Breast cancer in males.

Male breast cancer is a rare disease, occurring in about 1% of all breast cancers. Can we learn from this uncommon illness? The answer should be a resounding yes, but we are far from understanding the whole story. This issue of the Asia–Pacific Journal of Clinical Oncology features a comprehensive review on male breast cancer by Field et al.1 We learn that the incidence of breast cancer in men may be increasing with elusive etiologies. We also learn that the prognosis is the same as female breast cancer patients, matching the stage by stage and other prognostic factors. However, we are told that 90% or more male breast cancers have positive estrogen receptors and very few (1–2%) have HER-2/NEU gene amplification expression. Therefore, common sense would have suggested that male breast cancer sufferers should have better prognosis than their female counterparts. But that is not the case by literature review. What are the possible explanations? The following speculations may shed some clues for future research: The proliferative drive or signal transduction pathway in male breast cancer may be quite different in that they may have shorter duration of response or early development of drug resistance. However, we do not have any clinical or laboratory evidence to substantiate this notion. Male patients may have more difficulties to accept the diagnosis of a female disease. Hence, they are more prone to be lost for follow-up or stop treatment early. That is, they may not get treated as vigorously as female patients. Again, we need more epidemiological data to support this idea. Or, the existing data on survival are not reliable as most if not all the data are retrospective. There is hardly any clinical trial on female breast cancers that included male patients. Therefore, a fair comparison is not possible. From their review, we understand that there are substantial differences between male and female breast cancers, such as genetic predisposing factors (BRCA2 mutation is the most common form in men as compared to BRCA1 in female patients), histopathology (much less lobular carcinoma in male than in female), hormonal receptors (male breast cancers have more frequent positive estrogen receptor than female patients) and response to aromatase inhibitor (aromatase inhibitors increase testosterone levels in male not in female and less effective in suppressing estrogen in male volunteers). This review paper also pointed out many missing pieces of information in all aspects of male breast cancer. There are hardly any prospective clinical phase II trials with aromatase inhibitors or chemotherapy agents such as taxanes, gemcitabine, vinorelbine which are commonly used in female breast cancer. Rightly so, the authors cautioned the routine use of aromatase inhibitors in men due to differences in endocrine response between both sexes. We are still lacking the essential genomic data in male breast cancer which may provide clues to explain this phenomenon. Although it is of importance and interest to know all the differences and similarities between male and female breast cancer patients, we need to consider what we can do to utilize this information to elicit clues to solve some of the unknown mysteries and advance our knowledge. Unfortunately, not much can be done by a single institution or study group for the time being. Perhaps, one immediate step to be taken should be to form an international study group. Then, prospective phase II studies may become a reality in the near future, as there are too few cases of male breast cancer in any single institution. In essence, clues may be discovered among controversies and from insufficient data, but it requires confirmation and validation. In this case, we need worldwide concerted efforts to study this rare disease: male breast cancer.

Breast cancer is a frequently diagnosed cancer in women, but the incidence of male breast cancer has also shown an increasing trend. Male and female breast cancers have some similarities, including risk factors and breast symptoms. Invasive ductal carcinoma is the most common type of breast cancer in both males and females. Even though fewer men than women are affected by breast cancer, male breast cancers are diagnosed at a more advanced stage and frequently have worse prognosis than their female counterparts. Through this case series, we are sharing a few unusual presentations of cancers in the male breast. In this case series of three patients, we will discuss the similarities and differences in male and female breast cancer. We aim to highlight the need to identify men at high risk and the importance of investigating any breast symptoms in men promptly.

