Type I tumors have low grade serous, clear cell, endometrioid, and mucinous histological features
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abstract
Highlights
- •Genotyping and next generation sequencing can identify actionable mutations.
- •High frequency of clinically actionable mutations was found in type I EOC patients.
- •RAS mutated type I EOC patients received genotype-matched MEKinhibitor combinations.
- •Tumor shrinkage and sustained responses were seen in this patient population.
Abstract
Background
Genomic
alterations that activate the MAPK signaling pathway frequently occur
in Type I Epithelial Ovarian Cancers (EOCs). We evaluated therapeutic
response outcomes in patients with type I EOC treated with
genotype-matched therapy on clinical trials enrolled in a prospective
molecular profiling program.
Material and methods
Formalin
fixed paraffin embedded tumor tissues were prospectively screened for
genomic alterations using MALDI-ToF mass-spectrometry platform or
targeted sequencing using the Illumina MiSeq TruSeq Amplicon Cancer
Panel. Treatment outcomes on genotype-matched trials were
retrospectively reviewed using RECIST version 1.1 and Gynecological
Cancer Intergroup CA125 related-response criteria
Results
55
patients with type I EOC underwent molecular profiling, 41 (75%) low
grade serous (LGS), 9 (16%) clear cell (CC), and 5 (9%) mucinous (MC)
histologies. Thirty-five patients (64%) were found to have ≥1 somatic mutations: 23 KRAS, 6 NRAS, 5 PIK3CA, 2 PTEN, 1 BRAF, 1 AKT, 1 TP53, and 1 CTNNB1. Fifteen patients were subsequently enrolled in genotype-matched phase I or II trials, including 14 patients with KRAS/NRAS
mutations treated with MEK inhibitor targeted combinations. Among 14
RECIST evaluable patients, there were 7 partial responses (PR), 7 stable
disease (SD) and 1 disease progression (PD). CA125 responses were
observed in 10/10 evaluable KRAS/NRAS mutant patients treated with MEK inhibitor combinations
Conclusions
Genotyping
and targeted sequencing of Type I EOCs frequently identifies actionable
mutations. Matched treatment with MEK-based combination therapy in KRAS and/or NRAS mutant type I EOC patients is an active therapeutic strategy.
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