Penetrance estimates for BRCA1, BRCA2 (also applied to Lynch syndrome) based on presymptomatic testing: a new unbiased method to assess risk?

PURPOSE: The identification of BRCA1, BRCA2 or mismatch repair (MMR) pathogenic gene variants in familial breast/ovarian/colorectal cancer families facilitates predictive genetic testing of at-risk relatives. However, controversy still exists regarding overall lifetime risks of cancer in individuals testing positive. METHODS: We assessed the penetrance of BRCA1, BRCA2, MLH1 and MSH2 mutations in men and women using Bayesian calculations based on ratios of positive to negative presymptomatic testing by 10-year age cohorts. Mutation position was also assessed for BRCA1/BRCA2. RESULTS: Using results from 2264 presymptomatic tests in first-degree relatives (FDRs) of mutation carriers in BRCA1 and BRCA2 and 646 FDRs of patients with MMR mutations, we assessed overall associated cancer penetrance to age of 68 years as 73% (95% CI 61% to 82%) for BRCA1, 60% (95% CI 49% to 71%) for BRCA2, 95% (95% CI 76% to 99%) for MLH1% and 61% (95% CI 49% to 76%) for MSH2. There was no evidence for significant penetrance for males in BRCA1 or BRCA2 families and males had equivalent penetrance to females with Lynch syndrome. Mutation position and degree of family history influenced penetrance in BRCA2 but not BRCA1. CONCLUSION: We describe a new method for assessing penetrance in cancer-prone syndromes. Results are in keeping with published prospective series and present modern-day estimates for overall disease penetrance that bypasses retrospective series biases.

Pathology update to the Manchester Scoring System based on testing in over 4000 families.

BACKGROUND: While the requirement for thresholds for testing for mutations in BRCA1/2 is being questioned, they are likely to remain for individuals unaffected by a relevant cancer. It is still useful to provide pretesting likelihoods, but models need to take into account tumour pathology. METHODS: The Manchester Scoring System (MSS) is a well-used, simple, paper-based model for assessing carrier probability that already incorporates pathology data. We have used mutation testing data from 4115 unrelated samples from affected non-Jewish individuals alongside tumour pathology to further refine the scoring system. RESULTS: Adding additional points for high-grade serous ovarian cancer <60 (HGSOC=+2) and adding grade score to those with triple-negative breast cancer, while reducing the score for those with HER2+ breast cancer (-6), resulted in significantly improved sensitivity and minor improvements in specificity to the MSS. Sporadic HGSOC <60 years thus reached a score of 15-19 points within the 10% grouping consistent with the 15/113-13.2% that were identified with a BRCA1/2 pathogenic variant. Validation in a population series of ovarian cancer from Cambridge showed high sensitivity at the 10% threshold 15/17 (88.2%). CONCLUSIONS: The new pathology-adjusted Manchester score MSS3 appears to provide an effective and simple-to-use estimate of the 10% and 20% thresholds for BRCA1/2 likelihood. For unaffected individuals, the 20-point (20%) threshold in their affected first-degree relative can be used to determine eligibility at the 10% threshold.

New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study.

BACKGROUND: Over recent years genetic testing for germline mutations in BRCA1/BRCA2 has become more readily available because of technological advances and reducing costs. OBJECTIVE: To explore the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (EOC). METHODS: Between 1 July 2013 and 30 June 2015 women newly diagnosed with EOC were recruited through six sites in East Anglia, UK into the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study. Eligibility was irrespective of patient age and family history of cancer. The psychosocial arm of the study used self-report, psychometrically validated questionnaires (Depression Anxiety and Stress Scale (DASS-21); Impact of Event Scale (IES)) and cost analysis was performed. RESULTS: 232 women were recruited and 18 mutations were detected (12 in BRCA1, 6 in BRCA2), giving a mutation yield of 8%, which increased to 12% in unselected women aged <70 years (17/146) but was only 1% in unselected women aged ≥70 years (1/86). IES and DASS-21 scores in response to genetic testing were significantly lower than equivalent scores in response to cancer diagnosis (p<0.001). Correlation tests indicated that although older age is a protective factor against any traumatic impacts of genetic testing, no significant correlation exists between age and distress outcomes. CONCLUSIONS: The mutation yield in unselected women diagnosed with EOC from a heterogeneous population with no founder mutations was 8% in all ages and 12% in women under 70. Unselected genetic testing in women with EOC was acceptable to patients and is potentially less resource-intensive than current standard practice.

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families.

PURPOSE: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.