Predicting Late Recurrence in Male Estrogen Receptor-Positive Breast Cancer With Clinical Treatment Score Post-5 years: A SEER database analysis of 65,711 cases.

e13032 Background: Approximately 85% of male breast cancer (MBC) patients test negative for a BRCA mutation, and the role of genetic predisposition is unclear. Cancer risk counseling for unaffected relatives of BRCA-negative MBC patients relies on accurate cancer risk estimates, but there is limited data on the risk of breast cancer (BC) for relatives of these men. We characterized the association between MBC and family history of BC in patients who test negative for BRCA mutations in order to facilitate cancer risk counseling and to explore the possibility of unidentified MBC susceptibility alleles. Methods: We performed a case-control study of patients who had full length sequencing and large-rearrangement analysis for germline mutations in BRCA1/2 or the mismatch repair (MMR) genes at a commercial laboratory from 2006-2012. Cases were MBC patients who tested negative for a BRCA1/2 mutation (n = 3,647); controls were male colon cancer patients who tested negative for mutations in MMR genes (n = 4,269). Information on family history of BC was ascertained from test request forms completed by the ordering healthcare provider at the time of testing. Unconditional multivariable logistic regression models estimated odds ratios (OR) and 95% confidence intervals (CI) for associations between family history of BC in first- (FDR) and second-degree relatives (SDR) and MBC with adjustment for potential confounders (age, ethnicity, year of testing). Results: Compared to controls, MBC cases had higher odds of BC in a FDR or SDR (OR = 4.7; 95% CI 4.1, 5.3). Associations were strongest for family history of BC in 1 female FDR (OR = 3.9; 95% CI: 3.3, 4.6), ≥2 female FDR (OR = 7.5; 95% CI 5.0, 11.4), BC in a FDR < 45 years old (for cases diagnosed < 45, OR = 6.9; 95% CI 3.9, 12.4), a male FDR or SDR with BC (OR = 17.9; 95% CI 7.6, 42.1), and both a male and female FDR or SDR with BC (OR = 15.7; 95%CI 4.4, 55.3). Conclusions: MBC patients who test negative for a BRCA mutation have significantly higher odds of reporting family members affected by breast cancer, particularly with affected FDR < 45 years old, multiple affected relatives, and male relatives with BC. This data can guide risk counseling in MBC families, and suggests the existence of unidentified MBC susceptibility alleles.

539 Background: Male BC accounts for < 1% of all BC and is often diagnosed at later stage, which can result in higher mortality. Due to the rarity of this diagnosis, limited data exist on genomic alterations and prevalence of cancer susceptibility genes (CSG). We aimed to comprehensively describe the genomics of male BC and compare these to a FBC cohort across subtypes to provide insight on tumor biology and opportunities for targeted therapies. Methods: 275 male BC TBx or LBx were sequenced by Foundation Medicine (FM) using hybrid capture-based CGP. Both TBx and LBx were evaluated for all classes of genomic alterations (GA). Histological subtype, receptor status, and biopsy site were extracted from pathology reports. Paired samples with both TBx and LBx were available in 7 cases. The male BC TBx cohort with known receptor status (n = 253) was compared to a FBC cohort (n = 2855). Mutational prevalence in 5 breast CSG (ATM/BRCA1/BRCA2/CHEK2/PALB2) were compared along with their associated genomic LOH (gLOH) values. Results: Among male BCs, subtype distribution was: ER+/HER2- n = 210 (83%), ER+/HER2+ n = 22 (9%), TNBC n = 20 (8%). ER+/HER2+ male BC cases had higher rates of ERBB2 SV (22.7% v. 0.62%, p < 0.0001), PIK3CA (68.2% vs. 34%, p = 0.01), MDM2 amplifications (36% v. 4%, p < 0.0001) and GATA3 (36.6% v. 6.2%, p = 0.0002) than ER+/HER2+ FBC. In the ER+/HER2- cohort, male BC had more alterations in BRCA2 (13.8% v. 5.3%, p < 0.0001) and GATA3 (26% vs. 15%, p = 0.0004) and less alterations in TP53 and ESR1 (p < 0.0001 both). 28.6% of male BC v. 16.6% of FBC (p = 0.004) had one or more variants in one of 5 CSG of potential germline origin with a higher % of BRCA mutations in male BC vs. FBC (17.5% v. 9.9%, p = 0.0006). In the paired male BC Bx’s we saw genomic heterogeneity in a case showing 5 unique ESR1 alts and a PIK3CA SV unique to LBx done at the same time as TBx. We saw evidence of resistance with a shared BRCA1 alteration and several reversion mutations unique to LBx taken 471 days later, and a longitudinal pair with unique ESR1,PIK3CA and MTOR mutations in a LBx 547 days apart. Conclusions: Although male and female BC share some common alterations, our study revealed potentially important findings that may explain biological differences and provide treatment opportunities. Despite HR+/HER2+ male BC being rare, it was notable for increased co-mutations with ERBB2 SV, PIK3CA SV, and GATA3 SV, which can be associated with a worse prognosis but perhaps allow more novel combinations. ESR1 mutations appear more common in ER+/HER2- FBC reflective of treatment with aromatase inhibitors versus tamoxifen for male BC. TP53 mutations were more common in all subtypes of FBC. BRCA2 mutations and other potential germline CSG variants were more common in male BC, suggesting an opportunity for PARP inhibitors. LBx identified additional biomarkers and resistance mutations not seen in TBx.

