Tiffany Y. Sia

Optimizing Mainstreaming of Genetic Testing in Parallel With Ovarian and Endometrial Cancer Tumor Testing: How Do We Maximize Our Impact?

PURPOSE Although germline genetic testing (GT) is recommended for all patients with ovarian cancer (OC) and some patients with endometrial cancer (EC), uptake remains low with multiple barriers. Our center performs GT in parallel with somatic testing via a targeted sequencing assay (MSK-IMPACT) and initiates testing in oncology clinics (mainstreaming). We sought to optimize our GT processes for OC/EC. METHODS We performed a quality improvement study to evaluate our GT processes within gynecologic surgery/medical oncology clinics. All eligible patients with newly diagnosed OC/EC were identified for GT and tracked in a REDCap database. Clinical data and GT rates were collected by the study team, who reviewed data for qualitative themes. RESULTS From February 2023 to April 2023, we identified 116 patients with newly diagnosed OC (n = 57) and EC (n = 59). Patients were mostly White (62%); English was the preferred language for 90%. GT was performed in 52 (91%) patients with OC (seven external, 45 MSK-IMPACT) and in 44 (75%) patients with EC (three external, 41 MSK-IMPACT). GT results were available within 3 months for 100% and 95% of patients with OC and EC, respectively. Reasons for not undergoing GT included being missed by the clinical team where there was no record that GT was recommended, feeling overwhelmed, financial and privacy concerns, and language barriers. In qualitative review, we found that resources were concentrated in the initial visit with little follow-up to encourage GT at subsequent points of care. CONCLUSION A mainstreaming approach that couples somatic and germline GT resulted in high testing rates in OC/EC; however, barriers were identified. Processes that encourage GT at multiple care points and allow self-directed, multilingual digital consenting should be piloted.

Clinicopathologic and Genomic Analysis of Uterine Serous Carcinomas Arising From Endometrial Hyperplasia

Uterine serous carcinoma (USC) typically arises from atrophic endometrium but may be associated with hyperplasia in 5% to 10% of cases. We sought to identify USC with concurrent hyperplasia and (i) define if these are clonally related, and (ii) determine if USC associated with hyperplasia is genetically distinct from USC without hyperplasia. Patients diagnosed with USC and hyperplasia from their hysterectomy specimen between January 1, 2014 and February 29, 2022 were identified. Hyperplasia and carcinoma were separately subjected to tumor-normal panel sequencing. Their repertoire of genetic alterations was compared with that of a separate cohort of atrophy-associated USCs. Of 267 USCs with clinical sequencing and slides available for review, 8 with concurrent carcinoma and hyperplasia had sufficient tissue for molecular studies. In 7 (87.5%) of these 8 cases, USC and hyperplasia were clonally related and shared multiple mutations, including TP53 in 4 cases (57%). In 1 case (USC4), USC and hyperplasia were unrelated at the genetic level, and the hyperplasia was TP53 wild-type. In another case (USC5), USC and TP53 wild-type hyperplasia shared 1 of 11 mutations while being distinct at the copy number level. The prevalence of ARID1A mutations was higher in hyperplasia-associated USC compared with atrophy-associated USC (43% vs. 0%, respectively; P=0.02). USC and co-occurring hyperplasia were clonally related in most cases, commonly harboring TP53 hotspot mutations in both components. These results suggest an alternative origin of tumorigenesis in this rare subset of endometrial cancers.

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