‘Genetic profiling’ and ovarian cancer therapy (Review)

Abstract

Abstract. High variability observed among ovarian cancer patients in response to the same therapy and the related toxicity may be correlated to gene polymorphisms and genetic alterations affecting the metabolism of drugs commonly used to treat this tumor. Recent studies have shown a correlation between the polymorphisms characterizing GSTM1-T1 detoxifying enzymes and poor outcome in advanced ovarian cancer patients treated with platinum/paclitaxel-based chemotherapy. Multidrug resistance 1 (mdr-1) polymorphisms were found to be associated with resistance to paclitaxel treatment. Polymorphisms of MRP2, a protein involved in methotrexate, cisplatin and irinotecan active metabolite glucuronide transport, negatively affect platinum-based chemotherapy response. A similar occurrence has been observed with CYP1A1 Ile462Val and ercc1 C118T polymorphisms while patients who were carriers of MTHFR C677T polymorphism had a better response to methotrexate therapy, but an elevated risk of toxicity. Biological therapy with Bevacizumab, the anti-vascular endothelial growth factor has been shown to be less efficient in ovarian cancer patients carrying the polymorphism of the Interleukin-8 gene. Instead, polymorphisms in the XPD gene (Lys751Gln and Asp312Asn), a member of the nucleotide excision repair pathway, positively affects the response to therapy with carboplatin/paclitaxel. Therefore, the study of 'genetic profiling' is crucial to improving the clinician's ability to tailor effective therapy to the molecular profile of the patient while minimizing toxicities. This review describes clinical applications of the above genetic polymorphisms in ovarian cancer patients treated with platinum/paclitaxel-based chemotherapy.

Epigenetics in ovarian cancer

“…Alterations in DNA methylation have been hypothesized to play a role, because DNA methylation is one mechanism cells employ to respond to environmental stimuli [29]. Platinum-based chemotherapy is the primary line of drug therapy for all advanced stage EOC cases; carboplatin combined with paclitaxel is the standard of care, irrespective of histotype [86,87]. Early studies on breast and ovarian cancer cell lines reported sensitivity to platinum-based chemotherapy in cells with either mutant or hypermethylated BRCA1 [88–90].…”

Recent perspectives of epithelial ovarian carcinoma

“…In the past, commonly used drugs included cyclophosphamide, melphalan and chlorambucil (16). When cisplatin was introduced to clinical practice in 1978, platinum-based therapy was shown to generate a higher number of responsive patients, increase response duration and progression-free interval (16). Since then, platinum derivatives, such as cisplatin and carboplatin, have become the standard of care for ovarian cancer patients.…”

DNA methylation changes in epithelial ovarian cancer histotypes

“…Platinum (carboplatin) combined with a taxane (paclitaxel) is the primary therapeutic regimen in EOC, regardless of histological type [71,72]. Carboplatin is incorporated into DNA, inducing formation of adducts and eliciting mismatch repair which, in turn, activates apoptosis [73].…”