Testing For Hereditary Breast Cancer Research Articles

TP53 p.R337H Germline Variant among Women at Risk of Hereditary Breast Cancer in a Public Health System of Midwest Brazil.

Despite the high prevalence of TP53 pathogenic variants (PV) carriers in the South and Southeast regions of Brazil, germline genetic testing for hereditary breast cancer (HBC) is not available in the Brazilian public health system, and the prevalence of Li-Fraumeni syndrome (LFS) is not well established in other regions of Brazil. We assessed the occurrence of TP53 p.R337H carriers among women treated for breast cancer (BC) between January 2021 and January 2022 at public hospitals of Brasilia, DF, Brazil. A total of 180 patients who met at least one of the NCCN criteria for HBC underwent germline testing; 44.4% performed out-of-pocket germline multigene panel testing, and 55.6% were tested for the p.R337H variant by allelic discrimination PCR. The median age at BC diagnosis was 43.5 years, 93% had invasive ductal carcinoma, 50% had estrogen receptor-positive/HER2 negative tumors, and 41% and 11% were diagnosed respectively at stage III and IV. Two patients (1.11%) harbored the p.R337H variant, and cascade family testing identified 20 additional carriers. The TP53 p.R337H detection rate was lower than that reported in other studies from south/southeast Brazil. Nonetheless, identifying TP53 PV carriers through genetic testing in the Brazilian public health system could guide cancer treatment and prevention.

Limitations in next-generation sequencing-based genotyping of breast cancer polygenic risk score loci

Considering polygenic risk scores (PRSs) in individual risk prediction is increasingly implemented in genetic testing for hereditary breast cancer (BC) based on next-generation sequencing (NGS). To calculate individual BC risks, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) with the inclusion of the BCAC 313 or the BRIDGES 306 BC PRS is commonly used. The PRS calculation depends on accurately reproducing the variant allele frequencies (AFs) and, consequently, the distribution of PRS values anticipated by the algorithm. Here, the 324 loci of the BCAC 313 and the BRIDGES 306 BC PRS were examined in population-specific database gnomAD and in real-world data sets of five centers of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), to determine whether these expected AFs can be reproduced by NGS-based genotyping. Four PRS loci were non-existent in gnomAD v3.1.2 non-Finnish Europeans, further 24 loci showed noticeably deviating AFs. In real-world data, between 11 and 23 loci were reported with noticeably deviating AFs, and were shown to have effects on final risk prediction. Deviations depended on the sequencing approach, variant caller and calling mode (forced versus unforced) employed. Therefore, this study demonstrates the necessity to apply quality assurance not only in terms of sequencing coverage but also observed AFs in a sufficiently large cohort, when implementing PRSs in a routine diagnostic setting. Furthermore, future PRS design should be guided by the technical reproducibility of expected AFs across commonly used genotyping methods, especially NGS, in addition to the observed effect sizes.

Evaluation of hereditary/familial breast cancer patients with multigene targeted next generation sequencing panel and MLPA analysis in Turkey

Breast cancer, a worldwide leading cause of cancer in women, may occur in familial cases. Germline mutations in BRCA1/2 genes are responsible for 15% of the familial cases. With the power of next generation sequencing (NGS) analysis, it is possible to analyze genes related to hereditary susceptibility to breast cancer and investigate the genetic etiology more thoroughly.In this study, we investigated 30 genes identified frequent pathogenic alleles in Turkish population. The study includes 495 unrelated individuals diagnosed with breast cancer who are selected for genetic testing according to NCCN criteria for hereditary breast cancer. All patients were analyzed by NGS for BRCA1/2 genes. Deletion/duplication investigation by Multiplex ligation-dependent probe amplification (MLPA) and massive sequencing of 30 breast cancer-related genes (Oncorisk Gene Panel) were performed in a stepwise manner.BRCA1/2 variants are the most frequent pathogenic variants which are found in 45 of 495 (9.1%) patients. Four previously unreported, novel, pathogenic variants of BRCA2 gene are identified. In four cases, exonic deletions of BRCA1/2 genes are determined and there is no duplication of these genes. NGS panel investigation involving other moderate-high risk genes contributed genetic diagnosis in an extra 39 out of 419 (9.3%) cases.Our study presents the cost effectiveness of the gene panel approach. We suggest that gene panels should be the first-tier genetic testing for hereditary breast cancer and MLPA analysis of BRCA1/2 genes should be investigated as a complementary method of NGS analysis.

Abstract P2-09-10: Different CNVs account for 10.4% of pathogenic variants in 1418 patients referred for hereditary breast cancer testing

