Symecko, Heather

AbstractGermline genetic testing for inherited cancer risk is increasingly being performed with multigene panel testing with MUTYH often included on colorectal cancer‐ and polyposis‐focused panels, as well as on broader pan‐cancer panels. With up to 1%–2% of the general population being monoallelic MUTYH carriers, pathogenic/likely pathogenic (P/LP) variants in MUTYH are one of the most common findings on multigene cancer panels. However, little is known about patient experience and understanding of monoallelic MUTYH P/LP variants, nor whether such findings influence medical management recommendations and familial communication, which this study aims to better understand. Monoallelic P/LP MUTYH carriers were recruited from the Prospective Registry of Multiplex Testing (PROMPT) and completed a cross‐sectional self‐report survey on sociodemographic characteristics, medical and family history, experiences with MUTYH genetic testing, genetics and MUTYH knowledge, perceived cancer risk, and familial communication. Of 115 eligible PROMPT participants, 49 (43%) completed the survey who were primarily female (94%), white (96%), had a history of cancer (61%), and a median age of 51.4 years. Most participants (61%) reported satisfaction with how their healthcare provider managed their genetic test result and care, and 65% of survey participants reported their provider recommended colonoscopy based on their genetic test results. Participants' responses also reflected variable levels of knowledge regarding cancer risks and screening recommendations for MUTYH carriers. The majority (98%) of participants shared their genetic test results with at least some of their relatives; however, only 13% of eligible relatives reportedly underwent cascade testing. Taken together, this study provides needed insight into the overall experiences of monoallelic MUTYH carriers and highlights numerous areas for improvement in clinician education, communication, and management of these individuals.

1508 Background: With the expansion of multigene panel testing for cancer susceptibility, increasing numbers of patients are identified with pathogenic/likely pathogenic variants (P/LP V) in genes which do not have a clearly actionable increased risk of ovarian cancer (OC) (lifetime risk of OC >5%). However, there is concern that patients and/or providers may ascribe OC risk to such genetic findings with the potential for unnecessary oophorectomy (ooph). Methods: The Prospective Registry of Multiplex Testing (PROMPT) is an online registry for individuals with a genetic alteration detected on multiplex panel testing for cancer susceptibility. Participants self-enroll and complete baseline and annual follow-up questionnaires. PROMPT has enrolled 7388 participants (6936; 93.9% women) since September 2014. Results: 1566 women in the PROMPT registry reported ooph, the indications for which were reported as either cancer treatment (n=481, 30.7%) or benign disease (n=432, 27.6%). An additional 186 (12.8%) reported PV in genes associated with lifetime OC risk >5% ( BRCA1, BRCA2, RAD51C, RAD51D, BRIP, or Lynch syndrome genes). The remaining 467 did not have guideline based indications for ooph due to OC risk and are described further here. 92 (19.7%) had a variant of uncertain significance (VUS) in genes associated with OC, 241 (51.6%) had a personal history of breast cancer (BC) and no VUS in OC genes, and 119 (25.5%) had no personal history of BC and no VUS in OC genes. The majority of women had no family history (FH) of OC in first or second degree relatives (Table). Most ooph occurred prior to age 50. Of the 405 women with CHEK2 P/LP, 11.4% reported ooph (59% under age 50 when age known), as did 13.2% (of 228) with CHEK2 VUS, 8.8% (of 261) with ATM P/LP (66.7% under age 50), and 8.3% (of 387) with ATM VUS. In addition, of the 184 women with PALB2 P/LP, 14.1% reported ooph (35.3% under age 50) as did 11.6% (of 198) with PALB2 VUS. Of those who reported provider discussions, 47.2% stated “my provider recommended this” (including >60% in the OC gene VUS group) and an additional 25.2% stated “my provider presented this as an option, but not a requirement”. In those with no FH of OC, 45.8% stated that their provider recommended ooph. Conclusions: 10-15% of women with PV/VUS in genes not associated with a high risk of OC reported ooph without a clear indication. [Table: see text]

1527 Background: Prospective Registry of Multiplex Testing (PROMPT) is an online registry for individuals who have had multiplex panel testing for cancer susceptibility. The main objective of this registry is to ascertain families to allow penetrance calculations for mutations in less well characterized genes. Methods: Since September 2014, health care providers and commercial laboratories have given PROMPT information with the test results to eligible individuals. Participants with pathogenic mutations or variants of unknown significance in cancer susceptibility genes have self-enrolled in PROMPT. We have sent annual follow-up surveys to participants to capture updated personal and family histories, additional genetic testing in the family, and changes in cancer screening patterns. Results: To date, 5800 participants have enrolled in PROMPT and 2321 follow-up surveys are completed. Of those eligible for follow-up, 1980 (44%) have completed at least one survey. 134 (5.8%) reported a new cancer diagnosis since baseline. Breast cancer (37, 27.6%) and non-Melanoma skin cancer (35, 26.2%) were the most commonly reported new diagnoses. 5.7% of participants with an ATM variant, 5.2% of those with a BRCA2 variant, and 4.3% of those with a CHEK2 variant and at least one follow-up survey have reported a new primary cancer diagnosis (excluding non-Melanoma skin cancer). In addition, 70 (3%) participants reported a cancer recurrence since time of last follow-up. Bone (9, 12.9%) and liver (8, 11.4%) were the most common recurrence sites. 12.7% of those with a TP53 variant, 7.1% of those with a BARD1 variant, and 3.3% of those with an ATM variant and at least one follow-up survey have reported a recurrence. 59 (2.5%) participants had additional clinical genetic testing, and 555 (24%) participants reported clinical genetic testing of family members. Conclusions: PROMPT collects updated health information from participants to achieve the primary goal of determining cancer incidence among carriers of different mutations. Moreover, PROMPT has increased participant contacts through use of annual follow-up surveys and gene-specific surveys with subsets of participants. Ongoing efforts include obtaining pathology reports of new and recurrent cancer diagnoses on study.

PURPOSE Germline CDH1 pathogenic variants (PV) are associated with hereditary diffuse gastric cancer and lobular breast cancer. Although prevalence of CDH1 PV is low in the general population, detection of these variants is increasing with the growing use of multigene panel testing. Little is known about the experiences of individuals tested for CDH1 variants in the multigene panel testing era. METHODS Participants recruited from the Prospective Registry of Multiplex Testing completed a cross-sectional self-report survey regarding CDH1 genetic testing experiences, medical management, and psychosocial adaptation. RESULTS Discordance existed in interpretations of CDH1 results; 13.3% of cases had disagreements in variant classifications among commercial laboratories, and 21.4% had disagreements between participant self-report and ClinVar classification. Survey data were available from 57 individuals reporting either PV (n = 16) or variants of uncertain significance (VUS; n = 41). Those with PV were more likely than those with VUS to report receiving a recommendation for prophylactic gastrectomy, although only 40.0% of those with PV received this recommendation. Participants with VUS were less satisfied with their health care providers’ knowledge and reported less CDH1 knowledge, distress, and worry about discrimination. Participants with PV perceived greater breast cancer risks, but similar gastric cancer risks, as those with VUS. CONCLUSION Few individuals with CDH1 PV report receiving recommendations for prophylactic gastrectomy, and no differences in perceived gastric cancer risk were observed based on participants’ CDH1 results, suggesting serious unmet informational needs.