BRCA Non-carriers Research Articles

Pathologic complete response after neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers

BRCA1 and BRCA2 pathogenic variant carriers develop breast cancers with distinct pathological characteristics and mutational signatures that may result in differential response to chemotherapy. We compared rates of pathologic complete response (pCR) after NAC between BRCA1/2 variant carriers and noncarriers in a cohort of 1426 women (92 [6.5%] BRCA1 and 73 [5.1%] BRCA2) with clinical stage I–III breast cancer treated with NAC followed by surgery from 11/2013 to 01/2022 at Memorial Sloan Kettering Cancer Center. The majority received doxorubicin/cyclophosphamide/paclitaxel therapy (93%); BRCA1/2 carriers were more likely to receive carboplatin (p < 0.001). Overall, pCR was achieved in 42% of BRCA1 carriers, 21% of BRCA2 carriers, and 26% of noncarriers (p = 0.001). Among clinically node-positive (cN+) patients, nodal pCR was more frequent in BRCA1/2 carriers compared to noncarriers (53/96 [55%] vs. 371/856 [43%], p = 0.015). This difference was seen in HR+/HER2− (36% vs. 20% of noncarriers; p = 0.027) and TN subtypes (79% vs. 45% of noncarriers; p < 0.001). In a multivariable analysis of the overall cohort, BRCA1 status, and TN and HER2+ subtypes were independently associated with pCR. These data indicate that BRCA1 carriers may be more likely to achieve overall and nodal pCR in response to NAC compared with BRCA2 carriers and patients with sporadic disease. Further studies with a larger cohort of BRCA1/2 mutation carriers are needed, as a small sample size may have a restricted ability to detect a significant association between mutational status and pCR in sensitivity analyses stratified by subtype and adjusted for clinically relevant factors.

Abstract PO4-08-04: Comparison of Outcomes and Prognosis between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery versus Mastectomy for Breast Cancer

Abstract Introduction: While outcomes are similar following breast-conserving surgery (BCS) or mastectomy among patients with sporadic breast cancer, data are still controversial for germline BRCA pathogenic variant carriers. We previously compared outcome following BCS between BRCA pathogenic variant carriers and non-carriers, and reported higher ipsilateral breast recurrence and comparable prognosis in the carriers. The purpose of this current study was to compare outcomes among BRCA pathogenic variant carriers undergoing BCS versus mastectomy in long-term follow-up period. Methods: Women with a BRCA pathogenic variant and a stage 0-III breast cancer who underwent definitive surgery from 1987–2021 were retrospectively identified from institutional database. Factors including clinicopathologic information and treatment characteristics were identified. Subsequent local recurrence, regional recurrence, distant recurrence, contralateral breast cancer (CBC), breast cancer-specific survival (BCSS), and overall survival (OS) rates were compared between BCS and mastectomy using Kaplan-Meier method and log-rank test. The chi-square test and t-test were used to compare patient characteristics between the two groups. Results: A total of 232 BRCA mutation carriers with 257 cancers including 25 patients with synchronous bilateral breast cancer were identified. Surgical treatment included BCS for 82 cancers and mastectomy for 175 cancers including nipple-sparing mastectomy for 51 cancers. Patient age at surgery and cancer stage did not statistically differ between BCS and mastectomy groups. Comparing to patients choosing mastectomy, patients who underwent BCS were less likely to be aware of their genetic status before surgery and were more likely to receive radiation therapy (p &amp;lt; 0.001). Contralateral risk reducing mastectomy was performed in 22.5% (18/80) in the BCS group and 48.7% (74/152) in the mastectomy group (p &amp;lt; 0.001) concurrently or at any time after the first definitive surgery. Risk reducing salpingo-oophorectomy was performed in 40% (32/80) in the BCS group and 49% (75/152) in the mastectomy group (p = 0.17). At 7.5 years median follow-up, local recurrence rate was statistically higher in the BCS group than in the mastectomy group (20.0% in BSC vs. 4.6% in mastectomy, p = 0.043). In patients who underwent nipple-sparing mastectomy, 4.0% (2/51) had local subcutaneous recurrence and no nipple-areolar recurrence was observed. Median duration from the first definitive surgery to ipsilateral local recurrence was 10.0 years in the BCS group and 2.3 years in the mastectomy group. Regional lymph node recurrence (11.2% in BCS vs. 6.4% in mastectomy, p = 0.62), distant recurrence (13.7% vs. 9.2%, p = 0.84), CBC (15.0% vs. 8.6%, p = 0.70), BCSS (88.8% vs. 94.1%, p = 0.65) and OS (87.5% vs. 94.1%, p = 0.49) rates did not statistically differ between two groups. Conclusions: With 7.5 years median follow-up, higher local recurrence rate was observed in BCS than in mastectomy among BRCA pathogenic variant carriers. Our results found no statistical difference between BCS and mastectomy in regional recurrence, distant recurrence, CBC, and prognosis, indicating relatively higher risk in BCS. While BCS could be an option for BRCA pathogenic variant carriers willing to continue high-risk breast surveillance, shared decision making should be carefully performed based on the long-term local recurrence risk. Citation Format: Kumiko Kida, Junko Takei, Misato Suzuki, Megumi Okawa, Sakurako Kazama, Sakiko Kondo, Michiko Yamanaka, Atsushi Yoshida. Comparison of Outcomes and Prognosis between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery versus Mastectomy for Breast Cancer [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 PO4-08-04.

