Testing For Hereditary Breast Cancer Research Articles

Abstract P6-08-26: Clinical characteristics of breast cancer patients with ATM mutations

Abstract Background: Pathogenic ATM gene mutations are associated with increased risk of developing several cancers such as lymphoid, gastric, breast, central nervous system, skin, and other cancers. The relative risk of breast cancer is 2.3, with a higher risk seen for women under the age of 50 years. Only few and small studies have reported on the characteristics of breast cancers in women with ATM mutations. Here, we aimed to describe the clinical and pathological characteristics of a single institution largest cohort, to the best of our knowledge, of breast cancer patients with ATM mutations. Methods: Patients with breast cancer who presented to the University of Texas MD Anderson Cancer Center Clinical Cancer Genetics clinics and underwent genetic testing for hereditary breast cancer and were found to have an ATM mutation were included. A retrospective review of a prospectively maintained research database was performed for ATM mutation status as well as patient clinical and pathological characteristics. IRB approval was granted for this analysis. Results: Between 2012 and 2019, a total of 4093 breast cancer patients underwent genetic testing for hereditary breast cancer that included ATM gene testing. The median age of diagnosis of breast cancer was 49.3 (17-89), and median age at genetic testing was 52.1 (18-86). 72% of patients had stage 0-III and 3.2% stage 4 disease. Among patients with ATM pathogenic mutations, 37.7% (10) versus 21.7% (843) of ATM negative patients had a history of multiple primaries of any cancers. The table below shows characteristics of ATM pathogenic mutation carriers versus ATM negative patients. Conclusion: This is a single institution cohort of breast cancer patients with ATM mutations that show distinct clinical characteristics, such as multiple primary cancers. These findings could have therapeutic implications and should be confirmed in larger cohorts. Pathogenic Mutation of ATM ATM NegativesVariablesn%n%ERPositive4075.5221757.1Negative11.976019.6Unknown1222.690423.3PRPositive3667.9188448.5Negative59.4107027.6Pos/Neg00.010.03Unknown1222.692623.9Her2Positive1018.958611.3Negative2241.5206257.0Unknown2139.6123314.2Stage059.43178.2I1324.597825.2II1120.8106527.4III713.243611.2IV47.51243.2Unknown1324.596124.8Nuclear GradeI23.82596.7II1935.8111228.7III1120.8115629.8Unknown2139.6135434.9Triple Negative?Yes00.053913.9No3769.8222757.4Unknown1630.2111528.7 Citation Format: Loredana Militello, Angelica M Gutierrez Barrera, Constance Albarracin, Isabelle Bedrosian, Banu K Arun. Clinical characteristics of breast cancer patients with ATM mutations [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 P6-08-26.

Abstract P6-08-34: Genetic testing for hereditary breast cancer in Brazilian public health system: The experience of tumor board reference in a cancer center

Abstract Introduction: In Brazil, genetic testing for hereditary cancer predisposition syndromes, including Hereditary Breast Cancer (HBC), is not covered by the public health system (SUS) and was only incorporated in most private health insurance (PHI) plans after 2013. Nonetheless, considering that only 22% of the Brazilian population has access to private health system and the high cost of genetic testing in private laboratories, the majority of Brazilian women at risk for HBC do not have access to a genetic diagnosis. In this context, we have implemented at A.C.Camargo Cancer Center (ACCCC – a reference Cancer Center in Brazil which serves both the private and public health systems) a pilot program that offers genetic testing for SUS patients at risk for HBC. The goal of this study is to present the adopted clinical criteria and the corresponding detection rate of pathogenic variants in HBC genes observed in our cohort in comparison to detection rates observed in private health scenario. Methods: Since 2018, 34 cases of breast cancer patients from SUS under medical follow-up at ACCCC and at risk for HBC were discussed in multidisciplinary Tumor Board meetings. The Tumor Board team consists of health care professionals from different specialties, including medical oncologists, surgeons, pathologists, molecular biologists, and clinical geneticists. The clinical criteria defined for referring patients to genetic testing were: (1) personal history of triple negative breast cancer (TNBC) in any age; (2) personal history of non-TNBC developed before 30 years old, positive family history of cancer, and a PENN II model prediction of >15% risk in carry a BRCA1/2 mutation; and (3) personal history of BC in any age and a PENN II model prediction of >30% risk in carry a BRCA1/2 mutation. Detection rates of SUS patients were compared to BRCA1/2 results obtained during the same period from the ACCCC Laboratory of Genomics Diagnostics that serves manly PHI and private patients. Genetic tests were performed using different gene panels containing 26 or 94 genes. Results: Pathogenic (P) and likely pathogenic (LP) variants were detected in 38% of SUS patients (13/34), with a higher proportion of BRCA1 carriers (69% - 9 patients) than of BRCA2 (1 patient). Aside BRCA1/2 mutations that were detected in 10 patients (29%), P/LP variants were also identified in BRIP1, CHEK2, and PALB2 (1 patient each). The rate for BRCA1/2 P/LP variants in PHI cohort was 9.8% (23/234 patients), with a lower proportion of BRCA1 carriers (22%) than of BRCA2 (40%). It was identified a high rate of P/LP variants in TNBC from SUS cohort (62% - 10/16 cases) and a marked association of BRCA1 and TNBC, with 80% (8/10) of hereditary TNBC having BRCA1 mutations. The mean turnaround time for genetic test results was 4 months, varying from 2 to 8 months. From 11 patients with P/LP variants that already received the genetic test result, 5 underwent prophylactic contralateral mastectomy and/or bilateral salpingo-oophorectomy. Conclusions: The introduction of genetic testing for HBC made possible to tailor preventative measures for women at high risk, including prophylactic surgery and screening protocols. However, in many developing countries, the high cost of genetic tests and the lack of national policies prevent its application in clinical practice for the majority of the population. By defining more stringent clinical criteria for HBC genetic test, we detected a mutation rate three times as high as that detected in the private health scenario. With the continuity our study, we expect to contribute to the development of national standards for HBC screening and to encourage the implementation of consistent and cost-effective genetic testing under the real-life conditions of our public health system, maximizing the benefit for the population with the available resources. Citation Format: Dirce M Carraro, Giovana T Torrezan, Karina M Santiago, Maria\ Nirvana da Cruz Formiga, Solange M Sanches, Fabiana BA Makdissi, Breast Cancer Tumor Board Team. Genetic testing for hereditary breast cancer in Brazilian public health system: The experience of tumor board reference in a cancer center [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 P6-08-34.

