University of Texas MD Anderson Cancer Center, Houston, TX
Ji Son , Yingao Zhang , Mirella Nardo , Oriol Mirallas , Robert Tyler Hillman , Heather Y. Lin , Erick Campbell , Vijaykumar Holla , Amber Johnson , Natalie Clark , Pablo Alvarez-Ballesteros , Ying Yuan , Lauren Patterson Cobb , David Marc Gershenson , Amir A. Jazaeri , Pamela T. Soliman , Shannon Neville Westin , Funda Meric-Bernstam , David S. Hong
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.
RAS-pathway Inhibitor | RAS-mutated GYN Cancer Patients (n) | Median Overall Survival (months, 95% CI) | HR (95% CI) | p |
---|---|---|---|---|
Received | 62 | 101 (78-160) | 0.67 (0.47-0.96) | 0.031 |
Not received | 460 | 66 (53-79) |
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