Background: Low-grade serous ovarian cancer (LGSC) is a rare subtype of epithelial ovarian cancer, accounting for 5% of all cases. These cancers are marked by resistance to cytotoxic chemotherapy and frequently exhibit MAP kinase (MAPK) pathway mutations. LGSC is thought to arise either de-novo or develop from its putative precursor, serous borderline tumor (SBT).
Herein, we sought to characterize the genomic and immune landscape of LGSC and SBT.

Methods: De-identified records of 6,605 patients with ovarian cancer were retrospectively analyzed. Selection criteria included a histological diagnosis of low-grade serous ovarian cancer (LGSC) and serous borderline ovarian tumor (SBT) and tumor sequencing via the Tempus xT assay. Briefly, Tempus xT is a targeted, tumor-normal-matched DNA panel that detects
single-nucleotide variants, insertions and/or deletions, and copy number variants in 648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Immunological markers including tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 status were also assessed in this cohort. The prevalence of individual gene
alterations was described and compared by Chi-squared/Fisher’s Exact tests and adjusted for multiple testing using false discovery rate methods.

Results: A total of 132 LGSC and SBT samples were included in the analysis (LGSC, n = 108; SBT, n = 24). The median age at diagnosis was 55 years in LGSC and 57 years in SBT. Approximately 51% (n=55) of LGSC and 75% (n=18) of SBT had MAPK pathway-related gene mutations (p=0.032). Notably, BRAF mutations were significantly more prevalent in SBT compared to
LGSC cases (46% vs. 8%, q=0.001). The most common BRAF mutation was BRAF V600E, accounting for 82% of BRAF-mutated SBT and 50% of BRAF-mutated LGSC. In contrast, 11%of LGSC patients carried an NRAS mutation compared to 4% in SBT, although this result did not approach statistical significance. ATM (8.3%) was the most common non-MAPK altered gene in SBT, whereas CREBBP (3.7%) and HNF1B (3.7%) alterations were the most frequently altered non-MAPK genes in LGSC. Median TMB was the same in both LGSC and SBT (1.17 mutations/Mb) and 100% of patients in both cohorts with MSI results were low or stable. 3.6% of LGSC cases and 10% of SBT cases with PD-L1 testing were PD-L1 positive.

Conclusions:
In our cohort, SBT and LGSC share a similar microsatellite stable status, low PD-L1 expression, and a high percentage of MAP kinase pathway mutations. The higher incidence of BRAF mutations in SBT and increased frequency of NRAS mutations in LGSC suggest that MAPK pathway gene mutations may differentially impact the propensity for tumor behavior and malignant potential.

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