Distinct homologous recombination gene expression profiles after neoadjuvant chemotherapy associated with clinical outcome in patients with ovarian cancer
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.
Section snippets
Cohorts
HGOC tumors were obtained from a cohort of 96 patients who underwent staging and debulking surgery either upfront (PDS, n = 55) or after neoadjuvant therapy (NACT, n = 41) platinum-based combination chemotherapy. The study was approved by the Jewish General Hospital Research Ethics Board (protocol #15-070). All patients participating in this study gave informed written consent and tissue samples were kept in the gynecologic oncology tumor bank (ethics board protocol #03-041).
For each patient,
Patient and tumor characteristics
Clinical characteristics of patients are presented in Table 1. Patients in the neoadjuvant chemotherapy treatment (NACT) group presented at a significantly more advanced stage at diagnosis than chemotherapy naïve patients where samples were collected at primary debulking surgery (PDS). All other characteristics were not significantly different between the groups.
Gene expression in the PDS group and patient outcome
After controlling for both of the percent tumor content covariate and mutation score covariates, we found that only six of 19 HR genes
Discussion
In the search for new biomarkers to differentiate and predict outcome in patients with ovarian HGSCs, the evaluation of the expression of single genes has not led to clinically useful prognostic markers. Also, only a limited number of studies have attempted to correlate expression signatures of multiple genes with clinical outcomes, such as survival, recurrence [[20], [21], [22]], and surgical outcome [23], and such studies have shown inconsistent results. And few studies have investigated HR
Conflict of interest statement
The authors declare no potential conflicts of interest.
Acknowledgement
This work was supported by grants from AstraZeneca Canada, the Israel Cancer Research Fund, Gloria's Girls, The Anne-Marie and Mitch Garber Fund and the Susan and Jonathan Wener Fund.
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2019, DNA RepairCitation Excerpt :Further, the mutational profile of HR genes has been shown to be related to the overall prognosis. Kessous et al. found that the over-expression of HR genes, NBN, FANCF and RAD50 were associated with better prognosis in high grade ovarian cancer which specimens were obtained by surgery [234]. Norquist et al. found that harboring non-BRCA mutations was related to increased progression free survival and better overall survival in ovarian carcinomas [235].
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