Abstract B101: Characterizing somatic TP53 mutations in non-cancerous and high-risk fallopian tubes using ultra-deep sequencing

Abstract High-grade serous carcinoma (HGSC), the most common and pervasive subtype of ovarian cancer originates in the fallopian tube epithelium from precursor lesions carrying somatic TP53 mutations. These lesions may evolve into carcinomas, eventually spreading to the ovary and peritoneum1,2. Recent research in non-cancerous tissues and gynecologic liquid biopsies of individuals with and without HGSC have demonstrated that somatic TP53 mutations accumulate and clonally expand with age3–9. However, TP53 somatic evolution has not been characterized in the normal fallopian tube epithelium. In addition, it is not known whether TP53 mutations are more abundant in individuals with germline BRCA1/2 mutations (BRCA carriers), who are at a high risk of HGSC10. The goals of this study were to characterize age-related TP53 somatic mutations in non-cancer fallopian tube epithelium across the human lifespan and to determine whether the TP53 mutational landscape is altered in BRCA carriers. Our cohort consisted of 1) autopsy cases, spanning the ages of 0-91 years, from individuals without ovarian cancer (N=46) and 2) prophylactic surgery cases from BRCA carriers and non-carriers (N=26, ongoing analyses). Fallopian tube tissues were collected, frozen, and macrodissected using a 1mm biopsy punch, enriching for the fallopian tube epithelium. DNA was extracted from each sample, the sequenced for TP53 using ultra-deep duplex sequencing (mean depth: ~12,000x). In the normal fallopian tube epithelium collected across human lifespan, we found that the number of unique TP53 mutations and the size of pathogenic clones increased with age, showcasing somatic evolution and clonal expansion of TP53 in non-cancerous fallopian tube epithelium with age. We also found that the number of TP53 mutations in hotspot codons increased with age, suggesting that cancer-like mutations are positively selected as individuals age. We compared the normal fallopian tube TP53 mutations with HGSC TP53 mutations and demonstrated that the types of mutations (e.g. indels, splice, nonsense, missense, and silent mutations) in the aging fallopian tube closely mirrored the mutations types observed in HGSC. Data analysis from BRCA carriers is ongoing, but based on preliminary data, we anticipate a higher burden of pathogenic TP53 mutations, indicating that predisposition to HGSC in BRCA carriers may be related to an excess of TP53 somatic evolution in the fallopian tube. Altogether, our research demonstrates that TP53 somatic evolution is a normal aging phenotype in the fallopian tube, with more and larger pathogenic clones occurring later in life. We expect to determine whether this effect is more prominent in BRCA carriers, which would provide a much needed biological explanation to understand the increased risk of HGSC in these patients, opening new venues for better cancer prediction and prevention. Citation Format: Coleen Ann Coombes, Elizabeth U. Parker, Brendan F. Kohrn, Jeanne Uy Fredrickson, Elena Latorre-Esteves, Emma Hazard, Shreya Suresh, Marc R. Radke, Anh P. Vo, Barbara S. Norquist, Rosana Risques. Characterizing somatic TP53 mutations in non-cancerous and high-risk fallopian tubes using ultra-deep sequencing [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B101.

Risk Factors for Ovarian Cancer by BRCA Status: A Collaborative Case-Only Analysis.

Women with an inherited pathogenic variant in BRCA1 or BRCA2 have a greatly increased risk of developing ovarian cancer, but the importance of behavioral factors is less clear. We used a case-only design to compare the magnitude of associations with established reproductive, hormonal, and lifestyle risk factors between BRCA mutation carriers and noncarriers. We pooled data from five studies from the Ovarian Cancer Association Consortium including 637 BRCA carriers and 4,289 noncarriers. Covariate-adjusted generalized linear mixed models were used to estimate interaction risk ratios (IRR) and 95% confidence intervals (CI), with BRCA (carrier vs. noncarrier) as the response variable. IRRs were above 1.0 for known protective factors including ever being pregnant (IRR = 1.29, 95% CI; 1.00-1.67) and ever using the oral contraceptive pill (1.30, 95% CI; 1.07-1.60), suggesting the protective effects of these factors may be reduced in carriers compared with noncarriers. Conversely, the IRRs for risk factors including endometriosis and menopausal hormone therapy were below 1.0, suggesting weaker positive associations among BRCA carriers. In contrast, associations with lifestyle factors including smoking, physical inactivity, body mass index, and aspirin use did not appear to differ by BRCA status. Our results suggest that associations with hormonal and reproductive factors are generally weaker for those with a pathogenic BRCA variant than those without, while associations with modifiable lifestyle factors are similar for carriers and noncarriers. Advice to maintain a healthy weight, be physically active, and refrain from smoking will therefore benefit BRCA carriers as well as noncarriers.

Survival outcomes of patients with HER2/neu-positive breast cancer with germline BRCA mutations.

Breast cancer (BC) with germline BRCA1/2 mutations and their association with triple-negative BC has been thoroughly investigated. However, some carriers of BRCA1/2 mutations have human epidermal growth factor receptor 2 (HER2/neu)-positive BC, which has a different targeted therapy approach, and data are scarce for this patient population. The authors sought to characterize the clinical characteristics and outcomes of patients with HER2/neu-positive BC who had germline BRCA1/2 mutations. This was a retrospective analysis of data from 1099 patients diagnosed with HER2/neu-positive BC who were screened for germline BRCA mutations between 1996 and 2022. Clinicopathologic features and survival rates were analyzed by BRCA mutation status. Univariate and multivariable Cox proportional hazards regression models were used to analyze the association between clinical variables and outcomes. Of 1099 patients with HER2/neu-positive BC, 73 (6.6%) tested positive for BRCA1/2 mutations. Age, race, and tumor characteristics did not differ between BRCA noncarriers and carriers. At a median follow-up of 78.6months, the 5-year recurrence-free survival rate was 85% in BRCA carriers and 87% in noncarriers (p=.79), and the 5-year overall survival rate was 94% in BRCA carriers and 94% in noncarriers (p=.78). In a multivariable model, BRCA was not associated with recurrence-free survival (hazard ratio, 0.99; 95% confidence interval, 0.51-1.90; p=.96) or overall survival (hazard ratio, 0.83; 95% confidence interval, 0.33-2.07; p=.69). BRCA1/2 mutations occurred in 6.6% of patients with HER2/neu-positive BC and did not affect survival outcomes. Assessing the potential benefits of new treatment strategies, such as combining anti-HER2/neu therapies with poly(ADP-ribose) polymerase inhibitors, may lead to enhanced outcomes for these patients.

