Breast Cancer In BRCA1 Carriers Research Articles

Abstract GS02-13: Pregnancy after breast cancer in young women with germline BRCA pathogenic variants: results from an international cohort study

Abstract Background: Oncofertility counseling in BRCA carriers has unique challenges due to a possible negative impact of germline pathogenic/likely pathogenic variants (PVs) on reproductive potential and the indication to undergo risk-reducing bilateral salpingo-oophorectomy. While previous studies demonstrated the safety of pregnancy in women with prior breast cancer (BC) history, limited evidence exists in BRCA carriers specifically. We report the results of the largest study to date investigating likelihood of pregnancy after BC, reproductive and disease outcomes specifically in BRCA carriers. Methods: This was an international, multicenter, hospital-based, retrospective cohort study including young BRCA carriers with history of BC (NCT03673306). Eligible patients were women harboring germline PVs in BRCA1 and/or BRCA2 and diagnosed with stage I-III invasive BC at the age of ≤ 40 years between January 2000 and December 2020. BRCA healthy carriers or patients with BRCA variants of unknown significance, non-invasive BC, lack of follow-up, prior ovarian cancer or other malignancies without history of BC were excluded. Primary endpoints were pregnancy rate and disease-free survival (DFS). Overall survival (OS), BC specific survival (BCSS), pregnancy, fetal and obstetric outcomes were secondary endpoints. To mitigate the impact of guaranteed time bias, two survival analyses were performed: 1) Extended Cox model with occurrence of pregnancy as a time-varying covariate; 2) Case-control analysis by matching 1:3 patients with and without a pregnancy for type of BRCA PV, hormone receptor status, nodal status and year at diagnosis; moreover, each control had to have a disease-free interval longer than the time occurring between BC diagnosis and conception of the matched case. Results: From 78 centers worldwide, 4,732 patients were included, of whom 659 had at least one pregnancy after BC (pregnancy cohort) and 4,073 did not (non-pregnancy cohort). Patients in the pregnancy cohort were significantly more likely to carry BRCA1 PVs, to be younger at BC diagnosis, to have node-negative and hormone receptor-negative (HR-) BC (all p< 0.01). Pregnancy rate at 10 years was 22% (95% CI 21%-24%) overall, 18% (95% CI 16%-21%) and 26% (95% CI 24%-26%) in patients with HR+ and HR- BC, respectively (p< 0.01). Median time from BC diagnosis to conception was 3.5 years (IQR 2.2-5.3 years), significantly longer in patients with HR+ than HR- BC (4.3 vs 3.2 years, p< 0.01). Among 659 patients with a pregnancy after BC, 45 (6.8%) and 63 (9.6%) experienced an induced abortion or a miscarriage, respectively. Of the 517 (78.5%) patients with completed pregnancy, 54 (10.4%) had twins and 406 (78.5%) delivered at term (delivery ≥37 weeks). Among the 571 babies born, 5 (0.9%) had congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in DFS was observed between the pregnancy and non-pregnancy cohorts (unadjusted HR 0.97, 95% CI 0.82-1.15, p=0.74; adjusted HR [aHR] 0.99, 95% CI 0.81-1.20, p=0.90). Patients in the pregnancy cohort showed significantly better BCSS (HR 0.53, 95% CI 0.38-0.74, p< 0.01; aHR 0.59, 95% CI 0.41-0.86, p< 0.01) and OS (HR 0.52, 95% CI 0.38-0.72, p< 0.01; aHR 0.58, 95% CI 0.40-0.85, p< 0.01). Similar results were obtained in the case-control analysis. Subgroup analyses of survival endpoints according to patient, tumor and treatment characteristics will be presented at the conference. Conclusions: In this global study, 1 out of 5 young BRCA carriers conceived within 10 years after a BC diagnosis, higher than rates previously reported in unselected young BC populations. Pregnancy following BC in BRCA carriers did not appear to adversely impact maternal prognosis or fetal outcomes. These findings should be incorporated into oncofertility counseling of young BRCA carriers with BC. Citation Format: Matteo Lambertini, Eva Blondeaux, Elisa Agostinetto, Anne-Sophie Hamy-Petit, Hee Jeong Kim, Camila Chiodi, Rinat Bernstein-Molho, Florentine Hilbers, Katarzyna Pogoda, Estela Carrasco Lopez, Kevin Punie, Jyoti Bajpai, Michail Ignatiadis, Halle Moore, Kelly-Anne Phillips, Angela Toss, Christine Rousset-Jablonski, Fedro Alessandro Peccatori, Tiphaine Renaud, Alberta Ferrari, Shani Paluch-Shimon, Robert Fruscio, Wanda Cui, Stephanie Wong, Claudio Vernieri, Kathryn Ruddy, Maria Vittoria Dieci, Alexios Matikas, Mariya Rozenblit, Cynthia Villareal Garza, Laura De Marchis, Lucia Del Mastro, Fabio Puglisi, Maria Del Pilar Estevez-Diz, Kenny A. Rodriguez-Wallberg, Bela Mrinakova, Sarah Meister, Luca Livraghi, Florian Clatot, Rinat Yerushalmi, Carmine De Angelis, Rodrigo Sánchez-Bayona, Icro Meattini, Natalia Cichowska-Cwalińska, Martine Berlière, Mahmoud Salama, Ugo De Giorgi, Amir Sonnenblick, Hatem Azim, Ann Partridge. Pregnancy after breast cancer in young women with germline BRCA pathogenic variants: results from an international cohort study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-13.

