BRCA1 BRCA2 Research Articles

The frequency of HER2-low breast cancer among BRCA1, BRCA2, and PALB2 mutation carriers.

10509 Background: Human epidermal growth factor 2 (HER2) expression in breast cancer (BC) has historically been characterized as negative (0 or 1+ by immunohistochemistry (IHC); 2+ by IHC and not amplified by in-situ hybridization, ISH) or positive (2+ by IHC and amplified by ISH or 3+ by IHC). Recently developed therapies highlight the importance of identifying tumors that are HER2-low (IHC 1+, or 2+ with negative ISH). A minority of BC associated with germline BRCA1, BRCA2( BRCA1/2) or PALB2pathogenic variants (PV) are HER2-positive, but the proportion of BRCA1/2- and PALB2-associated HER2-negative BC that are HER2-low and may benefit from novel HER2-low therapies is unknown.This study aims to retrospectively identify the frequency of HER2-low BC in BRCA1/2 and PALB2 mutation carriers whose cancers were identified as HER2-negative. Methods: We conducted a retrospective chart review of 170 patients diagnosed with HER2-negative BC in the context of a BRCA1/2or PALB2PV at the University of Pennsylvania from 2003 to 2023. Genomic and cancer-specific characteristics including variant classification and receptor status were collected and are descriptively reported. Results: 170 individuals with BRCA1/2 or PALB2 PV developed 190 HER2-negative BC. Forty-seven percent of primary tumors that had been identified as HER2-negative were HER2-low (39% of BRCA1-, 56% of BRCA2-,60% of PALB2-associated BC; see Table). 17 individuals had 17 metastatic site biopsy reports available for review. Of these, 10 (59%) were HER2-low (1 BRCA1-, 8 BRCA2-, and 1 PALB2-associated). 6 of 17 (35%) individuals had discordant HER2 status in primary and metastatic samples; in all cases, the primary tumor was HER2 IHC 0 and the metastatic site was HER2-low. Conclusions: Despite the lower frequency of conventionally HER2-positive BC among individuals with BRCA1/ 2and PALB2PVs, the proportion of these BC that have low HER2 expression is substantial and similar to that of sporadic breast cancer. Discordance in HER2 status between primary and metastatic samples is observed. Individuals with BRCA1/2and PALB2HER2-negative BC may benefit from therapies for HER2-low BC; reevaluation of HER2 status on metastatic samples may identify additional candidates for such therapies. [Table: see text]

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 < 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.

Abstract P1-05-03: Prevalence of BRCA1/2 mutations in an underrepresented population of women with breast cancer: Observations from the City of Hope INSPIRE study

Abstract Table 1. Incidence of BRCA 1 and 2 mutations by Race and Ethnicity BRCA1 BRCA2 BRCA1 or 2 VUS/Negative Native American 0 1 1 6 Asian 2 3 5 150 Black/African American 3 2 5 48 Native Hawaiian or Pacific Islander 0 0 0 5 Other 1 1 1* 26 White 25 17 42 688 Unknown 0 0 0 20 Declined 1 0 1 24 TOTAL 32 24 55 967 * Patient had both BRCA1 and BRCA2 mutations Citation Format: Joanne Mortimer, Sidney S. Lindsey, Ilana Solomon, Wai Park, Duveen Sturgeon, Kathleen Blazer, Stacy Gray, Joseph Bonner, Xiaoyu Xia, Stephen Gruber. Prevalence of BRCA1/2 mutations in an underrepresented population of women with breast cancer: Observations from the City of Hope INSPIRE study [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 P1-05-03.

Controversies and Open Questions in Management of Cancer-Free Carriers of Germline Pathogenic Variants in BRCA1/BRCA2.