Clinical management of breast cancer in males: a report of four cases

Background: Male breast cancer is a rare cancer. According to the Japanese Breast Cancer Society's Breast Cancer Registry, there were 613 cases of male breast cancer in 2016. It is only 0.6% of all cases of breast cancer incidence. Because of its rarity, there have been no comprehensive studies on characteristics of male breast cancer in Japan. Therefore, there has been few specific treatments developed for male breast cancer. In this study, we investigated the prevalence and clinicopathological characteristics of male breast cancer in Japan, using the most reliable domestic data, the National Clinical Database (NCD). NCD is a database that collects medical information on diseases, treatments, and surgeries in Japan. In collaboration and cooperation with academic societies and academic organizations, NCD maintain and manage the collected data. The data are used in domestic research to evaluate the standards of medical care and support clinical research. This study conducted with a collaboration with NCD and the registration committee of Japan Breast Cancer Society. Materials and Methods: Clinicopathological data were collected from all breast cancer patients in NCD between 2012 and 2018. We compared the male and female breast cancer patients on age, stage, surgical technique, estrogen receptor (ER) status, progesterone receptor (PgR) status, HER2 expression, family history, comorbidities, and systemic treatment history. Results: 3,780 male and 590,636 female breast cancers were enrolled in the study. The median age was 71 years for men (56-87 years, 5-95 percentile) and 61 years for women (40-83 years). The clinical stage in males was 7.2% in stage 0, 36.3% in stage I, 33.4% in stage II, 12.4% in stage III, 1.4% in Stage IV and 4.5% in unknown, respectively. In females, 13.0%, 41.6%, 31.4%, 6.6%, 1.3% and 2.3%, respectively. Breast conserving surgery (BCS) was performed for 14.6% in men 46.2% in women. BCS rate in men is more frequent in Japan compared to in western countries (Ann Oncol. 2018 Feb 1;29(2):405-417). Hormone receptor-positive (HR+; ER+ and/or PgR+) HER2-negative (HER2-) was 88%, HR+HER2-positive (HER2+) was 8%, HR-HER2+ was 1% and HR-HER2- was 3% in men. 74%, 10%, 6% and 10% in women, respectively. The distribution of subtypes in men is similar to western countries. Comorbidity was reported in 42.3% of men and 66.8% of women. Hypertension, diabetes, cardiac disorder and cerebrovascular disorder were more common in men. Conclusion: Male breast cancer is 0.6% of all breast cancer in Japan. Stage III and HR+ is more frequent in male and its tendency is similar to data from western countries. BCS is underwent more frequent in Japan than in western countries. Citation Format: Akihiko Shimomura, Masayuki Nagahashi, Hiraku Kumamaru, Yutaka Yamamoto, Hiromitsu Jinno, Shigeru Imoto, Registration Committee of Japan Breast Cancer Society. Clinicopathological characteristics of male breast cancer in Japan from the national clinical database [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-79.

