BRCA1/2 genetic background-based therapeutic tailoring of human ovarian cancer: hope or reality?

Abstract

Ovarian epithelial tumors are an hallmark of hereditary cancer syndromes which are related to the germ-line inheritance of cancer predisposing mutations in BRCA1 and BRCA2 genes. Although these genes have been associated with multiple different physiologic functions, they share an important role in DNA repair mechanisms and therefore in the whole genomic integrity control. These findings have risen a variety of issues in terms of treatment and prevention of breast and ovarian tumors arising in this context. Enhanced sensitivity to platinum-based anticancer drugs has been related to BRCA1/2 functional loss. Retrospective studies disclosed differential chemosensitivity profiles of BRCA1/2-related as compared to "sporadic" ovarian cancer and led to the identification of a "BRCA-ness" phenotype of ovarian cancer, which includes inherited BRCA1/ 2 germ-line mutations, a serous high grade histology highly sensitive to platinum derivatives. Molecularly-based tailored treatments of human tumors are an emerging issue in the "era" of molecular targeted drugs and molecular profiling technologies. We will critically discuss if the genetic background of ovarian cancer can indeed represent a determinant issue for decision making in the treatment selection and how the provocative preclinical findings might be translated in the therapeutic scenario. The presently available preclinical and clinical evidence clearly indicates that genetic background has an emerging role in treatment individualization for ovarian cancer patients.

Assessment of the Prognostic Value of Two Common Variants of BRCA1 and BRCA2 Genes in Ovarian Cancer Patients Treated with Cisplatin and Paclitaxel: A Gynecologic Oncology Group Study

“…Patients with germline mutations have improved clinical outcomes following the platinum chemotherapy (9–11, 31, 37). Increased sensitivity to DNA-damaging anti-cancer drugs has been associated with BRCA1 or BRCA2 functional loss involving germline mutations or epigenetic changes.…”

“…It is proposed that BRCA1 mediates resistance to platinum agents involving activation of NER, HR, and FA/BRCA repair pathways and sensitivity to taxane-based chemotherapy involving mitotic spindle arrest followed by JNK/SAPK mediated apoptosis (16, 31, 37). Thus far most clinical studies have focused on BRCA1 deficiency as a potential biomarker of response to platinum chemotherapy but not as a marker of taxane resistance.…”

Implications of BRCA1 and BRCA2 mutations for the efficacy of paclitaxel monotherapy in advanced ovarian cancer

“…11 This sensitivity to platinum chemotherapy has however been reported to correlate inversely with sensitivity to microtubuleinterfering agents like taxanes in BRCA1 mutated cancer cells. 12 Inhibition of BRCA1 expression in ovarian cancer cell lines has been shown to increase cellular sensitivity to platinum compounds but reduce antitumour activity of taxanes. 11,13 In vitro data suggest that BRCA1-mutant breast cancer cells are resistant to paclitaxel, in contrast to BRCA1 wild type cells, 14 and breast cancer cells transfected with BRCA1 siRNA display a significant increase in resistance to paclitaxel.…”

Molecular Biomarkers in Ovarian Carcinoma

“…The lifetime risk of developing ovarian cancer is about 20%-50% in patients carrying BRCA mutations. [73] Some 85% of female breast cancer and 40% of ovarian cancer is associated with BRCA1 syndrome, whereas male breast cancer and 20% of ovarian cancer is associated with BRCA2 syndrome. BRCA-associated ovarian cancers are characterized by higher patient survival rates and a better response to platinum-based chemotherapy.…”