When compared to high grade serous ovarian cancer (HGSOC), low grade serous ovarian cancer (LGSOC) has distinct etiology, molecular, genetic, and clinical features. Limited testing, inconsistent histology, and small sample sizes have all impeded molecular investigations. To this end, researchers set out to conduct a molecular profile of LGSOC in a consistently sampled and histologically validated cohort. Caris Life Sciences analyzed 179 samples using various methods such as hot-spot and entire exome next generation sequencing (NGS), fusion gene analysis interrogating RNA, fragment analysis, in situ hybridization, and/or immunohistochemistry (Phoenix, AZ). 

Histology was validated in 153 specimens by a separate, unbiased histologic evaluation. Members of the mitogen-activated protein kinase (MAPK) pathway, including KRAS (23.7%, n = 36), NRAS (11.2%, n = 19), NF1 (7.9%, n = 5), and BRAF (6.6%, n = 10), were the most frequently altered genes (5% or greater). The 3/10 BRAF mutations were classified as Class III, whereas 7 were Class I V600E. About 80.2% (n = 130) of women expressed estrogen receptors, but only 27.8% (n = 45) of women expressed progesterone receptors. Almost half of the hormone-negative individuals had mutations in KRAS or NF1. In fact, not a single one had a mutated NRAS. The immunotherapy response markers were very low to completely absent. 

It was shown that the frequency of BRAF mutations is far lower than had previously been thought. Since 49.2% of hormone-negative specimens were KRAS or NF1 mutant, a role for combination therapy with hormonal and targeted therapy should be addressed because of enhanced MAPK activation leading to ligand-independent activation of ERα. It is likely that immunotherapeutic treatments will have a modest effect if there are no biomarkers indicating their effectiveness.

Source: sciencedirect.com/science/article/abs/pii/S0090825822018509