Breast Cancer Predisposition Genes Research Articles

Population-specific validation and comparison of the performance of 77- and 313-variant polygenic risk scores for breast cancer risk prediction.

The polygenic risk score (PRS) allows the quantification of the polygenic effect of many low-penetrance alleles on the risk of breast cancer (BC). This study aimed to evaluate the performance of two sets comprising 77 or 313 low-penetrance loci (PRS77 and PRS313) in patients with BC in the Czech population. In a retrospective case-control study, variants were genotyped from both the PRS77 and PRS313 sets in 1329 patients with BC and 1324 noncancer controls, all women without germline pathogenic variants in BC predisposition genes. Odds ratios (ORs) were calculated according to the categorical PRS in individual deciles. Weighted Cox regression analysis was used to estimate the hazard ratio (HR) per standard deviation (SD) increase in PRS. The distributions of standardized PRSs in patients and controls were significantly different (p < 2.2×10-16) with both sets. PRS313 outperformed PRS77 in categorical and continuous PRS analyses. For patients in the highest 2.5% of PRS313, the risk reached an ORof3.05 (95% CI,1.66-5.89; p=1.76×10-4). The continuous risk was estimated as an HRper SDof1.64 (95% CI,1.49-1.81; p<2.0×10-16), which resulted in an absolute risk of 21.03% at age 80 years for individuals in the 95th percentile of PRS313. Discordant categorization into PRS deciles was observed in 248 individuals (9.3%). Both PRS77 and PRS313 are able to stratify individuals according to their BC risk in the Czech population. PRS313 shows better discriminatory ability. The results support the potential clinical utility of using PRS313 in individualized BC risk prediction.

Abstract PO1-02-13: Germline mutation status of BRCA1/2 and other breast cancer predisposition genes as predictive and prognostic biomarker: Results of the GeparX study (GeparX-BRCA)

Abstract Germline mutation status of BRCA1/2 and other breast cancer predisposition genes as predictive and prognostic biomarker: Results of the GeparX study (GeparX-BRCA) Background: There is accumulating evidence that the RANK/RANKL signaling pathway plays a pivotal role in breast tumorigenesis, particularly in the development of BRCA1-mutated tumors. Targeting the RANK pathway has been shown to attenuate breast cancer (BC) proliferation in vitro and in vivo. Studies using bone modifying agents as adjuvant therapy showed reduced rates of bone metastases and improved BC survival, as well as prevention of treatment-induced skeletal events. The GeparX clinical trial assessed the use of denosumab in patients with primary BC as an adjunct to neoadjuvant chemotherapy for its ability to enhance pathological complete response (pCR) rate and improve outcome. The trial randomized 780 patients twice to a total of 4 treatment groups (to receive or not receive denosumab; to receive nab-paclitaxel 125 mg/m2 weekly for 12 weeks or days 1 and 8 every 3 weeks for 4 cycles, both followed by 4 cycles of epirubicin/cyclophosphamide, 90/600 mg/m2 every 2 weeks/every 3 weeks according to the investigator´s choice). Carboplatin was given in triple-negative breast cancer (TNBC), and trastuzumab biosimilar ABP980 plus pertuzumab was given in human epidermal growth factor-2-positive (HER2+) BC. Overall, the pCR (ypT0 ypN0) rate was 41% with denosumab vs 43% without; nab-paclitaxel at a dosage of 125 mg/m2 weekly resulted in a significantly higher pCR rate of 45% vs 39% with a dosage of 125 mg/m2 days 1 and 8 every 3 weeks. Research question: Does the germline mutation status of BRCA1/2 and other BC predisposition genes affect treatment outcome in the GeparX study? Methods: Genetic germline analyses assessing pathogenic variants in BRCA1/2 and 16 other BC predisposition genes were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany; 767 patients were included in this secondary investigation (308 TNBC, 306 HER2-/hormone receptor positive [HR+], 153 HER2+). Findings: Germline BRCA1/2 mutations were present in 91/767 patients (11.9%), with a higher mutation prevalence in TNBC (50/308, 16.2%) and HER2-/HR+ BC (37/306, 12.1%), and a low mutation prevalence in HER2+ BC (4/153, 2.6%). Overall, the pCR rate (ypT0 ypN0) was elevated in BRCA1/2 mutation carriers vs non-carriers (49.5% vs 41.1%, respectively; overall: OR 1.40, 95% CI 0.90-2.17; TNBC: OR 1.24, 95% CI 0.67-2.32; HER2-/HR+: OR 1.83, 95% CI 0.86-3.88). Highest pCR rates were observed in TNBC in BRCA1/2 mutation carriers vs non-carriers (60% vs. 54.7%, respectively). Highest pCR rate differences were observed HER2-/HR+ BC in BRCA1/2 mutation carriers vs non-carriers (32.4% vs. 20.8%, respectively). Regarding treatment arms, both BRCA1/2 mutation carriers and non-carriers benefitted most from nab-paclitaxel at a dosage of 125 mg/m2 weekly vs 125 mg/m2 days 1 and 8 every 3 weeks (BRCA1/2 mutation carriers: 55.3% vs 43.2%, respectively; OR 1.63, 95% CI 0.71-3.73; non-carriers: 43.7% vs 38.6%, respectively; OR 1.24, 95% CI 0.91-1.68). No beneficial effect was observed for denosumab vs no denosumab (51.1% vs 47.8% for BRCA1/2 mutation carriers, respectively; OR 1.14, 95% CI 0.50-2.60; 40.3% vs 41.9% for non-carriers, respectively; OR 0.94, 95% CI 0.69-1.27). Of the 617 BRCA1/2-negative patients, 59 patients carried mutations in other BC predisposition genes which did not predict therapy response compared to patients without any mutation. Conclusions: Irrespective of the treatment arm, higher pCR rates were observed in BRCA1/2 mutations carriers vs non-carriers. Both BRCA1/2 mutation carriers and non-carriers benefitted most from weekly nab-paclitaxel. No pronounced effect was observed for denosumab in either group. Key words: GeparX, denosumab, BRCA1/2 germline mutations, therapy response Funding: GeparX was financially supported by Amgen and BMS (Celgene). Citation Format: Rita K. Schmutzler, Theresa Link, Eric Hahnen, Mattea Reinisch, Jan Hauke, Marianne Just, Michael Untch, Corinna Ernst, Oliver Stötzer, Peter A. Fasching, Mohamad Kayali, Pauline Wimberger, Andreas Schneeweiss, Sandra Schmidt, Sabine Seiler, Christian Jackisch, Marc Thill, Kerstin Rhiem, Carsten Denkert, Valentina Nekljudova, Johannes Holtschmidt, Jens-Uwe Blohmer, Sibylle Loibl. Germline mutation status of BRCA1/2 and other breast cancer predisposition genes as predictive and prognostic biomarker: Results of the GeparX study (GeparX-BRCA) [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 PO1-02-13.

