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

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 by HercepTest immunohistochemistry (IHC), epidermal growth factor receptor (EGFR) mRNA level by RT-PCR, and EGFR protein by IHC were analyzed and compared with clinical outcome. HER-2 was determined by FISH in an academic reference/research laboratory and 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 immunostaining (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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 23 Pg. 7861-70 (Dec 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 19047115 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Quinazolines
• RNA, Messenger
• Lapatinib
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (genetics)
• Breast Neoplasms (drug therapy, genetics, mortality)
• Clinical Trials, Phase III as Topic
• Disease-Free Survival
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (biosynthesis, genetics)
• Female
• Gene Amplification
• Genes, erbB-2
• Humans
• Immunohistochemistry
• In Situ Hybridization, Fluorescence (standards)
• Kaplan-Meier Estimate
• Laboratories, Hospital (standards)
• Lapatinib
• Medical Laboratory Personnel
• Pathology, Clinical (standards)
• Physicians
• Quinazolines (therapeutic use)
• RNA, Messenger (analysis)
• Receptor, ErbB-2 (biosynthesis, genetics)
• Reproducibility of Results
• Reverse Transcriptase Polymerase Chain Reaction