Aromatase inhibitor (AI) therapy is the backbone of hormonal treatment in the metastatic setting for many patients with estrogen receptor (ER)-positive breast cancer. ESR1 mutations have emerged as a key mechanism of resistance to AI therapy for this patient population. Furthermore, ESR1 circulating mutations are an independent risk factor for poor outcomes after failure of an AI, and are often identifiable before clinical disease progression. CDK4/6 inhibitors appear to be attractive options for ESR1-mutant breast cancer.
In a secondary analysis of the BOLERO-2 trial, a double-blind phase 3 study that randomized patients with metastatic breast cancer to exemestane plus placebo or exemestane plus everolimus, Sarat Chandarlapaty, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, NY, and colleagues found that the prevalence of the Y537S and D538G mutations in ESR1 in patients with advanced, ER-positive breast cancer is more common than previously perceived. In addition, data suggest that the response to exemestane is blunted in patients with mutations in Y537S or D538G.
“We know that the mutations promote resistance to the most widely used anti-estrogen, known as aromatase inhibitors, but we didn’t know how frequently these mutations were present in the population of patients,” said Dr Chandarlapaty in an interview with JAMA Oncology.
All patients in BOLERO-2 had exposure to an AI, either in the adjuvant or metastatic setting. Patients were randomized to second-line hormone therapy with exemestane or the combination of exemestane and everolimus. The primary end point, progression-free survival (PFS), was increased by 4.5 months with the addition of everolimus in the overall BOLERO-2 cohort.
Baseline plasma samples were available for 541 of the 724 patients enrolled in BOLERO-2. “Rather than using tumor biopsies…we used plasma to look for essentially shed DNA, circulating free DNA from the tumor to look for the mutations,” he said.
From those 541 plasma samples, DNA was extracted and subjected to digital droplet polymerase chain reaction (PCR). Some 29% of patients had either the D538G or Y537S mutation. The D538G ESR1 mutation was found in samples from 15%, the Y537S ESR1 mutation was found in samples from 8%, and both mutations were found in samples from 5.5%.
Mutations occurred much less frequently in patients who received an AI in the adjuvant setting than in the metastatic setting (P <.001).
“The mutations are associated with shorter survival,” said Dr Chandarlapaty. Median overall survival was 32.1 months for patients with neither ESR1 mutation compared with 26 months for patients with only a D538G mutation, 20 months for those with only a Y537S mutation, and 15.2 months for those with both mutations.
Median PFS in the group with neither ESR1 mutation or only a D538G mutation was more than double with the addition of everolimus to exemestane. The combination had no effect on median PFS compared with exemestane alone in the group with a Y537S mutation.
The findings also support that “the detection of ESR1 mutations in circulating tumor DNA (ctDNA) by digital droplet PCR (ddPCR) is sensitive and highly correlates to the ESR1 mutational status in tumor tissue,” wrote Florian Clatot, MD, from INSERM in Rouen, France, in Oncotarget in a recent editorial. Plasma samples from ER-positive metastatic breast cancer patients can be regarded as “liquid biopsies,” he added, “and might help choosing the right treatment to the right patient at the right time in the near future. Indeed, a growing amount of evidence has supported the potential clinical utility of ESR1 mutational status assessment.”
“Prospective studies are needed to determine the best therapeutic options when circulating ESR1 mutations occur during AI exposure,” he noted. Early retrospective evidence from the PALOMA-3 study indicates that the CDK4/6 inhibitor palbociclib, when added to fulvestrant, may represent an attractive treatment option for ESR1 mutant cancer.
As in BOLERO-2, ESR1 mutations were found frequently in the PALOMA-3 population of patients with hormone receptor–positive metastatic breast cancer who had progressed after first-line AI therapy: 27% of 395 baseline plasma samples analyzed by ddPCR had at least one ESR1 circulating mutation.
In patients with ESR1 mutations, the median PFS in patients randomized to palbociclib plus fulvestrant was 9.4 months, compared with 4.1 months in the placebo plus fulvestrant arm (hazard ratio [HR], 0.52). In those without an ESR1 mutation, the improvement in median PFS was similar by adding palbociclib to fulvestrant compared with fulvestrant alone (9.5 months vs 3.8 months; HR, 0.44).
Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol. 2016;2:1310-1315.
Clatot F, Augusto L, Di Fiore F. ESR1 mutations in breast cancer (editorial). Aging. published online 2017 Jan 25. doi:10.18632/aging.101165.
www.ncbi.nlm.nih.gov/pmc/articles/PMC5310651/. Accessed June 5, 2017.
Turner NC, Jiang Y, O’Leary B, et al. Efficacy of palbociclib plus fulvestrant (P+F) in patients (pts) with metastatic breast cancer (MBC) and ESR1 mutations (mus) in circulating tumor DNA (ctDNA). J Clin Oncol. 2016;34(suppl):Abstract 512.