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PURPOSE Evidence-based guidelines recommend cascade genetic counseling and testing for hereditary cancer syndromes, providing relatives the opportunity for early detection and prevention of cancer. The current standard is for patients to contact and encourage relatives (patient-mediated contact) to undergo counseling and testing. Direct relative contact by the medical team or testing laboratory has shown promise but is complicated by privacy laws and lack of infrastructure. We sought to compare outcomes associated with patient-mediated and direct relative contact for hereditary cancer cascade genetic counseling and testing in the first meta-analysis on this topic. MATERIALS AND METHODS We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO No.: CRD42020134276). We searched key electronic databases to identify studies evaluating hereditary cancer cascade testing. Eligible trials were subjected to meta-analysis. RESULTS Eighty-seven studies met inclusion criteria. Among relatives included in the meta-analysis, 48% (95% CI, 38 to 58) underwent cascade genetic counseling and 41% (95% CI, 34 to 48) cascade genetic testing. Compared with the patient-mediated approach, direct relative contact resulted in significantly higher uptake of genetic counseling for all relatives (63% [95% CI, 49 to 75] v 35% [95% CI, 24 to 48]) and genetic testing for first-degree relatives (62% [95% CI, 49 to 73] v 40% [95% CI, 32 to 48]). Methods of direct contact included telephone calls, letters, and e-mails; respective rates of genetic testing completion were 61% (95% CI, 51 to 70), 48% (95% CI, 37 to 59), and 48% (95% CI, 45 to 50). CONCLUSION Most relatives at risk for hereditary cancer do not undergo cascade genetic counseling and testing, forgoing potentially life-saving medical interventions. Compared with patient-mediated contact, direct relative contact increased rates of cascade genetic counseling and testing, arguing for a shift in the care delivery paradigm, to be confirmed by randomized controlled trials.

1536 Background: Limited information exists regarding appropriate risk-reduction strategies for women with moderate and low penetrance ovarian cancer (OVCA) susceptibility mutations. We sought to assess current practice patterns for women with these genetic changes through a survey of members of the Society of Gynecologic Oncology (SGO). Methods: All full SGO members were e-mailed a survey consisting of two vignettes: 1) a 35-year-old premenopausal woman who desires pregnancy; 2) a 55-year-old postmenopausal woman with multiple comorbidities. Each vignette contained sub-scenarios in which the patient had either a BRCA1 (RR = 30-60), RAD51C (RR = 5.0) or ATM (RR 1.5-2.0) OVCA susceptibility mutation. Respondents were queried about their preferred management approach. Chi-square test was used for statistical analysis. Results: 193 (15%) of 1284 SGO members responded. 58% were in academic practice. For the premenopausal woman, 52%, 13% and 6% would perform an RRSO prior to age 40 in the setting of a BRCA1, RAD51C and ATM mutation respectively. 47%, 68% and 9% would perform RRSO at 40-50; and 0%, 9% and 23% would perform RRSO at menopause, depending on the gene mutated. For the postmenopausal woman with comorbidities, 98%, 85% and 42% would proceed with RRSO in the setting of a BRCA1, RAD51C and ATM mutation respectively; 2%, 8% and 39% would observe (with/without screening); and 0%, 7% and 19% would do further research prior to proceeding. Distribution of responses for carriers of RAD51C and ATM mutations were different from BRCA1 in both vignettes [p < 0.001]. Conclusions: Respondents were more likely to perform RRSO earlier and more frequently in the setting of a BRCA1 mutation compared to either a RAD51C or ATM mutation. However, there was lack of consensus in management of the moderate and low penetrance OVCA susceptibility mutations. These patterns likely reflect the limited information available regarding the timing and magnitude of risk associated with these genes. Given the immediate and long-term morbidity of oophorectomy, more data regarding age-specific risks and appropriate risk-reduction strategies for moderate and low penetrance OVCA susceptibility mutations is needed.

6608 Background: UKCTOCS is the largest randomized controlled trial to evaluate screening’s impact on ovarian cancer mortality, assigning women to multimodal screening (MMS) with serum CA125 interpreted with a risk algorithm; annual transvaginal ultrasound; or no screening (NS). There was a non-statistically significant 15% reduction in mortality over 11 years in MMS group. As most of the potential benefit of screening was seen after 7 years, follow-up is ongoing to determine if an observed stage shift translates into significant mortality reduction. The current study estimates the cost-effectiveness of an MMS screening program in the US. Methods: A modified Markov model was constructed using data from UKCTOCS to compare MMS to NS. Published estimates of the long term effect of MMS screening on ovarian cancer mortality were used to simulate mortality over 40 years from the start of screening. Base case costs included CA125, ultrasounds, clinical evaluations and false-positive surgeries, with an annual weighted cost of $35 in addition to an estimated risk algorithm cost of $100. The utility and costs of ovarian cancer treatment were incorporated into the model. Incremental cost-effectiveness ratios (ICERs) were calculated in 2016 U.S. dollars per quality-adjusted year of life saved (QALY). Additional sensitivity analyses were performed. Results: MMS is both more expensive and more effective in reducing ovarian cancer mortality over a lifetime than NS. Screening women from age 50 to 75 with MMS reduced mortality by 24% with an ICER of $98,062/QALY. If screening begins at age 60, MMS reduces mortality by 12%, with ICER below the willingness to pay threshold of $100,000/QALY only if the algorithm costs < $50. In probabilistic sensitivity analyses, the probability that screening from age 50-75 at an algorithm cost of $100 was less than $100,000/QALY was 41%. Conclusions: Ovarian cancer screening is potentially cost-effective in the US depending on final significance of mortality reduction and cost of the CA-125 risk algorithm. These results are limited by uncertainty around the effect of screening on ovarian cancer mortality beyond the 11 years of UKCTOCS.