Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib

Lisa A. Carey, Donald A. Berry, Constance T. Cirrincione, William T. Barry, Brandelyn N. Pitcher, Lyndsay N. Harris, David W. Ollila, Ian E. Krop, Norah Lynn Henry, Douglas J. Weckstein, Carey K. Anders, Baljit Singh, Katherine A. Hoadley, Michael Iglesia, Maggie Chon U. Cheang, Charles M. Perou, Eric P. Winer, Clifford A. Hudis

Research output: Contribution to journalArticle

  • 95 Citations

Abstract

Purpose Dual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (PCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features. Patients and Methods Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was PCR in the breast; correlative end points focused on molecular features identified by gene expression-based assays. Results Among 305 randomly assigned patients (THL, n 5 118; TH, n 5 120; TL, n 5 67), the PCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P 5 .13), with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in PCR with dual therapy in those with hormone receptor-negative disease (P 5 .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). PCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P , .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with PCR. Post-treatment residual disease was largely luminal A (69%). Conclusion PCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected PCR rates. These factors should be considered when interpreting and designing trials in HER2-positive disease.

LanguageEnglish (US)
Pages542-549
Number of pages8
JournalJournal of Clinical Oncology
Volume34
Issue number6
DOIs
StatePublished - Feb 20 2016

Fingerprint

Paclitaxel
Tumor Microenvironment
Gene Expression
Arm
Hormones
Therapeutics
Neoplasms
Neoadjuvant Therapy
human ERBB2 protein
Trastuzumab
lapatinib
Genomics
Disease-Free Survival
Breast
Breast Neoplasms
Biopsy
Messenger RNA
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. / Carey, Lisa A.; Berry, Donald A.; Cirrincione, Constance T.; Barry, William T.; Pitcher, Brandelyn N.; Harris, Lyndsay N.; Ollila, David W.; Krop, Ian E.; Henry, Norah Lynn; Weckstein, Douglas J.; Anders, Carey K.; Singh, Baljit; Hoadley, Katherine A.; Iglesia, Michael; Cheang, Maggie Chon U.; Perou, Charles M.; Winer, Eric P.; Hudis, Clifford A.

In: Journal of Clinical Oncology, Vol. 34, No. 6, 20.02.2016, p. 542-549.

Research output: Contribution to journalArticle

Carey, Lisa A. ; Berry, Donald A. ; Cirrincione, Constance T. ; Barry, William T. ; Pitcher, Brandelyn N. ; Harris, Lyndsay N. ; Ollila, David W. ; Krop, Ian E. ; Henry, Norah Lynn ; Weckstein, Douglas J. ; Anders, Carey K. ; Singh, Baljit ; Hoadley, Katherine A. ; Iglesia, Michael ; Cheang, Maggie Chon U. ; Perou, Charles M. ; Winer, Eric P. ; Hudis, Clifford A. / Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 6. pp. 542-549.
@article{1975f99144704758a21a853d032971dc,
title = "Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib",
abstract = "Purpose Dual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (PCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features. Patients and Methods Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was PCR in the breast; correlative end points focused on molecular features identified by gene expression-based assays. Results Among 305 randomly assigned patients (THL, n 5 118; TH, n 5 120; TL, n 5 67), the PCR rate was 56{\%} (95{\%} CI, 47{\%} to 65{\%}) with THL and 46{\%} (95{\%} CI, 37{\%} to 55{\%}) with TH (P 5 .13), with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in PCR with dual therapy in those with hormone receptor-negative disease (P 5 .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). PCR rates significantly differed by intrinsic subtype (HER2 enriched, 70{\%}; luminal A, 34{\%}; luminal B, 36{\%}; P , .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with PCR. Post-treatment residual disease was largely luminal A (69{\%}). Conclusion PCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected PCR rates. These factors should be considered when interpreting and designing trials in HER2-positive disease.",
author = "Carey, {Lisa A.} and Berry, {Donald A.} and Cirrincione, {Constance T.} and Barry, {William T.} and Pitcher, {Brandelyn N.} and Harris, {Lyndsay N.} and Ollila, {David W.} and Krop, {Ian E.} and Henry, {Norah Lynn} and Weckstein, {Douglas J.} and Anders, {Carey K.} and Baljit Singh and Hoadley, {Katherine A.} and Michael Iglesia and Cheang, {Maggie Chon U.} and Perou, {Charles M.} and Winer, {Eric P.} and Hudis, {Clifford A.}",
year = "2016",
month = "2",
day = "20",
doi = "10.1200/JCO.2015.62.1268",
language = "English (US)",
volume = "34",
pages = "542--549",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "6",

}

TY - JOUR

T1 - Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib

AU - Carey, Lisa A.

AU - Berry, Donald A.

AU - Cirrincione, Constance T.

AU - Barry, William T.

AU - Pitcher, Brandelyn N.

AU - Harris, Lyndsay N.

AU - Ollila, David W.

AU - Krop, Ian E.

AU - Henry, Norah Lynn

AU - Weckstein, Douglas J.

AU - Anders, Carey K.

AU - Singh, Baljit

AU - Hoadley, Katherine A.

AU - Iglesia, Michael

AU - Cheang, Maggie Chon U.

AU - Perou, Charles M.

AU - Winer, Eric P.

AU - Hudis, Clifford A.

PY - 2016/2/20

Y1 - 2016/2/20

N2 - Purpose Dual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (PCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features. Patients and Methods Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was PCR in the breast; correlative end points focused on molecular features identified by gene expression-based assays. Results Among 305 randomly assigned patients (THL, n 5 118; TH, n 5 120; TL, n 5 67), the PCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P 5 .13), with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in PCR with dual therapy in those with hormone receptor-negative disease (P 5 .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). PCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P , .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with PCR. Post-treatment residual disease was largely luminal A (69%). Conclusion PCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected PCR rates. These factors should be considered when interpreting and designing trials in HER2-positive disease.

AB - Purpose Dual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (PCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features. Patients and Methods Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was PCR in the breast; correlative end points focused on molecular features identified by gene expression-based assays. Results Among 305 randomly assigned patients (THL, n 5 118; TH, n 5 120; TL, n 5 67), the PCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P 5 .13), with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in PCR with dual therapy in those with hormone receptor-negative disease (P 5 .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). PCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P , .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with PCR. Post-treatment residual disease was largely luminal A (69%). Conclusion PCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected PCR rates. These factors should be considered when interpreting and designing trials in HER2-positive disease.

UR - http://www.scopus.com/inward/record.url?scp=84964308576&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964308576&partnerID=8YFLogxK

U2 - 10.1200/JCO.2015.62.1268

DO - 10.1200/JCO.2015.62.1268

M3 - Article

VL - 34

SP - 542

EP - 549

JO - Journal of Clinical Oncology

T2 - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 6

ER -