Satisfaction and Well-Being After Contralateral Prophylactic Mastectomy Among BRCA Mutation Carriers and Noncarriers: A Longitudinal Analysis of BREAST-Q Domains.

Contralateral prophylactic mastectomy (CPM) is recommended for BRCA mutation carriers; its use in noncarriers relies on patient choice. We characterized differences in satisfaction and well-being after CPM between BRCA carriers and noncarriers. BREAST-Q data were obtained before and after CPM with immediate reconstruction performed at a single institution from 2016 to 2022. Associations between BRCA status and satisfaction with breasts, psychosocial well-being, and sexual well-being were assessed, with adjustment for preoperative scores and relevant confounders. In total, 149 BRCA carriers and 842 noncarriers were included. Response rates varied over time (preoperative, 56%; 6 months, 78%; 1 year, 51%; 2 years, 52%; 3 years, 59%). BRCA carriers were younger (p < 0.001), with a higher rate of neoadjuvant chemotherapy (p < 0.001). More noncarriers had HR+/HER2- tumors (p < 0.001) and underwent endocrine therapy (p < 0.001). Baseline satisfaction with breasts was higher among BRCA carriers (median [interquartile range] score, 70 [53-82] vs. 58 [48-70]; p = 0.006); psychosocial (p = 0.20) and sexual (p = 0.14) well-being were not significantly different between groups. BRCA carriers had a greater decrease in satisfaction with breasts (p = 0.04) and psychological well-being (p = 0.05) from baseline to 6 months; decrease in sexual well-being (p = 0.38) was not significantly different between groups. On univariate and multivariable analyses, BRCA status was not associated with satisfaction with breasts, sexual well-being, or psychosocial well-being. Satisfaction and well-being were similar between BRCA carriers and noncarriers treated with CPM. Relative to noncarriers, BRCA carriers experienced a greater decline in satisfaction with breasts and psychological well-being at 6 months after CPM.

Pathologic complete response after neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers.

544 Background: Distinct pathological characteristics and mutational signatures in BRCA-associated breast cancers may result in differential response to chemotherapy but understanding of treatment response after neoadjuvant chemotherapy (NAC) is limited. We describe a single-institutional experience to compare rates of pathologic complete response (pCR) after NAC in BRCA carriers (g BRCA1/2) and noncarriers. Methods: From 11/2013 to 01/2022, 1426 consecutive women with clinical stage I-III breast cancer were treated with NAC followed by surgery. Baseline disease characteristics were compared between g BRCA1/2 and noncarriers using two-sample non-parametric tests. Conditional logistic regression was used to evaluate the association between BRCA status and pCR (i.e., ypT0/is pN0) adjusting for variables selected using backward elimination. Results: 92 (6.5%) and 73 (5.1%) had deleterious mutations in BRCA1 and BRCA2, respectively. Compared to noncarriers, g BRCA1/2 were younger (p&lt;0.001) with clinical T1 (p=0.002) and triple negative disease (TN) (57% vs 25% noncarriers, p&lt;0.001). Almost all patients received doxorubicin/cyclophosphamide/paclitaxel therapy (93%) with g BRCA1/2 more likely to receive carboplatin (p&lt;0.001). pCR rate was 42% of g BRCA1, 21% of g BRCA2, and 26% of noncarriers (p=0.001). Among clinically node positive (cN+) patients, nodal pCR was higher in g BRCA1/2 compared to noncarriers (53/96 (55%) vs 371/856 (43%), p=0.012). This difference was seen in ER+/HER2- (36% gBRCA1/2 vs 20% noncarriers; p=0.027) and TN subtypes (79% g BRCA1/2 vs 45% noncarriers; p&lt;0.001). Poorly differentiated tumors (p&lt;0.001), cN+ (p=0.010), lower cT stage (p=0.028), ductal histology (p&lt;0.001), TN and HER2+ receptor status (p&lt;0.001), absence of lymphovascular invasion (p&lt;0.001), carboplatin receipt (p=0.041), and BRCA1 status (p=0.001) were also associated with pCR on univariate analysis. After adjusting for differentiation and molecular subtype, BRCA1 status remained independently associated with pCR. Conclusions: g BRCA1 undergoing NAC have higher pCR rates relative to g BRCA2 and patients with sporadic disease. Across breast cancer subtypes, g BRCA1/2 more frequently converted to pN0. Defining biological mechanism for these findings would allow customization of treatment based on germline genetics. [Table: see text]

Hereditary Breast Cancer in Romania-Molecular Particularities and Genetic Counseling Challenges in an Eastern European Country.

In Romania, breast cancer (BC) is the most common malignancy in women. However, there is limited data on the prevalence of predisposing germline mutations in the population in the era of precision medicine, where molecular testing has become an indispensable tool in cancer diagnosis, prognosis, and therapeutics. Therefore, we conducted a retrospective study to determine the prevalence, mutational spectrum, and histopathological prediction factors for hereditary breast cancer (HBC) in Romania. A cohort of 411 women diagnosed with BC selected upon NCCN v.1.2020 guidelines underwent an 84-gene NGS-based panel testing for breast cancer risk assessment during 2018-2022 in the Department of Oncogenetics of the Oncological Institute of Cluj-Napoca, Romania. A total of 135 (33%) patients presented pathogenic mutations in 19 genes. The prevalence of genetic variants was determined, and demographic and clinicopathological characteristics were analyzed. We observed differences among BRCA and non-BRCA carriers regarding family history of cancer, age of onset, and histopathological subtypes. Triple-negative (TN) tumors were more often BRCA1 positive, unlike BRCA2 positive tumors, which were more often the Luminal B subtype. The most frequent non-BRCA mutations were found in CHEK2, ATM, and PALB2, and several recurrent variants were identified for each gene. Unlike other European countries, germline testing for HBC is still limited due to the high costs and is not covered by the National Health System (NSH), thus leading to significant discrepancies related to the screening and prophylaxis of cancer.