Abstract P2-02-03: Impact of genetic testing for hereditary breast cancer on supplemental breast imaging and false positive biopsy rates among young breast cancer patients

Abstract Introduction Annual mammography screening is recommended for women diagnosed with breast cancer for the early detection of local recurrence and new breast primaries. Younger women have higher breast density, which lowers the sensitivity of mammography for early detection. The American Cancer Society recommends breast MRI as an adjunct to mammography for women with known hereditary breast cancer syndromes. However, there is insufficient evidence on the use of breast MRI or ultrasound as an adjunct to screening mammography among young women with a personal history of breast cancer. Our objective was to investigate factors associated with use of supplemental screening among young breast cancer patients and the impact of supplemental screening on detection of breast cancer recurrence and false positive biopsy rates. Methods We conducted a retrospective analysis of women diagnosed with stage 0-III breast cancer at age 50 years or younger at Columbia University Irving Medical Center in New York, NY between 2007 and 2017. Patients were excluded if they had stage IV disease at diagnosis, bilateral mastectomy, or no breast imaging available in the CUIMC electronic health record (EHR). All clinical data was extracted from the EHR and tumor registry, including receipt and results of genetic testing. Supplemental screening was defined as use of breast ultrasound or MRI in the absence of breast symptoms and in the setting of a normal mammogram. Breast cancer recurrence and false positive biopsy were defined as any breast biopsy which did or did not show ductal carcinoma in situ (DCIS) or invasive carcinoma, respectively. Univariate and multivariate analyses were performed to assess the association between demographic and clinical factors and our main outcomes of supplemental screening and false positive biopsy. Results Among 681 evaluable women, mean age at diagnosis was 44 years (SD, 4.9) with 41.6% white, 28.2% Hispanic, 12.6% black, 11.7% Asian, and 5.9% other race/ethnicity. About 62.7% had private insurance and 23.1% Medicaid, and 47% had undergone genetic testing, including 20 (2.9%) with pathogenic variants. Over half (51%) had supplemental screening with either breast MRI or ultrasound, 130 (19.1%) had a false positive biopsy, and 52 (7.6%) had a breast cancer recurrence, with about half (51.9%) screen-detected. In multivariate analysis, supplemental screening was less likely among black and Hispanic women compared to whites (odds [OR]=0.56, 95% confidence interval [CI]=0.33-0.97 and OR=0.46, 95% CI=0.30-0.72, respectively), those with Medicaid compared to private insurance (OR=0.46, 95% CI=0.30-0.71), and women with lower breast density (OR=0.63, 95% CI=0.43-0.92). False positive biopsies were more frequent among women who underwent supplemental screening compared to those who did not (26.4% vs. 11.4%, p<0.001), however, screen-detected breast cancer recurrences were comparable (4.0% vs. 3.9%, p=0.209). Supplemental screening was associated with a greater than 2-fold increased risk of false positive biopsy (OR=2.77, 95% CI=1.78-4.32). Compared to young breast cancer patients who did not undergo genetic testing, women with pathogenic variants had a trend toward more supplemental screening (OR=2.28, 95% CI=0.82-6.36) and more false positive biopsies (OR=2.75, 95% CI=0.96-7.85). Conclusions Our findings suggest that decisions to engage in supplemental screening are influenced by insurance coverage and breast density. Furthermore, patients who receive supplemental screening were significantly more likely to have false positive biopsies, but had no difference in screen-detected breast cancer recurrences. Prospective studies are needed to better define optimal screening strategies for young breast cancer survivors. Citation Format: Vicky Ro, Ziyi Zhao, Samuel Pan, Katherine D. Crew. Impact of genetic testing for hereditary breast cancer on supplemental breast imaging and false positive biopsy rates among young breast cancer patients [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 P2-02-03.

