Hereditary Breast Cancer Patients Research Articles

Abstract 3947: Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population

Abstract Background: Hereditary cancer syndromes explain 5-10% of all cancer cases. Germline pathogenic variants in BRCA1 and BRCA2 genes (BRCA) are present in 2-3% of all breast cancer (BC), and 15% of all ovarian cancer (OC) cases. BRCA1 and BRCA2 pathogenic variants (PV) represent 25-28% of BC and 40% of OC patients with a positive familial history. BRCAs are the most studied genes for the prevalence, family history, preventive surgeries, and target treatment options in both BC and OC. There are other genes, important in the diagnosis, pathogenesis, and treatment options of the patients: TP53, PALB2, CHEK2, among others. This study aims to identify the prevalence of non- BRCA genes related to the development of hereditary breast and ovarian cancer syndrome in patients of Northeast Mexico. Methods: This is a multicenter study that recruited patients from two reference oncology centers in Nuevo Leon, Mexico: the CECIL (The CUCC Early Cancer Detection Clinic) Hereditary Cancer Registry and Hereditary Cancer Program from Tec Salud. From March of 2016 to March of 2023, a total of 872 patients meeting NCCN criteria were evaluated by Medical Geneticists from both centers and were tested with NGS multigene cancer panels. Results: A total of 665 (76.26%) patients with a clinical diagnosis of HBOC (Hereditary Breast Hereditary Cancer Syndrome) were included. We found 310 (46.6%) patients had at least one variant, 180 (58%) with at least one pathogenic variant, and 130 (41%) with a VUS (a variant of uncertain significance). BRCA1 was found in 79 (43.8%) and BRCA2 in 32 (17.7%) of all PV. Non-BRCA PV were found in 69 (38.3%) patients: 4 ATM, 2 BLM, 3 BRIP1, 22 CHEK2, 4 CDKN2A, 5 MUTYH, 10 PALB2, 4 RAD51C, 2 SDHA, 2 TP53, 2 WRN, CDH1, CDK4, DICER, MSH3, NBN, PTEN, RAD50, USH2A one of each. Is remarkable that 19 of the 22 patients with CHEK2 and 5 of the 10 patients with PALB2 had the recurrent PV c.707T>C and c.2167_2168del, respectively. Conclusions: Non-BRCA PV in Northern Mexico corresponds to one-third of the BC and OC cases, including HRD (homologous recombination deficiency) genes. HDR patient carriers are potential targets of iPARP therapies. This project reinforces the fact that multigene panels should be employed to ensure a complete diagnosis in hereditary cancer patients. Citation Format: Carlos H. Burciaga-Flores, Diana C. Perez-Ibave, Maria L. Garza-Rodriguez, Oscar Vidal-Gutierrez, Cynthia M. Villarreal-Garza, Dione Aguilar y Mendez. Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population [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 3947.

The knowledge of hereditary breast cancer, and attitude and intention towards genetic testing of the patients with high-risk hereditary breast cancer

Purpose: This study aimed to explore the knowledge of hereditary breast cancer (HBC) and attitudes and intention towards genetic testing of the patients with high-risk HBC, and to describe their differences according to the intention of genetic test. Methods: High-risk HBC patients (n = 138) who did not take genetic test or relevant counseling were recruited in D city, Korea. Participants completed questionnaires including demographic characteristics, knowledge of HBC, and attitudes and intention of genetic test. Results: The average score of knowledge on HBC was 9.59±2.32, and the average positive and negative attitude scores were 31.36±4.12 and 24.13±4.78, respectively. The benefit of genetic test rated as most important was “to help my daughters or sisters decide whether to undergo genetic testing” and “to motivate me to perform breast self-examination more frequently”. The most important perceived limitation was “if I were found to carry the gene, my concerns about my female offspring developing breast cancer would increase.” Of the participants, 40.6% indicated willingness to test their genes and 48.6% considered it. Participants with a partner (p=.043) and higher educational level (p=.005) showed significantly lower willingness to test. Conclusion: These results suggest that high-risk HBC patients understand important facts regarding the inheritance of breast cancer and genetic test and their interest in genetic testing is substantial. Considering previous reports that perceptions of the benefits of genetic testing were important predictors of genetic test utilization, the developments of educational and counseling programs to deliver proper knowledge are necessary.

321P Non-BRCA variants in hereditary breast and ovarian cancer patients in the northern Mexico population

321P Non-BRCA variants in hereditary breast and ovarian cancer patients in the northern Mexico population

Recent trends in hereditary breast cancer incidence by race and age in KwaZulu-Natal, South Africa: An 11-year single-centre retrospective study (2011-2021).