Pregnancy After Breast Cancer in Young BRCA Carriers

Young women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers. To investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers. International, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023. Pregnancy after breast cancer. Primary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer-specific survival, overall survival, pregnancy, and fetal and obstetric outcomes. Of 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer-specific survival and overall survival. In this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival. ClinicalTrials.gov Identifier: NCT03673306.

Pregnancy Associated Breast Cancer Among Israeli BRCA1/BRCA2 Carriers in a High-Risk Clinic

Female carriers of pathogenic sequence variants (PSVs) in the BRCA1 /BRCA2 (Breast Cancer gene - BRCA) genes are at a substantially high-risk for developing breast cancer (BC), hence are offered active surveillance scheme based on semiannual breast exam and imaging from age 25 years to facilitate BC early detection (mammography/breast ultrasound depending on the age, and MRI). However, there are not specific guidelines for screening in case of pregnancy or lactation. In the current study, we summarize the experience at the largest high-risk clinic in Israel. Data of consecutive BRCA-PSV carriers undergoing surveillance as well as diagnostic ultrasound at the Meirav high-risk clinic from January 2014 to 2021 who were pregnant and/or breastfeeding at time of follow-up were identified. Relevant clinical data including results of breast exam, breast ultrasonography, biopsies and histological results were retrieved. Percentage of biopsies with malignancy, cancer detection rate and positive predictive values were calculated. Data is presented in descriptive statistics. A total of 263 BRCA-carriers were included. Of these, 593 breast-ultrasonograms were performed in 263 BRCA-carriers for 292 pregnancies and 409 breast-ultrasonograms for 175 breastfeeding carriers. Of 36 breast biopsies in 292 pregnancies, 4 (PPV=11%) had BC diagnosed (high grade invasive). Of 175 breastfeeding women, 25 biopsies were performed and 2 (PPV=8%) were high grade invasive BC. Five of 6 BC were diagnosed in BRCA1 carriers, and 4/6 were screen detected. The rate of pregnancy-associated breast cancer was 6/292 (2.05%). The overall detection rate of pregnancy-associated BC in BRCA-carriers is relatively low (2.05%), but still much higher than that in the general population. Two thirds of the BC were detected by screening. Therefore, despite the changes of the glandular breast tissue at time of pregnancy and breastfeeding, screening plays an important role in early detection. Ultrasound should be considered as a screening tool during this period of life of high-risk patients.