Abstract PO2-08-09: Prevalence of germline genetic variants in breast cancer susceptibility genes among patients with metaplastic breast cancer

Abstract Background: Pathogenic or likely pathogenic variants (PV) in breast cancer (BC) susceptibility genes are present in approximately 5-10% of individuals with breast cancer and approximately 13-15% of those with triple-negative breast cancer (TNBC). Identifying patients with PV in BRCA1 and BRCA2 can inform selection of appropriate candidates for poly(ADP-ribose) polymerase inhibitors (PARPi), which have improved progression-free and overall survival in the metastatic and adjuvant settings, respectively. Metaplastic breast cancer (MpBC) is a rare, aggressive subtype of breast cancer that is often triple-negative and refractory to chemotherapy. To date, limited data describe germline genetic findings in patients with MpBC. Methods: We conducted a retrospective chart review including patients with pathology results at the Hospital of the University of Pennsylvania from 2021 through May 2023 demonstrating MpBC. Germline genetic test results and tumor histopathologic characteristics including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status were evaluated. Descriptive statistics as well as two-tailed t tests were used for data analysis. Results: Of 89 patients identified with MpBC, 51 had germline genetic testing results available for review. Nine patients (17.6%) had MpBC with PV in BC predisposition genes (PV-MpBC) and 42 (82.4%) had PV-negative MpBC (PVneg-MpBC). Seven patients (13.7%) had a PV in BRCA1, 1 (2.0%) in BRCA2, and 1 (2.0%) in CHEK2. Median age at diagnosis was 45 years for patients with PV-MpBC and 56.5 years for those with PVneg-MpBC (p=0.005). Among patients with PV-MpBC, 6 (66.7%) had ER and PR negative disease by ASCO-CAP guidelines and 3 (33.3%) had ER and/or PR positive disease. Among patients with PVneg-MpBC, 31 (73.8%) had ER and PR negative disease and 11 (26.2%) had ER and/or PR positive disease. All 9 patients with PV-MpBC had HER2-negative disease, one (11.1%) of whom had HER2-low disease. Among patients with PVneg-MpBC, 40 (95.2%) had HER2-negative disease, two (4.8%) of whom had HER2-low disease, and 2 (4.8%) had HER2-positive BC. Conclusions: The frequency of PV in breast cancer susceptibility genes among patients with MpBC is comparable to, and possibly higher than, the reported rates of such PV in patients with TNBC, for whom genetic testing is recommended. If confirmed in a larger dataset, germline testing should be considered for all patients with MpBC regardless of ER, PR, and HER2 status, as findings may help identify candidates for PARPi therapy and genetically-directed clinical trials. Citation Format: Kaitlin Demarest, Anupma Nayak, Payal Shah. Prevalence of germline genetic variants in breast cancer susceptibility genes among patients with metaplastic 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 PO2-08-09.

Abstract PS10-02: Association between Germline Mutation Status and Overall Survival among Women with Breast Cancer in Population-based Studies in the United States

Abstract Background: The influence of germline pathogenic variants (PVs) in breast cancer predisposition genes on overall survival (OS) after breast cancer diagnosis is not well defined, particularly for PVs in genes other than BRCA1 and BRCA2, and in the context of estrogen-receptor (ER) positive breast cancer. Even for BRCA1/2, OS estimates in women with breast cancer have primarily been derived from high-risk women qualifying for genetic testing due to young age at diagnosis or family history of cancer, and OS estimates by germline PV status from population-based studies are lacking. Methods: The study included 16,797 prospectively followed women with locoregional breast cancer within the population-based CARRIERS study who underwent surgical resection of the primary tumor. OS was compared between germline PV carriers and non-carriers (negative for germline PVs in 12 breast cancer predisposition genes) from the time of breast cancer diagnosis in a multivariable Cox proportional hazard regression analysis adjusting for age and menopausal status at diagnosis, race/ethnicity, ER status, type of surgery, use of adjuvant radiation, chemotherapy and endocrine agents, and prophylactic oophorectomy. Further subset analyses by race/ethnicity ER status of the primary tumor and adjusting for relevant covariates were also performed. Results: Germline PVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2 were detected in 5.6% of the women in the study [ATM: 142 (0.8%), BRCA1: 206 (1.2%), BRCA2: 260 (1.5%), CHEK2:167 (1.0%) and PALB2:116 (0.7%)]. Compared to non-carriers, a significant difference in OS was not observed for germline PV carriers in ATM, BRCA1, BRCA2, or CHEK2 in the overall study population. However, a trend towards worse OS was noted for PALB2 PV carriers compared to non-carriers although this was not statistically significant (Hazard Ratio (HR): 1.36, 95%CI: 0.98 – 1.89, p=0.06). Further subset analysis by race/ethnicity demonstrated that the OS was significantly worse among Black PALB2 PV carriers (HR: 3.11, 95%CI: 1.74 – 5.55, p&amp;lt; 0.001) but not in non-Hispanic White PALB2 PV carriers (HR: 1.00, 95%CI: 0.59 – 1.70, p=0.98) compared to non-carriers within the same race/ethnicity. Among 12,780 women with ER+ breast cancer, compared to non-carriers, OS was significantly worse in BRCA2 PV carriers (HR: 1.51, 95%CI: 1.06 – 2.16, p=0.02) and a trend towards worse OS was observed in BRCA1 PV carriers (HR:1.53, 95%CI:0.93 – 2.51, p=0.09). Among women with ER-negative breast cancer, a significant difference in OS was not observed between PV carriers in each of the five genes and non-carriers. Conclusions: The differences in OS by race/ethnicity in PALB2 PV carriers and by ER status of the tumor in BRCA2 PV carriers warrant further investigation of underlying tumor biology and assessment of endocrine sensitivity of breast cancer in germline PV carriers. Citation Format: Fergus Couch. Association between Germline Mutation Status and Overall Survival among Women with Breast Cancer in Population-based Studies in the United States [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 PS10-02.