Simple SummaryFemale carriers of germline pathogenic/likely pathogenic variants (P/LPVs) in the BRCA1/BRCA2 (BRCA) genes are at a substantially increased lifetime risk for developing breast, ovarian, and (to a lesser extent) other cancer types. Multiple national and international surveillance guidelines and recommendations to facilitate the early detection of cancer in these high-risk women have existed for more than 2 decades. Yet, inconsistencies pertaining to the medical management of cancer-free carriers linger, and surveillance recommendations are not globally harmonized. In this review, we discuss the differences between existing surveillance guidelines for BRCA P/LPV carriers, emphasizing the importance of future studies to enable guidelines harmonization and personalized risk stratification for optimal, effective surveillance strategies.Females harboring germline BRCA1/BRCA2 (BRCA) P/LPV are offered a tight surveillance scheme from the age of 25–30 years, aimed at early detection of specific cancer types, in addition to risk-reducing strategies. Multiple national and international surveillance guidelines have been published and updated over the last two decades from geographically diverse countries. We searched for guidelines published between 1 January 2015 and 1 May 2022. Differences between guidelines on issues such as primary prevention, mammography screening in young (<30 years) carriers, MRI screening in carriers above age 65 years, breast imaging (if any) after risk-reducing bilateral mastectomy, during pregnancy, and breastfeeding, and hormone-replacement therapy, are just a few notable examples. Beyond formal guidelines, BRCA carriers’ concerns also focus on the timing of risk-reducing surgeries, fertility preservation, management of menopausal symptoms in cancer survivors, and pancreatic cancer surveillance, issues that, for some, there are no data to support evidence-based recommendations. This review discusses these unsettled issues, emphasizing the importance of future studies to enable global guideline harmonization for optimal surveillance strategies. Moreover, it raises the unmet need for personalized risk stratification and surveillance in BRCA P/LPV carriers.

Genetic and clinical characteristics of BRCA-associated hereditary breast cancer in the West region of Kazakhstan.

Breast cancer is the most common cancer in women and is cause mortality in many countries. The purpose of this article is to determine the BRCA1 BRCA2 gene mutation polymorphisms, as well as to determine the clinical, histopathological and prognostic characteristics in patients with breast cancer in the western region of Kazakhstan. A study was conducted on the genotyping of 278 patients in the MC ZKMU Marat Ospanov with an established diagnosis of breast cancer, which revealed that out of 278 patients, of three cases were identified. In the age category up to 50 years, 70 cases were detected (25.1%) after 50 years 208 cases were identified (74%). Number of patients in stage I was 20 (7.1%) in stage second 204 (73%) and in stage third 54 (19%). By tumor size, 30 (10%) cases were T1, 194 (69%) cases were T2, 35 (12.5%) cases were T3 and 19 cases were T4 (6.8%). According to metastasis of the lymph nodes, no lymph nodes were detected in 107 (38%) cases, 1-3 l/n (Lymph Nodes) in 95 (34%) cases, 4-9 l/n in 12 (4%) cases, 10 l/n in 4 (1.4%) cases and unknown cases was 60 (21%). In 99.6% of patients no distant metastases was detected. According to the molecular classification of the tumor, Luminal type A is most found in this study 147 (52.8%), then Luminal type B 57 (20.5%), HER-2 positive 26 (9.3%) and Triple negative 48 (17.2%). By ethnicity the Kazakh race is 182 (65%) the Caucasian race was 96 (34%). Large population screening studies involving all BRCA1/2 polymorphisms are required to confirm the penetrance, frequency and significance of a wide range of variations of BRCA1/2 genes in the Kazakh population.

Germline risk assessment and genetic counseling in ovarian cancer patients of diverse self-reported race/ethnicity and ancestry (388)