Abstract 799: Reduced diversity of HLA class II alleles may contribute to the early manifestation of breast cancer in BRCA1 mutation carriers

Abstract Female carriers of germline BRCA1 mutation almost inevitably develop breast cancer (BC). However, the age of BRCA1-associated cancer onset varies widely. We hypothesize that age-related penetrance of BRCA1 mutations may depend on the inherited variability in the host immune system. We utilized high-throughput HLA-typing to describe 10 classical HLA class I/II loci for 90 young (<38 y.o.) and 73 elderly (>57 y.o.) BRCA1-mutated BC patients. 39% of young females were homozygous for two or more HLA-II loci; this was significantly higher than in the “elderly” cohort [OR = 3.23; p = 0.002]. In contrast, women who harboured identical alleles at HLA-B locus (class I) had increased chances to stay tumour-free to their older ages [OR = 3.02; p = 0.077]. Allele HLA-DBR1*11:03/04 was overtly overrepresented in elderly BRCA1-driven BC [11% vs. 3%, p = 0.006]. The frequencies of HLA-DRB1*01:01 and HLA-DQB1*05 were significantly higher in group of “young” patients [p = 0.020 and p = 0.011, correspondently]. The tumour immunogenicity was analyzed in early-onset and late-onset BC patients through the evaluation of the intratumoral density of cytotoxic T-lymphocytes (TILs) with anti-CD8 IHC staining. 5/10 carcinomas arisen in young BRCA1-carriers were classified as a “hot” phenotype with a high density of TILs across the tumour. Inversely, the BC developed in “elderly” women was characterized by the reduced levels of TILs. Conclusions: 1) the limited repertoire of HLA peptides caused by the homozygosity for HLA II loci may increase susceptibility to BC in BRCA1-carriers and manifest by early disease onset; 2) tumours from “elderly” BRCA1-associated patients have reduced levels of lymphocytic infiltration compared to “young” patients. The research is supported by RSF grant #19-15-00207 Citation Format: Ekaterina ShKuligina, Alexandr A. Romanko, Tatjana Jankevic, Aleksandr S. Martianov, Tatyana N. Sokolova, Alexandr O. Ivantsov, Evgeny N. Imyanitov. Reduced diversity of HLA class II alleles may contribute to the early manifestation of breast cancer in BRCA1 mutation carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 799.

The RAD52 S346X variant reduces risk of developing breast cancer in carriers of pathogenic germline BRCA2 mutations.

Women who carry pathogenic mutations in BRCA1 and BRCA2 have a lifetime risk of developing breast cancer of up to 80%. However, risk estimates vary in part due to genetic modifiers. We investigated the association of the RAD52 S346X variant as a modifier of the risk of developing breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. The RAD52 S346X allele was associated with a reduced risk of developing breast cancer in BRCA2 carriers [per‐allele hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.56–0.86; P = 0.0008] and to a lesser extent in BRCA1 carriers (per‐allele HR = 0.78, 95% CI 0.64–0.97, P = 0.02). We examined how this variant affected DNA repair. Using a reporter system that measures repair of DNA double‐strand breaks (DSBs) by single‐strand annealing (SSA), expression of hRAD52 suppressed the loss of this repair in Rad52−/− mouse embryonic stem cells. When hRAD52 S346X was expressed in these cells, there was a significantly reduced frequency of SSA. Interestingly, expression of hRAD52 S346X also reduced the stimulation of SSA observed upon depletion of BRCA2, demonstrating the reciprocal roles for RAD52 and BRCA2 in the control of DSB repair by SSA. From an immunofluorescence analysis, we observed little nuclear localization of the mutant protein as compared to the wild‐type; it is likely that the reduced nuclear levels of RAD52 S346X explain the diminished DSB repair by SSA. Altogether, we identified a genetic modifier that protects against breast cancer in women who carry pathogenic mutations in BRCA2 (P = 0.0008) and to a lesser extent BRCA1 (P = 0.02). This RAD52 mutation causes a reduction in DSB repair by SSA, suggesting that defects in RAD52‐dependent DSB repair are linked to reduced tumor risk in BRCA2‐mutation carriers.

Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline.

