Is it time to add BRCA1 promoter methylation testing in the arsenal of ovarian cancer diagnostic tools?

Dr. Blanc-Durand and colleagues describe the results of a retrospective analysis of BRCA1 hypermethylation status among patients with high-grade ovarian cancer. Promoter methylation was correlated with homologous recombination deficiency (HRD) status and progression-free survival (PFS) to determine clinical relevance.

Multiple studies have now demonstrated benefit to use of PARP inhibitors among tumors with evidence of HRD (1-5). Tumors with HRD are described by several different molecular characteristics including the presence of germline or somatic BRCA1 or BRCA2 mutations, germline or somatic mutations in other genes involved in homologous recombination pathways, and epigenetic silencing of BRCA or other homologous recombination (HR) genes. Other laboratories classify a tumor as HRD when there is evidence of genomic loss of heterozygosity, or if there is evidence of genomic instability when loss of heterozygosity is present +/− large-scale state transitions or telomere allele imbalance. Understanding the different causes and markers of HRD in epithelial ovarian cancer is an important ongoing area of research that aims to clarify which HRD tumors will benefit most from PARP inhibition.

Prior data demonstrate that germline and somatic BRCA1 and BRCA2 mutations as well as mutations in other homologous recombination pathway genes such as RAD51C, RAD51D and PALB2 are associated with improved responses to PARP inhibition (6). Whether silencing of those genes by promoter methylation represents another form of HRD, with the same prognostic significance has been questioned. Sahnane et al. evaluated the rate of BRCA methylation in to be 20/88 (22.7%) in a retrospective cohort, with 90% of tumors considered platinum sensitive at 6 months (7). A molecular analysis of tumors included in ARIEL2, the phase 2 study that demonstrated benefit of the PARP inhibitor, rucaparib, in recurrent high-grade ovarian carcinoma revealed that epigenetic silencing of BRCA1 in pretreatment samples (16.8%) was associated with improved response [PFS and objective response rate (ORR)] to rucaparib (6).

The current study by Dr. Blanc-Durand and colleagues shows that BRCA1 promoter methylation correlates with HRD. The authors classified BRCA1 promoter methylation into two categories: high and low. Interestingly, tumors classified as having both high and low levels of BRCA1 promoter methylation tumors were classified as HRD [based on Myriad test with genomic instability score (GIS) >42]. Although other studies have demonstrated that BRCA1 promoter methylation confers HRD, BRCA1 promoter methylation has not been shown to confer a survival benefit as would be expected with tumors with HRD or BRCA mutations (8,9).

In Blanc-Durand’s study, although the median PFS was not reached for the low group (n=11), there were three patients noted to have early relapse after primary treatment, despite high GIS score suggestive of HRD. Five (5/11, 45%) of the low methylation group tumors used for testing were sampled after neoadjuvant chemotherapy. The effect of chemotherapy on BRCA1 promoter methylation status is an important consideration. The ARIEL2 study group was able to compare archival tumor samples with pre rucaparib treatment tumor samples and showed that loss or decrease of methylation was associated with higher numbers of prior lines of chemotherapy (9). Although Dr. Blanc-Durand’s study was unable to draw any conclusions about the possible effect of chemotherapy on methylation status, it raises an important point about understanding the impact of chemotherapy on biomarker status.

If BRCA1 promoter methylation-HIGH represents a subset of tumors with a positive HRD test that will benefit from PARP, but the methylation status may be impacted by prior chemotherapy, knowledge of methylation status may need to be assessed after any prior chemotherapy rather than using archival samples. This has potential to give more precision to the currently available HRD tests which are not representative of changes that may have occurred in a tumor since treatment. With a clinical benefit of PARP inhibitor maintenance after upfront therapy for HR-deficient tumors (1,2,5), the timing of testing for HRD has shifted to the upfront setting. Where will BRCA1 promoter methylation testing fit in our current paradigm? The identification of additional indicators of HRD is important for patient accessibility, as well. An assay to detect BRCA1 promoter methylation is arguably more feasible worldwide than a single laboratory-developed score. As our understanding of the clinical significance of BRCA1 promoter methylation improves, so will our need to determine the best approach to clinical testing to ensure the maximal amount of information is obtained while limiting the financial toxicity.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-23-54/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-23-54/coif). L.S. is supported by Astra Zeneca and Merck and serves of the board for the Association of Community Cancer Centers. D.M.O. receives research funding from AbbVie, Advaxis, Agenus, Inc., Alkermes, Aravive, Inc., Arcus, Biosciences, Inc., AstraZeneca, BeiGene USA, Inc., Boston Biomedical, Bristol Myers Squibb, Clovis Oncology, Deciphera Pharma, Eisai, EMD Serono, Inc., Exelixis, Genentech Inc., Genmab, GlaxoSmithKline, GOG Foundation, Hoffmann-La Roche Inc., ImmunoGen, Inc., Incyte Corporation, IOVANCE Biotherapeutics, Karyopharm, Leap Therapeutics, Inc., Ludwig Institute for Ca, Merck & Co, Merck Sharp & Dohme Corp., Mersana Therapeutics, Inc., NCI, Novartis, NovoCure, NRG Oncology, OncoC4, Inc., OncoQuest Inc., Pfizer Inc., Precision Therapeutics, Inc., Prelude Therapeutics, Regeneron Pharmaceuticals, Inc., RTOG, Rubius Therapeutics, Seattle Genetics (SeaGen), Sutro Biopharma, SWOG, TESARO, Verastem, Inc. D.M.O. is supported by AbbVie, AdaptImmune, Agenus, Inc., Arquer Diagnostics, Arcus Biosciences, Inc., AstraZeneca, Atossa Therapeutics, Boston Biomedical, Cardiff Oncology, Celcuity, Clovis Oncology, Corcept Therapeutics, Duality Bio, Eisai, Elevar, Exelixis, Genentech Inc., Genelux, GlaxoSmithKline, GOG Foundation, Hoffmann-La Roche Inc., ImmunoGen, Inc., Imvax, InterVenn, INXMED, IOVANCE Biotherapeutics, Janssen, Jazz Pharmaceuticals, Laekna, Leap Therapeutics, Inc., Luzsana Biotechology, Merck & Co, Merck Sharp & Dohme Corp., Mersana Therapeutics, Inc., Myriad, Novartis, NovoCure, OncoC4, Inc., Onconova, Regeneron Pharmaceuticals, Inc., RepImmune, R Pharm, Roche Diagnostics, Seattle Genetics (SeaGen), Sorrento, Sutro Biopharma, Tarveda Therapeutics, Toray, Trillium, Umoja, Verastem, Inc., VBL Therapeutics, Vincerx Pharma, Xencor, Zentalis. D.M.O. serves on the GOG Foundation Board. The other author has no conflicts of interest to declare.

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