<b>Objectives:</b> To evaluate differences in rates of pathogenic/likely pathogenic germline variants (P/LPV) and subsequent genetic counseling by self-reported ancestry in epithelial ovarian cancer (EOC) patients (pts) undergoing tumor-normal sequencing for cancer care. <b>Methods:</b> EOC pts were prospectively consented to tumor-normal sequencing via a custom NGS panel (MSK-IMPACT) from January 2015 to December 2019, inclusive of germline analysis up to 88 genes. Designated EOC-associated genes included: <i>BRCA1 BRCA2, RAD51C, RAD51D, BRIP1, PALB2, ATM, MLH', MSH2, MSH6,</i> and <i>PMS2.</i> Variants of uncertain significance were not included. All women with new P/ LPV were referred to a Clinical Genetics Service (CGS) for counseling. Ancestry was defined using self-reported definitions of race/eth- nicity and designations of Ashkenazi Jewish (AJ) ancestry. Pts were categorized into mutually exclusive groups (AJ, Non-Hispanic [NH]- White, Non-White [Asian, Black/African American, Hispanic, other], or unknown). Patients identifying as AJ or Hispanic were classified as such, regardless of race. Clinical characteristics were analyzed using summary statistics. Associations between ancestry, mutation status, and CGS follow-up were assessed with non-parametric statistical tests (STATA V17). <b>Results:</b> Of 919 pts with EOC, 235 (25.6%) had a P/LPV, with 149 (16.2%) in an EOC-associated gene. Of those with P/LPV, 91 (38.7%) previously knew about this result for all genes, and 84 (56.4%) knew of this result for EOC-associated genes. For those with new findings, 80% presented for CGS counseling. The median age of EOC diagnosis for the entire cohort was 60 years (range: 16-90). Carriers of a P/LPV had a younger age at diagnosis compared with pts with sporadic EOC (59 vs 61, p=0.012). High-grade serous EOC (HGSOC) comprised 77% of cancers, and P/LPV carriers were more likely to have HGSOC than other histologies (85.5% vs 74.1%, p<0.001). Women were identified as NH-White (58%), AJ (17%), Asian (10%), Hispanic (6%), Black (5%) and unknown (4%) ancestries. The prevalence of P/LPV differed by ancestry for all genes (NH-White 22%, AJ 41%, Asian 28%, Hispanic 18%, Black 21%, unknown 21%, p<0.001). When assessing specifically for EOC-associated genes, a similar pattern was observed; AJ pts had the highest prevalence of P/LPV (25.6%). After removal of AJ pts, rates of EOC-associated P/LPV differed between NH-White (12%), Asian (25%), Hispanic (18%), and Black (21%) pts (p=0.021). There were no significant differences between ancestry groups in rates of prior knowledge of P/LPV or CGS follow-up rates for newly diagnosed pts with P/LPV. <b>Conclusions:</b> Rates of P/LPV, particularly in EOC-associated genes, were high in Non-White pts, particularly in Asian pts, compared with Non-AJ, NH-White pts. Rates of follow-up counseling were similar between ancestry groups. These findings highlight the need for universal genetic testing in all EOC pts regardless of ancestry, given the implications for treatment and cascade testing.

Frequency of homologous recombination deficiency in a large community-based cohort of epithelial ovarian cancer cases (597)

Frequency of homologous recombination deficiency in a large community-based cohort of epithelial ovarian cancer cases (597)

Association of germline genetic testing results with chemotherapy regimens received by women with early-stage breast cancer.