To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes. The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process. Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria. Patients with newly diagnosed BC and BRCA1/2 mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in BRCA1/2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in BRCA1/2 carriers. Radiation therapy should not be withheld in ATM carriers. For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in BRCA carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1/2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines.

Abstract P5-03-10: The spectrum of BRCA1 and BRCA2 mutations and clinicopathologic characteristics of young-onset breast cancer in BRCA-carriers and non-carriers

Abstract Background: For now, Seldom studies have reported that relationship between BRCA1/2 mutation and their clinical characteristics in young-onset breast cancers. This study is the first article which characterizes the risk factor profiles in Chinese patients selected by the age of onset (<40 years old).Patient and method:A total of 1371 consecutive unselected Chinese young-onset breast cancer patients were collected form Fujian Union hospital, China, screened for germline BRCA1/2 mutation. The full-exome sequencing in the next generation sequencing technology was performed in all patients to examine the BRCA1/2 mutation.Result: In our study, 25 (1.8%) and 61 (4.4%) patients were identified with BRCA1 and BRCA2 mutation among the unselected early-onset breast cancer patients, respectively. BRCA1 mutations were associated with pregnancies (p=0.026), BRCA1-carriers had a higher likelihood of HR positive(p<0.001), or HER-2 negative(p<0.001), or high grade(p=0.002) than non-carriers. Among BRCA2 mutations, the age of onset was younger than non-carriers(P=0.017), BRCA2-carriers were more likely to have lymph node metastasis(P=0.004). with HR positive or HER-2 negative were likely to detected positive for BRCA2(p<0.001). Citation Format: Lili Chen, Fangmeng Fu, Jinxing Lv, Chuan Wang. The spectrum of BRCA1 and BRCA2 mutations and clinicopathologic characteristics of young-onset breast cancer in BRCA-carriers and non-carriers [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 P5-03-10.

Risk of Contralateral Breast Cancer in Women with and without Pathogenic Variants in BRCA1, BRCA2, and TP53 Genes in Women with Very Early-Onset (<36 Years) Breast Cancer

Early age at diagnosis of breast cancer is a known risk factor for hereditary predisposition and some studies show a high risk of contralateral breast cancer in BRCA1 carriers diagnosed at very young ages. However, little is published on the risk of TP53 carriers. 397 women with breast cancer diagnosed <36 years of age were obtained from three sources: (i) a population-based study of 283 women diagnosed sequentially from 1980–1997 in North-West England, (ii) referrals to the Genomic Medicine Department at St Mary’s Hospital from 1990–2018, and (iii) individuals from (i) and the Family History Clinic at Wythenshawe Hospital South Manchester who tested negative for pathogenic variants (PV) in all three genes. Sequencing of BRCA1, BRCA2, and TP53 genes was carried out alongside tests for copy number for PV on all referred women. Rates of contralateral breast cancer were censored at death, last assessment, or risk-reducing mastectomy. In total, 47 TP53, 218 BRCA1, and 132 BRCA2 PV carriers were identified with breast cancer diagnosed aged 35 years and under, as well as a representative sample of 261 not known to carry a PV in BRCA1, BRCA2, and TP53. Annual rates of contralateral breast cancer (and percentage of synchronous breast cancers) were TP53: 7.03% (4.3%), BRCA1: 3.57% (1.8%), and BRCA2: 2.63% (1.5%). In non-PV carriers, contralateral rates in isolated presumed/tested non-carrier cases with no family history were 0.56%, and for those with a family history, 0.69%. Contralateral breast cancer rates are substantial in TP53, BRCA1, and BRCA2 PV carriers diagnosed with breast cancer aged 35 and under. Women need to be advised to help make informed decisions on contralateral mastectomy, guided by life expectancy from their index tumor.

Risk-reducing bilateral salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations.

Risk-reducing bilateral salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations.

Oncotype Dx recurrence score among BRCA1/2 germline mutation carriers with hormone receptors positive breast cancer.

