Domchek, Susan M.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

PURPOSE Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown. PATIENTS AND METHODS We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]). RESULTS Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% v 4.9% [ P = .02] and 7.1% v 4.2% [ P = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non–breast cancers was unrelated to mutation rate. TP53 and MSH6 mutations were significantly enriched in patients with MP-BC but not S-BC, whereas ATM and PALB2 mutations were significantly enriched in both groups compared with ExAC. CONCLUSION Mutation rates are at least 7% in all patients with BRCA1/2 mutation–negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age < 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.

Abstract Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li–Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G&gt;C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G&gt;C probands and one c.1000G&gt;A proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G&gt;C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3, and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G&gt;C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. Significance: TP53 c.1000C&gt;G;p.G334R is a pathogenic, Ashkenazi Jewish–predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.

e13680 Background: Multiplex genetic testing (MGT) simultaneously analyzes multiple cancer susceptibility genes and can reveal genetic variants of uncertain significance (VUS) that have unclear associations with cancer risks. Little is known about how people are prepared for receiving VUS results from MGT, or whether their emotional reactions differ based on the levels of cancer risk to which they may be susceptible. Methods: We recruited participants from the online Prospective Registry of Multiplex Testing (PROMPT). Those with only a VUS in a cancer predisposition gene completed a survey including measures of their MGT experience, distress (range 0-30; α = .87), uncertainty (0-45; α = .83), and positive experiences (0-20; α = .75). We used generalized linear modeling to examine how demographics, awareness of the possibility of VUS before testing, and level of cancer risks associated with their VUS gene were related to emotional outcomes. Results: Data were available from 661 individuals (40% response rate, 95% female, 90% white, 78% college graduate, 69% cancer history, age 23-93) with VUS in a gene of high risk (47%), moderate/low risk (35%) or limited evidence of risk (18%). Among the sample, 80.8% reported ever receiving cancer genetic counseling, and only 50.8% reported being aware of the possibility of VUS when deciding about testing. Participants reported low current distress ( M± SD= 3.25±5.19), uncertainty (9.18±8.35) and positive experiences (7.83±5.98). Distress was associated with younger age, less family cancer history, and being unaware of the possibility of VUS before testing; distress was also higher among those with VUS in a gene of high risk than those with VUS in a gene of moderate/low risk or limited evidence of risk ( ps≤.023). Uncertainty was associated with younger age, non-white race, less education, and being unaware of the possibility of VUS; uncertainty was also higher among those with VUS in a gene of high risk than those with VUS in a gene with limited evidence of risk ( ps≤.05). Fewer positive experiences were associated with more education and more family cancer history; those with VUS in a gene of high risk had fewer positive experiences than those with VUS in a gene with limited evidence of risk ( ps≤.03). Conclusions: Many individuals undergoing MGT may not fully understand the prospect of receiving VUS. Clinicians should consider patients’ background, preparation, and level of cancer risk to which they are potentially susceptible, as these factors may affect their emotional adaptation.

1508 Background: With the expansion of multigene panel testing for cancer susceptibility, increasing numbers of patients are identified with pathogenic/likely pathogenic variants (P/LP V) in genes which do not have a clearly actionable increased risk of ovarian cancer (OC) (lifetime risk of OC >5%). However, there is concern that patients and/or providers may ascribe OC risk to such genetic findings with the potential for unnecessary oophorectomy (ooph). Methods: The Prospective Registry of Multiplex Testing (PROMPT) is an online registry for individuals with a genetic alteration detected on multiplex panel testing for cancer susceptibility. Participants self-enroll and complete baseline and annual follow-up questionnaires. PROMPT has enrolled 7388 participants (6936; 93.9% women) since September 2014. Results: 1566 women in the PROMPT registry reported ooph, the indications for which were reported as either cancer treatment (n=481, 30.7%) or benign disease (n=432, 27.6%). An additional 186 (12.8%) reported PV in genes associated with lifetime OC risk >5% ( BRCA1, BRCA2, RAD51C, RAD51D, BRIP, or Lynch syndrome genes). The remaining 467 did not have guideline based indications for ooph due to OC risk and are described further here. 92 (19.7%) had a variant of uncertain significance (VUS) in genes associated with OC, 241 (51.6%) had a personal history of breast cancer (BC) and no VUS in OC genes, and 119 (25.5%) had no personal history of BC and no VUS in OC genes. The majority of women had no family history (FH) of OC in first or second degree relatives (Table). Most ooph occurred prior to age 50. Of the 405 women with CHEK2 P/LP, 11.4% reported ooph (59% under age 50 when age known), as did 13.2% (of 228) with CHEK2 VUS, 8.8% (of 261) with ATM P/LP (66.7% under age 50), and 8.3% (of 387) with ATM VUS. In addition, of the 184 women with PALB2 P/LP, 14.1% reported ooph (35.3% under age 50) as did 11.6% (of 198) with PALB2 VUS. Of those who reported provider discussions, 47.2% stated “my provider recommended this” (including >60% in the OC gene VUS group) and an additional 25.2% stated “my provider presented this as an option, but not a requirement”. In those with no FH of OC, 45.8% stated that their provider recommended ooph. Conclusions: 10-15% of women with PV/VUS in genes not associated with a high risk of OC reported ooph without a clear indication. [Table: see text]

