Clinical and genomic landscape of RAS pathway mutations in gynecologic cancers.
Authors: Son Ji , Zhang Yingao , Nardo Mirella , Mirallas Oriol , Hillman Robert Tyler , Lin Heather Y. , Campbell Erick , Holla Vijaykumar , Johnson Amber , Clark Natalie , Alvarez-Ballesteros Pablo , Yuan Ying , Cobb Lauren Patterson , Gershenson David Marc , Jazaeri Amir A. , Soliman Pamela T. , Westin Shannon Neville , Meric-Bernstam Funda , Hong David S. 
Published: June 2023

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Background: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic features, subtypes, co-mutations, and implications for therapy. Methods: Patients with gynecologic cancers who had next-generation sequencing at our institution between Feb 2010 and Aug 2022 were included. Clinical, histopathologic, and sequencing data were collected and analyzed. Overall survival was estimated using the Kaplan-Meier model. Results: Of the 3310 gynecologic cancer patients tested, 522 (15.8%) harbored a RAS mutation. For patients with mutation, median age was 56 (18-87) years, with cancer types including ovarian (43.5%), endometrial (43.4%), cervical (9.2%), and vulvovaginal (2.9%). Most patients (92.2%) had recurrence. The most common histology for each cancer included endometrioid in endometrial (60.8%), low grade serous in ovarian (34.4%), adenocarcinoma in cervical (60.4%), and melanoma in vulvovaginal (66.7%). Mucinous and clear cell differentiations were overrepresented (12.5% each). Median overall survival for all RAS-mutated patients was 69 months (95%CI 59-82), which was significantly better than in wildtype control of 56 months (95%CI 52-59, p = 0.022). Mutations observed were in KRAS (85.8%), NRAS (12.8%), and HRAS (3.3%). The most common mutant alleles for each were KRAS G12D (34.5%), KRAS G12V (31.7%), NRAS Q61R (34.3%), and HRAS G12S (17.6%). Of note, the incidence of KRAS G12C was 5.6% (0.8% overall). The most common co-mutations for RAS were PIK3CA (35.7%), PTEN (33.3%), TP53 (32.4%), and ARID1A (20.8%). This trend held for each mutation and cancer type. Of these, 64.7% were potentially actionable alterations, including 91.1% of PIK3CA, 83.7% of PTEN, and 50.0% of ARID1A. RAS pathway targeted therapies were administered to 62 patients (57 MEK, 5 BRAF, 5 KRAS G12C, 4 SHP2). The median overall survival for these patients was significantly improved (101 months, 95%CI 78-160) compared to RAS-mutated patients who did not receive a RAS pathway inhibitor (66 months, 95%CI 53-79, HR 0.7, p = 0.031). Of interest, novel KRAS G12C inhibitors showed durable benefit in 3 ovarian (high grade serous, low grade serous, clear cell) and 2 endometrial (mixed endometrioid, clear cell; mixed endometrioid, serous, mucinous) cancers with a clinical benefit rate of 100%, duration of objective response of 22 months, and ongoing responses at 5 and 16 months. Conclusions: Gynecologic cancers with RAS mutations have distinct histopathologic distribution and portend improved overall survival. The most commonly actionable co-mutations were PIK3CA, PTEN, and ARID1A, which may aid in combination therapy design. RAS pathway targeted therapy is associated with improved overall survival in this cohort and should be considered. [Table: see text]