BRCA1-associated Cancer Research Articles

Features and complexity of treatment of BRCA-associated ovarian cancer, chronic disease: literature review

We analyzed literature data on the peculiarities of the clinical manifestation and therapeutic approaches ofB RCA-associated ovarian carcinomas. The ESMO-ESGO consensus emphasised the importance of determining BRCA1/2 status in ovarian cancer patients for planning the entire treatment strategy. BRCA-associated carcinomas differ significantly from sporadic forms in terms of clinical course, response to systemic therapy, spectrum of drugs which are used for treatment, mechanisms of chemoresistance development, and prognosis. This category of patients needs new therapeutic approaches, including the development of tactics to overcome chemoresistance and modification of the entire combined treatment programme.

Skin metastasis of BRCA mutated prostate cancer: A case report and a brief review of literature.

Metastatic castration-resistant prostate cancer has a poor prognosis especially when harboring DNA damage repair gene mutations, nevertheless, in the case of pathogenic BRCA gene mutations, PARPi demonstrated a survival benefit and is a validated treatment. Nowadays, there is no data regarding unusual metastases after these drugs. Cutaneous metastases appear rarely in prostate cancer and were associated with a worse prognosis. Moreover, there are no consolidated data concerning skin tropism of prostate cancer cells, neither in the case of BRCA-associated cancers. Here, we report the case of a patient with a long history of BRCA1-mutated metastatic castration-resistant prostate cancer who developed a skin lesion on the scalp while on his fifth line of systemic therapy with olaparib. After a complete radical surgical excision, the pathology report showed prostate cancer localization. A diagnosis of skin metastasis from prostate cancer was reported. The patient then continued olaparib therapy; after 7 months from excision, he experienced further bone and biochemical progression but not cutaneous progression. A literature review of all reported cases of cutaneous metastasis in prostate cancer was conducted to shed light on the incidence, clinical presentation, diagnosis, treatment, and prognosis of this entity. We also reviewed published cases of skin metastasis in BRCA-associated cancers with an effort to correlate skin involvement with PARPi treatment, BRCAness status, and prognosis.

A ten-year overview of cancer genetic family history screening in Georgia's Latina population.

Population-based cancer genetic family history (FH) screening to identify families at high risk for BRCA-associated cancers has been endorsed by national public health policies. This report aimed to describe the utilization of FH screening services from 2013 to 2022 according to rurality and socioeconomic deprivation among Latinas in Georgia. Women who attended a medical appointment at participating Georgia Public Health Clinics were invited to complete FH screening. Screening results and participant zip code were reviewed. Area deprivation index (ADI) was measured at the census block group level and dichotomized (more deprived and less deprived). Rurality was measured through Rural-Urban Commuting Area (RUCA) codes and dichotomized (urban and rural). The ADI and RUCA codes were linked to participant data by zip code to characterize FH utilization among the Latina community. Of the 9,330 adult Latinas in Georgia that completed cancer genetic FH screening, 9,066 (97.17%) women screened negative, and 264 (2.83%) screened positive (i.e., FH suggestive of higher risk for carrying BRCA1/2 mutations compared to the general population). Screening completion was higher among Latinas in urban areas (n = 7,871) compared to rural areas (n = 1,459). Screening completion was also higher in more socially deprived areas (n = 5,207) compared to less socially deprived areas (n = 4,123). Georgia's FH screening program reached Latinas across Georgia, particularly those living in urban, socially deprived areas. To ensure equitable cancer genetic screening dissemination, future efforts should prioritize tailored outreach in rural regions and comprehensive evaluations to identify key determinants of screening trends among Georgia's Latina population.

Abstract A147: A ten-year overview of cancer genetic family history screening in Georgia’s Latina population

Abstract Introduction: Population-based cancer genetic family history screening to identify families at high risk for BRCA-associated cancers has been endorsed by national public health policies. This report aimed to describe the utilization of family history screening services from 2013 to 2022 according to rurality and socioeconomic deprivation among the Latina community in the state of Georgia. Methods: Self-identified Latina women who attended a medical appointment at participating Georgia Public Health Clinics were invited to utilize the cancer genetic family history screening services. Screening results and participant zip code were reviewed. Area deprivation index (ADI) was measured at the census block group level and assessed as a dichotomous variable (more deprived and less deprived). Rurality was measured through Rural-Urban Commuting Area (RUCA) codes and was assessed dichotomously (urban and rural). The ADI and RUCA codes were linked to participant data by zip code to characterize genetic service access among the Latina community. Results: We found 9,330 (3.31%) adult Latinas in Georgia completed cancer genetic family history screening from 2013-2022. In this sample, 9,066 (97.17%) women screened negative, and 264 (2.83%) women screened positive (i.e., family history suggestive of higher risk for carrying BRCA1/2 mutations compared to the general population). The family history screening program reached Latinas in 16 of 18 public health districts in Georgia. However, family history screening completion varied significantly across the 16 districts (mean=327 women, range: 2 - 1,337). FH screening completion was higher among Latinas in urban areas (n=7,871) than Latinas in rural areas (n=1,459). Latinas who lived in more socially deprived areas appeared to have a higher number of screening completion (n=5,207) than those living in less socially deprived areas (n=4,123) due to interaction with urbanicity. Conclusions: Georgia’s family history screening program was able to reach Latina women across the state of Georgia, particularly those living in urban, socially deprived areas. To ensure equitable cancer genetic screening dissemination, future efforts should prioritize tailored outreach in rural regions and a comprehensive evaluation to identify key determinants of screening trends among Georgia’s Latina population. Citation Format: Dayanna A. Ramírez León, Lauren E. Barber, Sheryl Gabram-Mendola, Cindy Snyder, Susan Vadaparampil, Lindsay Fuzzell, Lauren E. McCullough, Lynn Durham, Yue Guan. A ten-year overview of cancer genetic family history screening in Georgia’s Latina population [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A147.

