Triple-Negative Breast Cancer Classified from Whole-Genome Sequencing

Also, the cancer is more likely to spread and recur. The stage of breast cancer and the grade of the tumor will influence the prognosis. The five-year survival rate for TNBC is around 77% versus 93% for other breast cancer types.

An international team of scientists led by those at Lund University (Lund, Sweden) sequenced 254 TNBC tumors from patients from the Sweden Cancerome Analysis Network-Breast (SCAN-B) project, an ongoing population-based observational study of breast cancer patients in southern Sweden. By applying the previously developed machine-learning algorithm HRDetect to the genome sequences, the investigators divided the tumors into three groups: low, intermediate, and high, based on how deficient they were in homologous recombination-based gene repair. These groups had varying prognoses and responses to treatments.

After determining likely somatic drivers and pathogenic germline mutations for this cohort, the team applied the mutational signature-based algorithm HRDetect to examine the "BRCA-ness" or homologous recombination repair deficiency of these samples. Nearly 60% of the triple-negative tumors were classified as HRDetect-high; about 35% were HRDetect-low; and about 5% fell in an intermediate group. The scientists reported that the HRDetect-high group was enriched for patients under the age of 50 years, with high-grade tumors and a basal-like expression subtype. But as they noted, this group also included tumors with ER-staining, from middle-aged patients, and with non-basal-like gene expression profiles, suggesting that the HRDetect-high phenotype is enriched for the typical basal-like tumors found among young patients with triple-negative disease, but also encompasses others. This, they argued, suggests HRDetect represents a novel means of stratifying tumors.

Patients whose tumors fell into these different HRDetect groups also responded differently to treatment. Patients in the HRDetect-high group had the best outcomes of the three. These tumors were both more likely to respond to adjuvant chemotherapy as well as to PARP inhibitors. The HRDetect-intermediate group, meanwhile, had the worst outcomes, though the HRDetect-low group also had poor outcomes. But as the scientists noted, the molecular profiles of the HRDetect-intermediate and -low groups suggested potential actionable targets. The HRDetect-intermediate group, for instance, was enriched for tumors with Cyclin E1 (CCNE1) amplifications and for hypermutators of a rearrangement signature of long tandem duplications. The HRDetect-low group, meanwhile, was enriched for alterations to the PIK3CA/AKT1 pathway.

Johan Staaf, PhD, an associate professor of oncology and pathology, and first author of the study, said, “Using whole-genome sequencing, we can truly discriminate tumors that may or may not respond to current drugs among triple-negative breast cancer patients, a type of breast cancer that we still struggle to treat well.” The study was published on September 30, 2019, in the journal Nature Medicine.

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