Introduction: Due to the low incidence of male breast cancer, large scale prospective trials to guide therapy are lacking. Historically males with breast cancer present at more advanced stages than females and have been surgically treated with modified radical mastectomy. Recent studies suggest that breast-conserving therapy for early-stage male breast cancer yields similar outcomes as for female patients, and that sentinel lymph node biopsy (SLNB) can be used in place of axillary lymph node dissection (ALND) for appropriate clinically node-negative patients. Our study investigates trends in breast and axillary surgery for male breast cancer patients, focusing specifically on the treatment of early-stage disease. Methods: The National Cancer Database (NCDB) was utilized to identify male and female patients diagnosed with clinical T1-2 breast cancer from 2004-2016. Patient, tumor, facility, and surgical treatment factors were examined. Patients were stratified by surgery type: partial, unilateral, and bilateral mastectomy; simple versus modified radical mastectomy; SLNB (removal of ≤ 5 lymph nodes) and ALND (>5 lymph nodes). Trends in surgery type were compared between male and female patients and over the study period for each gender. Results: 9,782 males and 1,078,105 females with T1-2 breast cancer were identified. Men were significantly older at diagnosis than women (31.4% vs. 23.6% age >70, p<0.0001), were more often insured by Medicare (44.5% vs. 35.3%, p<0.0001), and had greater co-morbidity (21.9% vs. 15.6% Charlson Deyo Score >0). ER/PR+ disease (94.2% vs. 84.1%, p<.0001), moderate/high grade histology (85.4% vs. 77.8%, p<.0001) and lymphovascular invasion (24% vs. 15.3%, p<.0001) were also more common in males vs. females. The majority of all patients were clinically node negative (80.4% of males, 85% of females) and had AJCC clinical stage I or II disease (92.3% men, 95.2% women). Unilateral mastectomy was performed most commonly for men (67.1% men vs. 24.1% women, p<0.001), while women more frequently underwent partial mastectomy (64.7% women vs. 26.4% men, p<0.001). The rates of each surgery type remained disparate by gender and stable over the study period: male unilateral mastectomy rate 59.8% in 2004 and 66.1% in 2016; female partial mastectomy rate 65.9% in 2004, 68.4% in 2016. Modified radical mastectomy rates decreased in favor of simple mastectomy for both genders, 61.8% to 24.1% in males and 58.7% to 20.2% in females, 2004 to 2016. There was a similar overall increase in SLNB vs. ALND for all patients, though SLNB was not adopted as the more common procedure in male patients until 2009. In 2016, 78.2% of females and 65.3% of males underwent SLNB vs. 51.1% and 39.8% in 2004, respectively. Conclusions: Although breast-conserving therapy is the treatment of choice for female patients with early-stage breast cancer and could be similarly used to treat men with T1-T2 disease, the majority of male breast cancer patients continue to undergo unilateral mastectomy for early-stage disease. In more recent years, SLNB has surpassed ALND for men, mirroring the trend for women, though in a more delayed and gradual fashion. Partial mastectomy and SLNB warrant consideration for men with T1 and T2 breast cancer, in particular since male breast cancer patients present at older ages and with more co-morbidity than their female counterparts, and may benefit from de-escalation of surgical treatment. Citation Format: Rashi Singh, Lifen Cao, Anuja L Sarode, Michael Kharouta, Robert Shenk, Megan E Miller. Trends in breast and axillary surgery for T1-T2 male breast cancer: A study from the national cancer database [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-12.

