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BRCA Deficiency Implicated in Triple-Negative Breast Cancer Chemotherapy Response

NEW YORK (GenomeWeb) – The presence of transcriptional patterns associated with BRCA1 deficiency appear to portend better chemotherapy response and other potential treatment advantages for individuals with breast cancers missing estrogen receptor, progesterone receptor, or HER2 treatment response markers.

Researchers from the US and Hungary did exome sequencing on samples from more than two-dozen individuals with such triple-negative breast cancers (TNBC). Their analysis, appearing online today in PLOS Medicine, uncovered a BRCA deficient subset of TNBC cases that not only seemed to respond somewhat better response to conventional chemotherapy, but also contained higher loads of mutations that might serve as neoantigens for future immunotherapy approaches.

"The newly defined RNA-based BRCA-deficient subtype includes up to [50 percent] of the TNBC tumors that appear to be immune primed, and it would be interesting to investigate combinations of chemotherapy with immunotherapies, which could provide clinical benefit for these patients," senior author Christos Hatzis, a medical oncology researcher at Yale University, and his co-authors wrote.

The researchers used an Illumina HiSeq 2000 to sequence tumor exomes that had been captured with NimbleGen SeqCap EZv2 kits for 29 individuals with TNBC who were treated at the MD Anderson Cancer Center. These patients included 18 individuals with a complete response to anthracycline/taxane chemotherapy based on pathology and another 11 individuals with residual disease after neoadjuvant chemotherapy.

Although more than three-quarters of the TNBC tumors contained non-silent mutations affecting the TP53 genes, they noted that these alterations did not show ties to chemotherapy response.

In TNBC patients with mutations involving genes from androgen receptor- or FOXA1 transcription factor-regulated networks influenced by BRCA1, the team found that some 94 percent responded to the anthracycline/taxane chemotherapy, while 6 percent did not. On the other hand, amongst patients without these mutations, the response was less than 17 percent.

The researchers went on to analyze the new protein-coding sequences alongside DNA, RNA, and/or methylation sequencing data for up to 123 TNBC samples assessed for the Cancer Genome Atlas project, uncovering ties between BRCA1 deficiency, enhanced overall mutation rates, and chemotherapy response in TNBC.

The BRCA1 gene itself was mutated in one-fifth of the TNBC cases in the two research cohorts, particularly in tumors from patients who responded to chemotherapy. When the team folded in other forms of genomic data, it found that 47 percent of the TNBC cases could be considered deficient in BRCA1 or BRCA2 expression.

They further validated BRCA-deficient transcriptional patterns using array-based expression data for another 278 cases of basal-like breast cancer from the Molecular Taxonomy of Breast Cancer International Consortium.

"Although these findings will require validation in larger multi-institutional datasets, preferably originating from prospective clinical studies, they could provide the impetus for examining BRCA deficiency in TNBC in the context of increased [clonal mutation burden], with potentially improved response to immunotherapies," the authors concluded.