Implications of Incidental Germline Findings Identified In the Context of Clinical Whole Exome Sequencing for Guiding Cancer Therapy

PURPOSE Identification of incidental germline mutations in the context of next-generation sequencing is an unintended consequence of advancing technologies. These data are critical for family members to understand disease risks and take action. PATIENTS AND METHODS A retrospective cohort analysis was conducted of 1,028 adult patients with metastatic cancer who were sequenced with tumor and germline whole exome sequencing (WES). Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database and narrowed to high-quality submitters. RESULTS Median age was 59 years, with 16% of patients ≤ 45 years old. The most common tumor types were breast cancer (12.5%), colorectal cancer (11.5%), sarcoma (9.3%), prostate cancer (8.4%), and lung cancer (6.6%). We identified 3,427 P/LP variants in 471 genes, and 84% of patients harbored one or more variant. One hundred thirty-two patients (12.8%) carried a P/LP variant in a cancer predisposition gene, with BRCA2 being the most common (1.6%). Patients with breast cancer were most likely to carry a P/LP variant (19.2%). One hundred ten patients (10.7%) carried a P/LP variant in a gene that would be recommended by the American College of Medical Genetics and Genomics to be reported as a result of clinical actionability, with the most common being ATP7B (2.7%), BRCA2 (1.6%), MUTYH (1.4%), and BRCA1 (1%). Of patients who carried a P/LP variant in a cancer predisposition gene, only 53% would have been offered correct testing based on current clinical practice guidelines. Of 471 mutated genes, 231 genes had a P/LP variant identified in one patient, demonstrating significant genetic heterogeneity. CONCLUSION The majority of patients undergoing clinical cancer WES harbor a pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes common.

Urgent cancer genetic counseling and testing for young, premenopausal women with breast cancer (BC): Impact on surgical decision-making for contralateral risk-reducing mastectomy.

1533 Background: In women newly diagnosed with unilateral breast cancer (BC), contralateral risk-reducing mastectomy (CRRM) to decrease risk for additional primary BC is an appropriate option for some individuals, such as those with significantly increased risk due to a pathogenic variant (PV) in a breast cancer predisposition gene. Genetic testing at the time of BC diagnosis for young women has become more available and could aid in the decision-making process. We evaluated the trends for CRRM in a cohort of women diagnosed with BC at age ≤45 years who were seen in a multidisciplinary clinic where genetic counseling and testing is offered to each patient. Methods: A single institution, prospectively maintained database of patients seen in a BC multidisciplinary clinic between November 2014 and June 2019 was reviewed. Patients were included if they had non-metastatic, unilateral BC diagnosed ≤45 years of age, and underwent genetic testing at the time of BC diagnosis. Associations between surgical treatment (lumpectomy, mastectomy, or mastectomy with CRRM) and age at diagnosis, BC stage, family history, and genetic testing results were evaluated. Results: 184 patients were included in the analysis. The prevalence of a PV in a breast cancer predisposition gene was 15.8% (29/184; 1 in ATM, 12 in BRCA1, 8 in BRCA2, 5 in CH EK2, 2 in NBN, and 1 in NF1). 69% of the PV were in BRCA1 and BRCA2. 126 (68.4%) tested negative, and 29 (15.8%) had a variant of uncertain significance (VUS) in various genes. Overall, 63 patients (34.2%) elected to have CRRM. Of the 29 patients with a PV, 24 (82.8%) had CRRM. Women who chose CRRM were younger, more likely to test positive for a PV in a breast cancer predisposition gene, and more likely to have a significant family history of breast and/or ovarian cancer. Among the 155 patients who tested negative or had a VUS, there was no statistically significant association between CRRM and age (p = 0.58), test result (negative vs. VUS. p = 0.12), or family history (p = 0.32). Conclusions: For young women with BC seen in a multidisciplinary clinic, a younger age, significant family history, and positive genetic testing result were found to be associated with the decision to undergo CRRM. Among those without a genetic predisposition, having a VUS result was not associated with choosing CRRM. Incorporation of genetic services in the initial evaluation of young patients newly diagnosed with BC could add relevant information in surgical decision making and promote risk-appropriate management.

The genetics of inherited cancers

All cancer can be termed ‘genetic’ as the disease is caused by somatic cell mutations (alterations in the DNA code), which result in abnormal cellular growth and/or proliferation. Most of these mutations are sporadic (only occurring in the cancer cell), but some are due to the inheritance of a germline mutation in a cancer predisposition gene. Cancer predisposition genes can be rare and confer a high cancer risk (about 10-fold lifetime relative risk), or common and confer a low to moderately increased risk (from just over onefold, up to two- to threefold). They have been shown to be involved in causing some of most common cancers as well as some rare cancers. Cancer genetics will become part of mainstream clinical pathways for cancer care in the coming years and is likely to contribute to healthcare that is tailored to individual patients.

Subsequent Breast Cancer in Female Childhood Cancer Survivors in the St Jude Lifetime Cohort Study (SJLIFE)

PURPOSE Anthracycline-associated risk for subsequent breast cancer in childhood cancer survivors is hypothesized to be mediated by TP53 mutation-related gene-environment interactions. We characterized treatment/genetic risks and the impact of screening for breast cancer in the St Jude Lifetime Cohort. PATIENTS AND METHODS Female participants underwent risk-based assessments, prior health event validation, chest radiation dosimetry, and whole genome sequencing. Breast biopsy reports were reviewed. A subgroup (n = 139) underwent both breast magnetic resonance imaging and mammography. Multivariable regression was used to calculate hazard ratios (HRs) and 95% CIs. RESULTS Among 1,467 women, 56 developed 68 breast cancers at a median age 38.6 (range, 24.5 to 53.0) years. Cumulative incidences at age 35 years were 1% (no chest radiation) and 8% (≥ 10 Gy of chest radiation). In adjusted models, breast cancer was associated with 20 Gy or more of chest radiation versus none (HR, 7.6; 95% CI, 2.9 to 20.4), anthracycline exposure versus none (1 to 249 mg/m2: HR, 2.6; 95% CI, 1.1 to 6.2; ≥ 250 mg/m2: HR, 13.4, 95% CI, 5.5 to 32.5), and having a breast cancer predisposition gene mutation (HR, 23.0; 95% CI, 7.3 to 72.2). Anthracyclines 250 mg/m2 or greater remained significantly associated with increased risk of breast cancer in models excluding survivors with cancer predisposition gene mutations, chest radiation 10 Gy or greater, or both. Sensitivity/specificity were 53.8%/96.3% for mammography, 69.2%/91.4% for magnetic resonance imaging, and 85.8%/99.7% for dual imaging. Breast cancers detected by imaging and/or prophylactic mastectomy compared with physical findings were more likely to be in situ carcinomas, smaller, without lymph node involvement, and treated without chemotherapy. CONCLUSION Higher doses of anthracyclines are associated with increased risk of breast cancer independent of mutations in known cancer predisposition genes. Surveillance imaging identifies breast cancers less likely to require chemotherapy than those detected by physical findings.