Introduction: Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers (BC) and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Few studies have examined the genomic landscape of male BCas, with six male BCas included in The Cancer Genome Atlas (TCGA). Familial studies of male BCas have shown genomic changes similar to female BCa, while a larger targeted sequencing study of 59 male breast cancers identified recurrent mutations affecting PIK3CA and GATA3. To date, there is still limited information regarding the genomic landscape of male BCas; particularly in the context of identifying targeted treatments. To reveal genomic changes that characterize male BCas in the context of known cancer driver genes linked to prognosis and targeted agents, we performed a targeted sequencing study on 248 male BCas from the International Male Breast Cancer Program. Methods: 248 primary M0, ER+ve, HER2-ve male BCas enrolled in the Part 1 (retrospective joint analysis) International Male Breast Cancer Program of 1483 patients diagnosed between 1990-2010 (Cardoso et al. Annals of Oncology, 2018) were processed for nucleic acid extraction from formalin-fixed paraffin embedded (FFPE) tissues. Using the Thermo Fisher Scientific Oncomine Comprehensive Assay v3 (OCAv3), a validated targeted sequencing panel currently used in the NCI-MATCH trial (NCT02465060), we evaluated mutational and copy number variations (CNVs) of genes that are prognostic or predictive to targeted therapies currently in use in the clinic or late-stage clinical trials. The OCAv3 DNA pan-cancer panel assays 115 genes for determining mutational status (48 full coding and 67 hotspot) as well as copy-number assessment in 43 genes. The OCAv3 uses Ampliseq-based technology linked to the Oncomine NGS workflow to identify actionable mutations and CNVs Results: Of the 248 samples assayed, 216 passed strict quality control parameters (87.1%). Using the Oncomine NGS workflow, actionable mutations at ≥5% variant allele frequency (VAF) were most frequently identified in PIK3CA (29.2%), BRCA2 (11.1%), NF1 (11.6%), indels in TP53 (10.6%), ATR (5.6%), ATRX (5.1%), indel BRCA2 (5.1%), TP53 point mutations (4.6%), MET (4.6%), ATM (4.6%), NOTCH2 (4.6%), CHEK1 (4.2%), FANCI (4.2%), PTEN (3.2%) with a number of additional genes identified at lower frequencies. Gene amplifications were most frequently detected in MYC (24.5%), FGFR1 (14.8%), CCND1 (12%), FGF3 (9.7%), FGF19 (9.7%), MDM2 (6.5%), CDK4 (1.4%), FGFR3, MDM4, ERBB2 (0.9% each), and FLT3, AR, MYCL, CDK6, IGF1R, FGFR4, KRAS, AKT3 and ESR1 (0.5% each). Although the results here describe the mutations and copy-number changes deemed to be actionable, further analysis of all non-actionable somatic mutations and CNVs will be presented and compared to female BCas previously assayed using the same panel. Conclusion: In this targeted sequencing study of the largest series of male BCas to our knowledge, we have revealed that PIK3CA continues to be a frequently altered gene in both male and female BCas. However, there is an enrichment of mutations in genes related to DNA repair in male BCs. Interestingly, while MYC is commonly amplified in female BCa, a higher frequency of amplified cases were seen in male BCas, in contrast to female BCas. Together with our previously generated transcriptional profiling data in this data set, we believe that both common and unique biological processes comprising male and female BCas will ultimately improve their clinical management and move towards the goal of precision medicine. This work has been funded by the Breast Cancer Research Foundation (BCRF). Citation Format: Jane Bayani, Coralie Poncet, Cheryl Crozier, Quang M Trinh, Megan Hopkins, Aime Lambert Uwimana, Tammy Piper, Carrie Cunningham, Monika Sobol, Stefan Aebi, Kim Benstead, Oliver Bogler, Lissandra Dal Lago, Florentine Hilbers, Ingrid Hedenfalk, Larissa Korde, Barbro Linderholm, John Martens, Lavinia Middleton, Melissa Murray, Catherine Kelly, Cecilia Nilsson, Monika Nowaczyk, Stephanie Peeters, Aleksandra Peric, Peggy Porter, Carolien Schröder, Isabel T Rubio, Kathryn J Ruddy, Christi van Asperen, Danielle Van Den Weyngaert, Carolien HM van Deurzen, Elise van Leeuwen-Stok, Joanna Vermeij, Eric Winer, Lincoln D Stein, Sharon H Giordano, Fatima Cardoso, John MS Bartlett. The genomic landscape of male breast cancers using the oncomine comprehensive assay for actionable mutations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-03.

