Plasma ESR1 Mutations and the treatment of estrogen receptor-Positive advanced breast cancer

Charlotte Fribbens, Ben O'Leary, Lucy Kilburn, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Massimo Cristofanilli, Fabrice Andre, Sherene Loi, Sibylle Loibl, John Jiang, Cynthia Huang Bartlett, Maria Koehler, Mitch Dowsett, Judith M. Bliss, Stephen R D Johnston, Nicholas C. Turner*

*Corresponding author for this work

Research output: Contribution to journalArticle

290 Scopus citations

Abstract

Purpose ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor-positive advanced breast cancer. Materials and Methods In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI andinbaselineplasmafromthePALOMA3(Palbociclib Combined With Fulvestrant in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. Results In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wildtype ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P , .001). Conclusion ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.

Original languageEnglish (US)
Pages (from-to)2961-2968
Number of pages8
JournalJournal of Clinical Oncology
Volume34
Issue number25
DOIs
StatePublished - Sep 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Fribbens, C., O'Leary, B., Kilburn, L., Hrebien, S., Garcia-Murillas, I., Beaney, M., Cristofanilli, M., Andre, F., Loi, S., Loibl, S., Jiang, J., Bartlett, C. H., Koehler, M., Dowsett, M., Bliss, J. M., Johnston, S. R. D., & Turner, N. C. (2016). Plasma ESR1 Mutations and the treatment of estrogen receptor-Positive advanced breast cancer. Journal of Clinical Oncology, 34(25), 2961-2968. https://doi.org/10.1200/JCO.2016.67.3061