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ER-Positive Breast Cancer Outcomes Linked to New, Known Somatic Mutations

NEW YORK (GenomeWeb) – A new study is spelling out the somatic mutations linked to poorer or more promising prognoses for women with estrogen receptor-positive breast cancer — ranging from known predictors of patient outcomes to new ones not identified in the past.

"With all the breast cancer sequencing that's been done, it's tempting to think we've found everything of importance," first author Obi Griffith, an assistant professor of medicine and assistant director of  Washington University School of Medicine's McDonnell Genome Institute, said in a statement. "But this study tells us there is still more to discover."

Griffith and colleagues from Washington University and elsewhere sequenced 83 genes in hormone receptor-positive primary breast cancer samples from nearly 1,000 pre- or post-menopausal women. Based on mutations and patient survival patterns in these cohorts, as well as a subsequent validation analysis, they saw better-than-usual outcomes in cases involving the sorts of MAP3K1 or PIK3CA mutations that typically mark tumors from the luminal A breast cancer subtype.

Conversely, the team noted, recurrent mutations affecting TP53, and much rarer mutations involving the NF1, PIK3R1, or DDR1 genes, appeared to coincide with poorer overall survival in one or more of the estrogen receptor-positive breast cancer cohorts. The findings appeared online this week in Nature Communications.

From these and other results, the researchers suggested that "uncommon recurrent somatic mutations should be further explored to create a more complete explanation of the highly variable outcomes that typifies [estrogen receptor-positive] breast cancer."

"We would like to help doctors identify patients who are likely to do well versus those who are likely to have a recurrence," Griffith explained. "Those with mutations that are associated with a good prognosis may need less intensive therapy than they might otherwise receive. But if a patient's tumor has mutations linked to high risk of relapse, it’s useful to know that early so they can be treated with more aggressive therapies or even potential investigational therapies that could be targeted to their specific mutations."

The researchers began by retrospectively profiling somatic mutation patterns in formalin-fixed, paraffin-embedded tumor samples collected more than 20 years ago from 625 tamoxifen-treated, post-menopausal women from the University of British Columbia Tamoxifen Series (UBC-TAM) cohort and 328 pre-menopausal women enrolled through the National Cancer Institute of Canada (NCIC) MA12 trial, who received chemotherapy and were randomized to arms with or without tamoxifen treatment.

They went on to incorporate data for 175 estrogen receptor-positive breast cancer cases from a case-control study, along with validation data from the Molecular Taxonomy of Breast Cancer International Consortium  (METABRIC).

Following hybrid capture, Illumina HiSeq 2000 or 2500 sequencing, and somatic analysis steps, the team identified 17 genes that were recurrently affected by non-silent mutations and delved into the mutation hotspots in the genes.

When they incorporated information on patient outcomes, the researchers found prognostically favorable mutations in MAP3K1, PIK3CA, and other genes. They noted that poorer-than-usual outcomes were linked to TP53 mutations, as reported previously.

But new associations turned up as well. The team found that survival outcomes dipped in UBC-TAM cases that involved DDR1 mutations, or frameshift or nonsense mutations in NF1, for example, and across MA12 cases that included PIK3R1 mutations.

"The UBC-TAM and MA12 studies revealed different lists of potentially prognostic mutations," the authors wrote, noting that prognostic impacts of such mutations "are likely to be strongly affected by the use of systemic therapy, as well as by patient age at diagnosis."