NEW YORK – Epigenetic changes to the promoter regions of BRCA1 appear to have a different effect on treatment response than genomic alterations in BRCA1 or BRCA2 in triple-negative breast cancer (TNBC) or ovarian carcinoma patients, new research suggests.
For a study published in Science Translational Medicine on Thursday, researchers at the Jackson Laboratory for Genomic Medicine, the University of Washington Medical Center, the Fred Hutchinson Cancer Research Center, and other institutions built on prior research implicating BRCA1 promoter methylation in poorer response to alkylating agents relative to cases that involve germline mutations in BRCA1 or BRCA2.
“Because loss of BRCA activity has been associated with high sensitivity to DNA inter-strand cross-linking agents, such as platinum-based chemotherapies, several studies have tried to assess the value of different forms of [homologous recombination deficiency]-linked genomic alterations as predictors of treatment response in both [TNBC and ovarian carcinoma],” senior and corresponding author Edison Liu, a Jackson Laboratory researcher, and his colleagues wrote, adding that “there is a growing suspicion that distinct biological processes may be at play, especially in cancers where BRCA1 deficiency is due to gene silencing through promoter methylation.”
The researchers analyzed available clinical, whole-genome sequence, RNA sequence, and array-based methylation data for hundreds of early-stage TNBC or primary serious ovarian carcinoma patients treated with consistent platinum- and taxane-based chemotherapy regimens.
Together with results from experiments in patient-derived tumor xenograft models and engineered cell lines, the team’s genomic analyses of HRD and other features gleaned from the genomic data shored up the notion that altered BRCA1 promoter methylation is linked to poorer platinum-based chemotherapy responses than BRCA1/2 gene mutations (BRCAmut), even though the two have similar HRD features.
“Our results show that tumors with pathogenic mutations in either BRCA1 or BRCA2 (BRCAmut), those with BRCA1 silencing through promoter methylation (BRCA1meth), and those that are proficient for both BRCA1 and BRCA2 … are distinct clinical-therapeutic entities in their response to platinum chemotherapies,” the authors reported.
Although the BRCAmeth and BRCAmut tumors had overlapping downstream mutational signatures, the researchers explained, their results suggested that tumors may overcome the deficits caused by epigenetic changes in the BRCA1 promoter by shrugging off the promoter methylation changes to bolster BRCA1 expression in response to platinum-based chemotherapy, contributing to treatment resistance.
“The mechanistic heterogeneity of response to DNA-damaging chemotherapy across the different BRCA states can explain many of the inconsistencies seen in clinical trials where response outcomes are measured against genomic-based HRD assessments,” the authors wrote, “and provides an approach to formulate more precise predictive markers for therapeutic response in TNBC and [ovarian carcinoma].”
Even so, the functional analyses also revealed a subset of BRCA-proficient cancer cases featuring a specific immune transcriptional signal that did respond well to chemotherapy, prompting the authors to come up with a chemotherapy response prediction approach that incorporated both BRCA mutation status and immune signature clues.
Consequently, the authors argued that the work “underscores the importance of defining BRCA heterogeneity in optimizing the predictive precision of assigning response probabilities in TNBC and [ovarian carcinoma].”
Such approaches may be particularly important for tailoring treatments to TNBC or ovarian cancer patients most apt to respond, while dialing down the risk of adverse drug events in patients who may not require more toxic combination treatments.
“Given that the combination of checkpoint inhibitors and chemotherapy has become the recommended neoadjuvant regimen in TNBC despite an increase in adverse drug events,” the researchers explained, “the ability to de-escalate a toxic combination in a subset of patients with TNBC and [ovarian carcinoma] potentially identified by our decision tree would have a meaningful impact on cancer survivors.”