Gene expression assays are widely used to predict risk of recurrence in early breast cancer (BC). We report the 21-gene expression assay (Oncotype Dx) recurrence score (RS) distribution of 27 BRCA carriers with estrogen receptor (ER) positive BCs, identified at Hadassah Medical Center, combined with 2 previous studies. Treatment decision and outcomes of the 27 BRCA carriers were compared with an Israeli cohort of 1594 patients published recently. We found Oncotype Dx RS low (<18), intermediate (18-30) and high (>30) among 12 (21.4%), 23 (41.1%) and 21 (37.5%) of 56 BRCA1 carriers compared with 15 (17.2%), 49 (56.3%) and 23 (26.4%) of 87 BRCA2 carriers (p = 0.2). The corresponding distribution in a population of 82,434 women published by Genomic Health was 53.4%, 36.3% and 10.3% for low, intermediate and high RS (p < 0.001 for BRCA1 and BRCA2). Treatment decision regarding chemotherapy according to RS was similar in BRCA1, BRCA2 and the control group. Two of 27 carriers had distant recurrence: a BRCA1 carrier with RS of 18 and a BRCA2 carrier with RS of 22; both have an excellent response to chemotherapy. We found an approximately ∼3 fold increased rate of high RS among BRCA1 and 2 carriers with ER positive BC compared with the general BC population. These data might indicate that hormone positive BC in BRCA carriers are molecularly unique. The surprisingly good response to chemotherapy in the metastatic setting in 2 patients may suggest that the predictive value of low-intermediate RS in carriers merits further studies.

Abstract B43: A preponderance of post-menopausal HER2+ breast cancer in the Vietnamese population

Abstract Background: Though breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in women worldwide, relatively little is understood about the differences in prevalence and biology between various populations. For example, breast cancer is far less common in Asia than in North America, and the biology of breast cancer is likely different between these groups as well. There is some limited data to suggest that Asian breast cancer patients may have 35-40% rate of HER2+ breast cancer [1,2], as compared to 15-23% within the general American population [3,4]. Methods: To further examine this possibility, we reviewed our data at the Harris Health Systems' Smith Clinic in Houston, Texas from September 2010 through September 2014 to further characterize the Vietnamese breast cancer patients seen during that time. Using Fisher's Exact Test, we compared our subset of Vietnamese breast cancer patients with the publicly available SEER data from 2010[4]. Results: Among the Vietnamese patients from the Smith Clinic, we found that out of 33 patients with invasive breast cancer, 15 (45%) had HER2+ breast cancer. Interestingly, 64% of the HER2+ cohort was post-menopausal, and 50% of the post-menopausal women had HER2+ breast cancer. Compared with the 2010 SEER data that encompasses 28% of all US breast cancer patients diagnosed that year, regardless of race, the Smith Clinic Vietnamese cohort had a statistically significant higher rate of HER2+ breast cancer, with an odds ratio of 4.7 (45% vs. 15%, p &amp;lt;0.001). Among the women greater than 50 years old in both groups, the Vietnamese women had a higher rate of HER2+ breast cancer than the same age group in the SEER data group (odds ratio 7.0, p &amp;lt;0.001). Conclusion: The patterns observed in this small Vietnamese cohort, and others, do not mirror those seen in the general, multi-racial American breast cancer population. The rate of HER2+ breast cancer in the Smith Clinic Vietnamese group is twice that of the general American population. Other, larger studies have supported the findings of this small group, including a 242-patient study in Vietnam which demonstrated a 41% rate of HER2+ breast cancer; 55% of post-menopausal women had HER2 mutated tumors in this group [1]. Generally, other studies have associated older age and post-menopausal status with a lower rate of HER2+ breast cancer [5,6], but the opposite is true in these Vietnamese women. This unique pattern of breast cancer in Vietnamese women may suggest an underlying genetic or environmental driver, similar to the higher rate of triple negative breast cancer in BRCA1 carriers, or HER2+ breast cancer in women with p53 mutations. We plan to conduct further epidemiologic and genetic research in a larger cohort of Vietnamese breast cancer patients to determine whether an underlying germline genetic mutation or environmental exposure may explain this unusual pattern of breast cancer.

