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Mutation status may guide endocrine therapy for advanced breast cancer
Plasma analysis of ESR1 mutations may aid in the identification of appropriate endocrine therapy for patients with advanced breast cancer who progress after treatment with aromatase inhibitors, according to study results published in Journal of Clinical Oncology.
“Although diverse mechanisms of resistance to endocrine therapy have been described, recent evidence identified mutations in the ER gene (ESR1),” Nicholas C. Turner, MA, MRCP, PhD, consultant medical oncologist at The Royal Marsden NHS Foundation Trust and team leader at the Breakthrough Breast Cancer Research Centre at Institute for Cancer Research, London, and colleagues wrote. “ESR1 mutations occur rarely in primary breast cancer, but have a high prevalence in advanced breast cancers previously treated with aromatase inhibitors, implying evolution through selective treatment pressure.”
Turner and colleagues analyzed the effect of these mutations on sensitivity to standard endocrine therapies in two phase 3 randomized trials of women with advanced, estrogen receptor–positive breast cancer:
- The SoFEA trial, which compared exemestane (Aromasin, Pfizer) with fulvestrant (Faslodex, AstraZeneca)-containing regimens in patients with prior sensitivity to nonsteroidal aromatase inhibitors; and
- The PALOMA3 trial, which compared fulvestrant and placebo with fulvestrant and palbociclib (Ibrance, Pfizer) in women who progressed after initial endocrine therapy.
The researchers used multiplex digital polymerase chain reaction to analyze ESR1 mutations. They analyzed plasma samples in 161 women enrolled in the SoFEA trial, representing 22.4% of the patient population (n = 723); and in 360 women enrolled in the PALOMA3 trial, representing 69.1% of the patient population (n = 521).
The researchers identified ESR1 mutations in 39.1% of women in the SoFEA trial with available plasma (n = 63); 49.1% (n = 27) were polyclonal. They found that women with ESR1 mutations assigned fulvestrant had a median PFS of 5.7 months (95% CI, 3-8.5), compared with 2.6 months (95% CI, 2.4-6.2) for women assigned exemestane (HR = 0.52; 95% CI, 0.3-0.92).
Women with wild-type ESR1 achieved a longer, yet nonsignificant, median PFS when assigned exemestane (median, 8 months vs. 5.4 months; HR = 1.07; 95% CI, 0.68-1.67).
The researchers noted that the SoFEA trial was not sufficiently powered to detect a statistically significant OS difference; however, “the effects of ESR1 mutation on overall survival in patients treated with exemestane were consistent with the PFS analysis,” they wrote.
ESR1 mutations could be identified in 25.3% of the PALOMA3 study cohort (n = 91) with available plasma. Women with mutations assigned fulvestrant and palbociclib had a median PFS of 9.4 months (95% CI, 5.3-11.1), compared with 3.6 months (95% CI, 2-5.5) for fulvestrant and placebo (HR = 0.43; 95% CI, 0.25-0.74).
Fulvestrant plus palbociclib also significantly extended PFS in women with wild-type ESR1 (median, 9.5 months vs. 5.4 months; HR = 0.49; 95% CI, 0.35-0.7).
The researchers reported that among women in the PALOMA3 trial, ESR1 mutations appeared primarily in women who had prior therapy with aromatase inhibitors, with or without tamoxifen, rather than women with prior tamoxifen exposure only (28.9% vs. 2%; P < .001).
Study limitations included the retrospective nature of the biologic analyses of both trials, as well as the relatively small number of samples available from the SoFEA trial.
“Our data suggest that ESR1 mutation analysis may have clinical utility in directing further endocrine therapy, although further confirmatory studies are required,” Turner and colleagues wrote. “Our results demonstrate that ESR1 mutant and wild-type cancers seem to be distinct subtypes of breast cancer that differ in response to standard endocrine therapies. Future clinical trials in advanced breast cancer might consider using plasma DNA analysis to optimize endocrine therapy choice according to ESR1 mutation status.” – by Cameron Kelsall
Disclosure: Turner reports institutional research funding from and/or consultant roles with AstraZeneca, Novartis, Pfizer and Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures.