PMID- 30867034
OWN - NLM
STAT- MEDLINE
DCOM- 20190722
LR  - 20200225
IS  - 1465-542X (Electronic)
IS  - 1465-5411 (Print)
IS  - 1465-5411 (Linking)
VI  - 21
IP  - 1
DP  - 2019 Mar 11
TI  - PIK3CA alterations and benefit with neratinib: analysis from the randomized, 
      double-blind, placebo-controlled, phase III ExteNET trial.
PG  - 39
LID - 10.1186/s13058-019-1115-2 [doi]
LID - 39
AB  - 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.
FAU - Chia, Stephen K L
AU  - Chia SKL
AUID- ORCID: 0000-0001-7070-4386
AD  - British Columbia Cancer Agency, University of British Columbia, 600 West 10th 
      Avenue, Vancouver, British Columbia, V5Z4E6, Canada. schia@bccancer.bc.ca.
FAU - Martin, Miguel
AU  - Martin M
AD  - Instituto de Investigacion Sanitaria Gregorio Maranon, Universidad Complutense de 
      Madrid, Madrid, Spain.
FAU - Holmes, Frankie A
AU  - Holmes FA
AD  - Texas Oncology, P.A, Houston, TX, USA.
FAU - Ejlertsen, Bent
AU  - Ejlertsen B
AD  - Rigshospitalet, Copenhagen, Denmark.
FAU - Delaloge, Suzette
AU  - Delaloge S
AD  - Institut Gustave Roussy, Villejuif, France.
FAU - Moy, Beverly
AU  - Moy B
AD  - Massachusetts General Hospital Cancer Center, Boston, MA, USA.
FAU - Iwata, Hiroji
AU  - Iwata H
AD  - Aichi Cancer Center, Chikusa-ku, Nagoya, Japan.
FAU - von Minckwitz, Gunter
AU  - von Minckwitz G
AD  - Luisenkrankenhaus, German Breast Group Forschungs GmbH, Dusseldorf, Neu-isenburg, 
      Germany.
FAU - Mansi, Janine
AU  - Mansi J
AD  - Biomedical Research Centre, Guy's Hospital, King's College London, London, UK.
FAU - Barrios, Carlos H
AU  - Barrios CH
AD  - Pontifical Catholic University of Rio Grande do Sul School of Medicine, Porto 
      Alegre, Brazil.
FAU - Gnant, Michael
AU  - Gnant M
AD  - Department of Surgery and Comprehensive Cancer Centre, Medical University of 
      Vienna, Vienna, Austria.
FAU - Tomasevic, Zorica
AU  - Tomasevic Z
AD  - Daily Chemotherapy Hospital, Institute for Oncology and Radiology of Serbia, 
      Belgrade, Serbia.
FAU - Denduluri, Neelima
AU  - Denduluri N
AD  - Virginia Cancer Specialists, Arlington, VA, USA.
FAU - Separovic, Robert
AU  - Separovic R
AD  - University Hospital for Tumors, Sestre Milosrdnice University Hospital Center, 
      Zagreb, Croatia.
FAU - Kim, Sung-Bae
AU  - Kim SB
AD  - Asan Medical Center, University of Ulsan, Seoul, Korea.
FAU - Jakobsen, Erik Hugger
AU  - Jakobsen EH
AD  - Lillebaelt Hospital, Vejle, Denmark.
FAU - Harvey, Vernon
AU  - Harvey V
AD  - Auckland City Hospital, Grafton, Auckland, New Zealand.
FAU - Robert, Nicholas
AU  - Robert N
AD  - McKesson Specialty Health and The US Oncology Network, The Woodlands, TX, USA.
FAU - Smith, John 2nd
AU  - Smith J 2nd
AD  - Compass Oncology, Portland, OR, USA.
FAU - Harker, Graydon
AU  - Harker G
AD  - Utah Cancer Specialists, Salt Lake City, UT, USA.
FAU - Zhang, Bo
AU  - Zhang B
AD  - Puma Biotechnology, Inc., Los Angeles, CA, USA.
FAU - Eli, Lisa D
AU  - Eli LD
AD  - Puma Biotechnology, Inc., Los Angeles, CA, USA.
FAU - Ye, Yining
AU  - Ye Y
AD  - Puma Biotechnology, Inc., Los Angeles, CA, USA.
FAU - Lalani, Alshad S
AU  - Lalani AS
AD  - Puma Biotechnology, Inc., Los Angeles, CA, USA.
FAU - Buyse, Marc
AU  - Buyse M
AD  - International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium.
FAU - Chan, Arlene
AU  - Chan A
AD  - Breast Cancer Research Centre-WA, Perth & Curtin University, Nedlands, Australia.
