title: Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant.
abstract: Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy in patients with ER+ metastatic breast cancer. Little is known of the impact of these mutations in patients receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot mutations in ESR1 and PIK3CA from ctDNA were assayed in clinical trial samples from ER+ metastatic breast cancer patients randomized either to the SERD fulvestrant or fulvestrant plus a pan-PI3K inhibitor. ESR1 mutations are present in 37% of baseline samples and are enriched in patients with luminal A and PIK3CA-mutated tumours. ESR1 mutations are often polyclonal and longitudinal analysis shows distinct clones exhibiting divergent behaviour over time. ESR1 mutation allele frequency does not show a consistent pattern of increases during fulvestrant treatment, and progression-free survival is not different in patients with ESR1 mutations compared with wild-type patients. ESR1 mutations are not associated with clinical resistance to fulvestrant in this study.
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Spoerke
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Gendreau
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Walter
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Jiaheng
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Wilson
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Savage
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Aimi
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Mika K
authors.initials: MK
authors.lastname: Derynck
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Iris T
authors.initials: IT
authors.lastname: Chan
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Amler
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Garret M
authors.initials: GM
authors.lastname: Hampton
authors.affiliation: Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Johnston
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Krop
authors.affiliation: Barts Cancer Institute, Queen Mary University London, London EC1M 6BQ, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmid
authors.affiliation: Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Lackner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D004273:DNA, Neoplasm; C506487:ESR1 protein, human; D065171:Estrogen Receptor Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077267:Fulvestrant; D004958:Estradiol; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human