Molecular tumor profiling and therapy selection in advanced gynecological cancers: A retrospective cohort analysis from the Australian Molecular Screening and Therapeutics (MoST) Program.
Authors: Kee Damien , Lin Frank Po-Yen , Thavaneswaran Subotheni , Napier Christine E , Harrison Michelle L. , Beale Philip James , Lynch Jodi , Davis Alison J. , Ananda Sumitra , Lombard Janine Margaret , Friedlander Michael , Kansara Maya , Sebastian Lucille , Lee Chee Khoon , Ballinger Mandy L. , Simes John , Thomas David Morgan 
Published: June 2023

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Background: Gynecological (gyne) cancers are highly diverse with distinct sites of origin and histological subtypes that can limit development of evidence-based therapies. Comprehensive genomic profiling (CGP) has an increasing role in characterizing clinically relevant molecular subsets and in identifying actionable biomarkers with potential to guide therapy selection. Methods: MoST (ACTRN12616000908437) is an Australia-wide precision oncology program for adult patients (pts) with advanced cancers and limited treatment options. Tumor specimens are analysed by CGP and genomic results tiered by the level of evidence supporting matched therapies (https://topograph.info). Pts are followed for subsequent treatment and survival. Here, we present data for the MoST gyne cancer cohort. Results: Between Sept 2016 and Oct 2022, 533 gyne tumors were sequenced, with included pts having a minimum 4 months (mo) follow-up. Key histotypes included: ovarian serous (n=162) and non-serous (n=46) epithelial tumors; uterine carcinomas (n=99) and sarcomas (n=108); cervical carcinomas (n=51); germ cell and sex-cord stromal tumors (n=18); carcinosarcomas (n=33); and vulva/vaginal tumors (n=16). The median number of reported variants was 3 (IQR 2-5) and tumor mutational burden 3.1 mut/Mb (IQR 1.3—5.5, Range 0—284); 9 (2%) tumors were microsatellite unstable; and 22 (4%) had high level loss-of-heterozygosity (confirmed on validated genome-wide assays). The most common pathways involved in this pan-gyne cohort were: p53 (n=287, 54%), PI3K/AKT (n=227, 43%), cell cycle (n=182, 34%), and mitogen-activated protein kinase (n=91, 17%). Pathogenic mutations in BRCA1/2 were identified in 29 tumors (5%; 18 in ovarian serous cancers), whereas 81 tumors (15%) had alterations in other homologous recombination genes, most commonly uterine sarcomas (n=32, 30%). Actionable genomic biomarkers matched to a clinically active treatment (TOPOGRAPH tier 1-3) were identified in 207 (39%) tumors. In 19 pts (3.5%) who received Tier 1-3 matched therapy after CGP, a trend towards longer survival was observed (median OS 22.3 mo, 95% CI 17.3 to not reached) compared to those receiving unmatched therapy (n=65, median OS 14.9 mo, 10.2 to 22.1, p=0.052) following CGP. No OS difference was seen in pts who received matched investigational therapy (Tier 3B/4, n=31, median OS 17.0 mo, 8.1 to NR) versus only unmatched therapy (n=118, median OS 14.0 mo, 11.3 to 22.5; HR 0.97, 0.57 to 1.64; p=0.91). Conclusions: CGP identified actionable genomic results in nearly half of advanced gyne cancers, with enrichment in particular histotypes that supports testing above current standard of care. Trends in prolonged OS with subsequent matched therapies may be better realized with earlier testing and improved drug/clinical trial access.