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Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study

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Abstract

NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) is the first study to compare biological and clinical activity of fulvestrant 500 versus 250 mg in the neoadjuvant breast cancer setting. We hypothesized that fulvestrant 500 mg may be superior to 250 mg in blocking estrogen receptor (ER) signaling and growth. A multicenter, randomized, open-label, Phase II study was performed to compare fulvestrant 500 mg (500 mg/month plus 500 mg on day 14 of month 1) versus fulvestrant 250 mg/month for 16 weeks prior to surgery in postmenopausal women with ER+ locally advanced breast cancer. Core biopsies at baseline, week 4, and surgery were assessed for biomarker changes. Primary endpoint: change in Ki67 labeling index (LI) from baseline to week 4 determined by automated computer imaging system (ACIS). Secondary endpoints: ER protein expression and function; progesterone receptor (PgR) expression; tumor response; tolerability. ER and PgR were examined retrospectively using the H score method. A total of 211 patients were randomized (fulvestrant 500 mg: n = 109; 250 mg: n = 102). At week 4, fulvestrant 500 mg resulted in greater reduction of Ki67 LI and ER expression versus 250 mg (−78.8 vs. −47.4% [p < 0.0001] and −25.0 vs. −13.5% [p = 0.0002], respectively [ACIS]); PgR suppression was not significantly different (−22.7 vs. −17.6; p = 0.5677). However, H score detected even greater suppression of ER (−50.3 vs. −13.7%; p < 0.0001) and greater PgR suppression (−80.5 vs. −46.3%; p = 0.0018) for fulvestrant 500 versus 250 mg. At week 16, tumor response rates were 22.9 and 20.6% for fulvestrant 500 and 250 mg, respectively, with considerable decline in all markers by both ACIS and H score. No detrimental effects on endometrial thickness or bone markers and no new safety concerns were identified. This provides the first evidence of greater biological activity for fulvestrant 500 versus 250 mg in depleting ER expression, function, and growth.

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Acknowledgment

The authors gratefully acknowledge the collaboration of the Munich Study Centre, Munich, Germany, and would like to thank Sandra Cuscó, PhD, from Complete Medical Communications, who provided medical writing support funded by AstraZeneca. Final approval of the manuscript lay solely with the authors. The NEWEST study was funded by AstraZeneca.

Conflict of interests

Irene Kuter, Jose Bines and Nadia Harbeck have acted as consultants to or in advisory roles to AstraZeneca. Julia Gee and Robert Nicholson have received research funding from AstraZeneca. Elizabeth Lowe and Ugochi Emeribe are employees of AstraZeneca and hold stock ownership with AstraZeneca. Elizabeth Anderson and Francisco Sapunar are former employees of AstraZeneca. Elizabeth Anderson holds stock ownership with AstraZeneca. Roberto Hegg, Christian Singer and Rajendra Badwe have no conflicts of interest to disclose.

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Author notes

  1. Nadia Harbeck

    Present address: Breast Centre, Department of Obstetrics and Gynaecology, University of Cologne, Cologne, Germany

Authors and Affiliations

  1. Massachusetts General Hospital, Professional Office Building 228, 55 Fruit Street, Boston, MA, 02114, USA

    Irene Kuter

  2. Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, Wales, UK

    Julia M. W. Gee, Pauline Finlay & Robert I. Nicholson

  3. School of Medicine, University of Sao Paulo and Hospital Pérola Byington, Sao Paulo, Brazil

    Roberto Hegg

  4. Division of Special Gynaecology, Medical University of Vienna, Vienna, Austria

    Christian F. Singer

  5. Tata Memorial Hospital, Mumbai, India

    Rajendra A. Badwe

  6. AstraZeneca, Wilmington, DE, USA

    Elizabeth S. Lowe & Ugochi A. Emeribe

  7. Formerly AstraZeneca Pharmaceuticals, Macclesfield, UK

    Elizabeth Anderson & Francisco Sapunar

  8. Instituto de Câncer, Rio de Janeiro, Brazil

    José Bines

  9. Frauenklinik der Technischen Universität München, Munich, Germany

    Nadia Harbeck

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  1. Irene Kuter
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Corresponding author

Correspondence to Irene Kuter.