Bone drug could help prevent breast cancer in BRCA1 carriers

Bone drug could help prevent breast cancer in BRCA1 carriers

Abstract P5-02-06: Digital quantification of estrogen receptor expression in normal breast in post-menopausal women with breast cancer and association with tumor subtypes

Abstract Background: ER expression in normal breast epithelium (NBR) is higher in women with a history of breast cancer (BC) compared to controls. In adjuvant setting, metanalysis showed effective Tamoxifen treatment was restricted to ER positive cancers. However, it is also known prophylactic oophorectomy (a form of estrogen suppression) significantly reduces the incidence of BC in BRCA1 carriers. This is in contrast with the 80% rate of ER negative tumors in BRCA1 patients. The aim of this study is to quantify ER expression in NBR away from tumor in women with BC and to correlate it with BC subtypes. Methods: 204 consecutive patients were identified for whom NBR away from tumor was available. 27 reduction mammoplasty (RM) tissues from women with no history of BC were used as controls. Tissue microarrays were constructed and slides were stained with ER and scanned using Aperio XT Scan Scope. Normal terminal duct lobular epithelium was manually circled on scanned images and annotations were recorded in separate digital layers. ER staining was quantitated in marked areas of the electronic image using an optimized scoring nuclear IHC algorithm (Aperio technologies, Inc., Vista, CA). Clinical information and tumor characteristics (menopausal status, ER, HER2 expression, grade, size, number of positive nodes, stage) were recorded based on pathology reports and tumor registry data. Results: The mean ER positivity in NBR was 16 ± 12.4 % (range: 0-5-5.7%) for all patients with BC, 20.8±13.9% for postmenopausal (n=74) and 13.7 ±10.9% for peri+ premenopausal (n=170) subgroups. ER positivity was higher in patients with BC compared to those undergoing RM with no history of BC. ER positivity in NBR did not vary by tumor size, positive lymph nodes status, tumor grade, or stage in post-menopausal, and pre + perimenopausal women. Older age at diagnosis was significantly associated (p&amp;lt;0.0001) with ER in NBR. In post- menopausal women ER expression in NBR was significantly higher in patients with ER negative or triple negative tumors. Estrogen receptor expression in normal terminal duct lobular units of post-menopausal women with breast cancer in relation to tumor subtypes. Postmenopausal (N=74) NMean % (SD)P ValueTumor ER Status 0.05 Negative1427.4 (13.9) Positive6019.3 (13.6) Tumor HER2 Status 0.34 Negative5721.8 (14.9) Positive817.7 (5.7) Tumor Triple Negative 0.05 No5319.7 (13.6) Yes1228.5 (14.7) HER2 status was not known in some cases and was excluded from statistical calculations. Conclusion: This computer assisted image analysis study confirms ER expression in NBR increases with age and menopausal status in women with BC. We report, for the first time, a significant association between ER expression in normal breast epithelium with ER negative and triple negative cancers in post-menopausal women. Our study suggests that ER expression in normal epithelium may play a role in development of hormone receptor negative breast cancers. Citation Format: H Evin Gulbahce, Cindy Blair, Carol Sweeney, Rachel Factor, Mohamed Salama. Digital quantification of estrogen receptor expression in normal breast in post-menopausal women with breast cancer and association with tumor subtypes [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-02-06.

Genotype and phenotype correlation of breast cancer in BRCA carriers and non-carriers

Genotype and phenotype correlation of breast cancer in BRCA carriers and non-carriers

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers.

IntroductionMore than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.MethodsWe used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.ResultsThe estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10−6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement.ConclusionsDifferences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0492-9) contains supplementary material, which is available to authorized users.