10518 Background: Germline genetic testing is widespread after breast cancer diagnosis and increasingly informs treatment decisions; however, guidelines do not advise selecting chemotherapy regimens based on genetic testing results. It is unknown whether women with pathogenic variants (PVs) in BRCA1, BRCA2 ( BRCA1/2) or other cancer risk genes receive different chemotherapy regimens than women with negative genetic testing results. Methods: We linked Surveillance, Epidemiology and End Results (SEER) registry records from Georgia and California to clinical germline genetic testing results from four participating laboratories (Ambry, Bioreference/GeneDx, Invitae, and Myriad). For this analysis, we included patients who: 1) were diagnosed with stages I-III breast cancer, either hormone receptor-positive and HER2-negative (HR+HER2-) or triple-negative, in Georgia or California from 2013-2017; 2) received chemotherapy based on SEER records; and 3) linked to a genetic testing result. We further selected cases by genetic testing results: 50% PVs in BRCA1/2 or another cancer risk gene, 25% variant of uncertain significance (VUS) only and 25% negative. We extracted details of chemotherapy regimens from SEER text fields completed by registrars. We categorized regimens by drug classes reported (anthracycline, taxane, platinum, nitrogen mustard, other). We used multivariable models that controlled for age, race/ethnicity, stage, grade, surgical procedure, radiotherapy receipt and geographic site to test whether PV carriers received a more intensive chemotherapy regimen. For HR+HER2-, a more intensive regimen was defined as at least three drugs including an anthracycline and for triple-negative, as at least four drugs including an anthracycline and a platinum (versus fewer drugs). Results: 2,293 women were included, 1,451 with HR+HER2- and 842 with triple-negative disease. On multivariable analysis, receipt of a more intensive chemotherapy regimen was associated with having a BRCA1/2 PV among women with HR+HER2- disease (odds ratio 1.22, p = 0.036), but not among women with triple-negative disease. Moreover, platinum use was elevated in BRCA1/2 PV carriers with HR+HER2- disease (from an adjusted model: BRCA1/2 PV 10.9%, other PV 3.6%, VUS 5.6%, negative 5.7%), while in BRCA1/2 PV carriers with triple-negative disease, platinum use did not vary significantly by genetic results ( BRCA1/2 27.7%, other PV 27.7%, VUS 20.9%, negative 20.7%; p = 0.025 for interaction between genetic result and subtype). Conclusions: Compared to women with negative genetic testing results, women with BRCA1/2 PVs more often received a platinum and/or an anthracycline in chemotherapy regimens for early-stage, HR+HER2- breast cancer. This suggests potential over-treatment. No differences in chemotherapy regimen by genetic testing result were observed in triple-negative disease.

Screening for mutations in BRCA1 and BRCA2 genes and related perspectives for the healthcare system

In the article there were looked some aspects of the knowledge regarding mutations in BRCA1 BRCA2 genes that have been accumulated since the first report on role of these genes in the development of breast and ovarian cancer. Most of them have practical worth related to the detection of mutations, as well as the prevention and treatment of associated ovarian cancer (the article focuses specifically on ovarian cancer, conditioned to relatively less amount of information on this pathology). There has been paid attention to the rational assignment of a genetic test on the presence of mutations in BRCA genes.Keywords: ovarian cancer, mutations in BRCA1 BRCA2 genes, screening of the presence mutations in BRCA1 BRCA2 genes.

The spectrum of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries.

BRCA1 BRCA2 mutational spectrum in the Middle East, North Africa, and Southern Europe is not well characterized. The unique history and cultural practices characterizing these regions, often involving consanguinity and inbreeding, plausibly led to the accumulation of population-specific founder pathogenic sequence variants (PSVs). To determine recurring BRCA PSVs in these locales, a search in PUBMED, EMBASE, BIC, and CIMBA was carried out combined with outreach to researchers from the relevant countries for unpublished data. We identified 232 PSVs in BRCA1 and 239 in BRCA2 in 25 of 33 countries surveyed. Common PSVs that were detected in four or more countries were c.5266dup (p.Gln1756Profs), c.181T>G (p.Cys61Gly), c.68_69del (p.Glu23Valfs), c.5030_5033del (p.Thr1677Ilefs), c.4327C>T (p.Arg1443Ter), c.5251C>T (p.Arg1751Ter), c.1016dup (p.Val340Glyfs), c.3700_3704del (p.Val1234Glnfs), c.4065_4068del (p.Asn1355Lysfs), c.1504_1508del (p.Leu502Alafs), c.843_846del (p.Ser282Tyrfs), c.798_799del (p.Ser267Lysfs), and c.3607C>T (p.Arg1203Ter) in BRCA1 and c.2808_2811del (p.Ala938Profs), c.5722_5723del (p.Leu1908Argfs), c.9097dup (p.Thr3033Asnfs), c.1310_1313del (p. p.Lys437Ilefs), and c.5946del (p.Ser1982Argfs) for BRCA2. Notably, some mutations (e.g., p.Asn257Lysfs (c.771_775del)) were observed in unrelated populations. Thus, seemingly genotyping recurring BRCA PSVs in specific populations may provide first pass BRCA genotyping platform.

