Kenneth Offit

Comprehensive analysis of germline drivers in endometrial cancer

AbstractBackgroundWe sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features.MethodsGermline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests.ResultsOf 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P = .002), more often White (P = .009), and less obese (P = .025) and had differences in distribution of tumor histology (P = .017) and molecular subtype (P < .001). Among 231 gPVs, 74 (32%) exhibited biallelic inactivation within tumors. For high-penetrance gPVs, 63% (47 of 75) of ECs had biallelic alterations, primarily affecting mismatch repair (MMR) and homologous recombination related genes, including BRCA1,BRCA2, RAD51D, and PALB2. Biallelic inactivation varied across molecular subtypes with highest rates in microsatellite instability-high (MSI-H) or copy-number (CN)–high subtypes (3 of 12 [25%] POLE, 30 of 77 [39%] MSI-H, 27 of 60 [45%] CN-high, 9 of 57 [16%] CN-low; P < .001).ConclusionsOf unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.

Age-Related Germline Landscape of Endometrial Cancer: Focus on Early-Onset Cases

PURPOSE Early-onset endometrial cancer (eoEC) is increasing, and germline drivers may be enriched in younger patients. We sought to define germline pathogenic variants (gPVs) in those with EC by age. METHODS We identified patients with EC who underwent clinical tumor-normal sequencing from December 2014 to June 2021 and collected clinical variables. Logistic regression models evaluated associations between age at EC diagnosis and presence of gPV, biallelic inactivation, and Lynch Syndrome (LS). Age categories were defined as early-onset (eoEC, EC < 50 years) and late-onset (EC ≥ 70 years) and were compared with those diagnosed ages 50-69 years. RESULTS Among 1,625 patients with EC, the median age at diagnosis was 63 (range, 24-96) years. We observed gPV in 28 (16%) of 170 patients with eoEC, 152 (14%) of 1,066 patients diagnosed age 50-69 years, and 36 (9%) of 389 patients with late-onset EC ( P = .016). LS was enriched in eoEC, with 6.5% of patients diagnosed age <50 years having LS. In multivariable models compared with those with EC diagnosed age 50-69 years, eoEC was more likely to exhibit biallelic inactivation (odds ratio, 3.34 [95% CI, 1.44 to 7.35]) and be associated with LS (hazard ratio [HR], 3.49 [95% CI, 1.63 to 7.01]). Among early-onset EC, 14 (50%) of 28 gPV were high penetrance and 14 (50%) of 28 exhibited biallelic inactivation. However, heterogeneity was observed, and rates of gPV were 8.9% and 19%, biallelic inactivation was 0% and 11%, and LS was 2.2% and 8% in those diagnosed age <40 years and 40-49 years, respectively. CONCLUSION Rates of gPV, biallelic inactivation, and LS differ across age groups for EC, with high-penetrant genes driving tumorigenesis enriched in younger patients. However, very-early-onset EC may have different drivers and necessitates more research.

Germline Pathogenic Variants and Genetic Counseling by Ancestry in Patients With Epithelial Ovarian Cancer

Mutations in ovarian cancer risk genes are found in women of diverse ancestries, supporting genetic testing for ALL

Risk-Reducing Bilateral Salpingo-Oophorectomy for Ovarian Cancer: A Review and Clinical Guide for Hereditary Predisposition Genes

Pathogenic germline variants underlie up to 20% of ovarian cancer (OC) and are associated with varying degrees of risk for OC. For mutations in high-penetrance genes such as BRCA1/ 2, the role of risk-reducing bilateral salpingo-oophorectomy (RRSO) in cancer prevention is well-established and improves mortality. However, in moderate-penetrance genes where the degree of risk for OC is less precisely defined, the role of RRSO is more controversial. Although national guidelines have evolved to incorporate gene-specific recommendations, studies demonstrate significant variations in practice. Given this, our multidisciplinary group has reviewed the available literature on risk estimates for genes associated with OC, incorporated levels of evidence, and set thresholds for consideration of RRSO. We found that the benefit of RRSO is well-established for pathogenic variants in BRCA1/2 as well as BRIP1 and RAD51C/ D where the risk of OC is elevated beyond our threshold for RRSO. In PALB2, RRSO is particularly controversial as newer studies consistently demonstrate an increased risk of OC that is dependent on family history, making uniform recommendations challenging. Additionally, new guidelines for Lynch syndrome provide gene-specific risks, questioning the role of RRSO, and even hysterectomy, for MSH6 and PMS2 mutation carriers. Given these uncertainties, shared decision making should be used around RRSO with discussion of individual risk factors, family history, and adverse effects of surgery and premature menopause. Herein, we provide a clinical guide and counseling points.