Abstract AP04: INCREASING ACCESS TO GENETIC TESTING FOR HEREDITARY BREAST AND OVARIAN CANCER: EXPERIENCE FROM HIGH-VOLUME OB/GYN CLINIC IN TEXAS

Abstract INTRODUCTION: Currently most genetic testing for hereditary cancer risk is performed on individuals with strong personal and/or family histories of cancer. However, as much as 50% of people with a BRCA1 or BRCA2 gene mutation may not have significant family history. As a result, many people are often not identified as having a pathogenic mutation until after they or someone in their family has already been diagnosed with cancer. This study aims to provide insights into prevention of hereditary breast and ovarian cancer by providing broad access to testing in the ob/gyn care setting. METHODS: We describe the demographics and genetic results of 1,113 individuals who were referred by a physician to receive genetic testing for hereditary cancer risk from Color Genomics. The test is a next generation sequencing (NGS) based assessment of 30 genes associated with hereditary cancer risk. The physicians offered the Color Test to their patients at their wellness visit and provided education about genetic testing via online newsletter to inform patients and increase interest for the program. The OB/GYN practice consists of 22 clinicians and serves almost 50 thousand patients. RESULTS: More than 48,253 patients were sent information about this genetic testing via email. The email open rate was 39.6%. 1,113 individuals underwent testing. In the cohort, a total of 90 pathogenic or likely pathogenic variants were identified for an overall pathogenic rate of 8.1%. Twenty individuals (1.8%) were identified as having mutations in genes that increased risk of ovarian cancer (BRCA1, BRCA2, BRIP1, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, RAD51C, RAD51D, STK11 and TP53). The average age of the participant who underwent testing was 44.4 years of age. The cohort was 44% Caucasian. Nineteen patients reported Ashkenazi Jewish (AJ) ancestry; the pathogenic rate among people who indicated AJ ancestry was 21%. Health history was self-reported and 47 individuals reported a history of cancer. Only two individuals reported a personal history of ovarian cancer--both were negative for any pathogenic mutations. CONCLUSIONS: The cohort analyzed here included a broader population than has historically qualified for or been offered genetic testing for hereditary cancer risk. The approach taken by this OB/GYN practice highlights a novel way to identify people at increased risk for cancer due to inherited mutation. The practice identified 90 patients who were at increased risk for cancer, including 20 women who were at increased risk for ovarian cancer—none of whom were yet affected—highlighting the opportunity for prevention of ovarian cancer as well as other cancers. Citation Format: Carmelina Heydrich, Lily K Servais, Sarah A Popelka, Brian K Moreau, Katie N Allio, Anjali D Zimmer. INCREASING ACCESS TO GENETIC TESTING FOR HEREDITARY BREAST AND OVARIAN CANCER: EXPERIENCE FROM HIGH-VOLUME OB/GYN CLINIC IN TEXAS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP04.

117P - Multigene panel testing results for hereditary breast cancer in 1325 individuals: Implications for gene selection and considerations for guidelines

BackgroundThe application of the Next Generation Sequencing (NGS) technology has facilitated multigene panel testing for hereditary breast cancer (BC) in clinical practice. We performed a retrospective analysis of individuals referred for testing in our lab aiming to investigate the contribution of included genes and evaluate current genetic testing guidelines in BC. MethodsIn total, 1141 BC patients and 184 unaffected individuals with family history (FH) of BC were referred from physicians for testing using a multigene panel. Genomic DNA was enriched for targeted regions of 33 genes and sequencing was carried out using the Illumina NGS technology. The presence of large genomic rearrangements (LGRs) was investigated computationally and by Multiplex Ligation-dependent Probe Amplification (MLPA). ResultsA pathogenic variant (PV) was identified in 22% (291/1325) of analyzed individuals and in specific in 23.2% of BC patients and 14.1% of unaffected individuals (P=0.006). Among individuals with PVs, 49.1% were located in the BRCA1/2 genes whereas 8.6%, 22.7% and 19.6% occurred in other high, moderate and low-risk genes respectively. Notably, 21 of the 291 positive individuals (7.2%) carried clinically significant variants in two different genes and 6.5% had a LGR. A retrospective analysis of positive individuals showed that 88.3% of BC patients met the NCCN criteria for further genetic risk evaluation compared to 80.8% of unaffected individuals with FH of BC (P=0.269). In BRCA-positive cases, NCCN criteria were met in 92.3% of the referrals compared to 81.8% in individuals positive for other genes (P=0.008). ConclusionsExtended multigene panel testing in hereditary BC facilitates the detection of nearly twice as many individuals that could benefit from personalized management. In our cohort, the currently used selection criteria for HBOC failed to identify only 12.7% of individuals positive for pathogenic variants, suggesting strong selection strategies from physicians. However, our results indicate that selection criteria perform better for the identification of BRCA-positive BC patients and should be revised to facilitate towards the inclusion of BC patients with PVs in other genes. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Multigene panel testing for hereditary breast cancer: An analysis of 70 BRCA-negative Turkish patients