Breast cancer incidence has increased globally in the last decade, especially in low- and middle-income countries. In Sub-Saharan Africa, breast cancer trends have been described only in a few populations owing to the scarcity of population-specific data. Using data collected between 2011 and 2021 at Inkosi Albert Luthuli Central Hospital, this retrospective study describes demographic and genetic trends for hereditary breast cancer patients in the KwaZulu-Natal province, South Africa. Six hundred and forty-five patients were included, of whom 44.3% were Black, 36.8% Indian, 15.6% White and 3.2% Coloured. The number of annual new cases increased from eight in 2011 to 145 in 2021, with a notable increase among Blacks. The mean onset age was 46 years, and Black patients were diagnosed ~10 years earlier than White and Indian patients. Triple-negative breast cancers accounted for 20.3% of hereditary cases, and 51.1% of them were Black. Bilateral and recurrent breast cancers constituted 7.4%, while pathogenic sequence variants in BRCA1/2 were reported in 10.4% of all patients, and the majority were Blacks and Indians. Overall, the KwaZulu-Natal province has seen an increase in hereditary breast cancer incidence in the past decade. Despite testing negative for pathogenic sequence variants, Black women frequently presented with breast cancers that are BRCA1-like, while Indians presented with extensive family history. This suggests that South African patients may require unique approaches to interventions, such as early detection and awareness programs among Blacks and increased genetic screening among Indians.

Co-Occurrence of Germline Genomic Variants and Copy Number Variations in Hereditary Breast and Colorectal Cancer Patients.

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is an autosomal dominant disease associated with a high risk of developing breast, ovarian, and other malignancies. Lynch syndrome is caused by mutations in mismatch repair genes predisposing to colorectal and endometrial cancers, among others. A rare phenotype overlapping hereditary colorectal and breast cancer syndromes is poorly characterized. Three breast and colorectal cancer unrelated patients fulfilling clinical criteria for HBOC were tested by whole exome sequencing. A family history of colorectal cancer was reported in two patients (cases 2 and 3). Several variants and copy number variations were identified, which potentially contribute to the cancer risk or prognosis. All patients presented copy number imbalances encompassing PMS2 (two deletions and one duplication), a known gene involved in the DNA mismatch repair pathway. Two patients showed gains covering the POLE2 (cases 1 and 3), which is associated with DNA replication. Germline potentially damaging variants were found in PTCH1 (patient 3), MAT1A, and WRN (patient 2). Overall, concurrent genomic alterations were described that may increase the risk of cancer appearance in HBOC patients with breast and colorectal cancers.

Germline variants of uncertain significance, their frequency, and clinico-pathological features in a cohort of Sri Lankan patients with hereditary breast cancer

BackgroundNext-Generation Sequencing (NGS)-based testing in cancer patients has led to increased detection of variants of uncertain significance (VUS). VUS are genetic variants whose impact on protein function is unknown. VUS pose a challenge to clinicians and patients due to uncertainty regarding their cancer predisposition risk. Paucity of data exists on the pattern of VUS in under-represented populations. This study describes the frequency of germline VUS and clinico-pathological features in Sri Lankan hereditary breast cancer patients.MethodsData of 72 hereditary breast cancer patients who underwent NGS-based testing between January 2015 and December 2021 were maintained prospectively in a database and analyzed retrospectively. Data were subjected to bioinformatics analysis and variants were classified according to international guidelines.ResultsGermline variants were detected in 33/72(45.8%) patients, comprising 16(48.5%) pathogenic/likely pathogenic variants and 17(51.5%) VUS. Distribution of VUS in breast cancer predisposing genes were :APC:1(5.8%), ATM:2(11.7%), BRCA1:1(5.8%), BRCA2:5(29.4%), BRIP1:1(5.8%), CDKN2A:1(5.8%), CHEK2:2(11.7%), FANC1:1(5.8%), MET:1(5.8%), STK11:1(5.8%), NF2:1(5.8%). Mean age at cancer diagnosis in patients with VUS was 51.2 years. Most common tumour histopathology was ductal carcinoma 11(78.6%). 50% of tumours in patients having VUS in BRCA1/2 genes were hormone receptor negative. 73.3% patients had family history of breast cancer.ConclusionsA significant portion of patients had a germline VUS. Highest frequency was in BRCA2 gene. Majority had family history of breast cancer. This highlights the need to undertake functional genomic studies to determine the biological effects of VUS and identify potentially clinically actionable variants that would be useful for decision-making and patient management.