Abstract Background: Breast cancer is the most frequently diagnosed cancer in women and about 10% of breast cancer cases are hereditary. BRCA1 and BRCA2 are the genes most frequently associated with Hereditary Breast Cancer, although there are numerous other genes, such as PALB2, CHEK2 and ATM, that require to be considered as well. Germline Copy Number Variation (CNV) is one mutation type that is an important contributor to hereditary breast cancer. Nowadays, next-generation sequencing (NGS) technologies has contributed to multi-gene panel analysis used in clinical practice. Methods: In total, 1418 individuals were tested for breast cancer predisposition, using a solution-based capture approach. Targeted NGS was performed with a panel of 36 genes. The capture-based approach allowed for computational analysis of CNVs from NGS data. Results: We investigate the performance of the CNV module of the commercial software suite SeqPilot (JSI Medical Systems) and the non-commercial tool panelcn.MOPS. Both algorithms are specifically developed for CNV analysis of sequencing data reporting 99-100% sensitivity and up to 100% specificity for the prediction of CNVs up to the level of a single gene exon. All CNVs detected with these algorithms were then verified experimentally using the MLPA technique as an orthogonal assay. At least one pathogenic/likely pathogenic variant was identified in 289 samples (20.4%). CNVs accounted for 10.4% (30/289), referring to the deletion of one or more exons of a gene. Interestingly, 50% of deletions were single exon and approximately 36% of CNVs were detected in genes other than BRCA1/2. In specific, of the 30 CNVs detected, 60% occurred in BRCA1, 3.3% in BRCA2, 20% in CHEK2, 6.7% in FANCA, 6.7% in PMS2, and 3.3% in ATM. The majority of CNVs in BRCA1 were deletions of exons 19, 22, and 22-23 whereas deletions of exons 9-10 were the most common deletions in CHEK2. Detailed information of all CNVs detected is provided in Table 1. Conclusions: Our results suggest that CNV analysis should not be restricted to BRCA1/2 due to the significant proportion of CNVs (36%) in additional breast cancer predisposition genes. Furthermore, in silico CNV detection tools provide a cost-effective and feasible methodology for the identification of CNVs from NGS experiments. This outlines the clinical utility of comprehensive genetic testing that includes full sequencing and CNV analysis in hereditary breast cancer facilitating personalized management decisions for patients. Table 1.Pathogenic Copy Number Variations (CNVs) identified in this studyGeneHGVS nomenclatureOther nomenclature# detectedATMNM_000051:c.(-30+1_-29-1)_(331+1_332-1)deldeletion of exons 2-41BRCA1NM_007294:c.(5467+1_5468-1)-(*1_?)deldeletion of exon 237BRCA1NM_007294:c.(5406+1_5407-1)_(*1_?)deldeletion of exons 23-245BRCA1NM_007294:c.(5193+1_5194-1)-(5277+1_5278-1)deldeletion of exon 196BRCA2NM_000059:c.(6841+1_6842-1)_(7007+1_7008-1)deldeletion of exons 12-131CHEK2NM_007194:c.(908+1_909-1)_(1095+1_1096-1)deldeletion of exons 9-104CHEK2NM_007194:c.(792+1_793-1)_(846+1_847-1)deletion of exon 72FANCANM_000135:c.(1626+1_1627-1)_ (2852+1_2853-1)deldeletion of exons 18-291FANCANM_000135:c.(893+1_894-1)_(1359+1_1360-1)deldeletion of exons 11-141PMS2NM_000535: c.(903+1_904-1)_(988+1_989-1)deldeletion of exon 91PMS2NM_000535:c.(705+1_706-1)_(2006+1_2007-1)deldeletion of exons 7-111 Citation Format: Nikolaos Tsoulos, Konstantinos Agiannitopoulos, Georgia Pepe, Eirini Papadopoulou, Georgios N Tsaousis, Despina Apostolopoulou, Angeliki Meintani, Vassileios Venizelos, Christos Markopoulos, Rodoniki Iosifidou, Sofia Karageorgopoulou, Christos Christodoulou, Ioannis Natsiopoulos, Konstantinos Papazisis, Maria Vasilaki-Antonatou, Eleftherios Kabletsas, Amanta Psyrri, Stylianos Giassas, Dimitrios Ziogas, Efthalia Lalla, Anna Koumarianou, Christos Papadimitriou, Vahit Ozmen, Sualp Tansan, Kerim Kaban, Tahsin Ozatlı, Dan Tudor Eniu, Angelica Chiorean, Alexandru Blidaru, George Nasioulas. Different CNVs account for 10.4% of pathogenic variants in 1418 patients referred for hereditary breast cancer testing [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-10.

Association Between Genetic Testing for Hereditary Breast Cancer and Contralateral Prophylactic Mastectomy Among Multiethnic Women Diagnosed With Early-Stage Breast Cancer.

Increasing usage of multigene panel testing has identified more patients with pathogenic or likely pathogenic (P or LP) variants in low-moderate penetrance genes or variants of uncertain significance (VUS). Our study evaluates the association between genetic test results and contralateral prophylactic mastectomy (CPM) among patients with breast cancer. We conducted a retrospective cohort study among women diagnosed with unilateral stage 0-III breast cancer between 2013 and 2020 who underwent genetic testing. We examined whether genetic test results were associated with CPM using multivariable logistic regression models. Among 707 racially or ethnically diverse women, most had benign or likely benign (B or LB) variants, whereas 12.5% had P or LP and 17.9% had VUS. Racial or ethnic minorities were twice as likely to receive VUS. Patients with P or LP variants had higher CPM rates than VUS or B or LB (64.8% v 25.8% v 25.9%), and highest among women with P or LP variants in high-penetrance genes (74.6%). On multivariable analysis, P or LP compared with B or LB variants were significantly associated with CPM (odds ratio = 4.24; 95% CI, 2.48 to 7.26). Women with P or LP variants on genetic testing were over four times more likely to undergo CPM than B or LB. Those with VUS had similar CPM rates as B or LB. Our findings suggest appropriate genetic counseling and communication of cancer risk to multiethnic breast cancer survivors.