Objective: Although the molecular etiology of breast cancer is not clearly known, hereditary genetic causes are responsible for approximately 10%. In addition to BRCA1 and BRCA2 genes, there are many genes that cause breast cancer. In this study, we performed a hereditary cancer genetic panel test among hereditary breast cancer patients who are negative for BRCA1 and BRCA2 genes. Accordingly, the frequency of mutations, causing hereditary cancer among Turkish breast cancer patients, was investigated. Method: All the 70 patients were unrelated and provided BRCA testing criteria according to the National Comprehensive Cancer Network guidelines, but they were reported as unfavorable. Qiagen large hereditary cancer panel and Hereditary Cancer Solution v1.1 panel were used for sequencing. The sequencing process was performed on the Illumina MiSeq system. The data analyses were performed on QIAGEN Clinical Insight (QCI™) Analyze software and Sophia DDM software. Results: Of 70 patients, 6 (8.5%) were found to carry a pathogenic, and 1 (1.4%) were found to give a likely pathogenic mutation. Pathogenic variants were detected in ATM, NBN, PTEN, RAD51C genes; the likely pathogenic variant was discovered in the MUTYH gene. Only, PTEN:c.407G>A mutation was found in two patients; the other mutations were detected once in each patient. A nonsense alteration, RAD51C:c.907G>T, was described as novel variant. The variant of uncertain significance variants was detected in 10 patients (14.2%). Conclusions: It is essential to perform the hereditary cancer panel from index cases in families with high cancer incidence, whose BRCA1/2 negative and molecular background has not been elucidated, for preventive health policies. In addition, the identification of common familial cancer genes will guide personalized therapy planning.

The budgetary impact of genetic testing for hereditary breast cancer for the statutory health insurance

Objectives: Potential opportunities and challenges of predictive genetic risk classification of healthy persons are currently discussed. However, the budgetary impact of rising demand is uncertain. This project aims to evaluate budgetary consequences of predictive genetic risk classification for statutory health insurance in Germany.Methods: A Markov model was developed in the form of a cohort simulation. It analyzes a population of female relatives of hereditary breast cancer patients. Mutation carriers are offered intensified screening, women with a BRCA1 or BRCA2 mutation can decide on prophylactic mastectomy and/or ovarectomy. The model considers the following scenarios: (a) steady demand for predictive genetic testing, and (b) rising demand. Most input parameters are based on data of the German Consortium for Hereditary Breast and Ovarian Cancer. The model contains 49 health states, starts in 2015, and runs for 10 years. Prices were evaluated from the perspective of statutory health insurance.Results: Steady demand leads to an expenditure of €49.8 million during the 10-year period. Rising demands lead to additional expenses of €125.5 million. The model reveals the genetic analysis to be the main cost driver while cost savings in treatment costs of breast and ovarian cancer are indicated.Conclusions: The results contribute to close the knowledge gap concerning the budgetary consequences due to genetic risk classification. A rising demand leads to additional costs especially due to costs for genetic analysis. The model indicates budget shifts with cost savings due to breast and ovarian cancer treatment in the scenario of rising demands.

Consensus Guidelines on Genetic` Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons

BackgroundThe purpose of this consensus guideline is to outline recommendations for genetic testing that medical professionals can use to assess hereditary risk for breast cancer.MethodsLiterature review included large datasets, basic and clinical science publications, and recent updated national guidelines. Genetic testing to assess hereditary risk of cancer is a complex, broad, and dynamic area of medical research. The dominant focus of this guideline is limited in scope to breast cancer.ResultsThere is a lack of consensus among experts regarding which genes among many should be tested in different clinical scenarios. There is also variation in the degree of consensus regarding the understanding of risk and appropriate clinical management of mutations in many genes.ConclusionsGenetic testing should be made available to all patients with a personal history of breast cancer. Recent data are reviewed that support genetic testing being offered to each patient with breast cancer (newly diagnosed or with a personal history). If genetic testing is performed, such testing should include BRCA1/BRCA2 and PALB2, with other genes as appropriate for the clinical scenario and family history. For patients with newly diagnosed breast cancer, identification of a mutation may impact local treatment recommendations. Patients who had genetic testing previously may benefit from updated testing. Genetic testing should be made available to patients without a history of breast cancer who meet National Comprehensive Cancer Network guidelines. Finally, variants of uncertain significance are not clinically actionable and these patients should be managed based on their individual risk factors.

Multi gene panel testing for hereditary breast cancer - is it ready to be used?

Breast cancer is one of the most common malignancies and the leading cause of death among women worldwide. About 20% of breast cancers are hereditary. Approximately 30% of the mutations have remained negative after testing BRCA1/2 even in families with a Mendelian inheritance pattern for breast cancer. Additional non-BRCA genes have been identified as predisposing for breast cancer. Multi gene panel testing tries to cover and explain the BRCA negative inherited breast cancer, improving efficiency, speed and costs of the breast cancer screening.We identified 23 studies reporting results from individuals who have undergone multi gene panel testing for hereditary breast cancer and noticed a prevalence of 1–12% of non-BRCA genes, but also a high level of variants of uncertain significance.A result with a high level of variants of uncertain significance is likely to be more costly than bring benefits, as well as increase the anxiety for patients. Regarding further development of multi gene panel testing, more research is required to establish both the optimal care of patients with cancer (specific treatments like PARP inhibitors) and the management of unaffected individuals (chemoprevention and/or prophylactic surgeries). Early detection in these patients as well as prophylactic measures will significantly increase the chance of survival. Therefore, multi gene panel testing is not yet ready to be used outside clear guidelines. In conclusion, studies on additional cohorts will be needed to better define the real prevalence, penetrance and the variants of these genes, as well as to describe clear evidence-based guidelines for these patients.