Clinicopathologic characteristics of breast cancer in BRCA-carriers and non-carriers in women 35 years of age or less

PurposeBreast cancer diagnosed in women 35 years of age or less accounts for <2% of all breast cancer cases. Clinical and pathologic characteristics of early onset breast cancer are not well defined in BRCA mutation carriers and non-carriers. Methods194 women diagnosed with breast cancer at 35 years of age or less who had BRCA1/2 mutation testing were included in the study. Logistic regression models were fit to determine the associations between clinical variables and BRCA status. ResultsThirty-two (17%) and 12 (6%) patients had BRCA1 and BRCA2 mutations, respectively. BRCA1-carriers had a higher likelihood of a positive family history (FH) of breast and/or ovarian cancer (P = 0.001), or first-degree relatives diagnosed with breast cancer at <50 years old (P = 0.001) compared to non-carriers. BRCA2-carriers were more likely to have a FH of male breast cancer compared to noncarriers (P = 0.02). Among BRCA2-carriers, the age at first full-term pregnancy was younger in ER-negative cases compared with ERpositive cases (19.5 vs. 28.5 years old; P = 0.01). BRCA1-carriers with a later age at menarche were more likely to have a later stage at diagnosis (P = 0.04). Non-carriers with a lower BMI were more likely to have lymph node involvement (P = 0.03). ConclusionsSeveral associations were identified between reproductive risk factors or BMI and disease characteristics. Further characterization may result in a better understanding of the trends in young onset breast cancer in BRCA-carriers and non-carriers.

A prior diagnosis of breast cancer is a risk factor for breast cancer in BRCA1 and BRCA2 carriers.

The risk of breast cancer in carriers of BRCA1 and BRCA2 mutations is influenced by factors other than the genetic mutation itself. Modifying factors include a woman's reproductive history and family history of cancer. Risk factors are more likely to be present in women with breast cancer than in women without breast cancer, and therefore the risk of cancer in the two breasts should not be independent. It is not clear to what extent modifying factors influence the risk of a first primary or a contralateral breast cancer in BRCA carriers. We conducted a matched case-control study of breast cancer among 3920 BRCA1 or BRCA2 mutation carriers. We asked whether a past history of breast cancer in the contralateral breast was a risk factor for breast cancer. After adjustment for age, country of residence, and cancer treatment, a previous cancer of the right breast was found to be a significant risk factor for cancer of the left breast among BRCA1 or BRCA2 carriers (relative risk: 2.1; 95% confidence interval: 1.4 to 3.0; p < 0.0001). In a woman with a BRCA1 or BRCA2 mutation who is diagnosed with breast cancer, the risk of cancer in the contralateral breast depends on the first diagnosis. That observation supports the hypothesis that there are important genetic or non-genetic modifiers of cancer risk in BRCA carriers. Discovering risk modifiers might lead to greater personalization of risk assessment and management recommendations for BRCA-positive patients.

Abstract P4-05-08: Oncotype Dx assay in BRCA positive ER positive breast cancer patients

Abstract Background: Oncotype DX is a 21-gene RT-PCR assay which quantifies the likelihood of breast cancer recurrence and the potential benefit of chemotherapy in patients with early stage, ER positive, Tamoxifen treated breast cancer. Breast cancer in BRCA carriers is considered more aggressive. The aim of our study was to evaluate whether Oncotype Dx recurrence score distribution is different in breast cancer patients with inherited BRCA mutation. Methods: The Oncotype DX assay has been used at Hadassah Medical Center since 2004 on specimens from over 450 patients. We analyzed and compared clinicopathological characteristics and Oncotype Dx recurrence scores of BRCA carriers versus non- BRCA or unknown status of BRCA patients. Results: Ten patients had validated inherited BRCA mutation, five of them are BRCA1 carriers and five BRCA2 carriers. There were no significant differences in the clinicopathological characteristics between the two groups. Oncotype Dx recurrence score distribution between low, intermediate and high risk groups was not significantly different. The mean recurrence score was 18.48 for the non- BRCA or unknown status of BRCA patients and 22.8 for the BRCA carriers patients. This difference was not statistically significant. Conclusion: Estrogen receptor positive breast cancer tumors from BRCA carriers does not display a significantly different Oncotype Dx recurrence score result distribution. These preliminary data suggest Oncotype Dx assay might be used to help tailor treatment in this subset of patients, although further follow up is needed. All patients evaluated for oncotype_DX All evaluated (except BRCA+) n = 456BRCA positiveP valueAgeMean57.4557.60.7 Median5857 Range56 (25-81)34 (42-76) T stageT167.7%70%0.9 T230.7%30% T31.6%0% Tumor sizeMean1.71.360.2 Median1.51.26 Range7.8 (0.2-8)1.3 (0.7-2) GradeGrade 1-278.8%60%0.15 Grade 321.2%40% RSLow50%40%0.57 Intermediate39.8%40% High10.2%20% RSMean18.4822.80.16 Median17.522.5 Range64 (0-64)27 (12-39) Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-08.

Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience.

To compare the pathologic complete response (pCR) rate and relapse-free survival (RFS) and overall survival (OS) after neoadjuvant systemic chemotherapy (NST) in patients with breast cancer with and without deleterious BRCA1 and BRCA2 mutations. A total of 317 women who underwent BRCA genetic testing and were treated with NST for breast cancer between 1997 and 2009 were included in the study. The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models were fit to determine the associations between BRCA status, pCR, and survival. Fifty-seven (18%) and 23 (7%) patients had BRCA1 and BRCA2 mutations, respectively. Twenty-six (46%) of 57 BRCA1 carriers achieved a pCR, compared with three (13%) of 23 BRCA2 carriers and 53 (22%) of 237 BRCA noncarriers (P < .001). In the multivariate logistic model, BRCA1 status (odds ratio [OR] = 3.16; 95% CI, 1.55 to 6.42; P = .002), estrogen receptor (ER) negativity (OR = 1.96; 95% CI:1.05 to 3.65; P = .03) and concurrent trastuzumab use (OR = 4.18; 95% CI, 2.04 to 8.57; P < .001) remained as independent significant predictors for a pCR. At a median follow-up of 3.2 years, 69 patients (22%) experienced a disease recurrence or death. No significant differences were noted in survival outcomes with respect to BRCA status and type of NST received. However, among BRCA1 carriers, patients who achieved a pCR had better 5-year RFS (P = .001) and OS (P = .01) rates than patients who did not. BRCA1 status and ER negativity are independently associated with higher pCR rates in patients with breast cancer. Overall prognosis of breast cancer in BRCA carriers is similar to sporadic breast cancers.

Prevalence and characterization of BRCA1 and BRCA2 germline mutations in Chinese women with familial breast cancer

Although there are some studies to investigate germline mutations in BRCA1/2 genes in Chinese women with familial breast cancer, many of them suffer relatively small sample size. In this study, we screened germline mutations in BRCA1/2 genes in a cohort of 409 Chinese women with familial breast cancer from north China by using a PCR-sequencing assay. A total of 43 deleterious mutations in BRCA1/2 genes were identified in this cohort, including 17 novel mutations and 6 recurrent mutations. The frequencies of BRCA1 and BRCA2 mutations were 3.9% (16/409) and 6.6% (27/409), respectively; the mutation rate of BRCA2 was 1.7-fold higher than that of BRCA1. The entire mutation rate of BRCA1/2 was 10.5% in this cohort; however, the mutation rate of BRCA1/2 genes was 23.0% in 78 familial breast cancer patients whose tumors were diagnosed at or before the age of 40. The mean age at diagnosis of breast cancer in BRCA1 carriers (42.8 years) and BRCA2 carriers (45.1 years) was younger than non-carriers (51.0 years) in this cohort (P = 0.005; P = 0.01, respectively). In addition, both BRCA1 carriers and BRCA2 carriers were more likely to exhibit triple-negative breast cancer (ER-, PgR-, and HER2-) than non-carriers (BRCA1 carriers vs. non-carriers, 69.2 vs. 23.0%, P = 0.001; BRCA2 carriers vs. non-carriers, 45.8 vs. 23.0%, P = 0.01). Our study suggested that the spectrum and characteristics of BRCA1/2 mutations in Chinese familial breast cancer exhibit some unique features, and Chinese women with familial breast cancer whose tumors are diagnosed at or before the age of 40 are good candidates for BRCA1/2 testing.