Online Provision of BRCA1 and BRCA2 Health Information: A Search Engine Driven Systematic Web-Based Analysis.

BRCA genetic testing is available for UK Jewish individuals but the provision of information online for BRCA is unknown. We aimed to evaluate online provision of BRCA information by UK organisations (UKO), UK Jewish community organisations (JCO), and genetic testing providers (GTP). Google searches for organisations offering BRCA information were performed using relevant sets of keywords. The first 100 website links were categorised into UKOs/JCOs/GTPs; additional JCOs were supplemented through community experts. Websites were reviewed using customised questionnaires for BRCA information. Information provision was assessed for five domains: accessibility, scope, depth, accuracy, and quality. These domains were combined to provide a composite score (maximum score = 5). Results were screened (n = 6856) and 45 UKOs, 16 JCOs, and 18 GTPs provided BRCA information. Accessibility was high (84%,66/79). Scope was lacking with 35% (28/79) addressing >50% items. Most (82%, 65/79) described BRCA-associated cancers: breast and/or ovarian cancer was mentioned by 78%(62/79), but only 34% (27/79) mentioned ≥1 pancreatic, prostate, melanoma. Few websites provided carrier frequencies in the general (24%,19/79) and Jewish populations (20%,16/79). Only 15% (12/79) had quality information with some/minimal shortcomings. Overall information provision was low-to-moderate: median scores UKO = 2.1 (IQR = 1), JCO = 1.6 (IQR = 0.9), and GTP = 2.3 (IQR = 1) (maximum-score = 5). There is a scarcity of high-quality BRCA information online. These findings have implications for UK Jewish BRCA programmes and those considering BRCA testing.

Mitomycin C in the treatment of early triple-negative locally advanced BRCA-associated breast cancer

Rationale. BRCA1 associated triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. At the same time, carcinomas that develop in carriers of BRCA1 mutations are characterized by extremely high sensitivity to DNA-damaging chemotherapy. Mitomycin C alone or in combination with platinum agents has already demonstrated promising results in the treatment of BRCA-associated ovarian cancer (OC) and metastatic breast cancer. In this article, we present the results of a retrospective study aimed at comparing standard neoadjuvant chemotherapy regimens (NACT) with mitomycin-based regimens for primary locally advanced BRCA1-associated TNBC.The aim of the study is to determine the effectiveness of the combination of mitomycin and platinum compounds during neoadjuvant therapy in patients with primary locally advanced BRCA1 – associated TNBC.Materials and methods. The study included 89 patients diagnosed with primary locally advanced BRCA1-associated TNBC. Patients were divided into three groups depending on the therapy: 1) 4 cycles of anthracycline and cyclophosphamide followed by 12 weekly injections of paclitaxel (n = 48) (AC + T), 2) 4 cycles of anthracycline and cyclophosphamide followed by 12 weekly injections of paclitaxel and carboplatin (n = 27) (AC + TCbP), 3) mitomycin C plus platinum followed by 12 weekly injections of paclitaxel (n = 14) (MR + T). Pathological complete response (pCR) rates were compared.Results. The pCR rate in the MP+T group was 10/14 (71%). In patients with BRCA1-associated breast cancer who received AC + T and AC + TCbP regimens as NACT, the pCR rate was 17/48 (35%) and 19/27 (70%), respectively. The difference in pCR rate between mitomycin-containing therapy and the standard AC + T regimen was statistically significant (p = 0.03); the frequency of regressions was comparable to the frequency in the AC + TCbP group. During the 20-month follow-up period, no relapses were observed in the MR + T group. Relapses were more frequent in the AC + T group compared with the AC + TCbP group (16/48 (33%) vs 1/27 (4%), p = 0.003, Fisher’s exact test). The toxicity profile of the mitomycin-containing regimen included hematologic adverse events, the most common of which were anemia and leukopenia. Compared to standard regimens, nausea was significantly less pronounced. No patients reported alopecia with this regimen.Conclusions. The addition of mitomycin C to neoadjuvant therapy for BRCA1-associated TNBC may be a promising treatment option for this category of patients and merits further study.