BRCA1 and BRCA2 Mutations Other Than the Founder Alleles Among Ashkenazi Jewish in the Population of Argentina

In Ashkenazi Jewish (AJ) high risk families 3 mutations [2 in BRCA1 (c. 68_69del and c.5266dup) and 1 in BRCA2 (c.5946del)] account for the majority of high risk breast and ovarian cancer cases in that ethnic group. Few studies with limited number of genotyped individuals have expanded the spectrum of mutations in both BRCA genes beyond the 3 mutation panel. In this study, 279 high risk individual AJ were counseled at CEMIC (Centro de Educación Médica e Investigaciones Clínicas), and were genotyped first for the 3 recurrent mutation panel followed by Next Generation Sequencing (NGS) of BRCA1 BRCA2 in 76 individuals who tested negative for the first genotyping step. Of 279 probands (259 women), 55 (50 women) harbored one of the 3 mutations (19.7%); Of 76 fully sequenced cases (73 women), 6 (5 women) (7.9%) carried a pathogenic mutation: in BRCA1, c.2728C>T - p.(Gln910*); c.5407-?_(*1_?)del and c.5445G>A - p.(Trp1815*); in BRCA2, c.5351dup - p.(Asn1784Lysfs*3); c.7308del - p.(Asn2436Lysfs*33) and c.9026_9030del - p.(Tyr3009Serfs*7). Of 61 mutation carriers the distribution was as follows: 11 cancer free at the time of genotyping, 34 female breast cancer cases with age range 28–72 years (41.6 ± 9.3), 3 male breast cancer cases with age range 59–75 years (65 ± 7.3), 6 breast and ovarian cancer cases with age range 35–60 years (breast 40.4 ± 5.2; ovary 47.8 ± 7.2) and 7 ovarian cancer cases with age range 41–77 years (60.6 ± 13.3). This information proved highly useful for counseling, treatment, and prevention for the patient and the family. In conclusion comprehensive BRCA1/2 testing in AJ high risk breast ovarian cancer cases adds valuable clinically relevant information in a subset of cases estimated up to 7% and is therefore recommended.

DNA damage and repair (DDR) gene variants and outcomes in localized and metastatic prostate cancer (mPC).

304 Background: Moderate frequencies of DDR gene variants exist in mPC. Their prognostic role in localized and mPC is unclear. This study aims to characterize DDR variants in a cohort of hormone sensitive localized and mPC and assess for association with outcome. Methods: A retrospective cohort of men with PC and ≥ 2 follow up visits at DFCI and targeted next generation sequencing of prostate or metastatic tissue was identified. Biomarker (BM) positive was defined as pathogenic changes in the following DDR genes: ATM BAP1 BRCA1 BRCA2 BRIP1 CHEK2 MSH2 MSH6 PALB2 PMS2. For localized PC, outcome endpoints included event-free survival (EFS) (time from prostate biopsy to PSA relapse/metastasis/death), metastasis-free survival (MFS) (time to metastasis/death), time to castration resistance (CRPC), and death (OS); for mPC, outcome events included time from androgen deprivation start to CRPC and OS. BM status was descriptively summarized. Kaplan-Meier method and Cox regression model assessed associations of BM status with clinical outcomes. Results: Of the 237 men included, 16 (7%) were BM positive; 12 (6%) in 205 localized PC, 6 (14%) in 43 mPC. BM positive genes included 9 (4%) ATM, 6 (3%) BRCA2, and 2 (0.8%) CHEK2. In men with localized PC, EFS events occurred in 58% (7/12) BM positive vs 34% (66/193) BM negative at median follow up of 3.1 years; BM positive trended toward a shorter EFS (median 1.9 vs 5 years) than BM negative (HR 2.17, 95%CI 0.99-4.76). MFS events were observed in 17% (2/12) BM positive vs 7% (15/193) BM negative. CRPC events occurred in 17% (2/12) BM positive vs 6% (11/193) BM negative. In men with mPC, there were CRPC events in 100% (6/6) BM positive vs 67% (25/37) BM negative at median follow up of 3.3 years; BM positive trended toward a shorter time to CRPC (median 4 vs 8.8 months) compared to BM negative (HR 1.87, 95%CI 0.76-4.64). There was no association between BM status and OS. Conclusions: DDR variants appear infrequently in localized PC but may portend a shorter time to PSA relapse and metastasis. Similarly, DDR variants in mPC may be associated with a shorter time to CRPC. Low frequency of variants and short follow up limit these analyses. The prognostic value of DDR variants remains unclear and requires further research.