LA  - eng
SI  - ClinicalTrials.gov/NCT00878709
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20190311
PL  - England
TA  - Breast Cancer Res
JT  - Breast cancer research : BCR
JID - 100927353
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Quinolines)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - JJH94R3PWB (neratinib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/pharmacology/*therapeutic use
MH  - Biomarkers, Tumor/*genetics
MH  - Breast/pathology
MH  - Breast Neoplasms/genetics/mortality/*therapy
MH  - Chemotherapy, Adjuvant/methods
MH  - Class I Phosphatidylinositol 3-Kinases/*genetics
MH  - Disease-Free Survival
MH  - Double-Blind Method
MH  - Female
MH  - Follow-Up Studies
MH  - Humans
MH  - Middle Aged
MH  - Mutation
MH  - Patient Selection
MH  - Prognosis
MH  - Quinolines/pharmacology/*therapeutic use
MH  - Receptor, ErbB-2/antagonists & inhibitors/metabolism
PMC - PMC6417207
OTO - NOTNLM
OT  - Breast cancer
OT  - Drug targets
OT  - Neratinib
OT  - PIK3CA
OT  - Predictive
OT  - Prognostic
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The study protocol was approved by 
      the institutional ethics committee at participating sites; the study was 
      conducted in accordance with the 2008 Declaration of Helsinki. All patients 
      (intention-to-treat [ITT] population) provided written informed consent; patients 
      in the correlative cohort signed an optional consent form relating to primary 
      tumor collection for exploratory biomarker analyses. CONSENT FOR PUBLICATION: Not 
      applicable COMPETING INTERESTS: SKLC received honoraria from Novartis, 
      Hoffmann-La Roche, Pfizer, and AstraZeneca. MM received grants and personal fees 
      from Roche/Genentech, Novartis, Amgen, AstraZeneca, Pfizer, Pharmamar, and Lilly. 
      BE received research funding from NanoString, Novartis, and Roche, and travel, 
      accommodations, or expenses from AstraZeneca. SD received honoraria from Puma, 
      Pfizer, AstraZeneca, Roche, and Lilly; consulting or advisory role from Puma, 
      Pfizer, AstraZeneca, Roche, and Lilly; research funding from Puma, Pfizer, 
      AstraZeneca, Roche, and Lilly; and travel and accommodations expenses from 
      Pfizer, Roche, and AstraZeneca. BM acted in a consulting or advisory role 
      (immediate family member) for Motus GI. HI received honoraria from Chugai, 
      AstraZeneca, and Eisai, and consulting or advisory role for Chugai, Pfizer, 
      Daiichi-Sankyo, AstraZeneca, and Lilly. GvM received research funding from 
      Pfizer, Amgen, Roche, Teva, Novartis, AstraZeneca, Celgene, Myriad, AbbVie, and 
      Vifor. JM received research funding from Roche, Macrogenics, and Puma 
      Biotechnology Inc. CHB received grants and personal fees from GlaxoSmithKline, 
      Roche, and Novartis outside the submitted work. MG received research funding from 
      Sanofi-Aventis, Pfizer, Smith Medical, Novartis, Roche, GlaxoSmithKline, and 
      personal fees from Novartis, Roche, GlaxoSmithKline, AstraZeneca, Nanostring 
      Technologies, and Accelsiors. ND received research funding from Amgen and 
      Genentech. SBK received research funding from Novartis, Sanofi-Aventis, 
      Kyowa-Kirin Inc., and Dongkook Pharma Co. Ltd. NR acted in a consulting or 
      advisory role for New Century Health and Bristol-Myers Squibb and received 
      research funding from Side-Out Foundation. JS II acted in a consulting or 
      advisory role for BMS and Novartis. BZ, LDE, and ASL are employed by Puma 
      Biotechnology, Inc. MB is employed by the International Drug Development 
      Institute (IDDI) and holds stock of IDDI. YY was employed by Puma Biotechnology 
      at the time of the research but is now employed by QED Therapeutics Inc. FAH, ZT, 
      RS, EHJ, VH, GH, and AC declare that they have no competing interests. 
      PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional 
      claims in published maps and institutional affiliations.
EDAT- 2019/03/15 06:00
MHDA- 2019/07/23 06:00
PMCR- 2019/03/11
CRDT- 2019/03/15 06:00
PHST- 2018/09/19 00:00 [received]
PHST- 2019/02/04 00:00 [accepted]
PHST- 2019/03/15 06:00 [entrez]
PHST- 2019/03/15 06:00 [pubmed]
PHST- 2019/07/23 06:00 [medline]
PHST- 2019/03/11 00:00 [pmc-release]
AID - 10.1186/s13058-019-1115-2 [pii]
AID - 1115 [pii]
AID - 10.1186/s13058-019-1115-2 [doi]
PST - epublish
SO  - Breast Cancer Res. 2019 Mar 11;21(1):39. doi: 10.1186/s13058-019-1115-2.