“Taken together, these results suggest that the selection pressure provided by aromatase inhibitor exposure is one of the main mechanisms of ESR1 mutation increase,” concluded Dr. Clatot. “ESR1 mutations are a strong and independent marker of poor prognosis but do not have any predictive value with the treatments used in our cohort.”
Mutations after progression on prior endocrine therapy
Dr. Nicholas C. Turner
In the second study, Nicholas C. Turner, MD, PhD, a medical oncologist at the Royal Marsden Hospital and Institute of Cancer Research, London, and colleagues analyzed data from a subset of 395 women from PALOMA-3.
The randomized phase III trial tested fulvestrant combined with palbociclib (Ibrance), an oral inhibitor of cyclin-dependent kinases 4 and 6, or placebo. All of the women enrolled had experienced progression on prior endocrine therapy in the adjuvant, advanced, or metastatic setting.
The investigators looked for 12 ESR1 mutations in circulating tumor DNA from baseline plasma samples using the BEAMing (beads, emulsion, amplification, magnetics) digital PCR technique and droplet digital PCR screening.
Overall, 27% of the women had ESR1 mutations before starting therapy on the trial, Dr. Turner reported. Mutations were seen in those who had received a prior aromatase inhibitor, but not in those who had received only prior tamoxifen. “So it’s quite clear these mutations are not a mechanism of resistance to tamoxifen, suggesting that tamoxifen must have at least some activity against these mutations,” he commented.
In addition, ESR1 mutations were more common in patients who had been sensitive versus not to prior endocrine therapy of any type (30.3% vs. 12.8%) and in patients who had been sensitive versus not specifically to prior aromatase inhibitor therapy (34.6% vs. 11.1%).
Stratified analyses showed that palbociclib was similarly superior to placebo in terms of progression-free survival whether patients were positive for an ESR1 mutation (9.4 vs. 4.1 months; hazard ratio, 0.52; P = .0052) or negative (9.5 vs. 3.8 months; hazard ratio, 0.44; P less than .0001).
“Detection of estrogen receptor mutations was strongly associated with acquired resistance to prior aromatase inhibitors,” Dr. Turner said.
“Palbociclib offered high efficacy regardless of the estrogen receptor mutation status,” he added. “And because in this patient population estrogen receptor mutations are detected frequently, the combination of palbociclib and fulvestrant presents an attractive treatment option for patients who have been previously treated with and progressed on aromatase inhibitors.”