Prevalence of pathogenic germline variants detected by multigene sequencing in unselected Japanese patients with ovarian cancer.

Pathogenic germline BRCA1, BRCA2 (BRCA1/2), and several other gene variants predispose women to primary ovarian, fallopian tube, and peritoneal carcinoma (OC), although variant frequency and relevance information is scarce in Japanese women with OC. Using targeted panel sequencing, we screened 230 unselected Japanese women with OC from our hospital-based cohort for pathogenic germline variants in 75 or 79 OC-associated genes. Pathogenic variants of 11 genes were identified in 41 (17.8%) women: 19 (8.3%; BRCA1), 8 (3.5%; BRCA2), 6 (2.6%; mismatch repair genes), 3 (1.3%; RAD51D), 2 (0.9%; ATM), 1 (0.4%; MRE11A), 1 (FANCC), and 1 (GABRA6). Carriers of BRCA1/2 or any other tested gene pathogenic variants were more likely to be diagnosed younger, have first or second-degree relatives with OC, and have OC classified as high-grade serous carcinoma (HGSC). After adjustment for these variables, all 3 features were independent predictive factors for pathogenic variants in any tested genes whereas only the latter two remained for variants in BRCA1/2. Our data indicate similar variant prevalence in Japanese patients with OC and other ethnic groups and suggest that HGSC and OC family history may facilitate genetic predisposition prediction in Japanese patients with OC and referring high-risk patients for genetic counseling and testing.

The effect of a celebrity health disclosure on demand for health care: trends in BRCA testing and subsequent health services use.

In May 2013, an internationally renowned celebrity-Angelina Jolie-disclosed her receipt of BRCA1/BRCA2 (BRCA) testing and subsequent double mastectomy in a highly publicized editorial. Publicity surrounding celebrity health services use increases awareness of important health issues and demand for health services. We aimed to describe BRCA testing trends before and after Jolie's disclosure, breast cancer-related services use following testing, and test reimbursement trends. MarketScan Commercial Claims data were used to compare trends in BRCA testing before and after Jolie's health disclosure using an interrupted time series model among women aged 18-64. We used modified Poisson regression to estimate risks for health services use (surgical consult, mastectomy, mammography, magnetic resonance imaging, genetic counseling) following BRCA testing. BRCA testing rates increased from 12.5 to 19.0 tests/100,000 women between January 2013 and October 2014. Immediately following Jolie's disclosure, testing increased by approximately 37% (p<0.001). Although BRCA testing increased, use of post-testing follow-up services declined after Jolie's disclosure. Mean insurance reimbursement and patient out-of-pocket spending on the test decreased by 3 and 36%, respectively. While genetic testing uptake increased following Jolie's disclosure, subsequent health services use associated with BRCA mutations declined, suggesting that celebrity disclosures may be associated with potential genetic testing overuse.

PO18 BRCA1/BRCA2 (BRCA) testing in young women with breast cancer: patterns; motivations and implications for treatment decisions

PO18 BRCA1/BRCA2 (BRCA) testing in young women with breast cancer: patterns; motivations and implications for treatment decisions

Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers: A WECARE Study Report

BackgroundWomen with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers. MethodsA population-based, nested case–control study was conducted within a cohort of 52,536 survivors of unilateral breast cancer (UBC). Cases were 603 women with CBC and controls were 1199 women with UBC individually matched on age at diagnosis, race, year of first diagnosis and cancer registry. All women were tested for BRCA1 and BRCA2 mutations. Radiation absorbed dose from the initial radiotherapy (RT) to the CBC location within the contralateral breast was reconstructed from measurements in a tissue-equivalent phantom and details available in the therapy records. FindingsAmong women treated with radiation, the mean radiation dose was 1.1Gy (range=0.02–6.2Gy). Risk of developing CBC was elevated among women who carried a deleterious BRCA1/BRCA2 mutation (rate ratio, RR=4.5, confidence interval, CI=3.0–6.8), and also among those treated with RT (RR=1.2, CI=1.0–1.6). However, among mutation carriers, an incremental increase in risk associated with radiation dose was not statistically significant. InterpretationMultiplicative interaction of RT with mutation status would be reflected by a larger association of RT with CBC among carriers than among non-carriers, but this was not apparent. Accordingly, there was no clear indication that carriers of deleterious BRCA/BRCA2 mutations were more susceptible to the carcinogenic effects of radiation than non-carriers. These findings are reassuring and have important clinical implications for treatment decisions and the clinical management of patients harbouring deleterious BRCA1/BRCA2 mutations. FundingAll work associated with this study was supported by the U.S. National Cancer Institute [R01CA097397, U01CA083178].

Molecular pathways: understanding the role of Rad52 in homologous recombination for therapeutic advancement.

The Rad52 protein was largely ignored in humans and other mammals when the mouse knockout revealed a largely "no-effect" phenotype. However, using synthetic lethal approaches to investigate context-dependent function, new studies have shown that Rad52 plays a key survival role in cells lacking the function of the breast cancer type 1 susceptibility protein (BRCA1)-BRCA2 pathway of homologous recombination. Biochemical studies also showed significant differences between yeast and human Rad52 (hRad52), in which yeast Rad52 can promote strand invasion of replication protein A (RPA)-coated single-stranded DNA (ssDNA) in the presence of Rad51 but hRad52 cannot. This results in the paradox of how is hRad52 providing Rad51 function: presumably there is something missing in the biochemical assays that exists in vivo, but the nature of this missing factor is currently unknown. Recent studies have suggested that Rad52 provides back-up Rad51 function for all members of the BRCA1-BRCA2 pathway, suggesting that Rad52 may be a target for therapy in BRCA pathway-deficient cancers. Screening for ways to inhibit Rad52 would potentially provide a complementary strategy for targeting BRCA-deficient cancers in addition to poly (ADP-ribose) polymerase (PARP) inhibitors.

512PD - Portuguese High-Risk Breast/Ovarian Cancer: Survival Analysis

ABSTRACT Introduction Even if only 5–10% of breast cancer (BC) is due to genetic predisposition (mainly related to BRCA1/2 mutations), its incidence, the high risk of these families and the possible prophylactic interventions make the study of these cases relevant. Scarce data suggest different survival in BRCA1 and BRCA2 associated ovarian cancer (OC). We aimed to analyze the survival of our BRCA1/2 BC and OC survivors. Table: 512PD Female breast cancer Ovarian cancer BRCA1 BRCA2 Alu BRCAwt BRCA1 BRCA2 Alu BRCAwt N 33 20 35 302 2 8 8 12 Mean age at diagnosis (y) 43,5 40,1 45,9 68,3 47,2 55,8 Mean OS (months) 107,59 145,23 144,70 78,47 40,45 57,92 86,48 64,14 N of deaths 5 4 7 51 1 4 1 7 Patients and methods Review of all BRCA1/2 cancer survivors identified until September 2011. All patients underwent pre and post-test counselling and were pre-screened for the c.156_157insAlu BRCA2 Portuguese founder mutation [Machado et al, 2007]. Negative patients were further analysed by CSCE and MLPA. Date of diagnosis and survival was obtained for 3 BRCA positive patients subgroups: BRCA1, BRCA2 (non c.156_157insAlu) and Alu (c.156_157insAlu). The control group (BRCAwt ) consisted on index patients screened during the same period, who were not BRCA1/2 positive and for whom we found information in the Southern Portuguese Cancer Registry (ROR-Sul). Results Nine hundred and eighty consecutive index patients were screened and 139 BRCA1/2 positive families were identified: 44 BRCA1 and 95 BRCA2 (44 c.156_157insAlu). A total of 99 BC (88 female + 11 male) and 18 OC were identified in these families. Mean age at diagnosis and overall survival data for the 3 BRCA subgroups and control, regarding BC and OC are resumed in table1. Further clinical characterization (stage, presence of multiple cancers, prophylactic surgeries) is under way. Table1. Overall survival in pts with BC and OC: BRCA1/2 carriers vs wtBRCA1/2. Conclusion BC was the more frequent type of cancer in these patients and BRCA1/2 carriers show a higher overall survival comparatively to BC pts with wt BRCA (P = 0,0197). The overall survival for OC is better for BRCA2 carriers ((P = 0,0310). OC numbers are small and more follow up of these and future identified carriers are needed. Disclosure All authors have declared no conflicts of interest.