Abstract 813: Clinical significance of pathogenic variants in germline BRCA1/2 wild type patients at risk for hereditary breast cancer

Abstract Objectives: Approximately, 5-10% of breast cancer (BC) are related to inherited germline mutations. Homologous recombination repair (HRR) of DNA is the most important theory in hereditary cancer, in which BRCA1/2 are the most recognized and tested genes. Genetic testing for hereditary BC has changed significantly. Increasing evidence suggests parallel multigene testing of HRR gene. Methods: NGS-based germline multigene-panel testing of 105 HRR gene was performed on 159 high risk BC patients with at least one of the following risk factors: triple negative BC, early onset (≤45y), family history of BC and bilateral BC. Capture-base targeted sequencing was performed on white blood cells using a panel consisting of 105 genes related to homologous recombination repair of DNA. Results: Among the 159 patients of median age 40, All the patients had early stage infiltrating ductal carcinoma. 12 patients (7.55%) had pathogenic BRCA1/2 mutation. We investigated the prevalence of 21 pathogenic germline pathogenic mutations beyond BRCA1/2 from 21 patients spanning 13 HRR genes, resulting in a prevalence rate of 13.21% for pathogenic germline mutations in high risk germline BRCA1/2 WT BC patients. PALB2 is the most common gene with pathogenic mutation (n=5). In these 21 patients, 18 (85.71%) were diagnosed with BC before the age of 45, within 7 patients (33.33%) even younger than 35 years old. 7 of them (33.33%) had bilateral BC; one had triple negative BC (4.76%) and 5 patient (23.81%) had a family history of BC. Nearly half of the patients (n=9) presented at least 2 of the risk factors. Conclusions: Our study confirms the clinical significance of testing non-BRCA genes, and suggests multigene panel testing for patients at risk for hereditary BC as a routine in patients with those risk factors, especially young and bilateral BC patients even without family history of BC. Citation Format: Xiaying Kuang, Nan Shao, Ying Lin. Clinical significance of pathogenic variants in germline BRCA1/2 wild type patients at risk for hereditary breast cancer [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 813.

Genetic Variation and the Role of Multigene Panel Testing for Hereditary Breast Cancer: A Single-Institution Experience.

BackgroundBreast cancer is the second leading cause of cancer death in women. There are multiple pathogenic mutations in addition to BRCA1/2 that are implicated in causing hereditary breast cancer.Methods and resultsWe conducted a retrospective analysis of 1568 patients with breast cancer diagnosed between January 1, 2015, and December 31, 2018. The age range is 23-87. Among the study population, 26% had genetic testing and 8% of those were found to carry a pathogenic variant, as designated in NCCN (National Comprehensive Cancer Network) Guidelines. Of that 8%, 3.4% were BRCA1 and BRCA2 mutations, and the rest were other prevalent pathogenic variants.DiscussionExpanded panel testing has the potential to increase the detection rate of pathogenic variants compared to testing for BRCA1/2 alone. Diagnostic accuracy of genetic causes of breast cancer has a significant clinical impact on patients and their families in terms of targeted treatment and prevention strategies. There is a strong need for further understanding of genetic patterns and variations in hereditary breast cancer. Awareness of the possibility of moderate to low penetrance genes and variants of uncertain significance (VUS) is important to assist with appropriate genetic counseling. We believe that physicians should consider re-testing with an expanded panel if patients previously had BRCA1 and BRCA2 testings only with a negative result as it may identify additional mutations.

Genetic testing and surgical treatment after breast cancer diagnosis: Results from a national online cohort.

Genetic testing for hereditary breast cancer has implications for breast cancer decision-making. We examined genetic testing rates, factors associated with testing, and the relationship between genetic testing and contralateral prophylactic mastectomy (CPM). Patients with breast cancer (2000-2015) from The Health of Women Study were identified and categorized as low, moderate, or high-likelihood of the genetic mutation using a previously published scale based on period-relevant national guidelines incorporating age and family history. Genetic testing and CPM rates were compared using univariate and multivariate logistic regression. Among 4170 patients (median age 56-years), 38% were categorized as high-likelihood of having a genetic mutation. Among high-likelihood women, 67% underwent genetic testing, the odds of which were increased among women of higher-education and White-race (p < .001). Among 2028 patients reporting surgical treatment, 385 (19%) chose CPM. CPM rate was highest among mutation-positive women (41%), but 26% of women with negative tests still underwent CPM. Independent of test result, genetic testing increased the odds of CPM on multivariate analysis (adjusted-OR: 1.69; 95% CI: 1.29-2.22). Genetic testing rates were higher among women at high-likelihood of mutation carriage, but one-third of these women were not tested. Racial disparities persisted, highlighting the need to improve testing in non-White populations. CPM rates were associated with mutation-carriage and genetic testing, but many women chose CPM despite negative testing, suggesting that well-educated women consider factors other than cancer mortality in selecting CPM.