Effectiveness and tasks of breast MRI surveillance for high-risk women with cancer susceptibility genes other than BRCA1/2: a single institution study.

In Japan, with the introduction of multigene panel testing, there is an urgent need to build a new medical system for hereditary breast cancer patients that covers pathogenic variants other than BRCA1/2. The aim of this study was to reveal the current status of breast MRI surveillance for high-risk breast cancer susceptibility genes other than BRCA1/2 and the characteristics of detected breast cancer. We retrospectively examined 42 breast MRI surveillance with contrast performed on patients with hereditary tumors other than BRCA1/2 pathogenic variants at our hospital from 2017 to 2021. MRI exams were evaluated independently by two radiologists. Final histopathological diagnosis for malignant lesions were obtained from surgical specimen. A total of 16 patients included TP53, CDH1, PALB2, ATM pathogenic variants and 3 variant of unknown significance. 2 patients with TP53 pathogenic variants were detected breast cancer by annual MRI surveillance. The rate of cancer detection was 12.5% (2/16). One patient was detected synchronous bilateral breast cancer and unilateral multiple breast cancers (3 lesions in 1 patient), so there were 4 malignant lesions in total. Surgical pathology of 4 lesions were 2 ductal carcinoma in situ, 1 invasive lobular carcinoma, and 1 invasive ductal carcinoma. MRI findings of 4 malignant lesions were detected as 2 non mass enhancement, 1 focus and 1 small mass. All of 2 patients with PALB2 pathogenic variants had previously developed breast cancer. Germline TP53 and PALB2 were strongly associated with breast cancer, suggesting that MRI surveillance is essential for breast cancer-related hereditary predisposition.

Abstract P6-02-17: A Real-World Study of BRCA1 and BRCA2 Germline Mutations among High Hereditary Risk Subjects and Patients with Breast and Ovarian Cancer in Lebanon

Abstract Background: The prevalence of pathogenic BRCA mutations in high hereditary risk breast cancer patients (pts) in ethnic Lebanese Arab women was 5.6% in a study published in 2015 (El Saghir, et al. The Oncologist). In this study, we look at real world practice prevalence of BRCA mutations among pts with breast and/or ovarian cancer referred for testing because of positive family history (FH) and/or young age at the American University of Beirut Medical Center (AUBMC). Methods: The study was approved by the Institutional Review Board at AUBMC. We retrospectively collected clinical, radiological, pathological and genetic information on breast and ovarian cancer pts at a high hereditary risk for whom Sanger sequencing of all coding exons and immediately flanking intronic regions of BRCA1 and BRCA2 was performed between January 1, 2010 and Jan 1, 2019 at AUBMC. Between Jan 2019 and Aug 2020, Next Generation Sequencing (NGS) of 70 cancer-associated genes was referred to and done in Centogene labs (Germany). 346 subjects were included in the study; 235 pts with breast and/or ovarian cancer, and 101 subjects of young age or with a positive family history. Results: 210 pts had breast cancer (209 females, 1 male); 81 were diagnosed at age ≤40, 81 aged 41-50, and 48 aged >50. 185 pts had BRCA sequencing and 25 had NGS panel testing. 31 pts had ovarian cancer; 28 had BRCA testing and 3 had NGS. 3 pts had ovarian and breast cancer; all had Sanger sequencing, 1 male pt with both breast and prostate cancers had BRCA testing. The 101 subjects who were tested in the setting of positive FH of cancers or a known deleterious mutation in first degree family members were either target tested for the known familial mutation or had BRCA screening. The incidence of BRCA1 and BRCA2 mutations in women with breast cancer was 8.5% (18/210 patients) and 19.3% (6/31 patients) in women with ovarian cancer. Of the 3 pts who had both breast and ovarian cancer, 1 had a BRCA1 mutation. Almost all patients with hereditary breast cancer had a positive FH and the majority were < 40 years of age. 8 out of 13 BRCA1 pts had Triple Negative disease (61%). Of the 101 subjects with no history of cancer, 9 out of 30 with relatives who had BRCA1 mutation carried the same mutation, and 3 out of 15 with BRCA2 carried the mutation. The remaining 56 pts were tested because of positive FH; 3 out of 56 had a pathogenic mutation (1 BRCA1, 1 BRCA2 and 1 RAD51D). Of the 28 pts who had NGS panel sequencing, 1 patient had RAD51D, 1 had a PALB2 mutation, 1 had BARD1 and 1 had APC risk variant. Conclusions: In this real-world practice study of patients and subjects referred for germline mutation testing. BRCA mutation rate in pts with breast cancer was 8.5% (18/210) and 19% in ovarian cancer (6/31). Young age (< 40 years) and a positive FH are the most useful criteria to select pts with breast cancer for mutation testing, especially in the setting of limited resources. This is the first study to report a 20% rate of BRCA pathogenic variants in patients with ovarian cancer in Lebanon and Arab countries; we highlight the need to refer all ovarian cancer pts for counseling and genetic testing. NGS is important to detect mutations other than BRCA1 and BRCA2 in our population where 50% of cases are below age 50. Table 1. Incidence of BRCA1/2 mutations, age, and family history in pts with breast and ovarian cancer. Citation Format: Nagi El Saghir, Nadine Safi, Ahmad Masri, Firas Kreidieh, Deborah Mukherji, Nada Assaf, Rami Mahfouz, Hiba Moukadem. A Real-World Study of BRCA1 and BRCA2 Germline Mutations among High Hereditary Risk Subjects and Patients with Breast and Ovarian Cancer in Lebanon [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 P6-02-17.

