Originally published as JCO Early Release 10.1200/JCO.2008.18.1925 on July 20 2009

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Google Scholar Articles by Finn, R. S. Articles by Di Leo, A. PubMed PubMed Citation Articles by Finn, R. S. Articles by Di Leo, A. Social Bookmarking                            What's this?

Estrogen Receptor, Progesterone Receptor, Human Epidermal Growth Factor Receptor 2 (HER2), and Epidermal Growth Factor Receptor Expression and Benefit From Lapatinib in a Randomized Trial of Paclitaxel With Lapatinib or Placebo As First-Line Treatment in HER2-Negative or Unknown Metastatic Breast Cancer

From the Geffen School of Medicine at University of California, Los Angeles; Norris Cancer Center, University of Southern California, Los Angeles, CA; Medicine Development Centre Oncology, GlaxoSmithKline, Middlesex, United Kingdom; and Sandro Pitigliani Medical Oncology Unit, Prato, Italy.

Corresponding author: Richard S. Finn, MD, 10833 Le Conte Ave, 11-934 Factor Bldg, Los Angeles, CA 90095; e-mail: Rfinn{at}mednet.ucla.edu.

Purpose Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) with activity in HER2-amplified metastatic breast cancer (MBC). Its role in non–HER2-amplified MBC remains unclear. EGF30001, a phase III trial of lapatinib and paclitaxel versus paclitaxel and placebo, demonstrated lapatinib does not significantly benefit HER2-negative or HER2-unselected patients with MBC. Published data support interactions between steroid hormone and peptide growth factor signaling. We hypothesized that molecular subgroups may exist within EGF30001 that would benefit from lapatinib.

Methods A blinded, retrospective biomarker evaluation was performed using immunohistochemistry to semiquantitate estrogen (ER), progesterone (PR), and EGFR expression. HER2 amplification was determined by fluorescent in situ hybridization. Effects of these biomarkers on event-free survival (EFS) were examined in patients with available tissue (n = 493).

Results Lapatinib improved median EFS in HER2-amplified, ER- or PR-positive MBC (n = 36; 5.7 v 4.5 months; P = .351); benefit was greater and statistically significant in HER2-amplified, ER-negative, PR-negative MBC (n = 42; 8.3 v 5.0 months; P = .007). In HER2-negative, ER-positive MBC, median EFS improvement varied by degree of PR expression (H-score): no benefit if PR-strong (n = 133; 9.3 v 7.3 months; P = .373), benefit if PR-weak (n = 50; 7.3 v 2.4 months; P = .026), and potential antagonism if PR-negative (n = 40; 3.7 v 7.2 months; P = .004). No benefit was seen in triple-negative MBC (n = 131; median EFS, 4.6 v 4.8 months; P = .255). EGFR expression was not correlated with benefit from lapatinib.

Conclusion Although subgroups are small, these analyses support the hypothesis that semiquantitative determination of hormone receptor status may be a surrogate for EGFR and/or HER2 dependency.

Supported by grants from GlaxoSmithKline, and a National Institutes of Health Loan Repayment Program award (R.S.F.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00075270 [ClinicalTrials.gov] .

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?