Abstract PS8-08: Impact of genetic testing for hereditary breast cancer on screening and risk-reducing surgeries among multi-ethnic breast cancer survivors

Abstract Introduction Current guidelines for cancer risk management for hereditary breast cancer focus on individuals with pathogenic/likely pathogenic variants (P/LP) in high penetrance genes. There is little consensus on prophylactic mastectomy for low/moderate penetrance genes or variants of uncertain significance (VUS). Furthermore, many guidelines for enhanced breast cancer screening are targeted to unaffected carriers, but not breast cancer survivors. Given the increasing use of multigene panel testing, more patients are receiving results of P/LP in low/moderate penetrance genes or VUSs. We aimed to investigate how multigene panel results impacted surgical and screening decisions among breast cancer patients. Methods We conducted a retrospective analysis of women diagnosed with stage 0-III breast cancer at Columbia University Irving Medical Center in 2013 or later, who received germline genetic testing. Clinical data were extracted from the electronic health record (EHR), tumor registry, and genetic testing portals. Patients were excluded if they had stage IV disease at diagnosis, had bilateral mastectomy before 2013, or had missing genetic test results or surgical reports. For the screening analysis, patients were excluded if they had bilateral mastectomy or did not have breast imaging in the EHR. Surgery type was defined by the most advanced breast surgery received. Enhanced screening was defined as use of breast ultrasound or MRI in the absence of breast symptoms and in the setting of a normal mammogram. Univariable and multivariable analyses were performed to assess the association between clinical factors and receipt of bilateral mastectomy or enhanced screening. Results Among 715 evaluable women, about two-thirds were 50 years or younger, with 45% white, 12% black, 27% Hispanic, 11% Asian, and 4% other. Most patients (69.5%) had benign/likely benign (B/LB) genetic test results, while 91 (12.7%) had P/LP and 127 (17.8%) had VUS. VUS rates were higher among racial/ethnic minorities (27% Asian, 25% Hispanic, 19% black) compared to white women (10%). About 31% of women underwent bilateral mastectomy, 25% unilateral mastectomy, and 45% lumpectomy. Bilateral mastectomy rates among patients with P/LP variants were higher compared to those with VUS or B/LB results (66% vs. 27% vs. 26%), particularly P/LP in high-penetrance genes (76%) compared to other genes (45%). On multivariable analysis, compared to patients with B/LB genetic results, P/LP was significantly associated with bilateral mastectomy (odds ratio [OR]=5.72, 95% confidence interval [CI]=3.43-9.53). Younger age at diagnosis and family history of breast cancer were also associated with bilateral mastectomy. Among patients with breast cancer screening data, almost half (43%) received enhanced screening (59% ultrasound, 25% MRI, 16% both). On multivariable analysis, patients with P/LP variants and age of diagnosis under 50 were more likely to receive enhanced screening (OR=4.43, 95% CI=1.59-12.33 and OR=1.92, 95% CI=1.09-3.38, respectively). Hispanic women compared to non-Hispanic whites and those with Medicaid rather than private health insurance were less likely to undergo enhanced screening. Conclusions We demonstrated that detection of P/LP variants on multigene panel testing influences surgical and screening decisions among breast cancer patients. Patients with VUS, a group enriched for racial/ethnic minorities, appropriately have similar surgical and screening decisions as those with B/LB results. Our findings suggest adequate genetic counseling and communication of cancer risk to multi-ethnic breast cancer survivors. Citation Format: Vicky Ro, Tarsha Jones, Meghna S Trivedi, Julia E McGuinness, Thomas Silverman, Wendy K Chung, Rita Kukafka, Katherine D Crew. Impact of genetic testing for hereditary breast cancer on screening and risk-reducing surgeries among multi-ethnic breast cancer survivors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-08.

Abstract PS8-16: Differences in the benefit of multi-gene panel (MGP) genetic testing between African American and white women with invasive breast cancer