Abstract PO1-20-07: Valosin-containing protein (VCP)/p97: A novel breast cancer susceptibility gene?

Abstract Introduction: Mutations in the valosin-containing protein (VCP, also known as p97) gene are associated with autosomal dominant inclusion-body myopathy with early-onset Paget disease and frontotemporal dementia. VCP is an ATPase that subserves a variety of cellular functions, prominently, organelle biogenesis and ubiquitin-dependent protein degradation. Recently, VCP has also been shown to physically interact with BRCA1 and is postulated to orchestrate the response to DNA double-strand breaks, a critical molecular prelude to homologous recombination DNA repair. Moreover, VCP is also involved in the removal of trapped poly [ADP-ribose] polymerase 1 (PARP1) from chromatin and may play a key role in the response of tumor cells to PARP inhibitors. Whether VCP acts as a breast cancer predisposition gene is currently unknown. These observations raise speculation as to whether pathologic variation in VCP may predispose to breast cancer. Case Description: A 45-year-old female presented with early-age, locally advanced invasive ductal carcinoma, grade 2, ER &amp;lt; 1%, PR 10%, HER2 IHC 3+, FISH ratio 5.4. The patient completed 6 cycles of neoadjuvant PTH and was surgically downstaged to ypT1bN1a at the time of her left mastectomy. She declined adjuvant radiation. She received 1 dose of trastuzumab emtansine which was discontinued due to intolerance and transitioned to complete 1 year of adjuvant trastuzumab and pertuzumab. Her medical history is significant for inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia, which was diagnosed at age 36 after presenting with proximal muscle weakness. Bone scan was consistent with Paget’s disease and neurocognitive testing did not identify any abnormalities. Diagnosis was confirmed via whole genome germline sequencing which identified a pathogenic variant in VCP [c.463C &amp;gt;G (p.Arg155Gly)]. Germline resequencing of 155 known cancer predisposition genes did not identify any pathogenic variants. Whole exome genomic analysis of the patient’s breast cancer revealed an elevated homologous recombination score ( &amp;gt; 42), consistent with molecularly important role of VCP in homologous recombination breast cancer DNA repair. The patient’s family history is significant for muscular dystrophy in multiple family members on her paternal side, each of whom was deceased prior to age 60. Her paternal half-sister has both inclusion body myopathy and breast cancer, and her paternal cousin was diagnosed with breast cancer at age 46 (unknown genetic testing for each). No history of cancer on her maternal side. Discussion: This case raises the intriguing question of whether the VCP gene represents a heretofore unrecognized breast cancer predisposition gene. Further investigation into the role of VCP in tumorigenesis is warranted, and additional population studies are necessary to confirm VCP’s role in breast cancer predisposition. Given that cancers with homologous recombination deficiencies benefit from PARP inhibitors and VCP is involved in the function of the PARP1 protein, patients with mutations in the VCP gene may benefit from PARP inhibition. Citation Format: Alexis LeVee, Duveen Sturgeon, Joanne Mortimer, Kevin McDonnell. Valosin-containing protein (VCP)/p97: A novel breast cancer susceptibility gene? [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 PO1-20-07.

Abstract PO5-22-10: Are contralateral prophylactic mastectomy rates impacted by ASBrS guidelines to offer germline genetic testing to all patients with breast cancer? Results from a large, prospective, single-institution cohort