Clinical significance of pathogenic variants in germline BRCA wild type patients at risk for hereditary breast cancer.

e13127 Background: Approximately, 10% of breast cancer (BC) are related to inherited germline mutations. BRCA1/2, the most recognized and tested genes, are responsible for 50% of hereditary BC. Genetic testing for hereditary BC has changed significantly. Increasing evidence suggests parallel multigene testing. Methods: NGS-based germline BRCA status assessment was performed on 209 high risk BC patients with at least one of the following risk factors: triple negative BC, early onset ( < -45), with a family history of BC, bilateral BC and male BC. Multigene-panel testing was subsequently offered to patients with at least 2 of the risk factors and WT germline BRCA. Capture-base targeted sequencing was performed on white blood cells using a panel consisting of 53 hereditary cancer-related genes, spanning 229kb of human genome. Results: Among the 209 patients screened, only 12 patients had pathogenic BRCA1/2 mutation. Next, we investigated the prevalence of non- BRCA pathogenic germline pathogenic mutations in patients with at least 2 risk factors. Thirty-seven patients met the criteria and only 23 patients had sufficient WBC DNA for sequencing. This cohort had a median age of 42, with a majority carrying infiltrating ductal carcinoma. Except for one bilateral BC patient who had stage IV disease, all other patients had early stage disease. We identified 5 pathogenic mutations from 5 patients spanning 4 genes: PALB2, PTEN, ATM and WRN, resulting in a prevalence rate of 20% for pathogenic germline mutations in high risk germline BRCA WT BC patients. Two patients carried mutations in PALB2, one with a frameshift and another with a splice mutation. Mutation types for PTEN, ATM and WRN were splice mutation, stop gain mutation and frameshift mutation, respectively. All 5 patients were diagnosed with BC before the age of 40. Three of them had bilateral BC; one had triple negative BC and another patient had a family history of BC. Conclusions: Our study confirms the clinical significance of testing non- BRCA genes, and suggests multigene panel testing for patients at risk for hereditary BC. Such approach increases the identification of hereditary BC, thus impacting clinical decision-making.

Enhancing access to genetic cancer risk assessment (GCRA) in Monterrey, Mexico: The beginning of a prevention program.

e13150 Background: In limited-resource countries like Mexico, GCRA is not routinely provided due to elevated costs, lack of public coverage for testing and prophylactic surgeries, and limited GCRA expertise or awareness among providers and patients. Thus, GCRA services in Mexico are 20 years behind higher income countries, resulting in suboptimal care and limited opportunity for prevention. The Breast Cancer Center TecSalud established formal GCRA services for underserved patients by recruiting a cancer geneticist who provides care at no added expense to patients, building academic collaborations for training and research with City of Hope, and enabling free genetic testing through the Clinical Cancer Genomics Community Research Network, supported in part by the Breast Cancer Research Foundation. Aim: To report the uptake of the GCRA program by patients and relatives at TecSalud from January 2016 - December 2018. Methods: Eligibility includes Mexican women who meet hereditary breast cancer testing criteria and family members of mutation carriers. Risk reduction procedures are covered by Seguro Popular and/or the NGO Fundación Santos y de la Garza Evia. Results: GCRA was offered to 255 patients and 74 at risk relatives, with an increasing reach (proportion of those eligible who access the program). A significant growth of cascade testing and access to risk reduction surgery over time are noted. Conclusions: A growing number of referrals and GCRA visits shows improving reach, possibly due to engagement of the multidisciplinary team and increased patient awareness. The expansion of cascade testing and performance of risk-appropriate surgeries reflects a maturing prevention program. Key determinants of our progress are collaborations that provided us with crucial mentorship, access to genetic assays, as well as the increasing involvement of local leaders, administrators and benefactors for the establishment of vital clinical and research capacity. Multilevel efforts should continue to enhance the delivery of standard of medical care for the most vulnerable and underserved high-risk patients and families. [Table: see text]

Abstract P2-14-04: Genetic testing and bilateral mastectomy for women with breast cancer: Does testing matter more than the test result?

