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

Abstract

Purpose: 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 (LGSCs). Experimental design: Patients with LGSC tumors that 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. Results: Following central pathology re-review, 119 patients with LGSC were identified for analysis. One hundred ten (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; mitogen-activated protein kinase (MAPK) pathway alterations were found in 60% (n=71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis >50 years (p=0.02) and platinum-sensitive disease (p=0.03). On multivariate analysis, MAPK pathway alterations (p=0.02) and platinum sensitivity (p=0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; 7 pathogenic germline mutations, including 1 bi-allelic MUTYH mutation (c.1187G>A (p.Gly396Asp)) and 6 mono-allelic alterations, were identified. Somatic loss of the wildtype allele (loss of heterozygosity) in the tumor at the locus of the germline mutation was only observed in the bi-allelic MUTYH mutation carrier. There were no germline BRCA1/2 mutations. Conclusions: This study showed MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC.

Molecular characteristics and clinical behaviour of epithelial ovarian cancers

“…LGSOC comprises only around 5% of OC diagnoses. Typical LGSOC is characterised by late stage at diagnosis (≤10% stage I-II, 80% stage III, 10-20% stage IV) (Table 1) and prolonged post-relapse survival [39][40][41]. While LGSOC is often described as demonstrating more indolent behaviour, it frequently occurs in younger women (median 46-48 years) [40,42] and therefore affects a disproportionate number of life years compared to other histotypes.…”

“…Typical LGSOC is characterised by late stage at diagnosis (≤10% stage I-II, 80% stage III, 10-20% stage IV) (Table 1) and prolonged post-relapse survival [39][40][41]. While LGSOC is often described as demonstrating more indolent behaviour, it frequently occurs in younger women (median 46-48 years) [40,42] and therefore affects a disproportionate number of life years compared to other histotypes. LGSOC is low grade by definition [39][40][41], and demonstrates high levels of intrinsic chemoresistance (objective response rate to first-line platinum-based chemotherapy ≤25%) [43].…”

Update on new treatments for rare ovarian tumours

“…Apart from oestrogen-related tumour driving, MAP kinase signalling pathway deregulation (through KRAS, BRAF, NRAS or ERBB2 alterations) is a major contributor; indeed, it has been estimated to be present in roughly 60% of LGSOC [26][27][28]. Nevertheless, the MILO (NCT01849874) trial failed to demonstrate improved progression-free survival (PFS) with binimetinib (versus chemotherapy) in recurrent LGSOC [29].…”

Molecular characteristics of low‐grade serous carcinoma in effusions

“…Mutations in other genes, as well as more extensive genomic changes, the latter including losses of chromosome domains 1p36 and 9p, have been reported 10,13,21 . Mutations affecting the MAPK pathway have been reported to be associated with early‐stage disease and/or better prognosis in some studies 11,16,17 but not in others 12,13 …”

“…In several studies, molecular analysis has shown that the mitogen-activated protein kinase (MAPK) pathway is frequently altered in LGSC, with KRAS, NRAS and BRAF mutations most often detected, while TP53 mutations, a hallmark of HGSC, are rare or absent. [6][7][8][9][10][11][12][13][14][15][16][17][18] MAPKs are signalling proteins consisting of the extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun amino-terminal kinases 1-3 (JNK1-3), p38 (α, β, γ, and δ), and ERK5 families. They regulate critical cellular processes, including cellular development, differentiation, proliferation, and apoptosis.…”