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.

Detection of BRCA1/2 pathogenic variants in patients with breast and/or ovarian cancer and their families. Analysis of 3,458 cases from Lower Silesia (Poland) according to the diagnostic algorithm of the National Cancer Control Programme.

Breast and ovarian cancers are among the most common malignancies in the female population, with approximately 5–10% of cases being hereditary. BRCA1 and BRCA2 with other homologous recombination genes are the most tested genes in hereditary breast and ovarian cancer (HBOC) patients. As next-generation sequencing (NGS) has become a standard and popular technique, such as for HBOC, it has greatly simplified and accelerated molecular diagnosis of cancer. The study group included 3,458 HBOC patients or their relatives from Lower Silesia (Poland) (a voivodeship located in south-west Poland inhabited by 2.9 million people). All patients were tested according to the recommendations from the National Cancer Control Programme of the Ministry of Health for the years 2018–21. We tested 3,400 patients for recurrent pathogenic variants for the Polish population: five BRCA1 founder variants (c.5266dup, c.181T>G, c.4035del, c.3700_3704del, and c.68_69del), two PALB2 variants (c.509_510del, c.172_175del) and three CHEK2 variants [c.1100del, c.444+1G>A, g.27417113-27422508del (del5395)]. Next 260 patients from the study group were chosen for the BRCA1/2 NGS panel, and additionally selected marker pathogenic variants were tested using Sanger sequencing and MLPA methods in 45 and 13 individuals, respectively. The analysis of BRCA1/2 in the 3,458 patients with HBOC or their relatives revealed 144 carriers of 37 different pathogenic variants (22 in BRCA1 and 15 in BRCA2). Among all detected variants, 71.53% constituted founder pathogenic BRCA1 variants. Our study has revealed that for the Lower Silesian population, the first-line BRCA1/2 molecular test may be limited to only three variants in BRCA1—c.5266dup, c.181T>G, and c.4035del—but the aim should be to provide a full screening test of HBOC critical genes. The key and still growing role of molecular diagnostics of neoplasms, which includes HBOC, is undeniable. Therefore, it is necessary to provide complete and optimal therapeutic and prophylactic algorithms in line with current medical knowledge.

Risk-reducing mastectomy for women with hereditary breast and ovarian cancer (HBOC): analytical results of data from the Japanese Organization of HBOC.

Risk-reducing mastectomy is one option for women with hereditary breast and ovarian cancer to reduce the risk of breast cancer. We analyzed data of the Japanese Organization of Hereditary Breast and Ovarian Cancer on women who were diagnosed as hereditary breast and ovarian cancer by BRCA germline genetic testing between 2010 and 2019 to reveal the rate and likelihood of risk-reducing mastectomy. There were 412 women with BRCA1, 271 with BRCA2 and 4 with both female pathogenic variants. Ninety (13.1%) received risk-reducing mastectomy. The rates of risk-reducing mastectomy were statistically significantly higher in women with BRCA1 pathogenic variants than BRCA2, in women who had breast cancer than those who did not, in women with a breast cancer family history than in those without, in mothers than in those without children, in women who were receiving surveillance with MRI than those who were not and in women who received risk-reducing salpingo-oophorectomy than in those who did not on univariate analyses. The ages when they received the genetic testing were statistically significantly younger in the women receiving risk-reducing mastectomy than those who did not receive it. The women with BRCA1 pathogenic variants, personal history of breast cancer, mothers, those receiving MRI surveillance and younger women were independently significantly more likely to receive risk-reducing mastectomy based on multivariate analysis. The rate of risk-reducing mastectomy was not high in Japan; however, risk-reducing surgery was approved by the Japanese National Medical Insurance for hereditary breast and ovarian cancer patients with breast and/or ovarian cancer in 2020, so this rate will increase.

