Abstract
Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy. 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. 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. 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.
Highlights
Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy
Lapatinib has been approved in combination with capecitabine for the treatment of women with HER-2-positive metastatic breast cancer that has progressed after treatment with an anthracycline, a taxane, and trastuzumab [1]
This study characterizes the association of lapatinib responsiveness with the status of two different biomarkers, HER-2 and epidermal growth factor receptor (EGFR), in two clinical trials of chemotherapy with or without added lapatinib.We show that HER-2 gene amplification/overexpression status, not EGFR status, is associated with lapatinib responsiveness in breast cancer patients
Summary
Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy. 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. Lapatinib has been approved in combination with capecitabine for the treatment of women with HER-2-positive metastatic breast cancer that has progressed after treatment with an anthracycline, a taxane, and trastuzumab [1]. Because lapatinib inhibits both HER-2 and EGFR [2], there are several unanswered questions about which patients with breast cancer are most likely to benefit from this form of targeted therapy and which type of HER-2 determination method is most appropriate. Recent reports suggest that women with HER-2-negative breast cancer who do not meet established criteria for HER-2-positive disease on central review might benefit from adjuvant trastuzumab treatment, raising questions about the criteria used for patient selection with this targeted www.aacrjournals.org
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