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Breast Cancer Chemotherapy Response Linked to Homologous Recombination Deficiency Score

NEW YORK (GenomeWeb) – Breast cancer tumors containing mutational signatures resembling those found in individuals with risky versions of the BRCA1 or BRCA2 genes appear to be more likely to respond to platinum-based chemotherapy, according to new research by a team from the BC Cancer Agency and the University of British Columbia.

As they reported in this month's issue of Clinical Cancer Research, the investigators did whole-genome sequencing on tumor and matched normal samples from 93 individuals with advanced breast cancer, including 33 treated with platinum-based chemotherapy. By applying the HRDetect tool to these sequences, they were able to narrow in on tumors with BRCA1/2 mutation or homologous recombination deficiency (HRD)-related mutational signatures.

When the team considered the HRDetect profiles in combination with clinical outcomes such as overall survival, therapy duration, and clinical improvement, it found that the presence of HRD mutational signatures — marked by higher HRDetect scores — typically corresponded to better treatment response and overall survival times that rose by a median of 1.3 years.

"We found that whole-genome sequencing of breast cancers can reveal mutational patterns characteristic of HRD that identify patients who are likely to respond well to platinum-based chemotherapies," senior author Steven Jones, a researcher affiliated with Canada's Michael Smith Genome Sciences Centre at BC Cancer Agency and the UBC medical genetics department, said in a statement.

Jones also noted that "all seven cancers with pathogenic BRCA1 or BRCA2 mutations had high HRDetect scores," further supporting the effectiveness of the HRDetect tool for finding HRD tumors.

Using Illumina HiSeq2000 or HiSeq2500 instruments, he and his colleagues did genome sequencing on tumor-normal pairs from 93 individuals with advanced breast cancer who were participating in the Personalized Oncogenomics study. They also generated RNA sequence data for 92 of the tumor samples.

From the sequences, the team gleaned patterns at nearly 1.2 million single nucleotide changes and almost 11,400 structural variants, identifying new and known mutation signatures associated with everything from aging to breast cancer itself.

In clusters of tumors that were particularly mutation-rich, the team saw signs of HRD or APOBEC deaminase enzyme-related mutagenic activity. Feeding data on the alterations identified in the tumor sequences into the HRDetect prediction tool highlighted 19 HRDetect-high cases, 37 cases with low HRDetect scores, and 37 moderate HRDetect score tumors.

While many of the tumors with high HRDetect scores contained pathogenic germline or somatic BRCA1/2 mutations, the researchers reported, they also saw several tumors with high scores that contained germline mutations classified as variants of uncertain significance. More than half of the HRDetect-high tumors fell into the basal-like breast cancer subtype, while HRDetect-low score tumors more often came from the luminal B or normal-like tumor subtypes.

The team uncovered significant ties between platinum-based chemotherapy response and elevated HRDetect scores, which could be identified in more of the tumors than known pathogenic BRCA1/2 mutations. Whereas cases with low HRDetect score tumors had median overall survival times of 122 days after platinum treatment, the HRDetect-high score cases had 384 day median survival times following the treatment. 

"Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer," Jones and his co-authors wrote. "We demonstrate that HRD mutation signatures may offer clinically relevant information independently of BRCA1/2 mutation status and hope this work will guide the development of clinical trials."