Molecular phenotypes and clinical characterization of familial hereditary breast cancer among half and full sisters

BackgroundPreliminary clinical observations show that contemporaneous hereditary breast cancer (CHBC) patients suffered breast cancer at an early age, which requires further analysis.Methods38 familial hereditary breast cancer patients (18 CHBC patients and 20 non-CHBC patients) were screened out and 152 non-hereditary breast cancer patients were used as control subjects. Clinical pathologic subtypes, age, tumor location, histological grade, lymph node metastasis, and molecular phenotype expression (ER, PR, HER-2, Ki-67, CK5/6, E-cad, P63, and P120) were compared across all subgroups.ResultsThe incidence of CHBC was 9.47% (18/190) in breast cancer patients. The average ages of onset of CHBC patients, non-CHBC patients, and non-hereditary breast cancer patients were 49.06 ± 6.42, 60.75 ± 9.95 and 61.69 ± 14.34 respectively; whereas there were no significant differences with respect to pathological type or tumor location. There were significant differences in some histological grading (grade II/III), lymph node metastasis and PR expression between hereditary and non-hereditary breast cancers (P < 0.05; P < 0.05 and P < 0.005, respectively). Significantly different HER-2 expression was observed when comparing all hereditary or CHBC patients with non-hereditary breast cancers (P < 0.05 and P < 0.005, respectively). There were significant differences in E-cad and P63 between contemporaneous hereditary and non-hereditary breast cancers (P < 0.005 and P < 0.05, respectively).ConclusionsCHBC patients accounted for 9.47% (18/190) of breast cancer patients, had earlier disease onset, and showed differences compared to non-hereditary breast cancer patients with respect to molecular phenotype and clinical characteristics.

Genetic, clinic and histopathologic characterization of BRCA-associated hereditary breast and ovarian cancer in southwestern Finland

We have analyzed the histopathological, clinical, and genetic characteristics in hereditary breast and ovarian cancer patients of counselled families from 1996 up to today in the southwestern Finland population. In this study we analyzed the incidence of different BRCA1 and BRCA2 pathogenic variants (PV). 1211 families were evaluated, and the families were classified as 38 BRCA1 families, 48 BRCA2 families, 689 non-BRCA families and 436 other counselled families (criteria for genetic testing was not met). In those families, the study consisted of 44 BRCA1 breast and/or ovarian cancer patients, 58 BRCA2 cancer patients, 602 non-BRCA patients and 328 other counselled patients. Breast cancer mean onset was 4.6 years earlier in BRCA1 carriers compared to BRCA2 (p = 0.07, a trend) and ovarian cancer onset almost 11 years earlier in BRCA1 families (p < 0.05). In BRCA families the onset of ovarian cancer was later than 40 years, and BRCA2-origin breast cancer was seen as late as 78 years. The BRCA PV (9%) increases the risk for same patient having both ovarian and breast cancer with a twofold risk when compared to non-BRCA group (4%) (95% CI p < 0.05). Triple-negativity in BRCA1 (42%) carriers is approximately 2.6 times vs more common than in BRCA2 carriers (16%) (p < 0.05). The risk ratio for bilateral breast cancer is approximately four times when compared BRCA2 (17%) and other counselled patients’ group (4%) (p < 0.05). 27% southwestern BRCA2-families have a unique PV, and correspondingly 39% of BRCA1-families. The results of this analysis allow improved prediction of cancer risk in high-risk hereditary breast and ovarian families in southwestern Finland and improve long term follow-up programs. According to the result it could be justified to have the discussion about prophylactic salpingo-oophorectomy by the age of 40 years. The possibility of late breast cancer onset in BRCA2 carriers supports the lifelong follow-up in BRCA carriers. Cancer onset is similar between BRCA2 carries and non-BRCA high-risk families. This study evaluated mutation profile of BRCA in southwestern Finland. In this study genotype–phenotype correlation was not found