Commentary on Diagnostics and treatment of BRCA-associated cancers with olaparib — expert position statement

Commentary on Diagnostics and treatment of BRCA-associated cancers with olaparib — expert position statement

Diagnostics and treatment of BRCA-associated cancers with olaparib — expert position statement

Diagnostics and treatment of BRCA-associated cancers with olaparib — expert position statement

Abstract PO4-06-06: Clinical Implications of Body Mass Index (BMI) in BRCA-associated Advanced Breast Cancer Patients Treated With PARP (Poly ADP-Ribose Polymerase) Inhibitors

Abstract Background: PARP inhibitors (PARPi) have demonstrated promising results in patients with advanced as well as early breast cancer carrying germline BRCA1/2 pathogenic variants (PV). Although there is increasing attention to the effect of BMI on the outcomes of cancer patients, there is limited data on its effect on BRCA-associated advanced breast cancer patients receiving PARPi therapy. In this report, we evaluate the effect of BMI on the outcomes of advanced breast cancer patients with a BRCA PV and who received PARPi therapy. Methods: Patients with BRCA 1/2 germline PVs who presented to the University of Texas MD Anderson Cancer Center Breast Medical Oncology clinics and were treated with PARPi between 2008-2022 as part of their treatment for metastatic or recurrent disease were included in the analysis. The patients were divided into four groups according to BMI level as follows: underweight (< 18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (≥30 kg/m2). Descriptive statistics, the Kaplan-Meier method, the Cox proportional hazards regression model, and Fisher’s exact test were used to report patient characteristics and outcomes. Progression-free survival (PFS) was calculated from the start of the PARPi therapy to the time of progression or death. Overall survival (OS) was calculated from the start of the PARPi therapy to the time of death of any cause. Results: One hundred and seven patients were treated with PARPi. The median BMI was 25.9 kg/m2 (14.8-61.2). In patients who received ≥2 cycles of PARPi, the overall response rate was 100% in the underweight group (n=4, 3.8%), 65.8% in the normal weight group (n=43, 41%), 64% in the overweight group (n=30, 28.6%), and 58.3% in the obese group (n=28, 26.7%). The median PFS was 5.4 months, 9.2 months, 9 months, and 8.6 months in underweight, normal weight, overweight, and obese patients, respectively. While the obese patients had a better outcome in terms of PFS (p = 0.0288), there was no significant difference observed in OS between BMI groups. Conclusion: In this analysis, we showed that obese patients with BRCA-associated advanced breast cancer had a better PFS. Future studies analyzing body composition parameters in BRCA-associated breast cancer patients treated with PARPi therapy could shed more light on the impact of obesity on outcomes. Citation Format: Fatma Akkoc Mustafayev, Mark Munsell, Rachel Layman, Clinton Yam, Angelica Gutierrez Barrera, Banu Arun. Clinical Implications of Body Mass Index (BMI) in BRCA-associated Advanced Breast Cancer Patients Treated With PARP (Poly ADP-Ribose Polymerase) Inhibitors [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 PO4-06-06.

Abstract PO2-19-11: NOBLE – Neoadjuvant Olaparib and Durvalumab for patients with BRCA-associated TripLE Negative Breast Cancer