Additional information

On behalf of the NEWEST Investigators.

The details of the investigators participating in the study are given in Appendix.

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Appendix

Appendix

Austria: Guenther Steger (AKH Wien, Wien); Ernst Kubista (AKH Wien, Wien); Roland Reitsamer (Abteilung spezielle Gynäkologie und Brustambulanz, Salzburg); Susanne Taucher (Univ. Klinik für Frauenheilkunde, Innsbruck). Brazil: Miriam H. H. Federico (INRAD-HCFMUSP Centro de Oncologia, São Paulo); Arthur Malzyner (Clinicia Oncologia Medica, São Paolo); Isabel Aparecida D. Capuchinho/Tatiane C. Motta (Fundação Pio XII, São Paolo); Antônio Matsuda (CEPON - Centro de Estudo Rodovia Admar Gonzaga Km, Florianópolis); Roberto Hegg (Hospital Pérola Byington, São Paulo); José Bines (Instituto do Câncer (INCA) HCIII, Rio de Janeiro); Agliberto Barbosa (ICVAC - Instituto do Câncer Arnaldo Vieira de Carvalho, São Paolo); Sérgio Lago (Centro Clínico Hospital São Lucas, Porto Alegre); Célia Tosello de Oliveira (IBCC - Coordenadoria de Pesquisa, São Paolo); Alessandra Morelle (Hospital Femina, Porto Alegre); Auro del Giglio (Centro de Estudos da Disciplina de Hematologia e Oncologia da FMABC, Santo André); Ruffo de Frietas (Programa de Mastologia do Hospital das Clínicas da Universidade Federal de Goiânia, Goiânia). Germany: Nadia Harbeck (Klinikum rechts der Isar der Technischen Universitätfrauenklinik und Poliklinik, München); Toralf Reimer (Universitätsklinikum RostockFrauenlinik, Rostock); Serban-Dan Costa (Otto-von-Guericke Universität, Magdeburg); Iris Schrader (Henriettenstiftung Frauenklinik, Hanover); Jens-Uwe Blohmer (Sankt-Gertrauden-Krakenhaus Frauenheilkunde und Gerburtshilfe, Berlin). United Kingdom: Mike Dixon (Western General Hospital, Edinburgh); Alastair Thompson (Ninewells Hospital and Medical School, Dundee); Daniel Rea (University Hospital Birmingham, Birmingham). India: Jem Prabhakar (Regional Cancer Centre, Trivandrum); Rajan Badwe (Tata Memorial Hospital, Mumbai); Dinesh Doval (Rajiv Gandhi Cancer Institute & Research Centre, New Delhi); Kamlesh Bokil (Ruby Hall Clinic, Maharashtra); Simhadri Chandra Sekhar Rao (Apollo Hospital, Hyderabad); Shekhar Patil (Bangalore Institute of Oncology, Bangalore). United States: Pat Whitworth (Nashville Breast Center, Nashville, TN); Issam Makhoul (University of Arkansas for Medical Sciences [UAMS], Little Rock, AR); Irene Kuter (Massachusetts General Hospital, Boston, MA); Paula Silverman (University Hospitals of Cleveland, Cleveland, OH); Melanie Royce (University of New Mexico HSC Cancer Research and Treatment Center, Albuquerque, NM); Gary Unzeitig (Doctors Hospital, Laredo, TX).

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Kuter, I., Gee, J.M.W., Hegg, R. et al. Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study. Breast Cancer Res Treat 133, 237–246 (2012). https://doi.org/10.1007/s10549-011-1947-7

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