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

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

162P Prevalence and spectrum analysis of germline BRCA1 and BRCA2 variants of unclear significance in HBOC Syndrome: Decoding the mysterious signals of the genome

About 10-20% of hereditary breast and/or ovarian (HBOC) cancer patients undergoing germline BRCA1/2 genetic testing harbour Variants of Uncertain Significance (VUS). Poor is the knowledge about the prevalence of germline BRCA1/2 VUS in HBOC patients of Southern Italy. Our study is aimed at describing the spectrum of these variants detected in HBOC patients in order to improve the patient’s stratification with the identification of potentially high-risk BRCA variants helpful for patient clinical management.

Abstract 887: Clinicopathological and genetic features of breast cancer in Algerian population: A multicenter study

Abstract Background: Breast cancer is the most commonly diagnosed cancer and the leading cause of morbidity and mortality among Algerian women.The objective of this retrospective cohort study was to analyze some clinicopathological and molecular characteristics of breast cancer diagnosed between 2011 and 2019. Here we also report the experience of our research laboratory for the screening of BRCA1 and BRCA2 genes in hereditary breast and ovarian cancer (HBOC) patients. Materials and Methods: The population study included 7655 consecutive breast cancer patients. Data were collected from cancer registries of three medical oncology services and two anti-cancer centers located in north central region and eastern region of Algeria, respectively. Breast cancers were diagnosed between 2011 and 2019. Patient and tumor information included: age at diagnosis, menopausal status, receptor status, Ki-67 score, histological type,TNM stage and histological grade. Recurrent germline mutations on BRCA1 and BRCA2 genes previously found in Algerian patients were screened using PCR-Sanger sequencing in 230 HBOC patients. In addition, 18 HBOC patients were analyzed by NGS using a cancer panel of 30 hereditary cancer genes or BRCA1/2 genetic test. Results: The median age at diagnosis of the patients was 49.52 years. Data for age at diagnosis were available for 7389 patients. 55.29% patients were diagnosed under the age of 50 years and 55.83% had a premenopausal status. Data for receptor status were available for a total of 5599 patients. Of these, 55.75% patients were luminal A, 19.79% were TNBC, 17.39% were luminal B and 7.05% were HER2+. Data for Ki-67 score were available for 3357 cases. We noticed that 62.73% patients had a Ki-67 score ≥ 20% and 37.27% had a score &amp;lt;20%. Data for histological tumor type were available for 6145 cases. 84.28% patients had invasive ductal carcinoma followed by 8.84% with invasive lobular carcinoma. Data for TNM stage were available for 3524 cases. We identified 59.3% patients with stage III, 22.3% with stage II and 9.5% with stage IV. Data for histological grade were available for 6693 patients. We found 67.45% patients with grade II and 25.51% with grade III, respectively. 10 distinct BRCA1 germline mutations have been detected in 18 families and 5 distinct BRCA2 germline mutations have been identified in 5 families. The BRCA1 recurrent mutation c.83_84delTG has been detected in 5 unrelated families.The BRCA1 recurrent mutation c.2125_2126insA has been identified in 3 unrelated families. In addition, the BRCA1 c.181T&amp;gt;G has been found in two unrelated families. Interestingly, our results also showed differences in the distribution of the mutation spectrum of BRCA1 and BRCA2 genes between the eastern region and the north central region of Algeria. Conclusion: Our current study will contribute in developing optimal clinical trial protocols and personalized management strategies for breast cancer patients. Citation Format: Farid Cherbal, Leticia Ledmila Saada, Massila Nehar, Kamelia Yatta, Lydia Souha Zerrouki, Wafa Abdou, Chiraz Mehemmai, Hadjer Gaceb, Wassila Benbrahim, Hassen Mahfouf, Kada Boualga. Clinicopathological and genetic features of breast cancer in Algerian population: A multicenter study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 887.

The other side of the coin: dissecting molecular mechanisms behind hereditary breast cancer in search of therapeutic opportunities

Over the last quarter century several genetic alterations have been implicated in hereditary breast cancer (HBC). Two papers recently published in the New England Journal of Medicine explored the mutation prevalence in breast cancer predisposition genes across a large population of affected and unaffected subjects. These analyses designated ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C and RAD51D as the core set of genes associated with a significantly increased risk of developing breast cancer. A deeper understanding of the biological role of these genes unearths an intricate mechanism involving DNA repair and cell cycle regulation. Exploiting these inherited alterations for targeted treatments, as is currently the case with PARP inhibitors, may provide additional therapeutic opportunities for HBC patients.