Abstract Background The standard of care for patients with early triple-negative breast cancer (TNBC) is neoadjuvant chemotherapy followed by surgery. Recently, immune checkpoints inhibitors (ICI) added to neoadjuvant chemotherapy have shown efficacy. Among TNBC, BRCA mutations and other homologous recombination deficiency (HRD) signals are relatively frequent. As opposed to other types of breast cancer, TNBC show a high neoantigen load, a large number of tumour infiltrating lymphocytes (TILs), and a high PD-L1 expression. In BRCA/HRD breast cancer, PARP inhibitors (PARPi) exhibit a distinct anticancer activity. In addition, they show immunomodulatory effects by promoting PD-L1 expression and DNA damage, increasing neoantigen load. Chemotherapy-free regimens combining PARPi and ICI result in promising synergistic activity as shown in the metastatic setting, supporting investigation in the neoadjuvant setting. Trial design NOBLE is an EORTC phase 2, randomized, international, multicentre, open label, clinical trial. Eligible patients will undergo central screening for tumoral BRCA/HRD (Institute Curie, 455 patients), 152 patients will be randomized 1:1 between olaparib vs olaparib and durvalumab for 4 cycles (16 weeks) of neoadjuvant treatment. Thereafter, patients will undergo surgery. All patients will be followed-up to 2 years (y) after surgery. The trial will be conducted in 3 steps (screening/randomization): Step 1 – Feasibility (60/20): to assess the central testing failure rate, the turn-around time for central testing and the prevalence of tBRCA/HRD; Step 2 (193/64) – Futility; and Step 3 (202/152) – Expansion of recruitment. The primary endpoint is the rate of pathologic complete response (pCR) at the time of surgery, defined as ypT0/is ypN0. Secondary endpoints are response based on RECIST v1.1, surgery rate, 2-y event-free-survival, 2-y overall survival, safety, and quality of life. The study is expected to be activated in early autumn 2023 and the primary endpoint will be available approximately 5 years after the screening of the first patient. Main inclusion criteria Histologically confirmed primary TNBC, defined as: - ER and PgR ≤ 10% - HER2-negative per ASCO CAP guidelines Stage T1c-T2 N0-N1 M0 BRCA mutation and/or HRD based on methylation as determined by central testing ECOG status 0-1 Written informed consent Age ≥18 years No prior systemic therapy nor surgery for the current Main exclusion criteria Previous treatment with a PARPi or an immune-checkpoint inhibitor History of previous invasive breast cancer Bilateral and/or multifocal and/or multicentric BC Autoimmune or inflammatory disease Specific aims The aim of this study is to provide a safe and effective neoadjuvant treatment free of chemotherapy to a distinct subpopulation among patients with TNBC. We will evaluate the pCR after neoadjuvant treatment with olaparib alone and with olaparib in combination with durvalumab in patients with TNBC showing a BRCA1/2 mutation or HRD based on methylation. Statistical methods The sample size was calculated based on the minimax Simon two-stage design including an interim analysis for futility of the primary endpoint. Decision rules are pre-specified in the study protocol. Each treatment arm will be analyzed independently. There will be no formal comparison between the two experimental treatment arms. A minimization technique will be used for random treatment allocation stratifying for the type of HRD alteration, PD-L1 expression level and for TILs. Accrual We expect to start recruiting in September 2023. We aim to screen 455 patients to randomize 152 patients. Contact information for people with a specific interest in the trial Etienne Brain (study coordinator): etienne.brain@curie.fr Anne-Sophie Hamy-Petit (study co-coordinator): anne-sophie.hamy-petit@curie.fr Citation Format: Emanuel Buhrer, Eleni Xenophontos, Anne-Sophie Hamy-Petit, Jose Casas-Martin, Céline Callens, Thomas Meyskens, Coralie Poncet, Anastasia Lanzi, Etienne Brain. NOBLE – Neoadjuvant Olaparib and Durvalumab for patients with BRCA-associated TripLE Negative 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 PO2-19-11.

Abstract PO5-21-07: Mitomycin: its developmental role in the treatment of patients with BRCA - associated triple-negative early and locally advanced breast cancer

Abstract Rationale. BRCA-associated triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with high sensitivity to chemotherapy, which leads to increased interest in the development of new strategies for neoadjuvant treatment of patients with a triple-negative tumor phenotype. The aim of the study is to determine the role of adding platinum to standard neoadjuvant systemic therapy in patients with primary BRCA-associated TNBC, to evaluate the effect of platinum preparations on relapse-free survival in patients of this category, to determine the role of adding mitomycin to platinum in patients with primary BRCA-associated TNBC. Materials and methods. The study included 80 patients diagnosed with primary BRCA - associated TNBC, divided into 3 groups according to the treatment. Each group was subdivided depending on the final pathomorphological result and the presence of relapses. Results. 80 patients with primary BRCA-associated TNBC were divided into 3 groups depending on the ongoing neoadjuvant chemotherapy (NACT). Group I included 48 (60%) patients who received the AC-T regimen, in group II — NAC according to the AC-TCarb regimen, 27 (33.75%) patients, in group III — NAC with mitomycin in combination with cisplatin, 5 (6.25%) of patients. A comparative analysis of the results of the frequency of achieving complete pathomorphological regression (pCR), depending on the addition of a platinum drug to standard NAC, showed the advantage of group II compared to group I (73.7% vs. 41.2%, respectively, p = 0.0433). Taking into account the ongoing NAC regimens, with a median follow-up of 20.7 months, patients of group I had a slightly higher risk of relapse compared to patients of group II (p = 0.099). Patients of group III demonstrated the achievement of pCR in 66.6% of cases (2/3) during the full course of NAC, 2 patients of group III did not complete the planned course of NAC for medical reasons, due to the development of a pronounced nephrotoxic effect. During the observation period of group III, no cases of relapse were recorded. Conclusions.The addition of platinum drugs to the standard anthracycline/taxane NAPCT regimen in patients with primary BRCA-associated TNBC, results in a higher pCR rate, which entails a reduced risk of disease recurrence.The use of the new NAC regimen with mitomycin in combination with platinum compounds has promising results in patients with this oncopathology, which deserves a more detailed clinical evaluation.Performinga full course of planned NAC has a positive tendency in achieving pCR in patients of this category. Keywords: BRCA1/2 mutation; triple negative breast cancer; platinum preparations; mitomycin; neoadjuvant chemotherapy. Citation Format: Petr Krivorotko, Evgeniy Imyanitov, Diana Enaldieva, Elena Zhiltsova, Roman Donskih, Anna Sokolenko, Laysan Shaikhelislamova, Larisa Gigolaeva, Tengiz Tabagua, Alexander Komyakhov, Kirill Nikolaev, Konstantin Zernov, Sergey Yerechshenko, Roman Pesotsky, Nikolay Amirov, Alexander Emelyanov, Viktoria Mortada, Yana Bondarchuk, Vladislav Semiglazov. Mitomycin: its developmental role in the treatment of patients with BRCA - associated triple-negative early and locally advanced 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 PO5-21-07.

