BRCA1/2 mutations and expression: Response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer

Abstract

Objective

Our objective was to determine the rate of BRCA1/2 deficiency in platinum-sensitive and platinum-resistant tumors from a cohort of unselect patients with advanced epithelial ovarian cancer (EOH).

Methods

BRCA1/2 mutation analysis was performed in 29 patients with platinum-sensitive EOC and 24 patients with platinum-resistant disease. Germline DNA was analyzed in mutation carriers when normal tissue was available. BRCA expression was ascertained by quantitative rt-PCR. Associations between BRCA mutation status and expression levels and parameters of platinum response were analyzed.

Results

Fifteen of 53 (28.3%) EOC tumors had BRCA1/2 mutations. Twelve mutations were in BRCA1, while 3 involved BRCA2. Of the 12 mutation-carriers with normal tissue available for DNA analyses, 33.3% of the mutations were found to be somatic. Three mutations were novel. The majority of BRCA mutations (73%) were identified in patients with platinum-sensitive disease. In total, 38% of platinum-sensitive tumors were found to have a BRCA mutation, compared to 17% of the platinum-resistant patients. A statistical trend toward platinum-sensitive disease was seen in BRCA mutation carriers (p = 0.079). Nineteen (36%) study patients had some form of BRCA deficiency, and these patients were less likely to have platinum-resistant tumors (OR = 0.29; p value = 0.048).

Conclusions

BRCA mutations occurred more frequently in platinum-sensitive EOC than platinum-resistant disease. The high overall frequency of BRCA deficiency in EOC underscores the importance of tumor profiling as therapies targeting the DNA repair pathway are being investigated.

Introduction

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic cancer diagnosed in the United States [1]. Five-year survival rates are 5–30% for patients with advanced disease, despite aggressive surgical cytoreduction combined with platinum/taxane-based chemotherapy [2], [3], [4], [5]. An understanding of the mechanisms by which genetic and protein alterations may affect EOC pathogenesis is therefore critical in any effort to target these alterations with novel therapeutic drugs.

While the majority of advanced EOC represents sporadic disease, hereditary cases also occur as a result of mutations in BRCA1, BRCA2, and the mismatch repair genes associated with Lynch syndrome. Germline mutations in BRCA1 and BRCA2 have been found in approximately 10–13% of EOC, and confer a 20–60% lifetime risk of developing the disease [6], [7], [8], [9], [10]. Somatic mutations in the BRCA genes have also been identified in EOC [11]. While previous reports have suggested that germline BRCA mutations may be associated with improved survival rates and increased sensitivity to platinum-based chemotherapy [12], [13], [14], [15]. A recent publication by Yang et al. demonstrated that the OS advantage was seen in patients with only BRCA2 mutations and not BRCA1 [16]. Additionally, these investigators found an 11% loss of BRCA1 expression due to methylation, and this was independent of germline status and again was not associated with OS [16]. The consequences of varying levels of BRCA expression in both BRCA-mutated and wild-type tumors have conflicting results [17], [18], [19], [20], [21], [22]. Better delineation of genetic alterations, germline and somatic as well as epigenetic alterations in the BRCA genes and the relationship to expression levels may aid in identifying patients with homologous repair deficiency and may identify patients who will benefit from targeted therapies.

Hennessy et al. recently reported the frequency of BRCA1/2 alterations and expression in a large cohort of patients (N = 235) with advanced EOC [11]. They demonstrated that 30% of unselected EOC patients had BRCA deficiency, as defined by BRCA1/2 mutations or expression loss, and may be candidates for poly (ADP-ribose) polymerase (PARP) inhibitors. As targeted therapies are developed for altered pathways, the role and incidence of BRCA mutations need to be better defined. The purpose of this study was to describe the incidence of germline and somatic BRCA1/2 mutations and expression in a series of patients with platinum-sensitive and platinum-resistant advanced EOC.