Abstract Background: Up to 10% of breast cancers are hereditary. Pathogenic variants (PV) in the BRCA1/2 genes are responsible for two thirds of hereditary breast cancer (BC). Additional non-BRCA genes (ATM, CHEK2, PALB2, etc.) have been identified as predisposing for BC. While genetic testing(GT) for hereditary BC traditionally involved testing mostly for mutations in the BRCA1/2 genes, next generation sequencing has enabled multiple BC genes to be simultaneously tested at a cost often lower than testing for BRCA1/2 alone. Consequently, MGP testing has been rapidly replacing BRCA1/2 only testing. Studies have demonstrated that MGP testing doubles the detection of PV. Because prior studies examining MGP findings have been mostly conducted in predominantly white populations, it is unknown if the use of MGP testing in African-American (AA) patients also results in increased detection of non-BRCA mutations and whether there are significant differences in the prevalence of PV between AA and white women with invasive BC. In this study, we sought to compare the rate and spectrum of PV between AA and White women with invasive BC undergoing MGP testing. Methods: In this retrospective study, we assessed the prevalence of PV and spectrum of mutations among a cohort of 680 racially diverse women diagnosed with invasive BC who underwent GT with a MGP between 2014 and 2019 at a single cancer center. This analysis included participants who had a documented diagnosis of invasive BC and completed MGP testing. Fisher’s exact tests were used to analyze differences between racial groups. Subjects previously signed informed consent to participate in research. Results: 680 women with invasive BC were included in the study. The study population was 79.4% non-Hispanic white, 10.6% AA, and 10% other. PV were identified in 13.4 % of the overall population. The prevalence of PV was 15.5% (84/540) in AA compared to 8.3% (6/72) in white women, but this difference was not statistically significant (p=0.14). In white women, the prevalence of PV was 5.9% (32/540) in BRCA1/BRCA2 and 9.6% (52/540) in non-BRCA genes. MGP testing allowed for the detection of 52 non-BRCA PV, including BC genes (CHEK2-17, ATM-7, PALB2-4, CDH1-2, BARD1-1, TP53-1, RAD50-1) and non-BC genes (MUTYH-8, NTHL1-2, BRIP1-2, PMS2-2, RAD51C-1, RAD51D-1, MSH6-1, FH-1, MITF-1). In AA patients, the prevalence of PV was 6.9% in BRCA1/2 and 1.4% in non-BRCA genes. MGP testing in AA women with invasive BC detected only one non-BRCA mutation in the gene MUTYH. VUS rates were higher in AA, 29.2% compared to whites, 19.3% with a trend towards a statistically significant difference (p=0.07). Conclusions: While MGP testing more than doubled the detection rate of PV in white patients with BC by detecting various non-BRCA PV, for AA patients the use of MGP testing did not result in many additional non-BRCA PV being identified in this analysis. However, MGP testing did result in a high VUS rate, 19.3%, without the added value of detecting additional PV that could be helpful to the patient and their family members by expanding opportunities for cancer prevention and early detection. We acknowledge that in this study sample of 10.6% AA women, this is an under-representation. Large population-specific studies should be done to confirm those findings. Given the known psychological harms to the patient and their family members in response to the uncertainty of VUS findings as well as the possible mismanagement of VUS results, well-designed studies should investigate the selection of who to consider for MGP testing rather than BRCA1/2 testing for hereditary BC to ensure that the benefits of MGP testing over BRCA1/2 only testing outweigh the risks associated with panel testing. Citation Format: Kristen Whitaker, Nicole Ventriglia, Karthik Devarajan, Elias Obeid. Differences in the benefit of multi-gene panel (MGP) genetic testing between African American and white women with invasive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-16.

How patients deal with an ambiguous medical test: Decision-making after genetic testing

ObjectiveWe know little about how patients make decisions when they receive a variant of uncertain significance result (VUS) from genetic testing. The purpose of this study was to elucidate a model of patient-informed decision-making after receiving a VUS result. MethodsUsing an adapted Mental Models Approach, we conducted semi-structured interviews with women who received a VUS result from genetic testing for hereditary breast cancer (N = 20) to explore factors they believed were relevant to their decision-making. Two coders used a coding scheme informed by experts in hereditary breast cancer to conduct analysis. Inter-coder reliability was α = .86. ResultsThree overarching decision themes emerged from the interviews: managing ambiguity, medical risk management, and sharing results with others. While participants noted some difficulty understanding their result, genetic counselors’ interpretations, psychosocial factors (e.g., risk perceptions), and competing extrinsic demands influenced their decisions. ConclusionComplex influences affect patient decision-making after a VUS result from genetic testing and may encourage health protective behavior. Practice ImplicationsEven patients who understand their test result could use support managing the ambiguity of their test result and sharing it with others.

Electronic health records contain dispersed risk factor information that could be used to prevent breast and ovarian cancer.

ObjectiveThe genetic testing for hereditary breast cancer that is most helpful in high-risk women is underused. Our objective was to quantify the risk factors for heritable breast and ovarian cancer contained in the electronic health record (EHR), to determine how many women meet national guidelines for referral to a cancer genetics professional but have no record of a referral.Methods and MaterialsWe reviewed EHR records of a random sample of women to determine the presence and location of risk-factor information meeting National Comprehensive Cancer Network (NCCN) guidelines for a further genetic risk evaluation for breast and/or ovarian cancer, and determine whether the women were referred for such an evaluation.ResultsA thorough review of the EHR records of 299 women revealed that 24 (8%) met the NCCN criteria for referral for a further genetic risk evaluation; of these, 12 (50%) had no referral to a medical genetics clinic.ConclusionsHalf of the women whose EHR records contain risk-factor information meeting the criteria for further genetic risk evaluation for heritable forms of breast and ovarian cancer were not referred.

A Modern Dilemma: How Experts Grapple with Ambiguous Genetic Test Results

Objective. Clinicians regularly use panel genetic testing to identify hereditary breast cancer risk, but this practice increases the rate of receiving an ambiguous test result, the variant of uncertain significance (VUS). VUS results are a growing and long-term challenge for providers and have caused negative patient outcomes. The objective of this study was to elicit expert opinions about patients' decision making after receiving a VUS result to provide future guidance for VUS disclosure. Methods. Using an adapted mental models approach, experts (N = 25) completed an online survey and in-depth interview eliciting qualitative judgments of the factors relevant to informed patient decision making after receiving a VUS result. Content analysis of interview transcripts clarified the basis for these judgments. Results. Participants identified 11 decisions facing patients after receiving VUS results grouped into ambiguity management or risk management. The experts also identified 24 factors relevant to each decision, which reflected 2 themes: objective factors (e.g., clinical information, guidelines) and psychosocial factors (e.g., understanding or risk perception). Conclusion. This study presents an adaptation of the mental models approach for communication under conditions of ambiguity. Findings suggest providers who present VUS results from genetic testing for hereditary breast cancer should discuss decisions related to ambiguity management that focus on hope for future reclassification, and be directive when discussing risk management decisions. Objective and psychosocial factors should influence both ambiguity and risk management decisions, but especially risk management decisions.

