Distinct homologous recombination gene expression profiles after neoadjuvant chemotherapy associated with clinical outcome in patients with ovarian cancer

Highlights

• Homologous recombination (HR) pathway is associated with outcome in ovarian cancer.

• Some HR pathway genes are associated with survival before and after chemotherapy.

• Different genes are associated with outcome before and after chemo.

Abstract

Objective

The expression of homologous recombination (HR) genes in high grade ovarian cancer (HGOC) samples from debulking surgeries were correlated to outcomes in patients selected for chemotherapy treatment regimens.

Study design

RNA was extracted from 96 fresh frozen tumor samples from debulking surgeries from chemotherapy naïve patients with HGOC (primary derived surgeries (PDS), n = 55) or following neoadjuvant chemotherapy treatment (NACT), n = 41). The samples were selected for high tumor content by a gynecological pathologist, and cancer cell content was further confirmed using a percent tumor content covariate, and mutation score covariate analysis. Gene expression analysis was performed using a tailored NanoString-based Pancancer Pathway Panel. Cox proportional hazard regression models were used to assess the associations between the expression of 19 HR genes and survival.

Results

In the PDS group, over-expression of six HR genes (C11orf30, NBN, FANCF, FANCC, FANCB, RAD50) was associated with improved outcome, in contrast to the NACT group where four HR genes (BRCA2, TP53, FANCB, RAD51) were associated with worse outcome. With the adding extent of debulking as a covariate, three HR genes (NBN, FANCF, RAD50), and only one HR gene (RAD51) remained significantly associated with survival in PDS and NACT groups, respectively.

Conclusion

Distinct HR expression profiles define subgroups associated with overall outcome in patients that are exposed to neoadjuvant chemotherapy and not only chemotherapy-naïve patients.

Introduction

High-Grade Serous Cancer (HGSC), the most common and deadly histological subtype of ovarian cancer [1], is also the most lethal gynecologic cancer [1]. Recent findings point to the significant clinical and molecular heterogeneity of HGSC [2,3]. In addition to the conventional prognostic factors such as stage, grade, histological type, and residual disease after surgery [3], recent studies have assessed the utility of predictive molecular biomarkers [[4], [5], [6], [7]]. Despite these efforts, no clinically validated predictive biomarkers are available that complement individual patient stratification.

The homologous recombination (HR) DNA repair pathway is essential to preserve genomic integrity, by allowing accurate repair of double-strand DNA breaks, and has been associated with the response to treatment and the overall outcome of patients with HGSC [8]. Germline and somatic molecular genetic defects in the HR pathway occur in up to 50% of HGSC cases [2]. Mutations in BRCA1 and BRCA2 (germline or somatic), which include gene silencing due to hypermethylation of BRCA1 promoter [9], account for the most frequent genetic deficiencies in HR pathway in HGSC tumors [2], and are associated with better overall responses to standard of care platinum-based chemotherapy and longer progression-free survival relative to non-mutated BRCA1/2 cases [10,11]. Somatic genetic defects in other HR pathway genes, such as RAD51 and BRIP1, have also been correlated with response to treatment [2,12,13]. The high frequency of loss of function somatic mutations in these other HR-related genes in HGSC tumors led to the concept of “BRCAness”, which refers to the presence of molecular genetic phenotypes similar to that observed in BRCA1/2-mutated cells [[14], [15], [16]].

The advent of new drugs, such as poly ADP ribose (PARP) inhibitors takes the advantage of the HR deficiency of HGSC tumors and improved progression free survival (PFS) has been shown in clinical trials of HGSC patients [17]. As PARP inhibitors are introduced into clinical settings, it is important to further define molecular biomarkers of BRCAness associated with improved response rates and survival, leading to a personalized approach for the treatment of HGSC. Towards this goal, this study has correlated the expression of HR pathway genes with clinical outcomes in patients with HGOC that were selected based on exposure to chemotherapy at debulking surgery.