PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial

Breast Cancer Research

Hiroji Iwata¹  Sung-Bae Kim²  Vernon Harvey³  Janine Mansi⁴  Arlene Chan⁵  Stephen K. L. Chia⁶  John Smith⁷  Zorica Tomašević⁸  Michael Gnant⁹  Suzette Delaloge^1,10  Miguel Martin^1,11  Marc Buyse^1,12  Erik Hugger Jakobsen^1,13  Gunter von Minckwitz^1,14  Beverly Moy^1,15  Nicholas Robert^1,16  Carlos H. Barrios^1,17  Bo Zhang^1,18  Yining Ye^1,18  Lisa D. Eli^1,18  Alshad S. Lalani^1,18  Bent Ejlertsen^1,19  Frankie A. Holmes^2,20  Robert Šeparović^2,21  Graydon Harker^2,22  Neelima Denduluri^2,23 

[1] Aichi Cancer Center;Asan Medical Center, University of Ulsan;Auckland City Hospital;Biomedical Research Centre, Guy’s Hospital, King’s College London;Breast Cancer Research Centre-WA, Perth & Curtin University;British Columbia Cancer Agency, University of British Columbia;Compass Oncology;Daily Chemotherapy Hospital, Institute for Oncology and Radiology of Serbia;Department of Surgery and Comprehensive Cancer Centre, Medical University of Vienna;Institut Gustave Roussy;Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense de Madrid;International Drug Development Institute (IDDI);Lillebaelt Hospital;Luisenkrankenhaus, German Breast Group Forschungs GmbH;Massachusetts General Hospital Cancer Center;McKesson Specialty Health and The US Oncology Network;Pontifical Catholic University of Rio Grande do Sul School of Medicine;Puma Biotechnology, Inc.;Rigshospitalet;Texas Oncology, P.A;University Hospital for Tumors, Sestre Milosrdnice University Hospital Center;Utah Cancer Specialists;Virginia Cancer Specialists;

关键词: Breast cancer;    Drug targets;    Neratinib;    PIK3CA;    Prognostic;    Predictive;   

DOI  :  10.1186/s13058-019-1115-2

来源: DOAJ

【 摘 要 】

Abstract Background Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. Methods Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. Results Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309). Conclusions Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. Trial registration ClinicalTrials.gov, NCT00878709. Trial registered April 9, 2009.

【 授权许可】

Unknown