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Estrogen Receptor Mutations in cfDNA Linked to Shorter Metastatic Breast Cancer Survival

NEW YORK (GenomeWeb) – Mutations in the estrogen receptor gene ESR1 appear to be linked to more aggressive disease and poorer patient outcomes in individuals with estrogen receptor-positive metastatic breast cancer, according to a study published today in JAMA Oncology.

In a secondary analysis for a phase 3 double-blind clinical trial known as BOLERO-2, researchers from Memorial Sloan-Kettering Cancer Center, Novartis Pharmaceuticals, the Medical University of Vienna, and the University of Texas MD Anderson Cancer Center used droplet digital PCR to search for the two most common ESR1 gene mutations in circulating cell-free DNA (cfDNA) isolated from the blood samples of women with metastatic breast cancer. All of the individuals had been previously treated with an aromatase inhibitor.

The researchers started with a group of more than 700 metastatic breast cancer patients enrolled in two dozen countries for a phase 3 randomized double-blind trial of the aromatase inhibitor exemestane (Pfizer's Aromasin) plus placebo or exemestane in combination with the mTORC1 inhibitor everolimus (Zortress or Certican from Novartis).

In cfDNA isolated from baseline blood samples, which were available for 541 of the patients, they used digital droplet PCR on the BioRad QX200 ddPCR system to search for the two most common ESR1 mutations, the estrogen receptor-activating mutations D538G and Y537S. The search uncovered D538G mutations in cfDNA from 114 of the individuals, and Y537S mutations in cfDNA from 72 patients. Thirty individuals had both mutations.

The team found that while individuals without such alterations survived for more than 32 months, on average, the individuals carrying the D538G mutation survived an average of less than 26 months. The Y537S mutation in ESR1 was associated with about 20 months of survival. In individuals with both mutations, average survival times were even lower, at about 15 months.

"[W]e found that [two] ESR1 mutations, Y537S and D538G, were highly prevalent in ER-positive [metastatic breast cancer] and associated with inferior outcomes," corresponding author Sarat Chandarlapaty, a human oncology and pathogenesis researcher at MSKCC, and his colleagues wrote.

Following the combination exemestane and everolimus treatment, the progression-free survival times appeared to be similar in individuals with the D538G mutation or in the individuals lacking either ESR1 mutation, the researchers reported. And across the BOLERO-2 cohort, the addition of everolimus was associated with a jump in progression-free survival: a median of 7.8 months versus 3.2 months in the exemestane plus placebo group.

The team was not able to see significant ties between the Y537S ESR1 mutation and progression-free survival times in the everolimus-treated group because of the limited number of cases in this group. There were hints that this mutation might interfere with the effectiveness of the mTOR inhibitor, though the allele has not been previously linked to changes to the mTOR pathway.

"The study lacked sufficient numbers of patients with Y537S to draw conclusions on everolimus benefit for this subgroup," the authors noted. However, they added, "our preliminary data showed a potential lack of benefit in those with either the Y537S mutation alone or with both Y537S and D538G."