BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer

Abstract

Background: Low-grade serous (LGS) ovarian cancer is a chemoresistant disease that accounts for 10% of serous ovarian cancers. Prior studies have reported that 28% to 35% of serous borderline (SB)/LGS ovarian tumors harbor a BRAF mutation, suggesting that BRAF inhibitors may be a rational therapeutic approach for this disease. In the current study, the authors sought to determine whether BRAF or KRAS mutation status was associated with disease stage and/or histology in patients with SB and LGS ovarian cancer.

Methods: Genetic profiles were constructed for 75 SB and LGS ovarian tumors to determine BRAF and KRAS mutation status. The incidence and identity of BRAF and KRAS mutations were defined, and the results were correlated with disease stage, response to treatment, and overall survival.

Results: Of 75 samples examined, 56 tumors (75%) had SB histology, and 19 tumors (25%) had LGS histology. Fifty-seven percent of tumors harbored either a KRAS mutation (n = 17) or a BRAF mutation (a valine-to-glutamate substitution at residue 600 [V600E]; n = 26). The BRAF V600E mutation was associated significantly with early disease stage (stage I/II; P < .001) and SB histology (P = .002). KRAS mutations were not associated significantly with disease stage or histology. Of the 22 patients (29%) who required chemotherapy, 20 had tumors with wild-type KRAS/BRAF, 2 had KRAS mutant tumors, and none had tumors that harbored a BRAF mutation. All patients with BRAF tumors remained alive at a median follow-up of 3.6 years (range, 1.9-129.3 months).

Conclusions: V600E BRAF mutations were present in 35% of patients who had SB/LGS ovarian cancers. The presence of the BRAF V600E mutation in SB/LGS ovarian cancer was associated with early stage disease and improved prognosis. The authors concluded that patients with SB/LGS ovarian cancer who require systemic therapy are unlikely to have BRAF mutant tumors.

Figure 1

A: Serous borderline tumor (SB) with papillary architecture and abundant micropapillae growing on the surface of the large, papillary fronds. Like LGS, SB tumors display low nuclear grade and a low mitotic index but lack stromal invasion. B: Low-grade serous carcinoma (LGS) with the typical invasion pattern of micropapillae embedded in stroma surrounded by an artifactual cleft. LGS carcinomas possess low nuclear grade and a low mitotic index compared to HGS. C: High grade serous carcinoma (HGS) with high nuclear grade and focal anaplasia, a markedly elevated mitotic index, and glandular architecture with abundant tufting and budding of cells.

Figure 2

Representative mass spectrometry (MS) trace and corresponding Sanger trace for three tumors harboring (A) BRAF V600E, (B) KRAS G12D, and (C) KRAS G12V mutations.

Figure 3

Figure 3A: Out of 75 patients with low-grade serous or serous borderline ovarian cancer, 17 harbored a KRAS mutation (G12D=11; G12V=6), 26 harbored a BRAF mutation, and 32 were WT for KRAS and BRAF mutation. Figure 3B: 62.5% of patients that were WT for KRAS and BRAF received chemotherapy either in the adjuvant or recurrent setting, compared to 11.8 % of KRAS mutant patients and 0% BRAF mutant patients.

Figure 3

Figure 3A: Out of 75 patients with low-grade serous or serous borderline ovarian cancer, 17 harbored a KRAS mutation (G12D=11; G12V=6), 26 harbored a BRAF mutation, and 32 were WT for KRAS and BRAF mutation. Figure 3B: 62.5% of patients that were WT for KRAS and BRAF received chemotherapy either in the adjuvant or recurrent setting, compared to 11.8 % of KRAS mutant patients and 0% BRAF mutant patients.

Figure 4

Figure 4A: Kaplan-Meier curve of overall survival (OS) for all 75 patients. Seven patients have died. Figure 4B: Kaplan-Meier curve of proportion of patients surviving by mutation type. Median OS has not yet been reached for any group.

Figure 4

Figure 4A: Kaplan-Meier curve of overall survival (OS) for all 75 patients. Seven patients have died. Figure 4B: Kaplan-Meier curve of proportion of patients surviving by mutation type. Median OS has not yet been reached for any group.