Abstract Background: It is unclear whether the release of the American Society of Breast Surgeons’ (ASBrS) guideline to offer germline genetic testing to all patients with breast cancer impacted contralateral prophylactic mastectomy (CPM) rates. The objective of this study was to describe trends of germline testing and CPM rates, and to determine predictors of CPM uptake. Methods: This is a retrospective review of two prospectively maintained single institutional databases: Dana-Farber/Brigham Cancer Center’s surgical database, merged with Dana-Farber Cancer Institute’s Genetics and Prevention database. Trends in germline testing and CPM rates were described, in relation to the February 2019 ASBrS guideline release, and a multivariable logistic regression model was used to determine factors associated with CPM utilization. Patients with unilateral stage 0-III breast cancer who underwent surgery between January 2016 and July 2020 were included. Patients were considered “tested” if they underwent germline genetic testing and results were disclosed before their index operation. CPM was defined as contralateral mastectomy performed at index operation or anytime thereafter, excluding mastectomy for a new contralateral breast cancer event. Results: Among 6,064 women in the cohort, 2,455 (40.5%) had germline genetic testing before their index surgery. Rates of testing significantly increased over the study period from 33.7% in 2016 to 64.9% in 2020 (p&amp;lt; 0.001). A total of 783/6,064 (12.9%) patients underwent CPM which was 40.7% (783/1,926) of the patients who underwent mastectomy. The CPM rate was 13.3% before the guideline release (2016 – January 2019) and 12.5% after (February 2019 – 2020). There was no significant change in CPM rate over time (p=0.527), including before (p=0.380) and after (p=0.220) the 2019 guideline release. The following factors were associated with increased CPM rates on multivariable logistic regression: identification of a pathogenic/likely pathogenic variant in a breast cancer predisposition gene (Adjusted Odds Ratio [Adj. OR] 24.43), genetic testing with a negative test result (Adj. OR 1.52), number of relatives with breast/ovarian cancer (Adj. OR 1.18 and 1.39, respectively for each additional relative), younger age (Adj. OR 0.97 if pre-menopausal, 0.91 if post-menopausal, for each year decrement), and cT2-3 tumors (Adj. OR 1.53 and 1.94, respectively as compared to other cT stages); all p&amp;lt; 0.05. Conclusions: Despite increasing germline genetic testing rates, CPM rates were stable over time, indicating that offering genetic testing to more patients does not increase CPM rates in our experience. Selection bias is most certainly contributing to the apparent association between CPM and genetic testing, even if there is a negative test result, as the classic indications for genetic testing are similar to those for CPM. Citation Format: Anna Weiss, Stephen Knapp, Danielle Braun, Brenna Barton, Monica McGrath, Samantha Stokes, Alison Laws, Laura Warren, Stefania Morganti, Filipa Lynce, Brittany Bychkovsky, Huma Rana, Dillon Davis, Jill Stopfer, Judy Garber, Tari King. Are contralateral prophylactic mastectomy rates impacted by ASBrS guidelines to offer germline genetic testing to all patients with breast cancer? Results from a large, prospective, single-institution cohort [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 PO5-22-10.

Abstract PO1-08-10: Impact of Oncologist-Led Genetic Counseling and Testing on Prophylactic Mastectomy Rates Among Multi-Ethnic Women with Operable Breast Cancer

Abstract Introduction: Approximately 5-10% of breast cancers are attributed to an inherited pathogenic variant (PV) in breast cancer predisposition genes, such as BRCA1 and BRCA2. Identifying women with hereditary breast cancer syndromes is critical to inform risk-appropriate screening and prevention strategies. For example, contralateral prophylactic mastectomy (CPM) has been shown to reduce the risk of new breast primaries without a demonstrated survival benefit. In a prior study, we found that women with pathogenic/likely pathogenic (P/LP) variants were over four times more likely to undergo CPM compared to those with benign/likely benign (B/LB) variants. In recent years due to expanded indications for genetic testing and social distancing during the COVID-19 pandemic, oncologist-led genetic testing and telehealth genetic counseling has gradually replaced in-person genetic counseling visits. We aimed to understand how changes in the delivery of genetic counseling and testing services impacted CPM rates among multi-ethnic women with operable breast cancer in the post COVID-19 period. Methods: We conducted a retrospective cohort study among 1,080 women diagnosed with unilateral breast cancer who underwent germline genetic testing between 2013 and 2022 at Columbia University Irving Medical Center (CUIMC) in New York, NY. The pre COVID-19 period was defined as 2013-2019 and the post COVID-19 period as 2020-2022. Demographics, including age, race/ethnicity and marital status, and clinical characteristics, such as year of diagnosis, breast cancer stage, tumor hormone receptor status, family history of breast cancer, and genetic test results, were extracted from the electronic health record (EHR). We used univariable and multivariable logistic regression analyses to estimate the odds ratio (OR) and 95% confidence interval (95% CI) associated with each variable and receipt of CPM. Results: Among 1080 evaluable women, mean age at diagnosis was 51.2 years old (SD, 12.3) with 39.6% non-Hispanic White, 27.8% Hispanic, 11.4% non-Hispanic Black, 9.0% Asian, and 12.2% multi-racial/other. Within the overall study population, 12.1% of women had P/LP variants and 21.4% had variants of unknown significance (VUS) results. Non-Hispanic Whites and Blacks had the highest frequency of P/LP variants, whereas VUS results were more common among Hispanics and Asians (see Table). Twenty-three percent of women in the study population underwent CPM. In multivariable analysis, younger age at diagnosis, more advanced stage breast cancer, family history of breast cancer, Hispanic race and P/LP results on germline genetic testing were associated with increased CPM rates. Hispanic women were over 60% more likely to undergo CPM compared to non-Hispanic White women (adjusted OR=1.63, 95% CI=1.07-2.47). No significant change in CPM rates was observed in the post-COVID era compared to the pre-COVID era. Conclusion: We aimed to understand how the transition to telehealth and oncologist-led genetic testing affected CPM rates. Although we did not observe a change in CPM rates in the post-COVID era, Hispanic women had significantly more VUS results and were over 60% more likely to undergo CPM compared to non-Hispanic White women. In future studies, we hope to improve risk communication of genetic test results and the risks and benefits of CPM, particularly in vulnerable and underserved populations. Table 1 Genetic testing results and rates of contralateral prophylactic mastectomy stratified by race/ethnicity in women diagnosed with operable breast cancer and undergoing germline genetic testing from 2013-2022 at Columbia University Irving Medical Center, New York, NY Citation Format: Alissa Michel, Kelly Luo, Vicky Ro, Matthew Fine, Meghna Trivedi, Wendy Chung, Roshni Rao, Tarsha Jones, Elana Levinson, Carrie Koval-Burt, Donna Russo, Ilana Chilton, Rita Kukafka, Katherine Crew. Impact of Oncologist-Led Genetic Counseling and Testing on Prophylactic Mastectomy Rates Among Multi-Ethnic Women with Operable 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 PO1-08-10.

Increased prevalence of germline pathogenic CHEK2 variants in individuals with pituitary adenomas.

CHEK2 is a cell cycle checkpoint regulator gene with a long-established role as a clinically relevant, moderate risk breast cancer predisposition gene, with greater risk ascribed to truncating variants than missense variants. We assessed 165 individuals with pituitary adenomas for CHEK2 variants. The study consisted of a primary cohort of 29 individuals who underwent germline and tumour whole exome sequencing, and a second, independent cohort of 136 individuals who had a targeted next-generation sequencing panel performed on both germline and tumour DNA (n=52) or germline DNA alone (n=84). We identified rare, coding, non-synonymous germline CHEK2 variants amongst 3/29 (10.3%) patients in our primary cohort and 5/165 (3.0%) patients overall, with affected patients having a range of hormone secretion types (prolactinoma, thyrotrophinoma, somatotrophinoma and non-functioning pituitary adenoma). No somatic variants were identified. Two variants were definitive null variants (c.1100delC, c.444+1G>A), classified as pathogenic. Two variants were missense variants (p.Asn186His, p.Thr476Met), classified as likely pathogenic. Even when considering the null variants only, the rate of CHEK2 variants was higher in our cohort compared to national control data (1.8% vs. 0.5%, P=0.049). This is the first study to suggest a role for the breast cancer predisposition gene, CHEK2, in pituitary tumorigenesis, with pathogenic/likely pathogenic variants found in 3% of patients with pituitary adenomas. As pituitary adenomas are relatively common and typically lack classical autosomal dominant family histories, risk alleles - such as these variants found in CHEK2 - might be a significant contributor to pituitary adenoma risk in the general population.

Abstract 5608: The BRCA1-associated role of CDK9 in response to DNA damage is independent of its canonical role in transcription

Abstract The understanding of the biological role of BRCA1 in maintaining genomic integrity through homologous recombination (HR) repair has driven the development of targeted treatments with PARP inhibitors (PARPi) in BRCA1-linked tumors with promising results. Recently, cyclin-dependent kinase 9 (CDK9) inhibitors have emerged as therapeutic options to treat cancer. We have previously implicated CDK9 in genome integrity maintenance through HR repair by modulating BRCA1 recruitment to double-stranded break sites. CDK9 is a component of the positive transcription elongation (PTEF-b) complex and more recently was proposed by the hereditary breast case-control (BEACCON) study as a putative breast cancer (BC) predisposition gene in non-BRCA families. Differently from BRCA1-linked BCs, loss-of-function mutations in CDK9 were significantly correlated with ER-positive and Lobular BCs. CDK9 expression is also elevated in metastatic and recurrent ovarian cancer (OC) tissue and correlates with poor prognosis in OC patients. Here we characterize the BRCA1/BARD1/CDK9 complex using protein-protein interaction assays. Our data indicate that the CDK9/BARD1 interaction occurs indirectly through BRCA1. We also generated a separation-of-function mutation in CDK9 (mutCDK9) that disrupts its interaction with BRCA1 but retains its kinase activity and preserves its role in transcription. We rescued the mutCDK9/BRCA1 interaction using a complementary mutation in BRCA1 (cmutBRCA1), that retains BRCA1 role in cell viability. Further, we employed CRISPR-based genome editing to generate genetically defined haploid HAP1 cell lines that express mutCDK9 in various TP53BP1 and BRCA1 backgrounds. The mutCDK9 cells preserve global RNA transcription and the phosphorylation status of the RNA polymerase II. We observed that mutCDK9 cells are more sensitive to the PARPi, rucaparib when compared to wild-type cells in proficient and deficient TP53BP1 backgrounds. However, mutCDK9 expression did not affect the sensitivity of HAP1 cells expressing cmutBRCA1. Collectively, our data suggest that CDK9 acts in genome integrity maintenance by HR through its interaction with BRCA1 independently of its canonical role in transcription. Citation Format: Thales C. Nepomuceno, Marcelo A. Carvalho, Alvaro N. Monteiro. The BRCA1-associated role of CDK9 in response to DNA damage is independent of its canonical role in transcription [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 5608.

Upgrade Rates and Breast Cancer Development Among Germline Pathogenic Variant Carriers with High-Risk Breast Lesions.

High-risk lesions (HRL) of the breast are risk factors for future breast cancer development and may be associated with a concurrent underlying malignancy when identified on needle biopsy; however, there are few data evaluating HRLs in carriers of germline pathogenic variants (PVs) in breast cancer predisposition genes. We identified patients from two institutions with germline PVs in high- and moderate-penetrance breast cancer predisposition genes and an HRL in an intact breast, including atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), and lobular neoplasia (LN). We calculated upgrade rates at surgical excision and used Kaplan-Meier methods to characterize 3-year breast cancer risk in patients without upgrade. Of 117 lesions in 105 patients, 65 (55.6%) were ADH, 48 (41.0%) were LN, and 4 (3.4%) were FEA. Most PVs (83.8%) were in the BRCA1/2, CHEK2 and ATM genes. ADH and FEA were excised in most cases (87.1%), with upgrade rates of 11.8% (95% confidence interval [CI] 5.5-23.4%) and 0%, respectively. LN was selectively excised (53.8%); upgrade rate in the excision group was 4.8% (95% CI 0.8-22.7%), and with 20 months of median follow-up, no same-site cancers developed in the observation group. Among those not upgraded, the 3-year risk of breast cancer development was 13.1% (95% CI 6.3-26.3%), mostly estrogen receptor-positive (ER +) disease (89.5%). Upgrade rates for HRLs in patients with PVs in breast cancer predisposition genes appear similar to non-carriers. HRLs may be associated with increased short-term ER+ breast cancer risk in PV carriers, warranting strong consideration of surgical or chemoprevention therapies in this population.