Application of Multilayer Evidence for Annotation of C-Terminal BRCA2 Variants.

Simple SummaryThe potential pathogenic role of germline BRCA2 c.9976A>T and c.10095delinsGAATTATATCT was evaluated in hereditary breast and ovarian cancer (HBOC) patients by investigating 2491 probands and verified in an independent cohort of 122,209 patients. Although the c.10095delinsGAATTATATCT variant was more prevalent among patients compared to control populations, no increased risk for cancer was found. No association between c.9976A>T and clinicopathological parameters or elevated risk for HBOC cases was detected. However, lung cancer was more prevalent in families carrying c.9976A>T compared to pathogenic BRCA1/BRCA2 carrier families. An increased frequency of pancreatic cancer was found in families where c.9976A>T occurred together with other pathogenic BRCA1 variants. The C-terminal stop codon variants showed no association with other pathogenic BRCA2 variants. No loss of heterozygosity (LOH) in tumor tissue and no allelic imbalance in RNA level were confirmed. The c.9976A>T variant may be considered as a potential risk for lung cancer, and a potential modifying factor in pancreatic cancer when it occurs along with the pathogenic BRCA1 variant, although this observation should be validated in a larger sample cohort.The clinical relevance of the BRCA2 C-terminal stop codon variants is controversial. The pathogenic role of the germline BRCA2 c.9976A>T and c.10095delinsGAATTATATCT variants in hereditary breast and ovarian cancer (HBOC) patients was evaluated. An association with clinicopathological parameters was performed in 2491 independent probands diagnosed with HBOC and in 122,209 cancer patients reported earlier. Loss-of-heterozygosity (LOH) in tumor samples and allelic imbalance in RNA extracted from peripheral blood cells were investigated. Neither c.10095delinsGAATTATATCT or c.9976A>T variants showed significant association with clinicopathological parameters or elevated risk for HBOC-associated tumors. Lung cancer was more prevalent in families carrying the c.9976A>T variant compared to pathogenic BRCA1 or BRCA2 carrier families. An increased prevalence of pancreatic cancer was found in families where c.9976A>T occurred together with other pathogenic BRCA1 variants. An increased risk for familial pancreatic, lung and upper aero-digestive tract cancers was confirmed in the validation set. Regarding BRCA2 C-terminal variants, no linkage with other pathogenic BRCA2 variants, no LOH in tumor tissue and no allelic imbalance in RNA level were confirmed. The c.9976A>T variant may be considered as a potential risk for lung cancer, and a potential modifying factor in pancreatic cancer when it occurs along with the pathogenic BRCA1 variant, although this observation should be validated in a larger sample cohort.

Abstract PS16-12: Double heterozygous pathogenic variants prevalence in a cohort of hereditary breast cancer patients