Stages at presentation, prognostic factors, and outcome of breast cancer in males

Background/Statement of Purpose: The role of cancer susceptibility genes in the male breast cancer population beyond BRCA1 and BRCA2 (BRCA) is not well defined. While breast cancer has been documented in men with pathogenic variants in a number of other breast cancer susceptibility genes (e.g. CHEK2, PALB2, PTEN), the yield of testing is not well documented nor are predictive clinical features of those likely to harbor causative variants. This study assesses the yield of pathogenic/likely pathogenic variants (collectively, PV) in male breast cancer patients who underwent multi-gene hereditary cancer panel testing. In addition, we aim to examine predictors of identifying a PV in this population. Methods: Clinical histories and test results were reviewed for men with a diagnosis of breast cancer who underwent panel testing that included a minimum of eight well-described breast cancer susceptibility genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, TP53) and up to 24 additional genes. Using t-test and two-tailed Fisher's exact test, we assessed whether age at diagnosis, family history of breast cancer, or the presence of selected second primary cancers (second breast, prostate, pancreatic, colon, or melanoma cancers) were associated with a greater likelihood of identifying a PV. Results: The clinical histories and test results of 381 men with breast cancer were reviewed, of whom 12.1% had at least one PV (46/381). When we limited our assessment to men who had not had prior negative BRCA testing, 13.3% had at least one PV (42/315). Variants were most commonly detected in BRCA2 (21) and CHEK2 (17), followed by PALB2 (4), BRCA1 (4), and ATM (2). A two sample t-test showed no significant difference (p=0.39) in the average age of diagnosis for those with a PV (62.5y, n=47) compared to those without a PV (60.9y, n=334). Two-tailed Fisher's exact test showed no association between having a PV and a history of a selected second primary (SP) cancer [10.8% (7/65) w/SP vs 12.3% (39/316) w/out SP; p=0.84]. Lastly, two-tailed Fisher's exact test showed those with a family history of breast cancer (fhx br) were more likely to have a PV [15.1% (32/212) fhx br vs. 8.3% (14/169) no fhx br], although this did not reach statistical significance (p=0.06). Conclusions: While BRCA2 remains the most common gene in which PVs are identified in men with breast cancer, a significant proportion of patients will have a PV in another well-described breast cancer susceptibility gene, particularly CHEK2, PALB2, and ATM. Therefore, it is reasonable to utilize a panel that is inclusive of these genes when testing male breast cancer patients. As the likelihood to harbor a PV was not significantly associated with age of onset, family history of breast cancer, or presence of a second primary, all men with breast cancer could consider genetic testing. Further study is warranted as the current sample size may limit the power to detect associations. Citation Format: Vogel Postula KJ, Andolina LM, Theobald K, McGill AK, Sutcliffe E, Arvai KJ, Murphy PD, Klein RT, Hruska KS. The role of multi-gene hereditary cancer panels in male patients with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD7-11.

Breast cancer in males is rare. Lobular carcinoma accounts for just 1.5% of male breast cancers due to the absence of lobules in the normal male breast. Pleomorphic lobular carcinoma is a rare, aggressive variant of lobular carcinoma. We report a rare case of pleomorphic lobular breast cancer in a male patient and present a review of the literature surrounding the presentation, management, and outcomes. To date, there is limited evidence regarding the management and the majority of treatment occurring in line with the treatment of invasive lobular carcinoma in females.

