HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer

Michael F. Press, Richard S. Finn, David Cameron, Angelo Di Leo, Charles E. Geyer, Ivonne E. Villalobos, Angela Santiago, Roberta Guzman, Armen Gasparyan, Yanling Ma, Kathy Danenberg, Anne Marie Martin, Lisa Williams, Cristina Oliva, Steven Stein, Robert Gagnon, Michael Arbushites, Maria T. Koehler

Research output: Contribution to journalArticlepeer-review

135 Scopus citations

Abstract

Purpose: Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy. Experimental Design: In available breast cancer tissue from EGF30001 (paclitaxel ± lapatinib in HER-2-negative/unknown metastatic breast cancer, n = 579) and EGF100151 (capecitabine ± lapatinib in HER-2-positive metastatic breast cancer, n = 399), HER-2 gene amplification by fluorescence in situ hybridization (FISH), HER-2 mRNA by reverse transcription-PCR (RT-PCR), HER-2 protein expression byHercepTest immunohistochemistry(IHC), epidermal growth factor receptor (EGFR) mRNA level byRT-PCR, and EGFR protein by IHC were analyzed and compared with clinical outcome. HER-2 was determined by FISH in an academic reference/research laboratoryand in a large, high-volume commercial reference laboratory. Results: The HER-2 gene was amplified in 47% (344 of 733) and IHC was 3+ in 35% (279 of 798), with significant correlation (P < 0.01) between FISH and IHC. Positive EGFR immuno-staining (IHC 1 +, 2+, or 3+) in 28% (213 of 761) correlated with EGFR mRNA levels by RT-PCR (r = 0.59; P < 0.01). HER-2 gene amplification/overexpression was associated with improved clinical outcomes (progression-free survival; P < 0.001) in both trials. A significant improvement in outcome was seen in FISH-positive and IHC 0, 1+, or 2+ patients. HER-2 mRNA expression correlated with HER-2 FISH (r = 0.83) and IHC status (r = 0.72; n = 138). No correlation was found between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER-2 status. Although a significant correlation with lapatinib responsiveness was observed among "HER-2-negative" breast cancer patients in the large, high-volume commercial reference laboratory, this was not confirmed in the academic reference/research laboratory. Conclusions: Women with HER-2-positive metastatic breast cancer benefit from lapatinib, whereas women with HER-2-negative metastatic breast cancer derive no incremental benefit from lapatinib.

Original languageEnglish (US)
Pages (from-to)7861-7870
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number23
DOIs
StatePublished - Dec 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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