Abstract D006: Community Research Collaboration to develop a promotor-based hereditary breast cancer education program for Spanish-speaking Latinos

Abstract Breast cancer is the most common cancer in Latinas and the leading cause of cancer death. Latinas tend to be diagnosed later, have poorer survival rates, and receive poorer quality care than white women. It has been well documented that women at high risk for hereditary breast cancer (women with strong family history, or BRCA1 or BRCA2 carriers) greatly benefit from genetic counseling, which enhances early cancer detection or risk-reduction strategies. Despite the growing availability of genetic counseling and testing for hereditary breast cancer, awareness and use of these services is low among Latinas. We developed a comprehensive, culturally-appropriate set of materials for a community health educator (promotor)-led hereditary breast cancer educational program for the Latino community. The conceptual framework used to design didactic curriculum and the program structure was based on the construct of “relational culture.” Materials were developed through an iterative process that involved exposure of the target populations to draft materials, discussion, and modification of materials. The focus groups took place in the cities of San Francisco, San Jose, Concord and Pittsburg between March 2018 and May 2019. We conducted 7 focus groups, including a total of 68 women (35 promotores, and 33 community members). On average, participants were 43 years old (SD= 11.62), and had been living in the U.S. for 16 years (SD= 7.55). Approximately eighty percent of the sample had limited English proficiency, fifty-one percent had public insurance, and forty-nine percent had a high school education. Sixty percent of them were unemployed, and seventy-two percent were born in Mexico. The conversation during the focus group sessions was directed towards hereditary breast cancer baseline knowledge, perceptions and learning preferences among Spanish-speaking Latino participants. A thematic analysis of the focus groups yielded five main themes: barriers, importance, dissemination, educational, and culture. 1) Barriers referred to the program’s ability to overcome traditional barriers to healthcare for Latinos; 2) Importance related to the significance of the program’s content; 3) Dissemination referred to the easiness and value of disseminating the information covered in the program; 4) Educational related to the program’s informational nature; and 5) culture referred to the program being perceived as culturally-appropriate. Results revealed that participants thought the materials were easy to understand, attractive, and engaging. They believed that the content would be easy to disseminate and important to the community. However, given that the materials encompassed genetics content, some promotores and community members expressed confusion, and feeling overwhelmed. To address this, materials were simplified, and additional didactic content was included. Future research is needed to determine the impact of the educational program on genetic counseling and screening behavior. Citation Format: Rebeca Almeida, Alejandra Lopez-Macha, Tania Dugatkin, Ysabel Duron, Laura Fejerman. Community Research Collaboration to develop a promotor-based hereditary breast cancer education program for Spanish-speaking Latinos [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D006.

Panel Testing for Hereditary Breast Cancer: More or Less?

Panel testing is increasingly being offered to patients. Currently, women may be offered a panel of up to 80 genes. Oncologists are tasked with understanding the indications for this testing as well as the potential implications. In this review, we outline which patients should undergo genetic testing for hereditary breast cancer, when this testing should be performed, and which genes should be tested for. Our understanding of hereditary breast cancer has drastically changed with the advent of next generation sequencing (NGS), and many additional genes have been associated with increased breast cancer risk. Some have advocated for genetic testing of all women with breast cancer. Routine genetic testing for all women with breast cancer is not warranted. Women with a phenotype associated with hereditary breast cancer, with a family history of cancer, or for whom a positive genetic test would change management should be offered genetic testing.

Points to consider: is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG)

Points to consider: is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG)

Abstract P6-08-06: Characteristics of ductal carcinoma in situ (DCIS) in patients who underwent multigene panel testing for hereditary breast cancer

Abstract Background: Multigene panel testing (MPG) for hereditary breast cancer has recently increased significantly. While clinical and pathological characteristics for invasive breast cancer in patients with non BRCA germline mutations is emerging, there is very limited data in patients with ductal carcinoma in situ (DCIS). This study evaluates the clinical and pathological characteristics of patients with DCIS who underwent MPG testing for hereditary breast cancer. Methods: Patients with DCIS who underwent MPG testing between 2014-2019 were identified from our prospectively maintained and IRB-approved research registry study and included in this analysis. Clinical and tumor characteristics were analyzed using descriptive statistics. Variables included in the analysis included: Age at diagnosis, family history of breast and ovarian cancer, tumor characteristics including ER/PR and nuclear grade and genetic testing results. Results: In this prospective cohort, 324 patients with DCIS underwent multigene panel testing. Age of diagnosis was 50.5 years (range: 18-86), a family history of breast and/or ovarian cancer was positive in 283 (87.3%) patients. Genetic testing results were as follows: Pathogenic or likely pathogenic mutations were found in 28 (8.6%) patients: BRCA1 2 (7.1%), BRCA2 6 (21.4%), PALB2 6 (21.4%), CHEK2 5 (17.9%), ATM 3 (10.7%), APC 2 (7.1%), BARD1 1 (3.6%), BRIP1 1 (3.6%), MSH2 1 (3.6%), MUTYH 1 (3.6%). The variant of uncertain significance rate was 16% (52): 7 (13.5%) in BRCA1 or 2 and 45 (86.5%) in other genes. 244 (75.3%) of patients had negative results. Conclusion: Our data demonstrates that, in addition to BRCA 1 and 2 genes, patients with DCIS have other hereditary genes involved. In fact, 71.4% of the germline mutations were in non-BRCA genes. Regardless of gene status, most patients had ER positive disease, this can have implications for chemopreventive therapy. Furthermore, patients with germline mutations have a higher percentage of nuclear grade III DCIS than gene negative patients. Larger studies are needed to evaluate the clinical implications of these findings. Genetic testing with a larger panel, other than BRCA1 and BRCA2 genes only, should be considered for patients with DCIS. NegativeBRCA1+BRCA2+PALB2+CHEK2+ATM+Variablesn%n%n%n%n%n%ERpositive17471.32100.0583.3350.0480.03100.0negative187.400.000.0116.7120.000.0unknown5120.900.0116.7233.300.000.0PRpositive15262.3150.0583.3350.0480.03100.0negative3815.6150.000.0116.7120.000.0unknown5422.100.0116.7233.300.000.0NGI187.4150.000.000.0240.000.0II10041.000.0116.7350.0240.0133.3III8534.8150.0466.7233.300.0266.7unknown4116.800.0116.7116.7120.000.0Totals244100.02100.06100.06100.05100.03100.0 Citation Format: Loredana Militello, Angelica M Gutierrez Barrera, Henry Kuerer, Constance Albarracin, Banu K Arun. Characteristics of ductal carcinoma in situ (DCIS) in patients who underwent multigene panel testing for hereditary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-06.

