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Researchers identify gene alterations linked to certain metastatic breast cancers
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SAN ANTONIO — Ten driver gene alterations appeared more common among a cohort of patients with metastatic hormone receptor-positive, HER2-negative breast cancer than those with early-stage disease, according to study results presented at San Antonio Breast Cancer Symposium.
“Metastatic breast cancers acquire new genomic alterations, suggesting a genome evolution or clonal selection,” Fabrice André, MD, PhD, associate professor in the department of medical oncology at Institute Gustave Roussy in France, said during a presentation.
Little is known about the genomic landscape of metastatic breast cancer.
Andre and colleagues performed whole-exome sequencing on 800 patients with metastatic disease to identify new potential targets and to better stratify patients eligible for innovative therapies.
Andre presented data on the first 629 patients. In that group, the most common subtypes were hormone receptor-positive, HER2-negative disease (n = 387); triple-negative disease (n = 186); and HER2-overexpressing breast cancer (n = 32).
“Of importance, 29 patients were pretreated with a CDK4 inhibitor, which proved to be significant when we described the genomic landscape,” André said.
Analysis revealed significant mutations in 23 driver genes.
Of these, 10 genes — including KMT2C (13%), NCOR1 (8%), NF1 (7%), and RB1 in 4% of women who did not receive a CDK4 inhibitor — were more frequently mutated in the metastatic setting than established in patients with early-stage disease.
Investigators observed shorter OS among patients with mutations in RB1 (median OS, 9 months; P = .0038) and NF1 (median OS, 13 months; P = .01).
KRAS mutations were identified among 3% of patients with metastatic disease, compared with a known frequency of less than 1% among patients with early-stage breast cancers.
When researchers compared copy number alterations between metastatic and early-stage breast cancer, 18 amplicons were identified more frequently among hormone receptor-positive, HER2-negative metastatic breast cancers.
Additionally, actionable alterations were observed among a greater proportion of patients with hormone receptor-positive, HER2-negative metastatic breast cancer than those with early-stage disease (73% vs. 55%, P < .01), as was enrichment of gene alterations in the MAPK/ERK pathway (37% vs. 22%) and HRD pathway (22% vs. 10%).
Researchers further analyzed the mutational signatures to better understand which mutational processes could drive cancer progression.
Patients with metastatic hormone receptor-positive, HER2-negative metastatic breast cancer had increased prevalence of APOBEC, S3 (homologous recombination deficiency), S10 (POLE-associated signature) and S17 signatures than those with early-stage hormone receptor-positive, HER2-negative breast cancer.
Researchers additionally observed an increased frequency of somatic biallelic loss-of-function mutations in genes on the homologous recombination deficiency pathway in patients with metastatic triple-negative breast cancer compared with those with early-stage disease (7% vs. 2%; P = .026).
“These mutational signatures could be a surrogate of genome evolution, and their detection is associated with poor outcomes,” André said. “A subset of metastatic triple-negative breast cancer patients present with somatic biallelic loss-of-function mutations in genes located in the [homologous recombination deficiency] pathway, which could represent a new population of patients eligible for PARP inhibitors.” – by Jennifer Southall
Reference:
Andre F, et al. Abstract GS1-08. Presented at: San Antonio Breast Cancer Symposium; Dec. 4-8, 2018; San Antonio.
Disclosures: Andre reports no relevant financial disclosures. Please see the abstract for all authors’ relevant financial disclosures.