Abstract
Objective: We assessed the genomic profile of four representative BRCA-mutated ovarian cancer (OC) patients treated with olaparib to investigate the relationship between intratumor heterogeneity and response to olaparib treatment. The main aim is to identify possible predictive biomarkers of response to olaparib through the analysis of HRD or not HRD genes and the definition of BRCA1 promoter methylation status.Methods: DNA, isolated from formalin-fixed, paraffin-embedded (FFPE) diagnostic OC tissues, was analyzed by FoundationOneCDx™. This assay detects alterations in a total panel of 324 genes, using the Illumina® HiSeq 4000 platform. Methylation analysis of the BRCA gene promoter was carried out by pyrosequencing with PyroMark Q24 platform (Qiagen), an in vitro nucleic acid sequence-based detection test based on pyrosequencing technology for quantitative measurements of methylation status.Results: Case #1 and #2 were defined Long-term responders since they received olaparib for 27 and 36 months, respectively. These remarkable results could be explained, at least in part, by the presence of somatic IDH1 mutation in case #1 and PI3K and SOX2 amplification in the case #2. In case #3, the somatic NF1 mutation appeared to be related to the short duration of response. In the case #4, in which the patients is on olaparib from 1 year achieving a stable disease, a somatic mutation of BRCA1 was recorded. Moreover, in all cases, levels of BRCA1 promoter were strictly related to olaparib response.Conclusions: Based on our experience, genomic analysis of tumor tissue at diagnosis might help to determine the future response to olaparib in advanced OC setting, revealing predictive biomarkers beyond BRCA 1-2 and HRD status.
Highlights
Olaparib, niraparib, and rucaparib are the three poly (ADP-ribose) polymerase inhibitors (PARPis) approved by regulatory authorities for treatment of advanced ovarian cancer (OC) patients.Olaparib was initially approved in December 2014 by the Food and Drug Administration (FDA) as monotherapy in patients with deleterious germ-line BRCA mutated (BRCAm) advanced OC treated with three or more prior lines of chemotherapy and by the European Medicines Agency (EMA) as maintenance treatment for platinum sensitive relapsed BRCAmOC
We investigated the genomic profile of BRCAm OC patients to assess the relationship between intratumor heterogeneity and response to olaparib treatment through analysis of mutations of homologous recombination deficiency (HRD) or not HRD genes and definition of BRCA1 promoter methylation status
From October 2015 to June 2016, due to retroperitoneal relapse, she received a second-line chemotherapy with carboplatin, paclitaxel and bevacizumab, obtaining a PR
Summary
Olaparib was initially approved in December 2014 by the Food and Drug Administration (FDA) as monotherapy in patients with deleterious germ-line BRCA mutated (BRCAm) advanced OC treated with three or more prior lines of chemotherapy and by the European Medicines Agency (EMA) as maintenance treatment for platinum sensitive relapsed BRCAmOC (germline or somatic mutations). In August 2017, based on the encouraging longterm efficacy results of Study 19 (phase II trial) [1], the FDA expanded the label of olaparib as maintenance treatment for recurrent OC patients who are in complete or partial response following platinum-based chemotherapy, irrespective of their BRCAm status and the number of prior lines received. The results of SOLO1 phase III study [2] demonstrated that olaparib maintenance therapy reduced significantly the risk of disease progression or death in patients with newly diagnosed BRCAm OC. In December 2018, the FDA approved olaparib in this setting
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