence, breast cancer","lastPublishedDoi":"10.21203/rs.3.rs-56325/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-56325/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eWe investigate L1CAM expression in ER positive/HER2 negative breast carcinomas. \u0026nbsp;The finding of a potential correlation between high L1CAM expression and recurrent/metastatic disease in luminal A and B breast carcinomas may be helpful for risk stratification and open opportunities for targeted therapies.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003e304 cases comprising 152 cases of ER positive, PR positive/negative and HER2 negative recurrent/metastatic breast carcinomas and 152 non-recurrent controls were included. ER, PR, HER-2, Ki-67 status, Nottingham grade, tumor size, tumor stage, number of foci, lymph node status, lymphovascular invasion, phenotype, laterality, age at diagnosis and first distant or local recurrence were recorded.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eL1CAM positive cases showed increased specificity for recurrence and these patients were significantly younger than L1CAM negative ones. Compared to L1CAM negative recurrent cases, L1CAM positive ones had a noticeably higher Ki-67, tended to be larger and recurred sooner. All L1CAM positive recurrent/metastatic cases were of the luminal B subtype compared to 67.3% of the L1CAM negative cases. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eL1CAM is highly specific for recurrence in a subset of breast cancer patients and may be associated with more aggressive behavior, particularly in luminal B breast cancers with higher Ki-67 expression. Further investigation about the prognostic value of L1CAM is warranted.\u003c/p\u003e","manuscriptTitle":"L1CAM Expression in Recurrent Estrogen Positive/HER2 Negative Breast Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-08-26 15:30:32","doi":"10.21203/rs.3.rs-56325/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":"25cc0a05-9977-47b6-8a93-3f2fdedb4cab","owner":[],"postedDate":"August 26th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":363713,"name":"Cancer Biology"},{"id":363714,"name":"Oncology"}],"tags":[],"updatedAt":"2020-12-19T21:23:08+00:00","versionOfRecord":[],"versionCreatedAt":"2020-08-26 15:30:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-56325","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-56325","identity":"rs-56325","version":["v1"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}