Long-Term Psychosocial Outcomes of BRCA1/BRCA2 Testing: Differences across Affected Status and Risk-Reducing Surgery Choice

Numerous studies have documented the short-term impact of BRCA1/BRCA2 (BRCA1/2) testing; however, little research has examined the long-term impact of testing. We conducted the first long-term prospective study of psychosocial outcomes in a U.S. sample of women who had BRCA1/2 testing. Participants were 464 women who underwent genetic testing for BRCA1/2 mutations. Prior to testing, we measured sociodemographics, clinical variables, and cancer specific and general distress. At long-term follow-up (Median = 5.0 years; Range = 3.4-9.1 years), we assessed cancer-specific and genetic testing distress, perceived stress, and perceived cancer risk. We evaluated the impact of BRCA1/2 test result and risk-reducing surgery on long-term psychosocial outcomes. Among participants who had been affected with breast or ovarian cancer, BRCA1/2 carriers reported higher genetic testing distress (β = 0.41, P < 0.0001), uncertainty (β = 0.18, P < 0.0001), and perceived stress (β = 0.17, P = 0.005) compared with women who received negative (i.e., uninformative) results. Among women unaffected with breast/ovarian cancer, BRCA1/2 carriers reported higher genetic testing distress (β = 0.39, P < 0.0001) and lower positive testing experiences (β = 0.25, P = 0.008) than women with negative results. Receipt of risk-reducing surgery was associated with lower perceived cancer risk (P < 0.0001). In this first prospective long-term study in a U.S. sample, we found modestly increased distress in BRCA1/2 carriers compared with women who received uninformative or negative test results. Despite this modest increase in distress, we found no evidence of clinically significant dysfunction. Although a positive BRCA1/2 result remains salient among carriers years after testing, testing does not seem to impact long-term psychologic dysfunction.

Phenocopy breast cancer rates in Israeli BRCA1 BRCA2 mutation carrier families: is the risk increased in non-carriers?

BRCA1 and BRCA2 mutation carriers have an increased risk for developing breast (and ovarian) cancer. Non-carriers from within such families (=true negatives) are counseled that their risk for developing breast cancer is similar to that of the average-risk population. Breast cancer diagnosed in a non-carrier from a family with a known mutation is coined phenocopy. The rate of breast cancer phenocopy and the risk for breast cancer in true negatives are unsettled. The rate of phenocopy breast cancer was assessed in non-carriers from Jewish families with a BRCA1 or BRCA2 mutation, identified at the Sheba medical center. Analysis was performed by t test for comparison of mean age at counseling or breast cancer diagnosis, and by calculating a standardized incidence ratio (SIR). Overall, 1318 females from 884 mutation carrying families (620 with BRCA1 264 with BRCA2 mutations) were genotyped, of whom 307 women from 245 families were assigned a true negative status (mean age at counseling 43.01 ± 13.03 years (range 19.7-92.8 years). Of these true negatives, 20 women (6.51-2.26% of families) developed breast cancer at a mean age of 54.1 ± 12.9 years (range 48.1 -60.1 years). The SIR for breast cancer in true negatives was not significantly different than the expected in the average-risk Israeli population [observed 20-expected 23.8 cases SIR = 0.84, 95% CI (0.51, 1.30)]. The rate of phenocopy breast cancer in non-carriers from Israeli BRCA1 BRCA2 mutation carrier families is 2.26% with no increased breast cancer risk over the average-risk population.