Tumor Characteristics of Bilateral Breast Cancer Compared with Unilateral Breast Cancer.

Bilateral breast cancer (BC) has an incidence of 1 to 3 %. This study aimed to describe the clinicopathologic characteristics and management of bilateral BC, estimate disease-free survival (DFS), and compare DFS with unilateral BC. A retrospective analysis was performed for patients who hadbilateral invasive BC or unilateral invasive BC and contralateral ductal carcinoma in situ (DCIS) treated at Mayo Clinic Rochester from 2008 to 2022. A 4:1 matched cohort of patients with unilateral invasive BC was used for comparison. The groups were compared using Wilcoxon rank-sum or chi-square tests. Disease-free survival was analyzed using the Kaplan-Meier method and log-rank test, with Cox proportional hazards regression used for multivariable analysis. The study identified 278 cases of bilateral breast cancer (177 cases of bilateral invasive cancer and 101 cases of unilateral invasive cancer with contralateral DCIS), representing 4.1 % of invasive BCs. Biologic subtype was concordant between sides in 79.8 % of the patients. Initial surgery was bilateral mastectomy for 76.6 %, bilateral lumpectomy for 20.5 %, and unilateral mastectomy with unilateral lumpectomy for 2.9 % of the patients. Pathogenic variants in breast cancer predisposition genes were present in 21.7 % of those tested. The patients who had bilateral BC presented with a higher cT category than the patients who had unilateral BC (p = 0.02), and a higher proportion presented with ILC (17.3 % vs 10.9 %; p = 0.004), estrogen receptor-positive (ER+) disease (89.2 % vs 84.2 %; p = 0.04), multicentric/multifocal disease (37.1 % vs 24.3 %; p < 0.001), breast cancer pathogenic variant (21.7 % vs 12.4 %; p = 0.02), and palpable presentation (48.2 % vs 40.8 %; p = 0.03). The patients with bilateral BC showed DFS similar to that for the unilateral BC cohort (p = 0.71). Bilateral BCs most commonly are biologically concordant between sides. Bilateral BC presented more commonly with larger tumors, lobular histology, ER+ status, multicentricity or multifocality, pathogenic variant, and palpable disease. Bilateral BC is not associated with worse DFS than unilateral BC.

Frequency of germline pathogenic variants in breast cancer predisposition genes among young Turkish breast cancer patients.

One of the most important risk factors for hereditary breast and ovarian cancer is young age. We aim to report the frequency of pathogenic/likely pathogenic variants in breast cancer predisposing genes in young (≤ 40years old) breast cancer patients who undergone 26-gene inherited cancer panel at our Breast Health Center. Medical records of breast cancer patients who were referred to genetic counseling based on NCCN criteria and were ≤ 40years of age are reviewed. The frequency of germline pathogenic/likely pathogenic variants who undergone 26-gene inherited cancer panel was analyzed. Among 414 breast cancer patients who were ≤ 40years of age, 308 undergone 26-gene inherited cancer panel and 108 had next generation sequencing (NGS)-based BRCA 1 and 2 genetic testing. Median age was 35 (22-40), Family history in first degree relatives was present in 14% of patients. Forty-five percent of patients met one of the NCCN criteria for genetic testing, 41% of them met two criteria, and 14% of patients fulfilled ≥ 3 criteria. Seventy pathogenic/likely pathogenic variants (PV/LPV) were found in 65 (21%) patients. PV/LPs in BRCA genes and non-BRCA genes represented 53% and 44% of all PV/LPVs, accounting for 12% and 10% of patients in the study cohort respectively. Two PVs were present in 5 patients and eleven PVs were novel. The most common PVs were in BRCA 1 (n:18), BRCA 2 (n:19), ATM (n:7), CHEK2 (n:7) and TP53 (n:5) genes. Thirty-one percent of the patients with triple-negative tumors and 25% of the patients with hormone receptor-positive tumors had PV/LPVs with panel testing. Family history in first degree relatives (p = 0.029), the number of met NCCN criteria (p = 0.036) and axillary nodal involvement (p = 0.000) were more common in patients with PVs. When combined with patient group (n:106) who had only BRCA1 and 2 gene testing, 16% of Turkish breast cancer patients ≤ 40years of age had PVs in BRCA genes. One fifth of Turkish breast cancer patients ≤ 40years of age had at least one PV/LPV in breast cancer predisposing genes with 26-gene inherited cancer panel. The frequency of PV/LPVs was higher in triple-negative young-onset patients compared to hormone receptor and Her-2 positive subtypes. Our findings regarding to frequency PV/LPVs in BRCA 1/2 and non-BRCA genes in young-onset breast cancer patients are in line with the literature.

Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer

BackgroundGenetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting.MethodsWomen with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records.ResultsIn 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding.ConclusionsThis study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.

