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Purpose: To guide use of multigene panels for germline genetic testing for patients with cancer., Methods: An ASCO Expert Panel convened to develop recommendations on the basis of a systematic review of guidelines, consensus statements, and studies of germline and somatic genetic testing., Results: Fifty-two guidelines and consensus statements met eligibility criteria for the primary search; 14 studies were identified for Clinical Question 4., Recommendations: Patients should have a family history taken and recorded that includes details of cancers in first- and second-degree relatives and the patient's ethnicity. When more than one gene is relevant based on personal and/or family history, multigene panel testing should be offered. When considering what genes to include in the panel, the minimal panel should include the more strongly recommended genes from Table 1 and may include those less strongly recommended. A broader panel may be ordered when the potential benefits are clearly identified, and the potential harms from uncertain results should be mitigated. Patients who meet criteria for germline genetic testing should be offered germline testing regardless of results from tumor testing. Patients who would not normally be offered germline genetic testing based on personal and/or family history criteria but who have a pathogenic or likely pathogenic variant identified by tumor testing in a gene listed in Table 2 under the outlined circumstances should be offered germline testing.Additional information is available at www.asco.org/molecular-testing-and-biomarkers-guidelines.

Purpose: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline (g) BRCA1 / 2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s) BRCA1 / 2 mutations or g/s mutations in homologous recombination (HR)-related genes other than BRCA1/ 2., Methods: Eligible patients had MBC with measurable disease and germline mutations in non- BRCA1 / 2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1 / 2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS)., Results: Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, s BRCA1 / 2 , ATM, or CHEK2 . In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with g PALB2 (ORR, 82%) and s BRCA1 / 2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for g PALB2 and 6.3 months (90% CI, 4.4 months to NA) for s BRCA1 / 2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone., Conclusion: PARP inhibition is an effective treatment for patients with MBC and g PALB2 or s BRCA1 / 2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond g BRCA1 / 2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.

Purpose: Women with a family history of breast cancer are frequently referred for hereditary cancer genetic testing, yet < 10% are found to have pathogenic variants in known breast cancer susceptibility genes. Large-scale genotyping studies have identified common variants (primarily single-nucleotide polymorphisms [SNPs]) with individually modest breast cancer risk that, in aggregate, account for considerable breast cancer susceptibility. Here, we describe the development and empirical validation of an SNP-based polygenic breast cancer risk score., Methods: A panel of 94 SNPs was examined for association with breast cancer in women of European ancestry undergoing hereditary cancer genetic testing and negative for pathogenic variants in breast cancer susceptibility genes. Candidate polygenic risk scores (PRSs) as predictors of personal breast cancer history were developed through multivariable logistic regression models adjusted for age, cancer history, and ancestry. An optimized PRS was validated in 2 independent cohorts (n = 13,174; n = 141,160)., Results: Within the training cohort (n = 24,259), 4,291 women (18%) had a personal history of breast cancer and 8,725 women (36%) reported breast cancer in a first-degree relative. The optimized PRS included 86 variants and was highly predictive of breast cancer status in both validation cohorts ( P = 6.4 × 10 -66 ; P < 10 -325 ). The odds ratio (OR) per unit standard deviation was consistent between validations (OR, 1.45 [95% CI, 1.39 to 1.52]; OR 1.47 [95% CI, 1.45 to 1.49]). In a direct comparison, the 86-SNP PRS outperformed a previously described PRS of 77 SNPs., Conclusion: The validation and implementation of a PRS for women without pathogenic variants in known breast cancer susceptibility genes offers potential for risk stratification to guide surveillance recommendations., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments. Elisha HughesEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad GeneticsPlacede TshiabaEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad GeneticsShannon GallagherEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad GeneticsSusanne WagnerEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics Patents, Royalties, Other Intellectual Property: Co-author of patents held by Myriad Genetics, no royaltiesThaddeus JudkinsEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics Travel, Accommodations, Expenses: Myriad GeneticsBenjamin RoaEmployment: Myriad Genetics Leadership: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics Research Funding: Myriad Genetics Patents, Royalties, Other Intellectual Property: Intellectual property held by employer Myriad Genetics (Inst) Travel, Accommodations, Expenses: Myriad GeneticsEric RosenthalEmployment: Myriad Genetic Laboratories Stock and Other Ownership Interests: Myriad Genetic LaboratoriesSusan DomchekHonoraria: AstraZeneca, Clovis Oncology, Bristol Myers Squibb Research Funding: AstraZeneca (Inst), Clovis Oncology (Inst) Open Payments Link: https://openpaymentsdata.cms.gov/physician/917904Judy GarberConsulting or Advisory Role: Novartis (I), GTx (I), Helix BioPharma, Konica Minolta, Aleta BioTherapeutics (I), H3 Biomedicine (I), Kronos Bio (I) Research Funding: Novartis (I), Ambry Genetics, Invitae Genetics, Myriad Genetics Other Relationship: Susan G. Komen for the Cure (I), American Association for Cancer Research, Diane Helis Henry Medical Foundation, James P. Wilmot Foundation (I), Adrienne Helis Malvin Medical Research Foundation (I), Breast Cancer Research Foundation, Facing our Risk of Cancer EmpoweredJohnathan LancasterEmployment: Myriad Genetics, Regeneron Stock and Other Ownership Interests: Myriad Genetics, RegeneronJeffrey WeitzelSpeakers' Bureau: AstraZenecaAllison W. KurianResearch Funding: Myriad Genetics (Inst) Other Relationship: Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, GenentechJerry S. LanchburyEmployment: Myriad Genetics Leadership: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics Patents, Royalties, Other Intellectual Property: I am an inventor on multiple patents filed by Myriad Genetics Travel, Accommodations, Expenses: Myriad GeneticsAlexander GutinEmployment: Myriad Genetics, Myriad Genetics (I) Stock and Other Ownership Interests: Myriad Genetics, Myriad Genetics (I), Gilead SciencesMark RobsonHonoraria: AstraZeneca Consulting or Advisory Role: Change Health Care Research Funding: AstraZeneca (Inst), Myriad Genetics (Inst), InVitae (Inst), AbbVie (Inst), Tesaro (Inst), Medivation (Inst), Pfizer (Inst) Travel, Accommodations, Expenses: AstraZeneca, Pfizer Other Relationship: Research to Practice, Clinical Care Options, Physician Education Resource Uncompensated Relationships: Merck, Pfizer, Daiichi Sankyo Open Payments Link: https://openpaymentsdata.cms.gov/physician/612669/summary No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

