Data from MAPK Pathway Genetic Alterations Are Associated with Prolonged Overall Survival in Low-Grade Serous Ovarian Carcinoma

Abstract

<div>AbstractPurpose:<p>To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC).</p>Experimental Design:<p>Patients with LGSC tumors who underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations; copy-number alterations; and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected.</p>Results:<p>Following central pathology rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic <i>KRAS</i> (33%), <i>NRAS</i> (11%), <i>EIF1AX</i> (10%), and <i>BRAF</i> (11%) alterations were the most common; MAPK pathway alterations were found in 60% (<i>n</i> = 71) of LGSCs. <i>KRAS</i> mutations were significantly associated with age at diagnosis more than 50 years (<i>P</i> = 0.02) and platinum-sensitive disease (<i>P</i> = 0.03). On multivariate analysis, MAPK pathway alterations (<i>P</i> = 0.02) and platinum sensitivity (<i>P</i> = 0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; seven pathogenic germline mutations were identified: <i>MUTYH</i> (<i>n</i> = 2), <i>BAP1</i> (<i>n</i> = 1), <i>RB1</i> (<i>n</i> = 1), <i>CHEK2</i> (<i>n</i> = 1), <i>APC</i> (<i>n</i> = 1), and <i>FANCA</i> (<i>n</i> = 1). There were no germline <i>BRCA1/2</i> mutations. One germline <i>MUTYH</i>-associated LGSC harbored loss-of-heterozygosity at the <i>MUTYH</i> locus, and the patient with the germline <i>BAP1</i> mutation also harbored a somatic <i>BAP1</i> frameshift mutation.</p>Conclusions:<p>This study showed that MAPK pathway alterations in LGSC, including <i>KRAS</i> mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-22-1623" target="_blank">See related commentary by Veneziani and Oza, p. 4357</a></i></p></div>