Breast cancer risk stratification using genetic and non-genetic risk assessment tools for 246,142 women in the UK Biobank

PurposeThe benefit of using individual risk prediction tools to identify high-risk individuals for breast cancer (BC) screening is uncertain, despite the personalized approach of risk-based screening. MethodsWe studied the overlap of predicted high-risk individuals among 246,142 women enrolled in the UK Biobank. Risk predictors assessed include the Gail model (Gail), BC family history (FH, binary), BC polygenic risk score (PRS), and presence of loss-of-function (LoF) variants in BC predisposition genes. Youden J-index was used to select optimal thresholds for defining high-risk. ResultsIn total, 147,399 were considered at high risk for developing BC within the next 2 years by at least 1 of the 4 risk prediction tools examined (Gail2-year > 0.5%: 47%, PRS2-yea r > 0.7%: 30%, FH: 6%, and LoF: 1%); 92,851 (38%) were flagged by only 1 risk predictor. The overlap between individuals flagged as high-risk because of genetic (PRS) and Gail model risk factors was 30%. The best-performing combinatorial model comprises a union of high-risk women identified by PRS, FH, and, LoF (AUC2-year [95% CI]: 62.2 [60.8 to 63.6]). Assigning individual weights to each risk prediction tool increased discriminatory ability. ConclusionRisk-based BC screening may require a multipronged approach that includes PRS, predisposition genes, FH, and other recognized risk factors.

Women with pathogenic variants in moderate penetrance breast cancer genes: How frequently do they meet high penetrance genetic testing criteria?

10584 Background: 5-10% of breast cancers are associated with germline pathogenic variants in breast cancer predisposition genes. 2-5% of these variants are in moderate penetrance (MP) genes, conferring a relative risk to develop breast cancer of 2-5. Various personal history (PH) and family history (FH)-based criteria for testing high penetrance genes, such as BRCA1 and BRCA2, have been proposed, but it is unknown to what extent women with pathogenic variants in MP genes may meet such criteria. We evaluated PH and FH of cancer among women with pathogenic variants in MP genes in a diverse and unselected patient cohort in New York City to determine how often they met well-established genetic testing criteria from the National Comprehensive Cancer Network (NCCN). Methods: Exome sequence data from ~16,000 female Bio Me Biobank participants were evaluated for expected pathogenic (per ClinVar, or predicted loss-of-function) variants in ATM, BARD1, BRIP1, CHEK2, NF1, PALB2, RAD51C, and RAD51D. We extracted demographic information, PH and FH of breast, ovarian, and/or pancreatic cancer, and PH and FH of genetic testing from participant questionnaires and electronic medical record review. We then determined which participants met current NCCN criteria (version 1.2023) for high penetrance breast, ovarian, and pancreatic cancer genetic testing. Results: We identified 252 women with expected pathogenic variants in MP genes: 105 CHEK2, 58 ATM, 35 BRIP1, 24 PALB2, 9 BARD1, 8 NF1, 8 RAD51D, and 5 RAD51C. 30% met NCCN criteria, including 30% of those with CHEK2 variants, 36% ATM, 14% BRIP1, 33% PALB2, and 30% with variants in BARD1, NF1, RAD51D, or RAD51C. 36% of those who met NCCN criteria had previously undergone clinical genetic testing. 29 of 33 (88%) women with a PH of breast cancer and 52 of 81 (64%) women with a FH of breast cancer met criteria. Conclusions: Current genetic testing criteria focus on identifying individuals harboring pathogenic variants in high penetrance cancer genes. However, in our study, a substantial portion of women with a pathogenic variant in a MP breast cancer gene also met such criteria, particularly when PH or FH of breast cancer were present. Only a third of those who met NCCN criteria had undergone clinical genetic testing. These findings suggest that the majority of women with genetic risk for breast cancer may be missed in clinical practice. Studies have shown that most physicians would change management strategies for patients with pathogenic variants, including variants in MP genes. As our understanding of genetic risk for breast cancer continues to evolve, we must explore strategies to improve identification and management of individuals with variants in MP breast cancer genes.

Genetic evaluations and testing rates for hereditary breast and ovarian cancer syndrome in a community oncology setting.

e22533 Background: Several professional medical societies recommend genetic evaluations and testing for individuals with a personal and/or family cancer history. The National Comprehensive Cancer Network (NCCN) outlines germline testing criteria for breast, ovarian, and pancreatic cancer predisposition genes. This study aims to assess the genetic evaluation and testing rates in community oncology centers among patients who qualify based on their personal history of cancer. Methods: A retrospective study assessed patients diagnosed at any Texas Oncology site between 1/01/2017 and 12/31/2019. Using NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic V1.2020, individuals with the following cancer diagnoses were included: epithelial ovarian, breast &lt; 45 years, triple negative breast &lt; 60 years, metastatic HER2 negative breast, male breast, exocrine pancreatic, or metastatic prostate. Data was obtained from electronic medical records. The project was approved by the Texas Oncology Privacy Board. Results: Of the 10,202 patients included, 6033 (59%) underwent genetic testing. Only 3660 (36%) had a genetic evaluation, and of those, 2720 (74%) were conducted within Texas Oncology. Younger patients were significantly more likely to be tested than those diagnosed at older ages (p = 2.2e-16). Testing rates were significantly higher (p = 8.95e-07) at sites that employ a provider with genetics training; moreover, the rates of evaluation and testing trended upward, the longer those providers had been offering genetics services. Of the patients without test results, most (76%) had neither a genetics referral nor germline test order documented, suggesting an opportunity for provider education. Conclusions: Most patients who met criteria underwent genetic testing, but the rates varied by cancer type. Patients with breast cancer were most likely to have genetic testing. This study proved that having a genetics provider on staff significantly improved testing rates for patients who qualify. However, given that 100% of the cohort qualified and only 59% underwent testing, quality improvement measures are needed to increase the rate of genetic evaluations and testing for these diagnoses. [Table: see text]

PALB2 germline mutations in a large cohort of Middle Eastern breast-ovarian cancer patients