Pathologic Findings at Risk Reducing Surgery in BRCA and Non-BRCA Mutation Carriers: A Single-Center Experience.

Risk-reducing surgery (RRS) is recommended in BRCA-mutated carriers because of their increased risk of developing ovarian cancer, while its role is still discussed for women harboring mutations in non-BRCA homologous repair genes. The aim of this study was to retrospectively evaluate the occurrence of pathological findings in a high-risk population undergoing RRS in San Matteo Hospital, Pavia between 2012 and 2022, and correlate their genetic and clinical outcomes, comparing them with a control group. The final cohort of 190 patients included 85 BRCA1, 63 BRCA2, 11 CHEK2, 7 PALB2, 4 ATM, 1 ERCC5, 1 RAD51C, 1 CDH1, 1 MEN1, 1 MLH1 gene mutation carriers and 15 patients with no known mutation but with strong familial risk. Occult invasive serous carcinoma (HGSC) and serous tubal intraepithelial carcinoma (STIC) were diagnosed in 12 (6.3%) women, all of them BRCA carriers. No neoplastic lesion was diagnosed in the non-BRCA group, in women with familial risk, or in the control group. Oral contraceptive use and age ≤45 at surgery were both found to be favorable factors. While p53 signature and serous tubal intraepithelial lesion (STIL) were also seen in the control group and in non-BRCA carriers, STIC and HGSC were only found in BRCA1/2 mutation carriers.

Ovarian cancer risk of Chinese women with BRCA1/2 germline pathogenic variants

Estimating the lifetime risk of ovarian cancer in Chinese women with BRCA1/2 germline pathogenic variants (PVs) is of great importance for the clinical management of BRCA1/2 carriers. This cohort study recruited 9903 unselected Chinese breast cancer patients whose BRCA1/2 status was determined. Of these, 3984 probands completed family history questionnaires, which investigated the health status of their relatives, including 11,997 female first-degree relatives. The ovarian cancer risk of BRCA1/2 germline pathogenic carriers was estimated using the ovarian cancer history of proband first-degree female relatives via the Kin-cohort method. Of the 3984 probands, 126 (3.2%) carried BRCA1 PVs, and 183 (4.6%) carried BRCA2 PVs. The estimated cumulative risks of ovarian cancer by age 70 were 15.3% (95% CI 8.4-18.6%) for BRCA1 carriers, 5.5% (95% CI 2.0-10.2%) for BRCA2 carriers, and 0.4% (95% CI 0.3-0.7%) for noncarriers. The cumulative risks of ovarian cancer were very low before the age of 40 for both BRCA1 and BRCA2 carriers and were an increase up to age 45. The cumulative ovarian cancer risk of BRCA1 carriers was approximately three times higher than that of BRCA2 carriers, and BRCA1 and BRCA2 carriers had 38- and 14-fold higher risks than non-BRCA carriers, respectively. The findings indicate that Chinese women with BRCA1/2 PVs have high risks of ovarian cancer in their lifetime, especially BRCA1 carriers. These results are useful for devising optimal strategies to reduce ovarian cancer risk in BRCA1/2 carriers.

Surgical Management of Inherited Breast Cancer: Role of Breast-Conserving Surgery.

Simple SummaryWhich should be the optimal surgical approach to breast cancer in the presence of high penetrance gene mutation represents a current clinical and scientific issue, lively debated and studied. Does inherited breast cancer always mean bilateral mastectomy? Scientific research is questioning the oncological safety of a conservative surgical approach in hereditary breast cancer. The present narrative review aims to explore the scientific panorama on this faceted and significant theme.Recent studies have demonstrated that hereditary breast cancer (BC) has a prevalence of 5–10% among all BC diagnoses. Nowadays, significant technological advances in the identification of an increasingly broad spectrum of genetic mutations allow for the discovery of an ever-growing number of inherited pathogenic (P) or likely pathogenic (LP) variants of breast cancer susceptibility genes. As the management of BC patients carrying mutations in the BRCA1/2 genes or other high-penetrance genes is currently a challenge, extensive research is being carried out and a lively scientific debate has been taking place on what the most appropriate local therapy, especially surgical treatment, of patients with inherited BC should be. In many studies, BC outcomes in BRCA carriers and non-carriers have been compared. A number of them showed that, when compared with mastectomy, breast-conserving surgery in BRCA patients is oncologically safe in terms of overall survival, although an increased risk of ipsilateral recurrence was reported. In these patients, devising a specific therapeutic strategy is an inevitably complex process, as it must take into consideration a series of factors, require a multimodal approach, guarantee personalization, strictly adhere to scientific international guidelines, and consider all available evidence. The present narrative review purposes to identify and illustrate evidence from significant selected studies that discussed those issues, as well as to suggest useful tools to clinicians managing this specific clinical condition in daily clinical practice.