Abstract Significant progress has been made in the identification of inherited genetic factors underlying hereditary cancers. Inherited pathogenic variants in cancer predisposition genes that confer moderate to high risk of breast cancer (BC) are found in 10% of BC cases. Pathogenic variants in BRCA1 and BRCA2 genes are the underlying alterations in hereditary BC. Women with a pathogenic variant in BRCA1 or BRCA2 are at substantially higher risk of developing breast, ovarian and pancreatic cancers and represent 25-28% of hereditary BC cases. The gold standard for molecular diagnosis of a hereditary cancer syndrome is aNext Generation Sequencing (NGS) panel that includes all genes known to confer moderate to high-risk for BC (TP53, PTEN, CHEK2, ATM, PALB2 STK11, RAD51C and BRIP1). Identifying who is eligible to perform genetic testing remains a challenge but presently age at the time of tumor diagnosis, family history and disease stage are still the best predictors. The identification of a germline pathogenic variant enables appropriate genetic counseling, risk-reducing interventions. The detection of variants in BRCA1, BRCA2 and PALB2 may also determine treatment options in patients with advanced or metastatic disease. The known non-BRCA1/2-associated hereditary BC comprise a heterogeneous group of tumors, for most of which the prevalence of histologic and immunohistochemical (IHQ) phenotypes are yet to be identified while triple-negative BC is the most prevalent in BRCA1 carriers. The co-occurence of more than one germline pathogenic variant in BC genes is a rare event and it may affect cancer risk and penetrance is still unknown. Only a few reports on cases and series of double mutation carriers have been described in BRCA1, BRCA2, PALB2, CHEK2, BLM or NBN. In this series case we report patients with double heterozygous (DH) mutation in BC, their age at diagnosis, presence of second neoplasia and cancer phenotype in moderate and high penetrance genes on germline panels. Considering this scenario, we performed an active search among the 2651 women from the Hereditary Cancer Registry at Hospital Sirio-Libanes, São Paulo, Brazil, between January 2013 and June 2020. We have included 229 patients with a histopathological confirmation of a BC who have tested positive for pathogenic/likely pathogenic variant. Of these, 4,3% (10/229) women were identified with DH mutation in high and moderate penetrance genes in BC (table 1). All patients carried a germline pathogenic variant in at least one high-penetrance gene. A total of 7 cases (7/10) carried at least one BRCA1/2 pathogenic variant. Two women (2/10) included had developed bilateral BC. The occurrence of a second primary cancer was described in three patients (3/10). The median age at first BC diagnosis was 36,7 years old. Two BC were found to be triple negative, five cases were of Luminal subtype and one was HER2+. The age at diagnosis is similar to most hereditary BC related to those developed by BRCA1 and TP53 germline variant carriers. In this case series there is no evidence of additive effect on the risk of tumor development. Larger series of DH mutation carriers are needed to estimate the risk in double heterozygous populations and to determine whether the presence of DH have a synergistic interaction or additive effect on cancer risk. Table1 - Breast Cancer double variantsBreast Cancer double VariantsGeneVariantAge of Breast Cancer onset IHQ statusBilateral BCOther prymary neoplasia (age)BRCA1c.5266dupC36 yoER- PR- HER2 +YesPancreas (40), Lung (53)TP53c.1010G&amp;gt;ABRCA1c.4165.4166delAG32yoN/ANoBreast (37), Skin (50)PALB2c.1240C&amp;gt;TBRCA1c.5266dupC33yoER - RP- HER2 -NoNoATMc.6729_6730delAABRCA1c.3748G&amp;gt;T33yoER- PR -HER2-NoNoRECQL4c.1568_1573delinsCCCCCBRCA2c.2516dupA49yoER+ PR+ HER2 -NoNoPMS2c.2182_2184delinsGBRCA2c.8960del32yoER+ PR+ HER2-NoNoATMc.901+1G&amp;gt;ABRCA1c.1687C&amp;gt;T38yoER+NoBreast Cancer (58)NBNc.1142delC PR +MUTYHc.536A&amp;gt;G Her2-TP53c.1010G&amp;gt;A35yoN/ANoNoMUTYHc.1187G&amp;gt;AATMc.4906C&amp;gt;T42yoER+NoNoTP53c.1010G&amp;gt;APR+HER2-PALB2c.2711G&amp;gt;A37yoER+yesNoCHEK2c.319+2T&amp;gt;APR+HER2-BRCA2c.8960del32yoER+ PR+ HER2-NoNo Citation Format: Thais Megid, Maria Isabel Achatz, Janina Pontes Pisani, Mariana Cartaxo. Double heterozygous pathogenic variants prevalence in a cohort of hereditary breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-12.

Four novel BRCA variants found in Chinese hereditary breast cancer patients by next-generation sequencing

Breast cancer is the most frequent cancer among women worldwide. Patients carrying mutations in breast cancer susceptibility genes like BRCA1 and BRCA2 (BRCA1/2) account for 5–10% of all breast cancer patients. Therefore, screening for susceptibility genes may reduce the incidence of breast cancer and improve prognosis. To provide evidence for mutation interpretation and targeted drug use in breast cancer patients, gene mutations were screened in 78 women diagnosed with sporadic breast cancer using a next-generation sequencing panel, confirmed by Sanger sequencing. Then the pathogenicity of the identified novel variants was explored using in vitro experiments including western blotting, co-immunoprecipitation and cell-migration assays. Four novel variants (BRCA2 L1390W, BRCA2 Glu432fs, BRCA1 P706L, and BRCA1 Cys882fs) were identified. BRCA2 Glu432fs decreased the expression of BRCA2 protein, enhanced cell migration and invasion ability, and prevented the protein from interacting with RAD51, resulting in a defect in the homologous recombination pathway. The identification of these novel BRCA variants and the confirmation of their pathogenicity have enriched the genetic database of breast cancer, especially in the Chinese population. Moreover, the variants are the genetic risk factors for hereditary breast cancer. Therefore, BRCA variant detection and genetic counseling for breast cancer patients are meaningful and important.