Incidence and Clinical Significance of ESR1 Mutations in Heavily Pretreated Metastatic Breast Cancer Patients

Overview

Journal Onco Targets Ther

Publisher Dove Medical Press

Specialty Oncology

Date 2015 Dec 10

PMID 26648736

Citations 30

Authors

Jiaxin Niu

Grant Andres

Kim Kramer

Madappa N Kundranda

Ricardo H Alvarez

Eiko Klimant

Ankur R Parikh

Bradford Tan

Edgar D Staren

Maurie Markman

Affiliations

Soon will be listed here.

Abstract

Background: ESR1 mutation has recently emerged as one of the important mechanisms involved in endocrine resistance. The incidence and clinical implication of ESR1 mutation has not been well evaluated in heavily pretreated breast cancer patients.

Methods: We conducted a retrospective review of advanced breast cancer patients with tumors who underwent next-generation sequencing genomic profiling using Foundation One test at Cancer Treatment Centers of America(®) regional hospitals between November 2012 and November 2014.

Results: We identified a total of 341 patients including 217 (59%) estrogen receptor (ER)+, 177 (48%) progesterone receptor (PR)+, 30 (8%) hormone receptor+/HER2 positive, and 119 (32%) triple negative patients. ESR1 mutation was noted in 27/222 (12.1%) ER+ or PR+ breast cancer patients. All ER+ patients received at least one line of an aromatase inhibitor. All 28 patients were found to harbor ESR1 mutations affecting ligand-binding domain with the most common mutations affecting Y537 (17/28, 60.7%) and D538 (9/28, 32.1%). In this cohort, 19 (67.9%) patients carried three or more, seven (25%) patients had one or two additional genomic alterations and one (3.6%) patient had an ESR1 mutation only. Of 28 patients, three patients were treated with fulvestrant immediately before and two patients were treated after next-generation sequencing testing; only one patient achieved stable disease for 8 months and the other four patients had progression of disease. In all, 3/3 (100%) patients before testing and 2/4 (50%) after testing treated with exemestane and everolimus achieved stable disease for at least 6 months.

Conclusion: ESR1 mutation was found in 12.1% of a large cohort of advanced breast cancer patients. Exemestane in combination with everolimus might be a reasonable option. Prospective studies are warranted to validate these findings.

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References

Frampton G, Fichtenholtz A, Otto G, Wang K, Downing S, He J . Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013; 31(11):1023-31. PMC: 5710001. DOI: 10.1038/nbt.2696. View

Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko I, Khasanov R . Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst. 2013; 106(1):djt337. PMC: 3906991. DOI: 10.1093/jnci/djt337. View

Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M . Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008; 26(10):1664-70. DOI: 10.1200/JCO.2007.13.5822. View

Toy W, Shen Y, Won H, Green B, Sakr R, Will M . ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013; 45(12):1439-45. PMC: 3903423. DOI: 10.1038/ng.2822. View

Roodi N, BAILEY L, Kao W, Verrier C, Yee C, Dupont W . Estrogen receptor gene analysis in estrogen receptor-positive and receptor-negative primary breast cancer. J Natl Cancer Inst. 1995; 87(6):446-51. DOI: 10.1093/jnci/87.6.446. View

Giatromanolaki A, Koukourakis M, Simopoulos C, Polychronidis A, Gatter K, Harris A . c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent. Clin Cancer Res. 2004; 10(23):7972-7. DOI: 10.1158/1078-0432.CCR-04-1068. View

Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo A . Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014; 20(7):1757-1767. PMC: 3998833. DOI: 10.1158/1078-0432.CCR-13-2332. View

Zhang Q, Borg A, Wolf D, Oesterreich S, Fuqua S . An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 1997; 57(7):1244-9. View

Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A . Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003; 21(11):2101-9. DOI: 10.1200/JCO.2003.04.194. View

10.

Baselga J, Campone M, Piccart M, Burris 3rd H, Rugo H, Sahmoud T . Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2011; 366(6):520-9. PMC: 5705195. DOI: 10.1056/NEJMoa1109653. View

11.

Jordan V, Curpan R, Maximov P . Estrogen receptor mutations found in breast cancer metastases integrated with the molecular pharmacology of selective ER modulators. J Natl Cancer Inst. 2015; 107(6):djv075. PMC: 6390275. DOI: 10.1093/jnci/djv075. View

12.

Arpino G, De Angelis C, Giuliano M, Giordano A, Falato C, De Laurentiis M . Molecular mechanism and clinical implications of endocrine therapy resistance in breast cancer. Oncology. 2010; 77 Suppl 1:23-37. DOI: 10.1159/000258493. View

13.

Robinson D, Wu Y, Vats P, Su F, Lonigro R, Cao X . Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013; 45(12):1446-51. PMC: 4009946. DOI: 10.1038/ng.2823. View

14.

. Comprehensive molecular portraits of human breast tumours. Nature. 2012; 490(7418):61-70. PMC: 3465532. DOI: 10.1038/nature11412. View

15.

Finn R, Crown J, Lang I, Boer K, Bondarenko I, Kulyk S . The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2014; 16(1):25-35. DOI: 10.1016/S1470-2045(14)71159-3. View

16.

Siegel R, Miller K, Jemal A . Cancer statistics, 2015. CA Cancer J Clin. 2015; 65(1):5-29. DOI: 10.3322/caac.21254. View

17.

Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko I, Khasanov R . Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010; 28(30):4594-600. DOI: 10.1200/JCO.2010.28.8415. View

18.

Yardley D, Ismail-Khan R, Melichar B, Lichinitser M, Munster P, Klein P . Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal.... J Clin Oncol. 2013; 31(17):2128-35. PMC: 4881332. DOI: 10.1200/JCO.2012.43.7251. View

19.

Nabholtz J, Buzdar A, Pollak M, Harwin W, Burton G, MANGALIK A . Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000; 18(22):3758-67. DOI: 10.1200/JCO.2000.18.22.3758. View

20.

Hortobagyi G . Everolimus plus exemestane for the treatment of advanced breast cancer: a review of subanalyses from BOLERO-2. Neoplasia. 2015; 17(3):279-88. PMC: 4372651. DOI: 10.1016/j.neo.2015.01.005. View