Genetic anticipation of breast cancer among BRCA1/BRCA2 mutation carriers: A retrospective study

To study the anticipation phenomenon among hereditary breast cancer patients, by evaluating trends in age at diagnosis and phenotype of breast cancer across two successive generation pairs of BRCA1/2 mutation carriers/non-carriers with breast cancer after reports of an earlier age of diagnosis in successive generations among BRCA1/2 mutation carrier families. A retrospective cohort study. Patient characteristics, pathologic data and survival were compared between mothers and daughters and between carriers and non-carriers. Overall, 126 patients were found, who formed 67 pairs of mothers and daughters diagnosed with breast cancer and genetically tested for BRCA mutations. Age at diagnosis was significantly younger in the daughter versus mother generation, in both groups of BRCA carriers/non-carriers. Tumor characteristics were not different between mothers and daughters. Survival analysis revealed a not significant better outcome for the daughter generation versus the mother generation. Breast cancer appeared to be diagnosed at an earlier age in successive generations among BRCA mutation carriers and non-carriers. The fact that we also observed a downshift at age of diagnosis in non-carrier pairs emphasizes that other factors (environmental, lifestyle, or social) may influence the age at diagnosis.

Computerized morphometry analysis of epithelial fimbriae nuclear symmetry in BRCA carriers may identify patients at risk for developing ovarian cancer.

Serous ovarian tumors may originate in epithelial cells of the fallopian tubes. Computerized morphometry was able to find significant alterations in the fallopian tube epithelium of healthy BRCA carriers. The purpose of this study was to identify a subgroup of BRCA carriers that may be at risk of developing serous ovarian cancer by evaluation of the epithelial nuclear symmetry in the fallopian tubes. Four groups of patients were analyzed; healthy patients, ovarian cancer patients, BRCA carriers, and BRCA noncarriers. All fallopian tubes appeared normal by H&E examination. The ImageProPlus software was used to assess the nuclear symmetry of 65 fimbriae epithelium cells and an artificial neural network algorithm aided in detecting a subpopulation among fimbriae of healthy BRCA carriers at risk for ovarian cancer. Significant differences were found between healthy patients and ovarian cancer patients, and between BRCA carriers and noncarriers. The algorithm was able to accurately predict BRCA carriers with associated ovarian cancer based on fallopian tube nuclear symmetry characteristics. These results reinforce the hypothesis that fimbriae epithelial cells of BRCA carriers may undergo early-stage changes that could predict the risk of progression toward malignancy.

Abstract 428: Long-term survival outcomes in Egyptian female breast cancer patients with and without BRCA mutations

Abstract Background: Prognostic impact of BRCA1 and BRCA2 mutations in breast cancer has been a subject of several studies over the past few years, with inconsistent interpretations. In an attempt to address this uncertainty, we aimed to study the association between BRCA1/2 mutation carriership and long-term survival outcomes for the first time in Egyptian female breast cancer patients. Patients and Methods: BRCA1/2 mutations were identified in 103 Egyptian female breast cancer patients using HRM analysis and direct sequencing. DNA for genotyping was extracted from whole blood samples submitted at recruitment. Clinicopathological data and long-term outcomes including date and site of disease progression, were retrieved from medical records until death or loss to follow-up. Outcome measures including overall survival (OS), disease-free survival (DFS), locoregional recurrence free survival (LRRFS) and metastasis free survival (MFS) were compared in all BRCA1 or BRCA2 mutation carriers versus non-carriers at 2, 5, 10, and 15 years after diagnosis. Results: Pathogenic variants (Class 5 according to American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines) were observed in 29 cases. The profile of the detected variants was previously reported. Median ages at diagnosis was 40 years (range, 24-57 years) in BRCA carriers and 48 years (range, 39-66 years) in non-carriers (P=0.008). BRCA carriers tended to have early onset breast cancer (48% versus 28%, P=0.05), more likely premenopausal (82% vs 54%, P=0.02), and with positive family history of breast cancer (45% vs 35%, P=0.024). Positive lymph node metastasis was more significantly observed in BRCA carriers (76% vs 53%, P=0.03). After median follow-up time of 6.9 years (range, 4.2-24.4 years), there was no significant difference in OS between BRCA carriers and non-carriers at 10 years: 71.1% [95%CI 51-84] vs 94.3% [84-98]; and at 15 years: 60.2% [38-77] vs 60.4% [43-74]; (P=0.36). No difference was detected in DFS between BRCA carriers versus non-carriers (DFS at 2 years: 83% [95%CI 65-92] vs 88% [76-93]; at 5 years: 34% [18-51] vs 61% [47-72]; and at 10 years: 16% [6-35] vs 35% [21-45]); (P=0.1); or MFS (at 2 years were: 83% [95%CI 65-92] vs 87.7% [76-93]; at 5 years: 38.3% [21-56] vs 62.7% [49-73]; and at 10 years: 17.9% [5-35] vs 38.4% [24-52]; (P=0.2). However, LRRFS was significantly worse in BRCA carriers as compared to non-carriers; at 5 years: 51.1% [28-69] vs 84% [70-92]; and at 10 years: 34.1% [10-40] vs 60.1% [50-75]; (P=0.018). Conclusion: To our knowledge, this is the first study in the Middle East to report the long-term prognostic implications of BRCA1/2 mutations in breast cancer. Though no significant difference was detected in the OS, yet BRCA carriers had high risk of locoregional recurrence and hence, BRCA screening and intensive surveillance should be implemented in the mainstream oncology practice in Egypt. Citation Format: Sherihan Galal AbdelHamid, Hala Osman El-Mesallamy, Hany AbdelAziz, Abdel-Rahman N. zekri. Long-term survival outcomes in Egyptian female breast cancer patients with and without BRCA mutations [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 428.