Abstract PO3-08-08: Basal-Luminal (BL) Cells in Histologically Normal and Malignant Breast Tissue from BRCA1 and BRCA2 Carriers

Abstract Background Single-cell studies of normal breast tissue in BRCA mutation carriers have led to the identification of a candidate cancer precursor cell, the basal-luminal (BL) cell. The localization of BL cells within normal, pre-malignant and malignant breast tissue architecture is not well characterized. Here, using cyclic immunofluorescence (CyCIF), we quantify and localize BL cells within normal and malignant breast tissues from BRCA1 and BRCA2 carriers. Methods Formalin-fixed paraffin-embedded breast tissue sections from 9 BRCA1 and 9 BRCA2 consented patients treated at Dana Farber Cancer Institute (2001-2019) were retrieved from the clinical archives and subjected to CyCIF for luminal and basal markers including CK5, CK14 and CK19. Using one section/case, cells co-expressing basal and luminal cytokeratins (CK14/CK19 and/or CK5/CK19) were visually identified in invasive carcinoma, ductal carcinoma in situ (DCIS) and in adjacent normal breast tissue. In histologically normal tissue, regions of interest (ROIs) with co-expressing cells were classified as terminal duct lobular units (TDLUs) or isolated ducts. Within each ROI, the quantity of BL cells was scored as low (1-5 cells), moderate (6-10 cells), or high ( >10 cells). Results The 9 BRCA1 tumors included 8 invasive ductal carcinomas/no special type and 1 tubular carcinoma. The 9 BRCA2 tumors included 4 invasive ductal carcinomas/no special type and 5 invasive carcinomas with ductal and lobular features. 496 ROIs were evaluated in histologically normal tissue: 297 from BRCA1 cases and 199 from BRCA2 cases. BL cells co-expressing CK14/CK19 and/or CK5/CK19 were identified in normal TDLUs and isolated ducts in both BRCA1 and BRCA2 cases. BL cells were more frequently identified in BRCA2 cases, with at least one BL cell present in 97/297 ROIs (33%) in BRCA1 cases and in 133/199 ROIs (67%) in BRCA2 cases (p< 0.01). 55% of BRCA2 ROIs had >10 BL cells each versus 42% of BRCA1 ROIs; however, this difference was not significant. Four BRCA1 cases showed a diffuse BL cell phenotype within the invasive carcinoma with either a diffuse or scattered BL cell phenotype within the DCIS. The BL cell phenotype was not seen diffusely in invasive carcinoma or DCIS in the other 14 cases; however individual tumor cells or small cell clusters with the BL cell phenotype were occasionally found. Conclusions BL cells are found in histologically normal TDLUs and isolated ducts in breast tissue from BRCA1 and BRCA2 carriers, with greater prevalence in BRCA2 carriers. The BL cell phenotype is present diffusely within tumor cells in almost half of BRCA1-associated cancers and none of the BRCA2-associated cancers in this small cohort. Further study of this interesting cell population is warranted in efforts to understand early changes in epithelium at high risk for the development of cancer. Citation Format: Rodrigo Fonseca Abreu, Tabata Alves Domingos, Roberto Bonfim Pimenta Peixoto, Ashka Patel, Krishan Taneja, McKenna Moore, Alicia Pollaci, Judy Garber, Nomeda Girnius, Deborah Dillon. Basal-Luminal (BL) Cells in Histologically Normal and Malignant Breast Tissue from BRCA1 and BRCA2 Carriers [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 PO3-08-08.