Purpose: Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction., Methods: Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status., Results: Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups., Conclusion: Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care.

Purpose: Short-term reactions to BRCA1 and BRCA2 (BRCA1/2) genetic test results have been described in several reports, but the long-terms effects of testing have not been examined extensively., Methods: We conducted an observational study to characterize the long-term impact of genetic testing for BRCA1/2 mutations in 167 women who had received genetic test results at least 4 years ago. We also evaluated the relationship between genetic testing-specific reactions and breast and ovarian cancer screening to determine the behavioral significance of adverse reactions., Results: Seventy-four percent of women were not experiencing any distress regarding their test result, 41% were not experiencing any uncertainty, and 51% had a score for positive experiences that was suggestive of low levels of adverse reactions in terms of family support and communication. Mutation carriers (odds ratio, 3.96; 95% CI, 1.44 to 10.89; P = .01) were most likely to experience distress. Only less time since disclosure was related significantly to experiencing uncertainty (odds ratio, 0.62; 95% CI, 0.44 to 0.88; P = .008). In terms of cancer screening, 81% of women had a mammogram during the year before study enrollment, 25% had magnetic resonance imaging (MRI), 20% had a transvaginal ultrasound, and 20% had a CA-125. Experiencing distress was associated significantly with having a CA-125 (χ(2) = 3.89, P = .05), and uncertainty was associated with having an MRI (χ(2) = 8.90, P = .003)., Conclusion: Our findings show that women are not likely to experience genetic testing concerns several years after receiving BRCA1/2 test results; distress and uncertainty are not likely to have adverse effects on screening among women at risk for hereditary disease.

Purpose: This study evaluated the process of recruiting African American women to participate in genetic counseling research for BRCA1 and BRCA2 (BRCA1/2) mutations with respect to referral, study enrollment, and participation in genetic counseling., Patients and Methods: African American women (n = 783) were referred for study enrollment., Results: Of 783 referrals, 164 (21%) women were eligible for enrollment. Eligible women were most likely to be referred from oncology clinics (44%) and were least likely to be referred from general medical practices (11%; chi(2) = 96.80; P = .0001). Overall, 62% of eligible women enrolled onto the study and 50% of enrollees completed genetic counseling. Women with a stronger family history of cancer (odds ratio [OR] = 3.18; 95% CI, 1.36 to 7.44; P = .01) and those referred from oncology clinics and community oncology resources (OR = 2.97; 95% CI, 1.34 to 6.58; P = .01) were most likely to enroll onto the study. Referral from oncology clinics was associated significantly with participation in genetic counseling (OR = 5.46; 95% CI, 1.44 to 20.60; P = .01)., Conclusion: Despite receiving a large number of referrals, only a small subset of women were eligible for enrollment. Oncology settings were the most effective at identifying eligible African American women and general medical practices were the least effective. Factors associated with enrollment included having a stronger family history of cancer and being referred from oncology clinics and community oncology resources. Referral from oncology clinics was the only factor associated significantly with participation in genetic counseling. Education about hereditary breast cancer may be needed among primary care providers to enhance appropriate referral of African American women to genetic counseling for BRCA1/2 mutations.

Purpose: Bilateral prophylactic oophorectomy (BPO) is widely used for cancer risk reduction in women with BRCA1/2 mutations. Many premenopausal women choose to take hormone replacement therapy (HRT) after undergoing BPO to abrogate immediate symptoms of surgically-induced menopause. Thus, we evaluated whether the breast cancer risk reduction conferred by BPO in BRCA1/2 mutation carriers is altered by use of post-BPO HRT., Methods: We identified a prospective cohort of 462 women with disease-associated germline BRCA1/2 mutations at 13 medical centers to evaluate breast cancer risk after BPO with and without HRT. We determined the incidence of breast cancer in 155 women who had undergone BPO and in 307 women who had not undergone BPO on whom we had complete information on HRT use. Postoperative follow-up was 3.6 years., Results: Consistent with previous reports, BPO was significantly associated with breast cancer risk reduction overall (hazard ratio [HR] = 0.40; 95%CI, 0.18 to 0.92). Using mutation carriers without BPO or HRT as the referent group, HRT of any type after BPO did not significantly alter the reduction in breast cancer risk associated with BPO (HR = 0.37; 95% CI, 0.14 to 0.96)., Conclusion: Short-term HRT use does not negate the protective effect of BPO on subsequent breast cancer risk in BRCA1/2 mutation carriers.