David Sanghyun Hong (The University of Texas MD Anderson Cancer Center) | 한빛사논문 > 한빛사

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The University of Texas MD Anderson Cancer Center

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Clin. Cancer Res., Apr 30 2024, | https://doi.org/10.1158/1078-0432.CCR-23-2819 Clinical and genomic landscape of RAS mutations in gynecologic cancers

Ji Son,¹ Yingao Zhang,^1,2 Heather Lin,³ Oriol Mirallas,^4,5 Pablo Alvarez Ballesteros,^4,6 Mirella Nardo,⁴ Natalie Clark,^1,7 R. Tyler Hillman,^1,* Erick Campbell,⁴Vijaykumar Holla,⁸ Amber M. Johnson,⁸Amadeo B. Biter,⁴ Ying Yuan,³ Lauren P. Cobb,¹ David M. Gershenson,¹ Amir A. Jazaeri,¹Karen H. Lu,¹ Pamela T. Soliman,¹ Shannon N. Westin,¹ Elizabeth D. Euscher,⁹ Barrett C. Lawson,⁹ Richard K. Yang,⁹ Funda Meric-Bernstam,⁴ David S. Hong⁴

¹Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

²Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA

³Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

⁴Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

⁵Research Unit for Molecular Therapy of Cancer (UITM), Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain

⁶Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain

⁷Department of Obstetrics and Gynecology, University of Louisville, Louisville, KY, USA

⁸Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

⁹Department of Anatomic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

^*CPRIT Scholar in Cancer Research

Corresponding author: David S. Hong, MD

Abstract

Background: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications.

Methods: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by Kaplan-Meier method, and multivariable analysis was performed using Cox proportional-hazards model.

Results: Of 3328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs 60 years non-mutated), had higher prevalence of endometriosis (27.3% vs 16.9%), and lower grades (grade 1/2, 43.2% vs 8.1%, all p<0.0001). Highest prevalence of KRAS mutation was in mesonephric-like endometrial (100%, n=9/9), mesonephric-like ovarian (83.3%, n=5/6), mucinous ovarian (60.4%), and low-grade serous ovarian (44.4%) cancers. After adjustment for age, cancer type, and grade, RAS mutation was associated with worse overall survival (HR=1.3, p=0.001). Specific mutations were in KRAS (13.5%), NRAS (2.0%), and HRAS (0.51%), most commonly KRAS G12D (28.4%) and G12V (26.1%). Common co-mutations were PIK3CA (30.9%), PTEN(28.8%), ARID1A (28.0%), and TP53 (27.9%), of which 64.7% were actionable. RAS+MAPK pathway-targeted therapies were administered to 62 patients with RAS-mutated cancers. While overall survival was significantly higher with therapy (8.4 years [95%CI 5.5-12.0] vs 5.5 years [95%CI 4.6-6.6], HR=0.67, p=0.031), this effect did not persist in multivariable analysis.

Conclusion: RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered.

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형식Research article
게재일2024년 04월 (BRIC 등록일 2024-05-14)
연구진국외 연구진
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