The PALB2 gene is a breast cancer (BC) and ovarian cancer (OC) predisposition gene involved in the homologous recombination repair pathway. However, the prevalence and clinicopathological association of PALB2 pathogenic/likely pathogenic (PV/LPV) variants in Middle East is still not fully explored. Total 918 BC/OC patients from Saudi Arabia were selected for PALB2 mutations screening using capture sequencing technology. Five heterozygous PVs or LPVs were identified in six cases, accounting for 0.65% (6/918) of entire cohort. Two cases (33.3%) harbored PVs and four cases (66.7%) carried LPVs. Four PVs/LPVs (80%) were frameshift along with one novel splicing LPV (c.2835-2_2835-1delinsTT). One recurrent LPV (c.3425delT: p.L1142fs) was identified in two cases. All six affected carriers have breast cancer diagnosis with median age of 39.5 years (range 34–49 years). Only two cases (33%) have documented family history of cancer. Breast cancer phenotype was invasive ductal unilateral cancer in all cases with 66.7% of hormone receptor positive and 16% of triple negative tumors. Germline PVs/LPVs in the PALB2 gene were observed in low frequency of 0.65% in Saudi BC and/or OC. Our study confirms one recurrent LPV and one novel LPV in Saudi breast cancer patients.

Germline multigene panel testing of patients with endometrial cancer.

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10-17] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE/POLD1; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria.

Abstract P5-03-07: Prevalence of Pathogenic Variants in Cancer Predisposition Genes in Women with Young Onset Breast Cancer

Abstract Introduction: Approximately 5% of breast cancers are diagnosed in women 40 years of age or younger. Known risk factors for young-onset breast cancer are few and can only account for a very small proportion of cases. In this study, we evaluated the contribution of mutations in 24 breast cancer predisposition genes in unselected Canadian women diagnosed with breast cancer at age 40 or younger. Methods: This study is a sub-study of the larger Reducing the bUrden of Breast cancer in Young women (RUBY) Study. In the RUBY study, women diagnosed with breast cancer at the age of 40 years or younger are recruited at the time of diagnosis from 33 centres across Canada. Participants in RUBY provided detailed demographic and clinical data, in addition to provision of serial biospecimens. Participants could elect to consent into the genetics substudy, and have genetic testing performed for pathogenic variants in 24 breast cancer predisposition genes, including ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL, STK11, TP53 and XRCC2. Sequencing was performed and all potentially pathogenic variants were confirmed with conventional Sanger sequencing. Pathogenic and likely pathogenic mutations were reported for all 24 genes. CanRisk scores for likelihood of having a pathogenic variant in 8 cancer predisposition genes (BRCA1 BRCA2, PALB2, CHEK2, ATM, RAD51C, RAD51D, and BRIP1) were generated for each participant. Results: 714 women consented and genetic testing was performed on the blood samples provided as a component of the RUBY study. The mean age of the participants was 35.8 years (range 23-40 years), and the mean CanRisk score was 13.7 (range 2.3-98.0). Overall, 150 pathogenic mutations (21.0%) were detected in 147 women (three participants had mutations in two genes). The most common pathogenic variants detected were in BRCA1 (48), BRCA2 (40), CHEK2 (24), ATM (10), and PALB2 (9), representing 87.3% of all pathogenic variants identified. The mean CanRisk score was 28.8% (range 3.2-98.0%) for those identified with a pathogenic variant compared to 9.6% (range 1.0-88.9%) for those with a negative result (p &amp;lt; 0.0001). The prevalence of pathogenic variants was 32.9% for women age 20-30 years, 27.5% for 31-35 years, and 16.7% for 36-40 years. Conclusions: Twenty-one percent of women with breast cancer at age 40 or younger had a pathogenic variant in a breast-cancer predisposition gene. The great majority of these pathogenic variants were found in genes (BRCA1, BRCA2, CHEK2, PALB2) for which there are validated breast cancer treatment recommendations. All women with young-onset breast cancer should be offered germline genetic testing at the time of breast cancer diagnosis to make informed surgical and medical treatment decisions. Citation Format: Kelly Metcalfe, May Lynn Quan, Steven Narod, Ellen Warner, Christine Friedenreich, Nancy Baxter, Aletta J. Poll, Mohammad Akbari. Prevalence of Pathogenic Variants in Cancer Predisposition Genes in Women with Young Onset Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-07.

Radiation-Induced Lymphopoenia and Treatment Outcome in Hereditary Breast Cancer Patients.

Many breast cancer (BC) predisposition genes encode proteins involved in DNA damage repair (DDR). Identification of germline pathogenic va-riants (PV) in DDR genes raises the question whether their presence can influence the treatment outcomes and potential radiation-induced toxicity in their carriers treated by adjuvant radiotherapy, which has not yet been answered conclusively. We retrospectively examined records of 213 BC patients treated by adjuvant radiotherapy, including 39 (18.3 %) BRCA1/2 PV carriers, 25 carriers (11.7 %) of PV in other breast cancer-predisposing genes, and 149 (70 %) non-carriers. Our goal was to examine 5-year disease-free survival (5y DFS) rates among the study groups and determine the impact of radiotherapy-induced lymphopoenia (RIL) on this outcome. While we found no significant difference in 5y DFS between non-carriers and carriers of BRCA mutations (86.4 % vs 78.4 % P = 0.24) or between non-carriers and other studied mutations (86.4 % vs 93.3 %; P = 0.27), respectively, we observed that the entire group of PV carriers had a significantly lower proportion of patients without RIL (P = 0.04) than the non-carriers. In contrast, subsequent analyses indicated a non-significant trend toward an increased 5y DFS in PV carriers with RIL. Our single-centre study indicated that the presence of PV in BC patients has an insignificant impact on DFS but can reduce the risk of RIL associated with adjuvant radiotherapy. It remains unclear whether this may result from the paradoxical activation of anti-tumour immunity in PV carriers with higher lymphocyte consumption resulting from higher immune effectiveness.