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Treatment-Resistant Breast Cancer Not Enriched for Targetable Mutations

NEW YORK (GenomeWeb) – In a prospective study, Mayo Clinic researchers have sequenced samples from breast cancer patients who did and who did not respond to chemotherapy to find that both groups harbored similar common genomic alterations.

As part of the Breast Cancer Genome-Guided Therapy (BEAUTY) study, the researchers analyzed genetic variants present in tumors from some 140 patients, some of whom experienced a pathological complete response and some of whom did not, and developed mouse avatars for a subset of patients.

As the researchers reported last week in the Journal of the National Cancer Institute, they found that recurrent targetable alterations were not enriched among patients who did not respond to treatment as compared to those who did. Still, they reported that xenografts derived from one patient helped researchers identify a drug to which the tumor appeared to respond.

"There is great interest to use tumor sequencing data to guide therapy," first author Matthew Goetz from the Mayo Clinic and co­chair of the BEAUTY study said in a statement. "However, there are limited data as to whether this approach is useful in women with newly diagnosed breast cancer who are recommended chemotherapy prior to breast surgery."

He and his colleagues enrolled 140 women into their study, noting that their chemotherapy response rate varied by breast cancer subtype. More than half of patients with triple-negative disease responded to treatment, while only 10 percent of those with luminal B disease did.

They generated sequencing data for pre-treatment tumor and germline samples to analyze genes frequently mutated in breast cancer as well as examine copy-number alterations and gene expression modulation. Across all tumor types, the gene PIK3CA was often mutated, while TP53 was commonly mutated among triple negative and HER2+ tumors regardless of ER status, the researchers reported.

However, Goetz and his colleagues found that common, targetable genetic mutations were not enriched among the chemotherapy-resistant tumors. The same mutations were just as common among the treatment sensitive tumors.

Patient-derived xenografts, however, did offer insight into potential therapeutic avenues. Using core needle biopsies, the researchers attempted to develop patient-derived xenografts from 113 samples. They had a take rate of about 27 percent, which they noted was influenced by ER expression.

Such patient mouse avatars were developed for two patients whose disease progressed during chemotherapy. For one of those patients, sequencing her tumor uncovered deleterious somatic mutations in PTEN, BRCA1, and CHEK1, among others, as well as IRF4 and MYC amplifications, which led the researchers to suspect that olaparib treatment might be effective. Mice implanted with either pretreatment or residual disease biopsy samples were randomized to receive either olaparib or placebo, and those given olaparib had significant smaller tumor sizes, the researchers reported.

They noted, however, that the patient's disease progressed too quickly for this information to be clinically useful.

"The simultaneous generation of avatars and tumor sequence data from patients that did not respond to chemotherapy has allowed our research team to prioritize the selection of the new agents to study in the laboratory," Goetz said.

His colleague, Mayo's Judy Boughey, added that the BEAUTY study is launching a follow-up project to "[bring] forward new drugs to women with chemotherapy resistant tumors."