Abstract Background: Genetic testing for hereditary breast cancer may allow women with breast cancer to make informed and individualized decisions regarding breast cancer treatment and strategies to reduce the risk of contralateral breast cancer. While rates of bilateral mastectomy (therapeutic mastectomy + contralateral prophylactic mastectomy) among women with unilateral breast cancers are known to be increasing, the factors influencing this decision and the role of genetic testing are poorly understood. We examined bilateral mastectomy rates and factors associated with bilateral mastectomy among women with unilateral breast cancer. Methods: We identified patients diagnosed with unilateral breast cancer from 2000-2015 from The Health of Women Study, a cohort study led by the Dr. Susan Love Research Foundation. We calculated rates of bilateral mastectomy among women who underwent surgical treatment for breast cancer. We used multivariable logistic regression models to evaluate factors associated with bilateral mastectomy. Results: Among 2,028 patients who underwent surgery for unilateral breast cancer, 19% underwent bilateral mastectomy. Forty-one percent (n= 84 of 205) of patients who underwent testing and tested positive for a deleterious mutation underwent bilateral mastectomy, compared to 26% (n= 439 of 1,689) of women who tested negative and 12.5% (n= 274 of 2,197) of those not tested. Among those with a negative genetic test, pre-test risk of harboring a genetic mutation (based on family history and age at diagnosis) was not associated with bilateral mastectomy (p=0.250). After adjusting for race, age, level of education, and pre-test mutation risk, the odds of bilateral mastectomy were 69% higher among patients who underwent genetic testing (OR 1.69, 95% CI 1.29–2.22, p<0.001) versus those who did not undergo genetic testing. This finding was consistent regardless of genetic test result. Multivariable analysis of factors associated with bilateral mastectomy Odds ratio95% Confidence Intervalp valueRisk Category Low riskReference--Moderate risk1.470.96 – 2.420.078High risk1.460.92 – 2.320.111 Genetic testing1.691.29 – 2.22<0.001 Genetic test result Not testedReference--Positive test2.711.66 – 4.46<0.001Negative test1.561.18 – 2.070.002*Adjusted for age, race, and level of education. Conclusions: Genetic testing among breast cancer patients, regardless of test result or pre-test mutation risk, is significantly associated with bilateral mastectomy. Many women (˜1/4) with a negative genetic test and at low risk of hereditary breast cancer, by family history and age at diagnosis, currently undergo bilateral mastectomy with unclear benefits. Further qualitative research will aim to elucidate reasons driving choice of bilateral mastectomy among women with breast cancer. Citation Format: Verdial FC, Bartek MA, Anderson BO, Javid SH. Genetic testing and bilateral mastectomy for women with breast cancer: Does testing matter more than the test result? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-04.

Abstract P5-09-01: Racial/ethnic differences in BRCA1/2 and multigene panel testing among young breast cancer patients

Abstract Background: Breast cancer (BC) patients diagnosed at age 50 and under are recommended to have germline genetic testing for hereditary BC due to a high likelihood of carrying a pathogenic mutation in a moderate or high penetrance risk gene. Completion of genetic testing among racial/ethnic minorities, particularly multigene panel testing, is understudied. We examined predictors of completion of BRCA1/2 and multigene panel testing among women with early onset BC and assessed racial/ethnic differences in genetic testing completion and results. Methods: We performed a retrospective cohort study of 1370 BC patients diagnosed at <50 years of age at Columbia University Medical Center (CUMC) from January 2007-December 2016.Data on socio-demographics, clinical factors, and genetic testing completion and results were collected from the medical record. We conducted descriptive statistics and univariate and multivariable logistic regression models. Results: Our study population had a median age of 44 years (range, 19-50); 44% non-Hispanic white, 24% Hispanic, 13% non-Hispanic black, 10% Asian, 9% other; 61% private insurance, 22% Medicaid, 17% other. Nearly half of the women (N=607; 44.3%) had genetic testing performed. In the multivariable regression model, genetic testing completion was less likely with increasing age at diagnosis (odds ratio [OR]=0.93; 95% confidence interval [CI]=0.91-0.95) and stage 0 or 4 BC compared to stage 1 (OR=0.67; 95% CI=0.46-0.97 and OR=0.35; 95% CI=0.19-0.64, respectively). Completion of genetic testing was more likely with a family history of BC (OR=5.55; 95% CI=3.92-7.87). Genetic testing completion did not vary by race/ethnicity or insurance coverage. Across all racial/ethnic groups, the frequency of pathogenic/likely pathogenic variants identified was 13.0% and 10.5% had at least 1 variant of uncertain significance (VUS). The highest VUS frequency was among Asians (21.2%). The percentage of women undergoing genetic testing increased over time from 18.5% in 2007 and reached a peak of 69.3% in 2015. From 2007 to 2016, the percentage of pathogenic/likely pathogenic variants detected increased from 3.4% to 9.1% and the VUS frequency rose from 3.4% to 13.3% with increasing use of panel testing. Frequency of pathogenic variants and VUS among women ≤ 50 years diagnosed with BC at CUMC (2007-2016) Pathogenic variantsVUSTotal81 (5.9%)74 (5.4%)BRCA144 (3.2%)10 (0.7%)BRCA221 (1.5%)10 (0.7%)ATM3 (0.2%)9 (0.6%)CHEK23 (0.2%)8 (0.5%)Other variants detected in: APC, BARD1, BRIP1, CDH1, CDKN2A, MEN1, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PHOX2B, PMS2, POLE, PTEN, RAD50, RAD51C, SDHA, STK11, TP53 Conclusions and Relevance: Nearly half of the women with early onset BC had genetic testing. We did not observe disparities in genetic testing by race/ethnicity or insurance coverage. Genetic testing completion, as well as the frequency of pathogenic/likely pathogenic variants and VUS detection, increased over time as panel testing replaced BRCA1/2 testing. Counseling on the likelihood of obtaining uncertain results should be provided to all patients undergoing hereditary BC genetic testing, particularly to racial/ethnic minorities. Citation Format: Trivedi MS, Jones T, Jiang X, Underhill ML, Bose S, Silverman T, Chung WK, Kukafka R, Crew KD. Racial/ethnic differences in BRCA1/2 and multigene panel testing among young breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-01.