Abstract ES6-1: Who should have germline testing for hereditary breast cancer?

Abstract Who should have germline testing for hereditary breast cancer? Several guidelines exist for who should be offered germline testing for mutations in breast and ovarian cancer susceptibility genes. NCCN guidelines currently recommend germline BRCA testing for all patients with epithelial ovarian /fallopian tube/primary peritoneal cancer, pancreatic cancer, metastatic/advanced prostate cancer. Testing is also recommended for anyone for whom a BRCA mutation has been identified in the family or for whom a tumor somatic BRCA mutation has been identified (in any tumor type). Among breast cancer patients, NCCN testing criteria include: young age at diagnosis, triple negative disease, Ashkenazi Jewish heritage, male gender, and a personal or family history of ovarian, pancreatic cancer, aggressive prostate cancer or other breast cancer. This year, USPSTF updated their genetic testing guidelines for BRCA1/2. These updates will be reviewed. It is important not to forget testing for germline mutations in other high-penetrance breast cancer susceptibility genes and to retest individuals who previously had BRCA genetic testing and may be appropriate candidates for multi-gene testing. Recently, the American Society of Breast Surgeons has endorsed germline testing for mutations in BRCA1/2 and PALB2 for all breast cancer patients. Data that led to this recommendation will be reviewed as well as arguments for and against this recommendation. It is noteworthy that only 0.6% of breast cancer patients who did not meet current NCCN guidelines for genetic testing were found to have a germline mutation in BRCA1 or BRCA2 and 0.8% in any high-penetrance breast cancer susceptibility gene. It is important for oncologists to be able to recognize which findings on a tumor genomic profile should prompt a recommendation for germline testing. This includes the ability to recognize cancer susceptibility genes amongst the list of actionable findings endorsed by the ACMG, as well as cancer susceptibility genes for which there are published management recommendations. Recently, it has been recommended that germline BRCA testing be offered to all Ashkenazi Jewish individuals regardless of personal or family history of cancer since one in forty Ashkenazi individuals have a mutation in one of three BRCA founder mutations. BRCA mutations are 10 times more common in people with Ashkenazi Jewish ancestry, and up to half of BRCA mutations in this population occur in individuals without a known family history. Three-site Ashkenazi BRCA testing allows streamlined inexpensive BRCA testing without variants of unknown significance (VUS). One concern relates to how large population testing can be carried out, highlighting the need for new genetic testing service models. Finally, arguments for and against population genetic testing for non-Ashkenazi individuals will be discussed. As the likelihood of identifying a mutation and the penetrance of the mutations identified decreases, and the frequency of VUS increases, the potential for causing harm through unnecessary screening and prevention strategies can outweigh the benefit of providing cancer risk information through testing. Citation Format: N Tung. Who should have germline testing for hereditary breast cancer? [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES6-1.

Abstract P6-08-11: Association between genetic testing for hereditary breast cancer and contralateral prophylactic mastectomy among young women diagnosed with early-stage breast cancer