Indolent triple negative breast cancer

Triple-negative breast cancer (TNBC), while not the most frequent subtype, has a surprisingly aggressive course and low sensitivity to current antitumour drugs. Detection of predictive BRCA-mutation and administration of targeted therapy in the first lines of treatment of metastatic TNRML can significantly affect the life expectancy of patients. The clinical case of patient O. with BRCA-associated bilateral metachronous metastatic breast cancer demonstrates how important it is to implement a personalised approach in time. During the patient’s treatment, it was important to constantly compare the initial morphological profile of the tumour and the clinical course of the disease in order to suspect a discrepancy and to revise the surgical material. The administration of systemic drug therapy, taking into account the genetic and immunohistochemical features of the tumour, made it possible to achieve prolonged recurrence-free periods in two consecutive lines of treatment with preservation of the patient’s decent quality of life.

Abstract 1757: Pan-cancer analysis identifies signatures of HRD-positivity in germline BRCA1/2 mutated non-BRCA associated cancers

Abstract Introduction: BRCA-associated cancers (breast, ovarian, pancreas, and prostate) with germline pathogenic mutations in BRCA1/2 (gBRCA1/2) are associated with homologous recombination deficiency (HRD) and benefit from platinum/PARPi. However, the role of gBRCA1/2 in non-BRCA assoc. cancers is poorly understood. HRD tumors present with ‘genomic scars’ that can be quantified in tumor profiling (“HRD-sum” score). We reasoned that the HRD-sum score together with germline mutation status (including loss of wild-type) is a strong correlate of HRD-positivity. Leveraging 42,448 prospectively sequenced patients across 63 cancer types, we sought to characterize the prevalence of the HRD-positivity in non-BRCA-assoc. cancers. Methods: Allele-specific copy number data was inferred using FACETS. HRD-sum was calculated as a sum of the numbers of telomeric imbalances, large-scale transitions and genome-wide losses of heterozygosity. Calculating each score was iteratively optimized to improve detection of the scars using MSK-IMPACT targeted sequencing data using patient-matched WES data from 1841 tumors as reference. Germline mutations were identified by a clinically validated pipeline and annotated for pathogenicity using ClinVar. After excluding low quality tumors, 27,375 patients were retained for analysis. “HRD-positive” tumors are those with gBRCA1/2 mutations, loss of wild type, and an HRD-sum score >=42. Results: Expectedly, gBRCA1/2 mutations were more frequent in BRCA-assoc. cancers (7.2%, 558 of 7,737 patients) compared to non-BRCA-assoc. cancers (2.6%, 500 of 19,638) (p=5e-60). Among non-BRCA-assoc. cancers, gBRCA1/2 were most common in esophagogastric (3.9%), lung (3%), hepatobiliary (2.9%), and bladder (2.8%) cancers. Although biallelic loss in gBRCA1/2 patients was sig. higher in BRCA-assoc. cancers (80% vs. 37% in non-BRCA-assoc.), several cancer types showed high rates of loss of wild-type including gBRCA1 tumors in hepatobiliary (5/5) and endometrial (10/11) cancers. HRD-sum scores in all gBRCA1/2 biallelic tumors were sig. higher (median 58) compared to monoallelic (26) or wild-type (25) tumors. Notably, the non-BRCA assoc. cancers with biallelic gBRCA1/2 harbored higher HRD-sum scores compared to monoallelic (median 51 vs. 22, p<0.0001). These include cancer types such as endometrial (64 vs. 37, p= 0.0014) and esophagogastric (62 vs. 45, p=0.0017). In all, 68% of gBRCA1/2 patients in BRCA-assoc. cancers showed HRD-positivity. Interestingly, 18% (91/500) of gBRCA1/2 patients in non-BRCA-assoc. cancers also showed HRD-positivity. These included 52% of esophagogastric, 28% of lung, and 22% of bladder cancer patients with gBRCA1/2. Conclusion: Using a robust measure to detect HRD scars from MSK-IMPACT panel data, we demonstrate evidence for BRCA-mediated tumorigenesis in an expanded spectrum of cancers with potential therapeutic relevance. Citation Format: Daniel M. Muldoon, Miika Mehine, Samuel Tischfield, A. Rose Brannon, Marc Ladanyi, Zsofia K. Stadler, David B. Solit, Alexander Drilon, Michael F. Berger, Yonina Murciano-Goroff, Chaitanya Bandlamudi. Pan-cancer analysis identifies signatures of HRD-positivity in germline BRCA1/2 mutated non-BRCA associated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1757.

Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy

Reversion mutations that restore wild-type function of the BRCA gene have been described as a key mechanism of resistance to Poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BRCA-associated cancers. Here, we report a case of a patient with metastatic castration-resistant prostate cancer (mCRPC) with a germline BRCA2 mutation who developed acquired resistance to PARP inhibition. Extensive genomic interrogation of cell-free DNA (cfDNA) and tissue at baseline, post-progression, and postmortem revealed ten unique BRCA2 reversion mutations across ten sites. While several of the reversion mutations were private to a specific site, nine out of ten tumors contained at least one mutation, suggesting a powerful clonal selection for reversion mutations in the presence of therapeutic pressure by PARP inhibition. Variable cfDNA shed was seen across tumor sites, emphasizing a potential shortcoming of cfDNA monitoring for PARPi resistance. This report provides a genomic portrait of the temporal and spatial heterogeneity of prostate cancer under the selective pressure of a PARP inhibition and exposes limitations in the current strategies for detection of reversion mutations.