The interest and knowledge of genetic counseling and genetic testing for hereditary breast cancer in a community hospital

The interest and knowledge of genetic counseling and genetic testing for hereditary breast cancer in a community hospital

Inequities in Genetic Testing for Hereditary Breast Cancer: Implications for Public Health Practice

Background and context: The Ontario Breast Screening Program for women with a genetic predisposition to breast cancer is 1 of the first international models of a government-funded public health service that offers systematic genetic screening to women at a high-risk of breast cancer. However, since the implementation of the program in 2011, enrolment rates have been lower than anticipated. While there may be several reasons for this to happen, it does call into consideration the 'inverse equity law', whereby the more advantaged in society are the first to participate and benefit from universal health services. An outcome of this phenomenon is an increase in the health divide between those that are at a social advantage vs those that are not. Aim: Using an intersectionality lens this review illuminates the role of the social determinants of health and social identity in creating possible barriers in the access to genetic screening for hereditary breast cancer, and the implications for public health practice in recognizing and ameliorating these differences. Strategy/Tactics: Although it remains too early to understand the exact cause for underenrolment in the OBSP high-risk screening program, this review serves to illuminate how screening programs that are used as targeted interventions to improve health outcomes must take into consideration the complexities associated with utilization and need across the entire population. A failure to do so may further disenfranchise socially disadvantaged individuals and widen the health equity gap that currently exists between population groups based on social location. Program/Policy process: The Ontario Breast Screening Program (OBSP) for High Risk Women is funded by the government; therefore, financial barriers in terms of access to care do not exist for individuals seeking screening. Despite this, the program has had low levels of enrolment based on their population targets (Cancer Care Ontario, 2012). Outcomes: While access to health care services is an important social determinant of health (Whitehead, 1992), the structure and design of health services can render them structurally unavailable and socially inacceptable to certain population groups (Gilson et al., 2007). Indeed, recent studies clearly demonstrate how socially disadvantaged individuals, such as those with lower levels of education, and those from ethnic minority groups consistently underuse health services despite the lack of a financial barrier to care (Maddison, 2011). What was learned: The way in which genetic testing is both accessed and used follow similar trends, such that higher levels of both income and education correlate with an increased awareness of genetic testing, a greater likely hood of receiving referrals for genetic testing, appropriateness of genetic counseling and the final decision to proceed with genetic testing.

Inequities in genetic testing for hereditary breast cancer: implications for public health practice.

The Ontario Breast Screening Program for women with a genetic predisposition to breast cancer is one of the first international models of a government-funded public health service that offers systematic genetic screening to women at a high risk of breast cancer. However, since the implementation of the program in 2011, enrolment rates have been lower than anticipated. Whilst there may be several reasons for this to happen, it does call into consideration the 'inverse equity law', whereby the more advantaged in society are the first to participate and benefit from universal health services. An outcome of this phenomenon is an increase in the health divide between those that are at a social advantage versus those that are not. Using an intersectionality lens, this paper explores the role of the social determinants of health and social identity in creating possible barriers in the access to genetic screening for hereditary breast cancer, and the implications for public health practice in recognising and ameliorating these differences.

Investigation of discordant sibling pairs from hereditary breast cancer (HBC) families.

1538Background: Women who undergo testing for hereditary breast cancer (HBC) may be offered a panel of up to 40 genes but the majority of women tested have no mutation identified on these panels. T...

Abstract PD1-11: Moderate risk genes matter: Multigene testing for hereditary breast cancer

Abstract Background: Many genes have been associated with hereditary breast cancer (BC). For some genes, the associated cancer risks have been debated; however, recent studies have helped resolve some uncertainties. For example, ATM, BARD1, CHEK2, and RAD51D were associated with a moderate risk of BC (odds ratio (OR) 2- to 5-fold) in a recent study by Couch et al. Though many BC susceptibility genes have NCCN® management guidelines for at least one cancer type, some lack recommendations for BC risk management and others are missing altogether due to limited data. We aim to examine the mutation frequencies of genes on a BC focused multigene panel test (MGPT) and the possible clinical impact of these findings. Methods: Sequential BC cases submitted to our laboratory for a BC focused MGPT between March 2012 and December 2016 were retrospectively reviewed. De-identified medical and family history data from test request forms and accompanying medical records as well as MGPT results were analyzed. Panel yield was assessed based on history of single or multiple primary diagnoses (MPD), level of BC risk, and clinical impact of test results. Results: Of 30,161 BC cases tested, 3,174 (10.5%) were positive for a mutation, and 143 (0.5%) had more than one mutation identified. Mutations in high (>5-fold risk) and moderate risk (<5-fold risk) BC genes were detected in 3.9% and 6.6% of BC patients, respectively. Furthermore, 80.0% of the gene mutations identified (8.4% of all BC patients) occurred in genes with NCCN® management guidelines for at least one cancer type. Detection rate also varied based on personal history, with mutations detected in 10.2% of single BC cases only, 12.7% of BC cases with MPD only, and 14.0% of cases with breast and other cancers (see Table for gene specific frequencies). Breast Cancer Only N (%)MPD Only N (%)Breast + Other Cancers N (%)ATM246 (1.0%)62 (1.5%)33 (1.9%)BARD158 (0.2%)19 (0.5%)3 (0.2%)BRCA1273 (1.2%)65 (1.7%)13 (0.8%)BRCA2336 (1.4%)68 (1.8%)36 (2.2%)BRIP169 (0.3%)6 (0.1%)7 (0.4%)CDH112 (0.1%)5 (0.1%)1 (0.1%)CHEK2412 (1.7%)105 (2.6%)58 (3.3%)CHEK2 (p.I157T)122 (0.5%)28 (0.7%)13 (0.7%)MRE11A31 (0.1%)6 (0.1%)2 (0.1%)MUTYH carrier312 (1.3%)44 (0.1%)31 (1.8%)NBN44 (0.2%)5 (0.1%)5 (0.3%)NF139 (0.2%)9 (0.3%)6 (0.4%)PALB2221 (0.9%)43 (1.1%)14 (0.8%)PTEN14 (0.1%)4 (0.1%)1 (0.1%)RAD5057 (0.2%)8 (0.2%)9 (0.5%)RAD51C32 (0.1%)13 (0.3%)2 (0.1%)RAD51D17 (0.1%)5 (0.1%)2 (0.1%)TP5347 (0.2%)16 (0.4%)12 (0.7%) Discussion: Findings from this large clinical testing cohort indicate that clinicians can expect approximately 3.9% and 6.6% of BC patients to have mutations in high and moderate risk genes, respectively. Though these values may shift as gene-specific BC risks continue to be refined, it is clear that moderate risk genes play a significant role in BC susceptibility. Five genes recently added to NCCN® management guidelines (BRIP1, NBN, NF1, RAD51C, and RAD51D) accounted for 9.9% of mutations identified (1.0% of all BC cases). Including these genes in MGPT provides patients and their families clinically relevant information about cancer risks and management options. Further studies are needed on genes such as BARD1 and RAD51D that have recently been shown to predispose to BC but lack guidelines for BC risk management. Citation Format: Jackson M, LaDuca H, Profato-Partlow J, Espenschied C. Moderate risk genes matter: Multigene testing for hereditary breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-11.

