Objectives:
Low grade serous ovarian cancer (LGSOC) is unique among epithelial ovarian cancer, differing from high grade serous ovarian carcinoma (HGSOC) in terms of its pathogenesis, molecular, genetic, and clinical features. To date, molecular studies on these malignancies have been hampered by small sample sizes. As such, mutation rates of the different cohort studies have shown a wide range of KRAS and BRAF mutation frequencies. The purpose of this study is to better understand aberrations inherent to LGSOC, in a homogenously tested, and histologically confirmed, cohort.
Methods:
In all, 185 cases with a referred reported diagnosis of LGSOC were retrospectively evaluated by a CLIA‐certified lab (Caris Life Sciences, Phoenix, AZ) using hot‐spot (46 genes) and whole exon (592 genes) next generation sequencing (NGS) technologies interrogating DNA, fusion gene analysis interrogating RNA (52 genes), fragment analysis (FA), in situ hybridization (ISH) and/or immunohistochemistry (IHC). PD‐L1 (SP142 antibody) positivity was 2+ staining intensity in at least 5% of tumor cells. A second independent histologic review of all cases is pending to confirm LGSOC.
Results:
Most specimens (99.5%, 184/185) underwent hot‐spot (n=106) or whole exon (n=78) NGS. The most frequently mutated genes included KRAS (27.2%, 50/184),
NRAS (10.3%, 19/184), BRAF (7.1%, 13/184) and PIK3CA (2.2%, 4/184). Copy number alterations (CNA) were detected in few genes: ADGRA2, FGFR1, HOOK3, NSD3,
PCM1, RPL5, SMAD2, and ZNF703 (all 1.3%, 1/77). For hormonal biomarkers, expression rates were as follows: AR, 41.5% (35/82); ER [using a cut‐off of 2+ staining in 75% of tumor cells], 81.5% (150/184); and PR, 31.5% (58/184). PD‐L1 expression was 3.7% (6/163) and no MMRd (0.0%, 0/6) by IHC was noted. No gene rearrangements (0.0%, 0/9), microsatellite instability (0.0%, 0/78) or high tumor mutational burden (0.0%, 0/74 using a cut‐off of >=17 mutations/Mb) were found.
Conclusion:
This study represents the largest cohort of molecular profiling in LGSOC. This will be further enriched by independent confirmation of histology. Based on our analysis, LGSOC has multiple targets supporting the use of hormone therapy and therapies against the MAPK pathway. Given the tumor genomic stability and low PD‐L1 expression, immunotherapies are not expected to have significant efficacy. Further studies to evaluate the prognostic value of different molecular profiles are ongoing.