Abstract Background: Contralateral prophylactic mastectomy (CPM) is a risk-reducing surgery offered to women with unilateral breast cancer intended to reduce the risk of contralateral breast cancer. The rate of CPM among women with unilateral early-stage breast cancer has risen in the United States over the past two decades, despite limited evidence for a survival benefit in the majority of patients. We evaluated sociodemographic and clinical factors, including receipt and results of BRCA1/2 genetic testing or multigene panel testing, associated with CPM among young women with unilateral early-stage breast cancer. Methods: We conducted a retrospective cohort study of women diagnosed with unilateral stage 0-III breast cancer at age ≤ 50 years between January 2007 and December 2017 at Columbia University Irving Medical Center (CUIMC) in New York, NY. Patients with bilateral breast cancer, male breast cancer, metastatic disease, or missing breast surgery information were excluded from the analysis. Demographics (age, race/ethnicity, marital status, primary health insurance) and clinical information (stage and year of diagnosis, family history of breast cancer) were collected from the electronic health record (EHR) and New York Presbyterian Hospital (NYPH) Tumor Registry. We also determined receipt of genetic testing (yes/no) and results (pathogenic/likely pathogenic [P/LP], variant of uncertain significance [VUS], negative). The primary outcome of interest was receipt of CPM. Multivariable logistic regression models were used to assess the association between demographic and clinical factors, including receipt and results of genetic testing, and CPM. Results: Among the 1207 women who met inclusion criteria, median age was 42.9 years (standard deviation [SD], 5.7 years), and 43% identified as non-Hispanic white, 27% Hispanic, 13% non-Hispanic black, 10% Asian, and 7% other. Nearly half (49.5%, N=597) underwent germline genetic testing for cancer susceptibility genes, and of those tested, 12.6% had P/LP variants (of which 69.3% were in BRCA1/2), 14.2% had VUSs, and 73.2% had negative results. Over one-quarter (27.7%, N = 334) underwent CPM, 29.8% had a unilateral mastectomy and 42.5% had lumpectomy. In multivariable analysis, women with a younger age at diagnosis, more advanced stage disease, and a family history of breast cancer were more likely to undergo CPM. There were no differences in CPM rates by primary health insurance. Asian women were less likely to undergo CPM compared to non-Hispanic white women (odds ratio [OR]=0.56, 95% confidence interval [CI]=0.34-0.95). Compared to women who did not undergo genetic testing, CPM rates were higher among those who had a P/LP variant (OR=5.12, 95% CI=2.94-8.89), those who had a VUS (OR=1.94, 95% CI=1.23-3.36) or negative results (OR=1.51, 95% CI=1.09-2.09). From 2007 to 2017, rates of genetic testing uptake in the study population increased from 17.9% to 67.1%, and CPM rates increased from 15.2% to 30.0%. Conclusions: Among young women with unilateral early-stage breast cancer, CPM rates were relatively high and increased over time. Women with P/LP variants were over 5 times more likely to undergo CPM compared to those who did not undergo genetic testing, however, even those with VUS or negative results were over 50% more likely to undergo CPM. The American Society of Breast Surgeons now recommends genetic testing for hereditary breast cancer among all women diagnosed with breast cancer. As multigene panel testing is increasingly utilized among women with breast cancer, further evaluation of its role in decisions regarding risk-reducing surgery such as CPM is warranted, particularly given the unclear implications of moderate-risk pathogenic variants and VUS results on contralateral breast cancer risk. Citation Format: Julia E McGuinness, Boya Guo, Meghna S Trivedi, Tarsha Jones, Wendy K Chung, Roshni Rao, Elana Levinson, Carrie Koval, Donna Russo, Ilana Chilton. Association between genetic testing for hereditary breast cancer and contralateral prophylactic mastectomy among young women diagnosed with early-stage breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-11.

Abstract P6-08-32: Genetic variation and the role of multi-gene testing for hereditary breast cancer: A single institution experience

Abstract Introduction: The introduction of multi-gene testing for hereditary forms of breast cancer has changed the clinical approach to genetic testing for breast cancer patients. Recent consensus guideline now recommends genetic testing for all patients with a personal history of breast cancer and updated testing to those who have had negative germline BRCA 1 and 2 testing. This is a single institutional experience regarding the use and outcomes of multi-gene testing and updated testing. Methods: This is a retrospective analysis of germline multi-gene testing for breast cancer patients at our institution. Information on tumor histology, personal and family history of cancer, age at diagnosis, and genetic testing information was obtained through records review. Results: Between January 1, 2015 and December 31, 2018, 1568 breast cancer patients were diagnosed or treated at our institution. Of those, 26% of the patients had genetic results (age range 23-87; median age 52; &amp;lt;1% Male; 88% non-Hispanic whites, 8% blacks, 2% Asians, 2% Hispanics). Eight percent of the patients were found to carry a pathogenic variant that the NCCN guidelines designated as sufficient evidence to have an increased risk for breast cancer. Of those, only 3.4% were BRCA 1 and 2 mutations. The prevalent pathogenic variants found in multi-gene testing were BRCA 1/ 2 (3.4%), CHEK2 (2.2%), PALB2 (1%), TP53 (1%), PMS2 (1%), MYTYH (0.74%), FANCC (0.25%), ATM (0.25%), MSH2 (0.25%), MSH6 (0.25%), NBN (0.25%), and RAD51C (0.25%). Fifteen patients had initial testing looking only for the presence of germline BRCA 1 and 2 mutations. Of those, updated expanded testing identified an additional two patients who carried a pathogenic variant that was previously unidentified. Conclusion: Multi-gene testing and expanded panel testing of all breast cancer patients could increase the detection of pathogenic variants and may have a potential clinical impact for patients and their family. Further understanding of genetic patterns and variation in multi-gene testing is needed. Increasing public awareness and decreasing the cost of genetic testing are also important to improve the rates of multi-gene testing. Citation Format: Kit Yu Lu, Meagan Smith, Julia Verbiar, Haleigh Minor, Jennifer Lapse, Latesha Blair, Lisa Torp. Genetic variation and the role of multi-gene testing for hereditary breast cancer: A single institution experience [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-32.