Abstract P4-06-18: Clinical application of multigene panel testing and genetic counseling for hereditary/familial breast cancer risk assessment: Prospective single center study

Abstract Background The identification of individuals at elevated risk for hereditary cancers has allowed the development of consensus recommendations for cancer screening and prevention. The introduction of multigene panels may identify more individuals with breast cancer gene mutations than does testing for BRCA1/2 alone. Therefore, the multigenerational panel increase the need for genetic counseling suggesting preventive approach or cancer-specific screening to patients and family members. The rapid clinical introduction of multigene panel testing, however, have several issues such as low- to moderate-risk gene mutations and clinical recommendations. We collect the mutation results and clinical recommendations after testing with multigene panel and giving genetic counseling. Methods We had developed multigene panel consisted of 64 genes related to hereditary cancer through previous study and prospectively enrolled 104 individuals who were appropriate candidates for hereditary breast cancer evaluation. The patients were tested with 64-gene panel(Celemics) and results were provided by us 4˜10 weeks later. We checked the family history of cancer and made a pedigree before testing. Result Among 104 participants, 26 patients harbored deleterious mutations, most commonly in high to moderate-risk breast/ovarian cancer genes (BRCA1/2, BRIP, RAD51 and RAD51D), Lynch syndrome gene(MSH6) and other genes(FH, SPINK1). We recommended the cancer-specific screening and/or preventive approach for mutation-positive patients and suggested additional genetic test for the family members. Among them, 6 (23%) patients received Risk reducing procedures (Prophylactic mastectomy or oophorectomy) and most of them(19 patients(73%)) received cancer specific screening. Conclusion We demonstrate the use of multigene panel testing for hereditary breast cancer and will suggest the process of the genetic counseling including indication and results analysis with multigene panel testing. Citation Format: Lee E-S, Han W, Kim Y, Rhu J, Park JH, Kim K-E, Ju YW, Kim R, Lee H-B, Moon H-G, Noh D-Y. Clinical application of multigene panel testing and genetic counseling for hereditary/familial breast cancer risk assessment: Prospective single center study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-18.

Genetic Testing for Hereditary Breast Cancer: The Decision to Decline

Genetic testing is important for comprehensive cancer care. Commercial analysis of the BRCA1/2 genes has been available since 1996, and testing for hereditary breast and ovarian cancer syndrome is well established. The National Comprehensive Cancer Network (NCCN) guidelines identify individuals for whom BRCA1/2 analysis is appropriate and define management recommendations for mutation carriers. Despite recommendations, not all who meet NCCN criteria undergo genetic testing. We assess the frequency that individuals meeting NCCN criteria decline BRCA1/2 analysis, as well as factors that affect the decision-making process. A retrospective chart review was performed from September 2013 through August 2014 of individuals who received genetic counseling at the Levine Cancer Institute. A total of 1082 individuals identified through the retrospective chart review met NCCN criteria for BRCA1/2 analysis. Of these, 267 (24.7%) did not pursue genetic testing. Of the Nontested cohort, 59 (22.1%) were disinterested in testing and 108 (40.4%) were advised to gather additional genetic or medical information about their relatives before testing. The remaining 100 (37.5%) individuals were insured and desired to undergo genetic testing but were prohibited by the expense. Eighty five of these 100 patients were responsible for the total cost of the test, whereas the remaining 15 faced a prohibitive copay expense. Financial concerns are a major deterrent to the pursuit of BRCA1/2 analysis among those who meet NCNN criteria, especially in patients diagnosed with breast or ovarian cancer. These findings highlight the need to address financial concerns for genetic testing in this high-risk population.