A comprehensive analysis of BRAF and KRAS mutation status in low-grade serous (LGS) and serous borderline (SB) ovarian cancer (OC).

Abstract

5030 Background: LGS OC develops in a step-wise pattern from serous cystadenoma to SB tumor to invasive LGSOC. LGSOC accounts for 6-22% of serous OC and is a chemoresistant disease. Prior studies have reported that LGS/SB ovarian tumors harbor BRAF mutations in 28-35% of cases, suggesting that LGS/SB OC may respond to mutant BRAF inhibitors. Methods: We genotyped 75 LGS and SB ovarian tumors for BRAF and KRAS hotspot mutations using a mass spectrometry based Sequenom assay. All samples were collected at MSKCC between 2000-2010. All specimens underwent two independent pathologic reviews for diagnostic confirmation and macrodissection to ensure 80% cellularity. The incidence and identity of BRAF and KRAS mutations were defined and results were correlated with stage, response to treatment, and outcome. Exon capture sequencing is underway to sequence all coding exons of 230 cancer associated genes to identify additional targetable alterations in LGS/SB OC. Results: Of 75 samples examined, 56(75%) were SB and 19(25%) LGS histology. 57% of samples showed KRAS mutation (KRAS+) (n=17, 23%) or BRAF mutation (BRAF+) (n=26, 35%). Mutation status was mutually exclusive. All BRAF + were V600E, KRAS+ were G12D (n=9) or G12V (n=8). BRAF+ was associated with early stage (I-II) at presentation and SB histology. 22 (29%) patients were treated with chemotherapy, 2 (9%) with KRAS + and 0 with BRAF+. 4(15%) BRAF+ patients underwent resection of recurrent disease. All BRAF+ patients are alive without evidence of disease at a median follow-up of 43.3 months (range 1.9- 129.3 months). Conclusions: V600E BRAF mutations are present in 35% of cases of SB/LGS ovarian cancer. Presence of BRAF + in SB/LGS OC is associated with good prognosis and surgical cure of disease. Patients with SB/LGS OC who require systemic therapy are unlikely to have BRAF+. Our group is performing a detailed search for additional targetable alterations in multiple signal transduction pathways through next generation sequencing technology. [Table: see text]