Plasma ESR1 Mutations and the Treatment of Estrogen Receptor-Positive Advanced Breast Cancer.
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.



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 and in baseline plasma from the PALOMA3 (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.



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 wild-type 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).



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.
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Charlotte
C
Fribbens
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Ben
B
O'Leary
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Lucy
L
Kilburn
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Sarah
S
Hrebien
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Isaac
I
Garcia-Murillas
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Matthew
M
Beaney
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Massimo
M
Cristofanilli
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Fabrice
F
Andre
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Sherene
S
Loi
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Sibylle
S
Loibl
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
John
J
Jiang
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Cynthia Huang
CH
Bartlett
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Maria
M
Koehler
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Mitch
M
Dowsett
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Judith M
JM
Bliss
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY.
Stephen R D
SR
Johnston
Charlotte Fribbens, Ben O'Leary, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Mitch Dowsett, and Nicholas C. Turner, Institute of Cancer Research; Charlotte Fribbens, Ben O'Leary, Stephen R.D. Johnston, and Nicholas C. Turner, Royal Marsden Hospital; Lucy Kilburn and Judith M. Bliss, The Institute of Cancer Research Clinical Trials and Statistics Unit, London, UK; Massimo Cristofanilli, Thomas Jefferson University, Philadelphia, PA; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Sherene Loi, University of Melbourne, Melbourne, Australia; Sibylle Loibl, German Breast Group, Neu-Isenburg, Germany; and John Jiang, Cynthia Huang Bartlett, and Maria Koehler, Pfizer, New York, NY. nicholas.turner@icr.ac.uk.
Nicholas C
NC
Turner
D000368:Aged; D000077384:Anastrozole; D000730:Androstadienes / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D018572:Disease-Free Survival; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000097:blood* / Q000235:genetics*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D011446:Prospective Studies; D011725:Pyridines / Q000008:administration & dosage; D012189:Retrospective Studies; D014230:Triazoles / Q000008:administration & dosage
D000730:Androstadienes; D004273:DNA, Neoplasm; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009570:Nitriles; D010879:Piperazines; D011725:Pyridines; D014230:Triazoles; D000077267:Fulvestrant; D000077384:Anastrozole; D004958:Estradiol; C500026:palbociclib; C056516:exemestane