BRCA1/2 Mutations and Long-Term Clinical Outcomes in Egyptian Breast Cancer Patients

Introduction: Clinical findings regarding the impact of BRCA1/2 mutational status on the prognosis of breast cancer patients are still controversial. We aimed to investigate the prognostic relevance of BRCA1/ 2 mutations on recurrence and long-term survival, for the first time, in Egyptian female breast cancer patients. Patients and Methods: The study cohort comprised 103 Egyptian female breast cancer patients previously tested for BRCA1/2 mutations using HRM analysis and direct sequencing. Clinicopathological and long-term clinical follow-up data including date and site of disease progression, were retrieved from medical records until death or loss to follow-up. Outcome measures including overall survival (OS), disease-free survival (DFS), recurrence-free survival, and metastasis-free survival (MFS) were compared in all BRCA1/ 2 mutation carriers versus non-carriers at 2, 5, 10, and 15 years after diagnosis. Results: The profile of the detected variants was previously reported. The American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines were used to re-classify the variants. The median follow-up time was 6.9 years (range, 4.2-24.4 years). BRCA carriers had significantly worse DFS than non-carriers, at 2 years 86.7% vs 88.2%; at 5 years 38.1% vs 57.8%; and at 10 years 21.6% vs 34.1% ( P=0.024). Negative estrogen receptor (ER) status (HR=2.44, 95%CI=1.33-4.47) and large tumor size (HR=2.19, HR=1.21-3.98) were also significant factors for worse DFS. Recurrence-free survival was significantly worse in BRCA carriers compared to non-carriers, at 5 years: 95.2% vs 98.2%; at 10 years: 54.4% vs 79.8%; and at 15 years 34.6% vs 61.7% ( P=0.005). BRCA carriers showed poorer OS and MFS, though not statistically significant [OS in BRCA carriers and non-carriers at 5 years: 81.6% vs 89.3%; at 10 years: 59.2% vs 60.6%; and at 15 years: 36.3 vs 59.2% ( P=0.42); and MFS at 2 years 86.7% vs 88.1%; at 5 years 44.5% vs 61.1% ; and at 10 years: 25.3% vs 38.2% ( P=0.41)]. Conclusion: To our knowledge, this is the first study in the Middle East to investigate long-term survival outcome of BRCA1/2 related breast cancer. We, herein, underline the necessity of implementing BRCA screening strategies and intensive surveillance in the mainstream oncology practice in Egypt.

Abstract PS8-15: The spectrum of germline susceptibility gene variants in Mexican patients with breast cancer (BC): A Prospective Multicenter study

Abstract Background: BRCA mutations are responsible for a significant proportion of hereditary breast and ovarian cancers. However, other cancer susceptibility genes are also associated with an increased risk of developing breast cancer (BC). In Mexico, approximately 15% of patients with BC have been identified with BRCA mutations. Despite our growing understanding of BRCA mutations, the contribution and characterization of non-BRCA mutations in Mexican patients with a BC diagnosis remains unknown. We aimed to investigate the spectrum of BC-associated mutations among Mexican patients with BC referred for genetic cancer risk assessment (GCRA) in the multinational Clinical Cancer Genomics Community Research Network (CCGCRN). Methods: Mexican patients with a primary BC who were enrolled in the IRB-approved CCGCRN registry protocol and underwent genetic counseling and multigene panel testing (MGPT) were included. Pathogenic and likely pathogenic variants (PV) in genes associated with increased BC risk were used for analyses. Clinical and demographic characteristics of BRCA and non-BRCA carriers were compared. Results: From December 2012 to February 2020, 725 Mexican patients with BC who had MGPT results with a median age (years) of 41 (range 25-76) were included. 142 (19.6%) patients carried a BC-associated PV. Of these, 98 (69.0%) carried BRCA PVs: 58 in BRCA1 (41.5%) and 40 in BRCA2 (26.7%). PVs in other BC-associated genes (n = 42) accounted for 29.5% of all observed PVs and were distributed as follows: PALB2 (n = 13), CHEK2 (n = 11), RAD51C (n = 6), ATM (n = 3), PTEN (n = 3), TP53 (n = 3), BRIP1 (n = 2), and CDH1(n = 1). Other actionable genes represented 3.5% of all PVs (PMS2 [n = 3]; MSH6 [n = 1]; MSH2 [n = 1]). Suspected founder mutations in Latinas, PALB2 c.2167_2168delAT (n = 5) and CHEK2 c.707T&amp;gt;C (n = 9), represented 33.3% (n = 14/42) of the detected non-BRCA PVs. Mean age at first cancer diagnosis (years) for BRCA and non-BRCA carriers was: 37 (range 26-58) and 42 (range 25-76) (p&amp;lt;0.05), respectively. Among carriers, those with BRCA PVs had a significantly greater proportion of triple-negative (TN) tumors compared to non-BRCA PVs (45.2% vs 9.5%; p&amp;lt;0.05). Conclusion: A significant proportion of Mexican women carried a BC-associated mutation and a third were non-BRCA PVs. Among non-BRCA PVs, recurrent PALB2 and CHEK2, which had previously been characterized in BRCA-negative US Latinas with BC, were the most common and confirms their presence and clinical impact in Mexico. BRCA carriers were younger and more commonly had the TN molecular subtype. Citation Format: Yanin Chavarri-Guerra, Cynthia Villarreal-Garza, Gubidxa Gutierrez Seymour, Dione Aguilar y Mendez, Jazmin Arteaga-Vazquez, Servando Cardona-Huerta, Adrian Daneri-Navarro, Azucena del Toro Valero, Alejandro Mohar-Betancourt, Andrés Rodríguez-Faure, Jose Luis Rodriguez-Olivares, Gregorio Quintero Beulo, Danielle Castillo, Kai Yang, Joseph Herzog, Rosa Mejia, Sharon Sand, Jeffrey N Weitzel. The spectrum of germline susceptibility gene variants in Mexican patients with breast cancer (BC): A Prospective Multicenter study [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 PS8-15.

Abstract PD10-08: Outcomes of germline BRCA carriers versus non-carriers in the french national metastatic breast cancer ESME cohort 2008-2016

Abstract BACKGROUND: Approximately 5% of breast cancer (BC) patients (pts) carry a deleterious germline BRCA mutation (gBRCAm). Retrospective studies suggest that overall survival (OS) is equivalent between gBRCAm carriers and non-carriers with metastatic BC (MBC). We aimed to use the large ESME multicentre national MBC database to compare outcomes of gBRCAm carriers, gBRCA wild-type (WT) and not tested (NT) pts. METHODS: We used the large ESME MBC database (NCT03275311), a unique national cohort of all consecutive pts who initiated a first-line treatment for MBC between 2008 and 2016 in one of the 18 French Comprehensive Cancer Centers. All pts with data available regarding gBRCA testing were selected for the present analysis. 26 pts with non-BRCA germline mutations were classified in the WT group. The primary endpoint was OS from date of treatment initiation in the 3 groups of patients: gBRCAm, gBRCA WT and gBRCA NT.Secondary endpoints were progression-free survival under first line treatment (PFS1), clinical and biological characteristics of the 3 groups and prognostic factors for OS. Multivariable analyses included the main known prognostic factors (age at MBC, MBC subtype, disease-free interval, presence of visceral disease, number of metastatic sites). They were conducted using Cox proportional analyses. RESULTS: 20624 pts were included in this analysis (414 gBRCAm, 1710 WT, 18500 gBRCA NT). Pts and disease characteristics are summarized in table 1. As expected, patients with gBRCAm were younger and had a higher rate of TNBC and G3 tumors. Median follow-up was 50.5 months (95%CI 49.7-51.5). Non-adjusted median OS was 30.6 months [21.9-34.3] in the gBRCAm group, 35.8 [32.2-37.8] in the WT and 39.3 [38.3-40.3] in NT groups. Median PFS1 was 7.9 months [6.6-9.3] in the gBRCAm group, 7.8 [7.3-8.5] in the WT and 9.7 months [ 9.5-10.0] in the NT groups. In multivariable analyses, OS and PFS were not significantly different between MBC patients with gBRCA and others (respective HRs 1.01 [0.88;1.17], p=0.87 and 0.94 [0.84;1.06], p=0.31). CONCLUSION: In this large scale real-life ESME MBC database analysis, outcomes of gBRCAm carriers with MBC do not differ from non carriers or not tested subgroups, when adjusted for other prognostic factors. Table 1: characteristics of patients and diseasegBRCAm. gBRCA WT. gBRCA NT Pvalue (chi-2)N = 414 N = 1710 N = 18500 Age (years) median [range]45 [23-82]48 [20- 88]61 [22-103]p&amp;lt;0.0001Grade 3 N (%) Missing data202 (57.7) 64598 (41.1) 2545337 (34.5)3036p&amp;lt;0.0001Triple negative breast cancer N (%)158 (38.2)370 (21.6)2331 (12.6)p&amp;lt;0.0001De novo MBC N (%)74 (17.9)359 (21)5914 (32)p&amp;lt;0.0001Disease-free interval (months) median [range]39.0 [-1.5- 425.7]36.3 [-2.1- 549.6]31.8 [-2.9- 657.8]p&amp;lt;0.0001Metastatic sites ≥3 N (%)113 (27.3)349 (20.4)3943 (21.3)p=0.008Visceral metastases N (%)279 (67.4)964 (56.4)10659(57.6)p=0.0002Central Nervous System Metastases N (%)66 (15.9)132 (7.7)1145 (6.2)p&amp;lt;0.0001 Citation Format: Audrey Mailliez, Veronique D'Hondt, Amelie Lusque, Olivier Caron, Luc Cabel, Antony Goncalves, Marc Debled, Laurence Gladieff, Jean-Marc Ferrero, Thierry Petit, Marie-Ange Mouret-Reynier, Jean-Christophe Eymard, Jean-Sébastien Frenel, Thibault De La Motte Rouge, Gaëtane Simon, Suzette Delaloge. Outcomes of germline BRCA carriers versus non-carriers in the french national metastatic breast cancer ESME cohort 2008-2016 [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 PD10-08.

Abstract PS13-10: Impact of BRCA mutation status on immune infiltration, chemosensitivity, and prognosis of breast cancer patients treated with neoadjuvant chemotherapy