Abstract B042: A screen to identify modifiers of BRCA1 protein level for cancer prevention and treatment

Abstract The breast cancer susceptibility gene 1 (BRCA1) is a nuclear phosphoprotein involved in DNA double-strand break (DSB) repair and maintenance of genome stability. A single BRCA1 mutation leads to reduced levels of functional BRCA1 protein, such that DSB repair is compromised. It has been proposed that BRCA1 is a haploinsufficient tumor suppressor gene in some contexts, which when lost accelerates the mutation rate of other critical genes thus increasing neoplastic transformation. BRCA1 expression levels are modified through exogenous exposures, and modulating BRCA1 expression may alter tumour onset, progression, and treatment options. We hypothesize that compounds that increase BRCA1 expression and function may prevent the outgrowth of BRCA1-associated breast cancer. By contrast, compounds that reduce BRCA1 protein level could be used as combination therapries in conjunction with poly-ADP ribose polymerase (PARP) inhibitors. To achieve these goals, we generated BRCA1-reporter cell lines. Using CRISPR-assisted genome editing, we endogenously tagged the BRCA1 protein with HiBiT, an 11 amino acid luminescent tag. BRCA1-targeting was verified by sequencing and immunoblotting, and functional validation was performed with known modulators of BRCA1 expression. Our tests confirmed that HiBiT-tagging allows for sensitive measurement of BRCA1 protein levels, therefore permitting screenability. BRCA1-reporter cells were subsequently used to conduct a pilot screen (64 epigenetic-modifying drugs) and a high-content screen (6,000 compounds). We identified several compounds that modified BRCA1 protein expression (B-score >3*SD). The epigenetic drug library yielded five repressors and two activators, and the high-content screen identified 163 repressors and 12 activators. Validation studies have confirmed that the activator drug, aloxistatin can elevate BRCA1-HiBiT levels in a dose-dependent manner. Additionally, aloxistatin treatment increased BRCA1 expression and function in a panel of breast cells. We have also assessed 9 down-regulators of BRCA1 from the pilot and high-content screens. Each of these nine compounds reduced the expression of BRCA1 protein and synergized with the PARP inhibitor olaparib to inhibit cancer cell growth. Collectively, our ongoing studies suggest that BRCA1 activation may reduce cancer phenotypes and BRCA1 repression can sensitize breast cancer cells to PARP-inhibition and other chemotherapies. Overall, using our reporter cell lines we have identified a number of unique compounds that effectively modify BRCA1 expression and function that may have utility in the treatment and prevention of BRCA1-associated cancers. Citation Format: Erin Sellars, Margarita Savguira, Joanne Kotsopoulos, Leonardo Salmena. A screen to identify modifiers of BRCA1 protein level for cancer prevention and treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B042.

Clinical characterization and therapeutic outcomes of patients (pts) with colorectal cancer (CRC) harboring somatic BRCA1/2 mutations.