Male breast cancer represents about 1% of all breast cancer diagnoses and, although there are some similarities between male and female breast cancer, the paucity of data available on male breast cancer makes it difficult to establish targeted therapies. To date, most male breast cancers (MBCs) are treated according to protocols established for female breast cancer (FBC). Thus, defining the transcriptional and epigenetic landscape of MBC with improved resolution is critical for developing better avenues for therapeutic intervention. In this study, we present matched transcriptional (scRNA-seq) and epigenetic (scATAC-seq) profiles at single-cell resolution of two treatment naïve MBC tumors processed immediately after surgical resection. These data enable the detection of differentially expressed genes between male and female breast tumors across immune, stromal, and malignant cell types, to highlight several genes that may have therapeutic implications. Notably, MYC target genes and mTORC1 signaling genes were significantly upregulated in the malignant cells of MBC compared to the female counterparts. To understand how the regulatory landscape of MBC gives rise to these male-specific gene expression patterns, we leveraged the scATAC-seq data to systematically link changes in chromatin accessibility to changes in gene expression within each cell type. We observed cancer-specific rewiring of several salient enhancers and posit that these enhancers have a higher regulatory load than lineage-specific enhancers. We highlight two examples of previously unannotated cancer-cell-specific enhancers of ANXA2 and PRDX4 gene expression and show evidence for super-enhancer regulation of LAMB3 and CD47 in male breast cancer cells. Overall, this dataset annotates clinically relevant regulatory networks in male breast tumors, providing a useful resource that expands our current understanding of the gene expression programs that underlie the biology of MBC.

e11630 Introduction: Male breast cancer is very rare, representing only between 0.7% and 1% of all breast cancers, and only half of them are early stage cases. Objective: The present study has been designed with the aim of studying retrospectively the clinical onset and evolution of male invasive breast cancer patients (stages I and II) treated at IOHM between 1997 and 2008. Methods: The records of 3,000 breast cancer cases followed between 1997 and 2008 were searched, looking for male stage I and II breast cancer patients. A database was designed following the recommendations of the Directors of Surgical Pathology of the USA. The information registered encompassed: adjuvant treatments, recurrence date and date of final consultation or death. Results: Twelve pts were identified. Mean age (range)= 66 yo (50–89 yo). Tumoral type= Invasive Ductal Carcinoma 12 pt. Tumoral subtype= NOS 9 pt (75%) Apocrine 2 pt (17%) Micropapillar 1 pt (8%). Nottingham´s grade= Grade 2: 8 pt, Grade 3: 3 pt, N/A=1 pt. Stage= I= 6 pt, II=6 pt. ER (Positve= 9 pt, Negative=1 pt, N/A= 2 pt). PR (Positve= 8 pt, Negative= 2 pt, N/A=2 pt). Her2neu (0+= 3 pt, 1+= 3 pt, 2+= 2 pt, N/A= 4 pt). Surgery= Mastectomy= 11 pt, Lumpectomy 1= pt. Radiotherapy=5 pt. Adjuvance= No=2 pt, Hormonotherapy (HT)= 3 pt, Chemotherapy (CHT) = 3 pt, CHT+HT= 4 pt. Recurrence= Yes= 2 pt, No= 10 pt. Survival: Dead= 1 pt, Alive =11 pt. Mean Time To Progression= Stage I =66 months, Stage II =42 months. Global survival: Stage I =66 months, Stage II =52 months. Conclusions: 1. Twelve stage I and II male breast cancer patients were identified out of 3000 (0.4%) breast cancer cases diagnosed and followed in the past 10 years at the IOHM. 2. Mastectomy was the surgical procedure in 11 of the 12 cases 3. Ten pt underwent adjuvant treatment. 4. With a mean follow up time of 60 months, all stage I patients are alive and there were no recurrences. Two of the 6 stage II pts progressed and one died. No significant financial relationships to disclose.

To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.