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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01289

Genomic profile and BRCA-1 promoter methylation status in BRCA mutated ovarian cancer: new insights in predictive biomarkers of olaparib response

 Elisena Franzese1,  Sara Centonze1,  Anna Diana1*, Angela Lombardi1,  Francesca Carlino1,  Luigi Pio Guerrera1, Ferdinando De Vita1, Michele Caraglia1, Sandro Pignata2, Fortunato Ciardiello1 and Michele Orditura1
  • 1Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Italy
  • 2National Cancer Institute G. Pascale Foundation (IRCCS), Italy

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 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 months 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 years 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.

Keywords: ovarian cancer, Genomic profiles, BRCA 1 /2 mutation carriers, promoter methylation, Olaparib (Lynparza™)

Received: 28 Aug 2019; Accepted: 06 Nov 2019.

Copyright: © 2019 Franzese, Centonze, Diana, Lombardi, Carlino, Guerrera, De Vita, Caraglia, Pignata, Ciardiello and Orditura. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Anna Diana, Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, 80138, Campania, Italy, annadiana88@gmail.com