134 Background: Somatic BRCA1/2 mutations in BRCA-associated cancers increase therapeutic sensitivity to platinum-based chemotherapies and PARP inhibitors, but the implications of BRCA mutations in non- BRCA-associated cancers such as CRC is unknown and hypothesized to be shaped by tumor lineage. We thus conducted a retrospective analysis of outcomes with platinum-based chemotherapy and PARP inhibition in pts with CRC, where the estimated prevalence of BRCA1/2 alterations is 3-4%. Methods: Pts with blood or tissue next generation sequencing (NGS) positive for a somatic BRCA1/2 variant and a diagnosis of CRC were identified from a single institution database. The pathogenicity of each mutation was annotated using public genomic databases (e.g. ClinVar). Pt characteristics were compared using Fisher’s exact test. Log-rank test was used for comparison of survival distribution among groups. Results: 8,258 NGS reports with a BRCA1/2 alteration from 1760 cancer pts were identified of which 189 (11%) had a diagnosis of CRC. 54/189 CRC pts (29%) had ≥1 pathogenic BRCA1/2 variant, 19 pts (10%) had ≥1 benign variant, and 134 pts (69%) had 1 ≥ variant of unknown significance (VUS); 26 pts (14%) had more than one BRCA1/2 variant. Pts with ≥1 pathogenic mutation (n=54) were more likely to have an inactivating DNA polymerase epsilon (POLE) mutation versus pts with only benign/VUS BRCA1/2 variants (n=135) (20% vs 6%, p=0.004) while prevalence of microsatellite instability (MSI-H) (19% vs 13%, p=0.37) and Ras/Raf (53% vs 53%, p=1.00) were similar between groups. Median progression free survival (PFS) among 115 CRC pts (unselected for BRCA1/2 pathogenicity) who received an oxaliplatin-based regimen for advanced disease in the 1st line (n=52) was similar to the median PFS among pts who received an irinotecan-based regimen (n=63) (7.0 mths vs 7.0 mths, p=0.48). Median PFS with an oxaliplatin-based regimen in the 1st line among 52 pts with pathogenic BRCA1/2 variants (n=13) was 5.1 mths vs 7.4 mths among pts with benign/VUS BRCA1/2 variants (n=39) (p=0.398). There were no significant differences in median PFS among pts with a pathogenic vs benign/VUS BRCA1/2 variants when the analysis was restricted to pts with BRCA1/2 variants identified in tissue (p=0.76) and to pts without co-occurring driver mutations (Ras/Raf, MSI-H, and/or POLE) (p=0.1). Overall survival in patients with advanced disease was similar between pts with a pathogenic (n=52) vs benign/VUS (n=122) BRCA variants (37.1 mths vs 45.1 mths, p=0.14). 6 pts (4 with pathogenic BRCA1/2 and 3 with VUS) received a PARP inhibitor after a median of 3 lines of treatment and the best response was disease progression in 6 pts (100%). Conclusions: In the context of CRC, somatic BRCA1/2 mutations frequently co-occur with pathogenic POLE mutations, but do not appear to confer therapeutic benefit to platinum-based chemotherapy and PARP inhibitors.

BRCA-associated ovarian cancer in the russian patient population. Analysis of the non-interventional study Ovatar

Purpose: To evaluate the proportion of BRCA1 / 2 mutations in patients with serous and endometrioid cancer of the ovary, fallopian tube, and peritoneum in Russia, to evaluate the percentage of germinal and somatic mutations, to identify the spectrum of mutations in BRCA1 / 2 genes, to evaluate clinical and morphological features of the BRCA-associated ovarian cancer (OC).Patients and methods: The study enrolled patients of 18 years and older with newly diagnosed serous and endometrioid cancer of the ovary, fallopian tube, and peritoneum. Biological material (blood, tumor tissue) was collected, followed by molecular genetic analysis. The method of mutations detecting in the blood were: allele-specific PCR, high-resolution melting (HRM), Sanger sequencing method. Advanced genetic testing included the use of generation sequencing (NGS) and multiplex amplification of ligated probes (MLPA). The collection of clinical data, family history, clinical and morphological characteristics of the tumor was performed.Results: 500 patients were included in the study, the evaluation of BRCA1 / 2 mutations was performed in 496 patients (99,2 %). The frequency of BRCA1 / 2 mutations in the Russian patient population was 28,4 % (n = 141 / 496). The incidence of germinal mutations was 23,5 % (n = 117 / 141), and somatic — 4,8 % (n = 24 / 141). Frequent mutations in the Russian population were identified in 50 % of cases. When analyzing the ethnicity of patients in the Russian Federation BRCA-associated OC was most common in Russian (83,6 %, n = 118 / 141), Ukrainian (4,2 %, n = 6 / 141) and Tatar (3,5 %, n = 5 / 141) women. A family history of cancer was detected in 44 % of patients (n = 62 / 141) with BRCA1 / 2 mutations.Conclusions: Due to the high frequency of germinal and somatic BRCA1 / 2 mutations in the Russian patients it is recommended to conduct the advanced testing methods not only in blood samples but also in tumor tissue.

Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant

BackgroundReports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype.MethodsWe identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells.ResultsGenome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability.ConclusionsThis is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.

Exploring the Clinical Implications of RPL3 Presence in BRCA-Associated Cancers: Unraveling the Interplay With Cancer Immunity.

Few studies have explored the expression profile of RPL3 in breast cancer (BRCA). Our research provided an in-depth analysis of RPL3 expression patterns in BRCA, highlighting its significance for therapy prediction and prognosis. RPL3 was notably elevated in malignant cells, and its expression level was closely associated with tumor size and overall survival outcomes. Our study also identified RPL3-related terms and pathways and revealed a strong correlation between RPL3 expression and breast carcinoma immunity, demonstrating inconsistent expression levels in various immune cell lines. In addition, we examined the relationship between RPL3 expression and tumor mutational burden (TMB) in BRCA. To assess the clinical implications of BRCA chemotherapy, we investigated the correlation between RPL3 expression levels and drug sensitivity. Our findings suggest that RPL3 plays a critical role in the BRCA process and is associated with immune infiltration, indicating its potential as a novel immunotherapy target in BRCA treatment. In summary, our research underscores the importance of RPL3 expression levels in tumorigenesis and its potential for guiding BRCA immunotherapy.