Clinical Relevance of BRCA1 Promoter Methylation Testing in Patients with Ovarian Cancer

Author:

Blanc-Durand Félix1ORCID,Tang Roseline2ORCID,Pommier Margaux2ORCID,Nashvi Marzieh2ORCID,Cotteret Sophie2ORCID,Genestie Catherine3ORCID,Le Formal Audrey4ORCID,Pautier Patricia1ORCID,Michels Judith1ORCID,Kfoury Maria1ORCID,Hervé Robert5ORCID,Mengue Sylvie5ORCID,Wafo Estelle6ORCID,Elies Antoine6ORCID,Miailhe Gregoire7ORCID,Uzan Jennifer7ORCID,Rouleau Etienne24ORCID,Leary Alexandra14ORCID

Affiliation:

1. 1Medical Oncology Department, Gynecology Unit, Institut Gustave Roussy, Villejuif, France.

2. 2Cancer Genetics Unit, Department of Biology and Pathology, Institut Gustave Roussy, Villejuif, France.

3. 3Pathology Unit, Department of Biology and Pathology, Institut Gustave Roussy, Villejuif, France.

4. 4INSERM U981, Institut Gustave Roussy, Villejuif, France.

5. 5Oncology Unit, Centre Hospitalier Polynesie Francaise, Papeete, French Polynesia.

6. 6Gynecology Unit, Centre Hospitalier Intercommunal Creteil, Créteil, France.

7. 7Gynecology Unit, Groupe Hospitalier Est Francilien, Jossigny, France.

Abstract

Abstract Purpose: Homologous recombination deficiency (HRD) is closely related to PARP inhibitor (PARPi) benefit in ovarian cancer. The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade ovarian cancer to HRD status and clinical behavior to assess its clinical relevance. Experimental Design: This is a retrospective monocentric analysis of patients centrally tested for genomic instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative droplet digital PCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing. Results: Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score ≥ 42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA wild-type ovarian cancer had high BRCA1 methylation levels. All of the highly methylated tumors were classified as HRD, achieving a positive predictive value of 100%. We detected 14% (11/79) low-methylated tumors (1%–69%), and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth, and 33.3 for BRCAwt unmethylated (P < 0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum. Conclusions: Patients with ovarian cancer with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be highly relevant to other tumor types for HRD prediction. See related commentary by Garg and Oza, p. 2957

Funder

UMR981

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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