Implementation of Comprehensive Genomic Profiling in Ovarian Cancer Patients: A Retrospective Analysis.

Comprehensive genomic profiling (CGP) allows for the detection of driver alterations at high resolution, but the limited number of approved targeted therapies and their high costs have contributed to its limited clinical utilization. We retrospectively compared data of 946 women with ovarian cancer (11.4% were referred to CGP, and 88.6% served as control) to examine whether CGP provides a prognosis benefit. Patient baseline parameters were similar between the groups. Cox regression analysis adjusted for age, disease stage at diagnosis, and recurrence status showed statistically significantly longer median overall survival (mOS) in the CGP group versus the control (73.4 versus 54.5 months, p < 0.001). Fifty-four patients (52.9%) had actionable mutations with potential treatments; twenty-six (48.2%) were treated with matched targeted therapy, showing a trend for longer mOS than the eighty-six women in the CGP group who were not given a suggested treatment (105.5 versus 63.6 months, p = 0.066). None of the genomic alterations predicted metastasis location. CCNE1 amplification and KRAS mutations were associated with shorter mOS. Patients with tumor mutation burden ≥4 mutations/megabase had longer mOS. High loss of heterozygosity was associated with longer mOS (99.0 versus 48.2 months, p = 0.004). CGP testing may provide both prognostic and predictive insights for treatment of patients with ovarian cancer. Prospective studies of larger cohorts are warranted.

Yield of targeted genotyping for the recurring pathogenic variants in cancer susceptibility genes in a healthy, multiethnic Israeli population.

BACKGROUND: Several recurring pathogenic variants in BRCA1/BRCA2 and other cancer susceptibility genes are encountered in ethnically diverse Jewish populations. The yield of genotyping for these recurring pathogenic variants in healthy Israeli individuals unselected for ethnicity, sex, or a family history of cancer has not been previously reported. METHODS: Individuals voluntarily participating in annual medical surveillance at the Institute of Medical Screening of Sheba Medical Center were offered genotyping for predominant pathogenic variants in BRCA1/BRCA2 and recurring variants in CHEK2, MUTYH, APC, and the Lynch syndrome genes via a chip-based assay at the oncogenetic service of Sheba Medical Center from May 15, 2018, to December 15, 2020. All study participants were unrelated to one another. The study was approved by the Sheba ethics committee. RESULTS: Overall, 1764 individuals, including 1008 females (57%), with a mean age of 54.2 years (range, 25-86 years) were genotyped. The yield of the testing was 4% (71 of 1764), and it was higher in Ashkenazi Jews (AJs) and mixed AJ-non-AJ participants (4.75% [58 of 1222]; 1.8% for BRCA1/BRCA2 pathogenic variants) than non-AJ patients (2.2% [9 of 401]; 1% for BRCA1 pathogenic variants). When BRCA1/BRCA2 pathogenic variants were excluded, 2.44% carried low-penetrance variants, including CHEK2 c.1283C>T (n = 3), APC c.3920T>A (n = 36), and heterozygous MUTYH c.1187G>A (n = 4). A family history of cancer was not associated with a higher yield of pathogenic variant detection. CONCLUSIONS: The observed rates of positive genotyping in a healthy, unselected, multiethnic Israeli population warrant consideration of the inclusion of targeted genotyping of selected pathogenic variants in high-penetrance and perhaps lower penetrance cancer susceptibility genes for all Jewish individuals in Israel, regardless of their ethnicity or family history of cancer.

Time trends in uptake rates of risk-reducing mastectomy in Israeli asymptomatic BRCA1 and BRCA2 mutation carriers.

BACKGROUND: The rate of risk-reducing bilateral mastectomy (RRBM) among cancer-free Israeli female BRCA1/BRCA2 mutation carriers was reportedly 13% in 2010. Current RRBM rates in Israel and factors seemingly associated with opting for RRBM were reevaluated. METHODS: Israeli female cancer-free BRCA1/BRCA2 mutation carriers, who were followed at the high-risk clinic at Sheba Medical Center between January 2011 and April 2020 were eligible. Univariate Cox regression and log-rank test were used to study the crude association between potential predictors and performance of RRBM. RESULTS: Overall, 427 cancer-free BRCA1 (n = 218) or BRCA2 (n = 209) mutation carriers were included. Median age at genotyping was 33.6 years (interquartile range 26.8-41.8 years), median follow-up 4.4 years (range 0.1-7.6 years). Overall, 41/427 (9.6%) participants underwent RRBM, all of them within 5 years of genotyping. Being married (HR-2.57, p = 0.017) and having a first degree relative with breast cancer (BC) (HR-2.19, p = 0.017) were positively associated with RRBM, whereas any previous benign breast biopsy was negatively associated (HR-0.48, p = 0.029) with performing RRBM. CONCLUSIONS: RRBM is still infrequently elected by Israeli BRCA1/BRCA2 mutation carriers, with married women with one relative with BC who have not undergone previous breast biopsy more likely to opt for RRBM.