Abstract Context: The majority of BRCA mutation carriers diagnosed with breast cancer (BC) are treated with chemotherapy. The effectiveness of standard neoadjuvant chemotherapy (NAC) in BRCA associated BC compared to noncarriers has been poorly explored. Objectives: To assess whether the BRCA mutation status modifies the immune infiltration, chemosensitivity, and prognosis of breast cancer. Methods: We retrospectively identified in our institutional database all consecutive patients with BRCA germline mutation status available treated with NAC between 2002 and 2012. Microbiopsy specimens and paired surgical samples were evaluated for pre-NAC and post-NAC immune infiltration (stromal TILs, str TILs; intratumoral TILs, IT TILs). Response to chemotherapy was assessed by pathological complete response (pCR) rates. Association of clinical and pathological factors with pCR, overall survival (OS), and relapse free survival (RFS) was assessed by univariate and multivariate analyses. Results: Overall, 267 patients were included in this study (46 BRCA carriers and 221 BRCA noncarriers). The median age at BC diagnosis was 40 years old, and most of the patients (n=227, 85%) were premenopausal. Patients repartition by subtype was as follows: luminal (n=90, 33.7%), TNBC (n=110, 41.2%), HER2-positive (n=67, 25.1%). BRCA mutation carriers were likely to have familial history of BC (73.9% vs. 52.3%, p = 0.012), and be diagnosed with TNBC (58.7% vs 37.6%; p = 0.006), than noncarriers. No pattern was significantly different between BRCA mutation subgroups regarding age, body mass index, histology, tumor size, grade or Ki67. TIL levels were available in 192 patients. Neither pre-NAC stromal TIL levels nor IT TILs were significantly different by BRCA status in the whole population, nor in each BC subtype. PCR rates were significantly higher in BRCA mutation carriers (p= 0.035), and this association remained statistically significant only in the luminal BC subtype (p=0.006) after stratification by BC subtype (Pinteraction= 0.056). After multivariate analysis, only BC subtype and pre-NAC str TILs were independent predictors of pCR. Post-NAC stromal and intra-tumoral TIL levels were significantly higher luminal subtype (p=0.009 and p=0.019, respectively). After a median follow-up of 90 months, RFS and OS were not different between BRCA carriers and noncarriers, neither in the whole population nor after stratification by BC subtype. Discussion: In our study, BRCA status was associated with an enhanced response to standard NAC, particularly in luminal BC patients, in addition to higher post-NAC TIL levels. Whether patients with luminal BC and BRCA mutation derive benefit from second line immunotherapy after NAC completion remains to determine. Citation Format: Beatriz Grandal, Clémence Evrevin, Eric Daoud, Elise Dumas, Nadir Sella, Clara Sebbag, Sonia Rozette, Isabelle Jardin, Lucie Laot, Florence Coussy, Claire Saule, Dominique Stoppa-Lyonnet, Sophie Franck, Claire Sénéchal, Enora Laas, Marick Lae, Diane De Croze, Fabien Reyal, Anne-Sophie Hamy. Impact of BRCA mutation status on immune infiltration, chemosensitivity, and prognosis of breast cancer patients treated with neoadjuvant chemotherapy [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 PS13-10.

Sharing genetic test results with family members of BRCA, PALB2, CHEK2, and ATM carriers

ObjectiveThis study explored motivators and challenges/barriers to sharing personal genetic test results (GTR) with family members (FM). MethodsSemi-structured, in-depth interviews were conducted with 62 women who had a pathogenic or likely pathogenic (P/LP) variant in aBRCA, PALB2, CHEK2, or ATM gene. Selective qualitative data analysis focused on eliciting motivators and challenges/barriers identified by participants when sharing their GTR with FM. ResultsMotivators to sharing personal GTR with FM included: health protection and prevention; moral obligation; decisional empowerment; familial ties; written resources; and contextualization for a familial cause for cancer. Challenges/barriers to family sharing included: concern for FM reactions; complexities of information; lack of closeness; perceived relevance; and emotional impact. ConclusionsAll motivators and challenges/barriers were identified across BRCA and non-BRCA carriers, demonstrating commonalities in family sharing of GTR among high- to moderate-penetrance hereditary BC (breast cancer) genes. Despite challenges/barriers, participants disclosed their GTR with most close FM, yet restrictions in communication and/or strain on the timing, manner of disclosing, and strategies used varied across certain FM. Practice implicationsThese findings offer healthcare providers and researchers preliminary practical implications for broadly improving family sharing interventions across P/LP variants in BC risk genes by demonstrating important elements to include in family sharing letters.

Genomic Profiling Comparison of Germline BRCA and Non-BRCA Carriers Reveals CCNE1 Amplification as a Risk Factor for Non-BRCA Carriers in Patients With Triple-Negative Breast Cancer.

Background: Differences in genomic profiling and immunity-associated parameters between germline BRCA and non-BRCA carriers in TNBC with high tumor burden remain unexplored. This study aimed to compare the differences and explore potential prognostic predictors and therapeutic targets.Methods: The study cohort included 21 consecutive TNBC cases with germline BRCA1/2 mutations and 54 non-BRCA carriers with a tumor size ≥ 2 cm and/or ≥1 affected lymph nodes. Differences in clinicopathological characteristics and genomic profiles were analyzed through next-generation sequencing. Univariate Kaplan–Meier analysis and Cox regression model were applied to survival analysis. Immunohistochemistry was used to confirm the consistency between CCNE1 amplification and cyclin E1 protein overexpression.Results: The cohort included 16 and five patients with germline BRCA1 and BRCA2 mutations, respectively. Patients with germline BRCA1/2 mutations were diagnosed at a significantly younger age and were more likely to have a family history of breast and/or ovarian cancer. Six non-BRCA carriers (11.11%) carried germline mutations in other cancer susceptibility genes, including five mutations in five homologous recombination repair (HRR) pathway genes (9.26%) and one mutation in MSH3 (1.85%). Somatic mutations in HRR pathway genes were found in 22.22 and 14.29% of the non-BRCA and BRCA carriers, respectively. PIK3CA missense mutation (p = 0.046) and CCNE1 amplification (p = 0.2) were found only in the non-BRCA carriers. The median tumor mutation burden (TMB) was 4.1 Muts/Mb, whereas none of the cases had high microsatellite instability (MSI). BRCA status did not affect disease-free survival (DFS, p = 0.15) or overall survival (OS, p = 0.52). CCNE1 amplification was an independent risk factor for DFS in non-BRCA carriers with TNBC (HR 13.07, 95% CI 2.47–69.24, p = 0.003). Consistency between CCNE1 amplification and cyclin E1 protein overexpression was confirmed with an AUC of 0.967 for cyclin E1 signal intensity.Conclusions: We found differences in genetic alterations between germline BRCA and non-BRCA carriers with TNBC and a high tumor burden. TMB and MSI may not be suitable predictors of TNBC for immune checkpoint inhibitors. Notably, CCNE1 amplification is a novel potential prognostic marker and therapeutic target for non-BRCA carriers with TNBC. Cyclin E1 may be used instead of CCNE1 to improve clinical applicability.