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2 , pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.

Abstract Background: Pathogenic variants detected in multi-gene cancer predisposition panels are increasingly used to counsel women regarding their risk for breast cancer. However, the clinical implications of moderate penetrance genes (e.g. CHEK2, ATM) remain unclear. Breast MRI is indicated for women with a lifetime risk of breast cancer of &gt;20%, and polygenic risk scores (PRS) based on common variants discovered in recent genome-wide association studies (GWAS) may identify women with pathogenic variants in CHEK2 and ATM who are above or below this level of risk. PRS may also stratify carriers with substantially elevated lifetime risks of breast cancer. Previous work found that PRS modified breast cancer risk in carriers of pathogenic variant in BRCA1 or BRCA2, but the joint effects of pathogenic variants and PRS have not been studied in samples drawn from the general population. There is also no published study evaluating the effect of PRS among women with pathogenic variants in genes other than BRCA1/2 and CHEK2. Here, we evaluated the joint effects of PRS and pathogenic variants in ten established breast cancer predisposition genes in a population-based case-control sample. Method: We analyzed 43,144 non-Hispanic European-ancestry individuals (20,988 controls and 22,120 cases) drawn from 7 cohorts and 2 population-based case-control studies in the CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium. Targeted sequencing was performed using a dual bar-coded QIAseq panel of breast cancer predisposition genes. Variant calling was conducted with Haplotype Caller and Vardict. The PRS was calculated based on 106 common variants using effect estimates from the largest published breast cancer GWAS. Genetic status was evaluated for 10 breast cancer predisposition genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NF1, PALB2 and TP53. Lasso Penalized regression was performed to assess the combined effect on overall breast cancer of pathogenic variants and common variants (including main and interaction effects between age, family history, carrier status and PRS). The fraction of women at &gt;2-fold increased risk (which is associated with approximately 20% lifetime risk of breast cancer) was calculated for pathogenic variant carriers and non-carriers of different family history and age groups (&lt;40, 40-50, 50-60, 60-70, &gt;70yrs old). Results: Among non-carriers, one standard deviation change in the PRS was associated with a 1.63x change in odds of breast cancer. The best-fitting risk model did not include any PRS-by-carrier interaction terms, implying the relative risk gradient associated with PRS among women with pathogenic variants is similar to that among non-carriers. For carriers of pathogenic variants in moderate penetrance genes with no family history of breast cancer, the PRS can identify 60.6% of ATM pathogenic variant carriers and 30% of CHEK2 pathogenic variant carriers that have less than 2-fold risk of breast cancer; when carriers have a family history of breast cancer, the PRS can identify 30% of ATM pathogenic variant carriers and 11.8% of CHEK2 pathogenic variant carriers with less than 2-fold risk of breast cancer. Conclusion: In our large, population-based case-control study, the effect of the PRS among pathogenic variant carriers was not significantly different than among non-carriers. However, the PRS may be particularly important for estimating breast cancer risk among carriers of pathogenic variants in moderate penetrance genes such as CHEK2 and ATM, enabling a more precise approach for MRI screening strategy and breast cancer risk management. Citation Format: Chi Gao, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Kun Y. Lee, Jie Na, Nicholas J. Boddicker, Raed Samara, Paul Auer, Leslie Bernstein, Mia Gaudet, Amy Trentham-Dietz, Song Yao, Christopher Haiman, Janet E. Olson, Susan Neuhausen, Jeffrey N. Weitzel, David E. Goldgar, Susan Domchek, Katherine L. Nathanson, Fergus J. Couch, Peter Kraft, on behalf of the CARRIERS consortium. Polygenic risk scores provide clinically meaningful risk stratification among women carrying moderate penetrance pathogenic variants in breast cancer predisposition genes: Results from the CARRIERS study [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 PD3-02.