Abstract
Next-generation sequencing (NGS) technology has advanced knowledge of the genomic landscape of ovarian cancer, leading to an innovative molecular classification of the disease. However, patient survival and response to platinum-based treatments are still not predictable based on the tumor genetic profile. This retrospective study characterized the repertoire of somatic mutations in advanced ovarian cancer to identify tumor genetic markers predictive of platinum chemo-resistance and prognosis. Using targeted NGS, 79 primary advanced (III–IV stage, tumor grade G2-3) ovarian cancer tumors, including 64 high-grade serous ovarian cancers (HGSOCs), were screened with a 26 cancer-genes panel. Patients, enrolled between 1995 and 2011, underwent primary debulking surgery (PDS) with optimal residual disease (RD < 1 cm) and platinum-based chemotherapy as first-line treatment. We found a heterogeneous mutational landscape in some uncommon ovarian histotypes and in HGSOC tumor samples with relevance in predicting platinum sensitivity. In particular, we identified a poor prognostic signature in patients with HGSOC harboring concurrent mutations in two driver actionable genes of the panel. The tumor heterogeneity described, sheds light on the translational potential of targeted NGS approach for the identification of subgroups of patients with distinct therapeutic vulnerabilities, that are modulated by the specific mutational profile expressed by the ovarian tumor.
Highlights
Epithelial ovarian cancer is still the deadliest form of gynecological malignancy
When an analysis was performed comparing two subgroups (>1 vs. 0 or 1), the time to recurrence (TTR) was significantly lower in patients carrying two somatic mutations in two genes compared to all others with high-grade serous ovarian cancers (HGSOCs) (Log-rank p = 0.046, Figure S2d) in both the univariate (HRuni = 2.25, 95% CI: 1.19–4.26, p = 0.012) and multivariate
(Log-rank p = 0.077, Figure S2f), but similar to the other results, significantly shorter overall survival (OS) was observed in patients carrying two somatic mutations in two genes compared to all others with HGSOCs in both the univariate (HRuni = 2.06, 95% CI: 1.19–3.56, p = 0.009) and multivariate (HRmult = 2.47, 95% CI: 1.50–4.07, p = 0.0001) analyses (Table 3)
Summary
Epithelial ovarian cancer is still the deadliest form of gynecological malignancy. The main prognostic factors identified for clinical outcome in patients with advanced ovarian cancer are tumor stage and mostly residual disease (RD) after PDS, with the goal of surgery being no visible tumor residue (RD = 0) [5,6]. Epithelial ovarian tumors are considered highly heterogeneous with different histological subtypes; based on pathological and molecular characteristics, these tumors have been grouped in type I or II [7,8]. Type I (5–10%) includes low-grade serous, mucinous, clear cell, and endometrioid ovarian carcinomas, are typically KRAS, PIK3CA, PTEN, or BRAF mutated, and diagnosed frequently at early stages.
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