Genomics of Estrogen Receptor-Positive Cancer Changes Following Metastasis

A genomic analysis revealed significant differences in the genomic landscape of estrogen receptor (ER)-positive metastatic breast cancers when compared with ER-positive primary tumors. These alterations frequently developed after treatment, and may be responsible for treatment resistance in metastatic patients.

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Many treatment advances have improved outcomes for patients with ER-positive breast cancer. However, a majority of this patient population will eventually develop therapeutic resistance.

Ofir Cohen, PhD, microbiologist at The Broad Institute of Massachusetts Institute of Technology and Harvard (Cambridge, MA), and colleagues conjectured that improved knowledge of genomic resistance mechanisms could lead to better disease management.

The researchers performed whole-exome sequencing and transciptome sequencing on biopsies from 88 patients with ER-positive metastatic breast cancers, all of whom were treatment resistant following one or two targeted therapies. Matched biopsies of treatment-naive primary tumors were available for 27 patients. Sequencing data were analyzed for point mutations, insertions and deletions, copy number alterations, translocations, and gene expression.

Whole-exome sequencing showed significant differences in gene alterations between metastatic tumors and treatment-naive primary tumors, including ESR1 mutations (n = 17; 19.3%; 32.86-fold enrichment), CCND1 amplification (n = 52; 59.1%; 2.3-fold enrichment), and MAP2K4 bialletic inactivation (n = 14; 15.9%; 3.04-fold enrichment).

When Dr Cohen and colleagues compared primary samples to metastatic samples from the same patient, they found numerous acquired alterations. These included ESR1, ERBB2, PIK3CA, PTEN, RB1, and AKT1

“We were able to identify multiple clinically relevant genomic and molecular alterations in the metastatic biopsies with implications for choice of next therapy, clinical trial eligibility, and novel drug targets,” Dr Cohen said during a press conference. “The bottom line is that tumors do evolve and the metastatic setting is different than the primary setting.”