Genomic Landscape in Metastatic ER+ Breast Cancer Differs From Primary Tumors

Whole exome and transcriptome sequencing found that the genomic landscape of estrogen receptor-positive metastatic breast cancer differs from that of primary tumors.

Whole exome and transcriptome sequencing found that the genomic landscape of estrogen receptor (ER)-positive metastatic breast cancer differs from that of primary tumors, according to a study presented today at the San Antonio Breast Cancer Symposium (SABCS), held December 6–10 in San Antonio, Texas. This could have implications for treatment decisions as well as other issues such as clinical trial design.

“We have treatments for ER-positive breast cancer that are very effective, but within the metastatic setting, drug resistance … frequently occurs,” said Ofir Cohen, PhD, of the Broad Institute and Dana-Farber Cancer Institute in Boston, who presented the study and spoke during a press conference. Though there is an urgent need to develop further treatments for this setting, he said “the genomic landscape is underexplored” compared with primary tumors. “[We wanted] to start closing that gap.”

The new analysis included whole exome sequencing of 149 metastatic biopsies, along with 44 matched primary tumors. The researchers also conducted transcriptome sequencing (RNA-seq) of 128 metastatic biopsies.

The whole exome sequencing showed that metastatic breast cancer samples have more frequent alterations in a number of genes compared to the primary tumor samples; these included ESR1, ERBB2, PIK3CA, PTEN, RB1, and AKT1.

ESR1 mutations were seen in 23% of the metastatic samples; based on the matched primary tumor samples, 14 of 15 of those were acquired in the metastatic setting. This was similar in mutations that occurred somewhat less frequently as well; for example, ERBB2 mutations were seen in 7% of the cohort, and 5 of 6 were acquired. RB1 mutations were seen in 6%, and 3 of 5 from the matched cohort were acquired in the metastatic setting.

“These have clear clinical implications, as finding those mutations may guide treatment choices for those patients,” Cohen said. For example, ESR1 mutations are related to resistance to aromatase inhibitors, while experimental data suggests that RB1 mutations can cause resistance both to existing endocrine therapies and to new CDK4/6 inhibitors.

Cohen also pointed out that tumors may evolve resistance through epigenetic or other mechanisms, but that if those mechanisms “leave a footprint” on the transcriptome, sequencing may still lead to insights into resistance states that don’t necessarily derive from exome mutations. “The take-home message here is that tumors do evolve, and the metastatic setting is different than the primary setting,” he said.

Virginia G. Kaklamani, MD, of the UT Health Science Center in San Antonio and co-director of the SABCS, spoke during the press conference and pointed out that each of the mutations found in the study has existing or in-development drugs targeting it. She said that elucidating the pathways of resistance could “lead toward specific targeted therapies, rather than using a cookie cutter approach that we use nowadays.”