PMID- 30903140
OWN - NLM
STAT- MEDLINE
DCOM- 20200806
LR  - 20231012
IS  - 1569-8041 (Electronic)
IS  - 0923-7534 (Print)
IS  - 0923-7534 (Linking)
VI  - 30
IP  - 6
DP  - 2019 Jun 1
TI  - A combinatorial biomarker predicts pathologic complete response to neoadjuvant 
      lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast 
      cancer.
PG  - 927-933
LID - S0923-7534(19)31194-9 [pii]
LID - 10.1093/annonc/mdz076 [doi]
AB  - BACKGROUND: HER2-positive (+) breast cancers, defined by HER2 overexpression 
      and/or amplification, are often addicted to HER2 to maintain their malignant 
      phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We 
      hypothesize that HER2 amplification levels and PI3K pathway activation are key 
      determinants of response to HER2-targeted treatments without chemotherapy. 
      PATIENTS AND METHODS: Baseline HER2+ tumors from patients treated with 
      neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen 
      receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central 
      laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) 
      (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined 
      by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 
      tumors. Results were correlated with pathologic complete response (pCR; no 
      residual invasive tumor in breast). RESULTS: Thirteen of the 56 patients (23%) 
      achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved 
      pCR, whereas 13/45 patients (29%) with HER2 ratio >/=4 and/or CN >/=10 attained pCR 
      (P = 0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type 
      (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) 
      with PI3K pathway alterations (P = 0.0133). Seven of the 16 patients (44%) with 
      HER2 ratio >/=4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) 
      patients not meeting these criteria achieved pCR (P = 0.0031). CONCLUSIONS: Our 
      findings suggest that there is a clinical subtype in breast cancer with high HER2 
      amplification and intact PI3K pathway that is especially sensitive to 
      HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio 
      and PI3K pathway status warrants validation to identify patients who may be 
      treated with HER2-targeted therapy without chemotherapy.
CI  - (c) The Author(s) 2019. Published by Oxford University Press on behalf of the 
      European Society for Medical Oncology. All rights reserved. For permissions, 
      please email: journals.permissions@oup.com.
FAU - Veeraraghavan, J
AU  - Veeraraghavan J
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center.
FAU - De Angelis, C
AU  - De Angelis C
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center.
FAU - Mao, R
AU  - Mao R
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center.
FAU - Wang, T
AU  - Wang T
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center; 
      Departments of Medicine.
FAU - Herrera, S
AU  - Herrera S
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center; 
      Pathology, Baylor College of Medicine, Houston, USA.
FAU - Pavlick, A C
AU  - Pavlick AC
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center.
FAU - Contreras, A
AU  - Contreras A
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center; 
      Pathology, Baylor College of Medicine, Houston, USA.
FAU - Nuciforo, P
AU  - Nuciforo P
AD  - Translational Genomics and Targeted Therapeutics in Solid Tumors, IDIBAPS, 
      Hospital Clinic de Barcelona, Barcelona, Spain.
FAU - Mayer, I A
AU  - Mayer IA
AD  - Medicine, Hematology/Oncology, Vanderbilt University, Nashville.
FAU - Forero, A
AU  - Forero A
AD  - Medicine, University of Alabama at Birmingham, Birmingham.
FAU - Nanda, R
AU  - Nanda R
AD  - Medicine, University of Chicago, Chicago.
FAU - Goetz, M P
AU  - Goetz MP
AD  - Department of Oncology, Mayo Clinic, Rochester.
FAU - Chang, J C
AU  - Chang JC
AD  - Houston Methodist Cancer Center, Houston Methodist Hospital, Houston.
FAU - Wolff, A C
AU  - Wolff AC
AD  - Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.
FAU - Krop, I E
AU  - Krop IE
AD  - Department of Medicine, Dana-Farber Cancer Institute, Boston.
FAU - Fuqua, S A W
AU  - Fuqua SAW
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center.
FAU - Prat, A
AU  - Prat A
AD  - Translational Genomics and Targeted Therapeutics in Solid Tumors, IDIBAPS, 
      Hospital Clinic de Barcelona, Barcelona, Spain.
FAU - Hilsenbeck, S G
AU  - Hilsenbeck SG
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center; 
      Departments of Medicine.
FAU - Weigelt, B
AU  - Weigelt B
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York.
FAU - Reis-Filho, J S
AU  - Reis-Filho JS
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York.
FAU - Gutierrez, C
AU  - Gutierrez C
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center; 
      Pathology, Baylor College of Medicine, Houston, USA.
FAU - Osborne, C K
AU  - Osborne CK
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center; 
      Departments of Medicine; Department of Molecular and Cellular Biology, Baylor 
      College of Medicine, Houston, USA.
FAU - Rimawi, M F
AU  - Rimawi MF
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center; 
      Departments of Medicine.
FAU - Schiff, R
AU  - Schiff R
AD  - Lester and Sue Smith Breast Center; Dan L. Duncan Comprehensive Cancer Center; 
      Departments of Medicine; Department of Molecular and Cellular Biology, Baylor 
      College of Medicine, Houston, USA. Electronic address: rschiff@bcm.edu.
LA  - eng
SI  - ClinicalTrials.gov/NCT00548184
GR  - R01 CA207270/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - P30 CA125123/CA/NCI NIH HHS/United States
GR  - P50 CA058183/CA/NCI NIH HHS/United States
GR  - R01 CA072038/CA/NCI NIH HHS/United States
GR  - P50 CA186784/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Ann Oncol
JT  - Annals of oncology : official journal of the European Society for Medical 
      Oncology
JID - 9007735
RN  - 0 (Biomarkers, Tumor)
RN  - 0VUA21238F (Lapatinib)
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  - P188ANX8CK (Trastuzumab)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Biomarkers, Tumor/genetics/metabolism
MH  - Breast Neoplasms/*drug therapy/genetics/metabolism/*pathology
MH  - Class I Phosphatidylinositol 3-Kinases/genetics/metabolism
MH  - Female
MH  - Follow-Up Studies
MH  - Gene Amplification
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Lapatinib/administration & dosage
MH  - Neoadjuvant Therapy
MH  - Phosphatidylinositol 3-Kinases/genetics/metabolism
MH  - Prognosis
MH  - Receptor, ErbB-2/antagonists & inhibitors/genetics/*metabolism
MH  - Remission Induction
MH  - Trastuzumab/administration & dosage
PMC - PMC6594453
OTO - NOTNLM
OT  - PIK3CA mutations
OT  - ErbB2 receptor tyrosine kinase
OT  - PTEN protein
OT  - breast cancer
OT  - fluorescent in situ hybridization
OT  - precision medicine
EDAT- 2019/03/25 06:00
MHDA- 2020/08/07 06:00
PMCR- 2020/06/01
CRDT- 2019/03/24 06:00
PHST- 2019/03/25 06:00 [pubmed]
PHST- 2020/08/07 06:00 [medline]
PHST- 2019/03/24 06:00 [entrez]
PHST- 2020/06/01 00:00 [pmc-release]
AID - S0923-7534(19)31194-9 [pii]
AID - mdz076 [pii]
AID - 10.1093/annonc/mdz076 [doi]
PST - ppublish
SO  - Ann Oncol. 2019 Jun 1;30(6):927-933. doi: 10.1093/annonc/mdz076.