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.

Abstract

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.

• Authors: Richard S Finn, Michael F Press, Judy Dering, Michael Arbushites, Maria Koehler, Cristina Oliva, Lisa S Williams, Angelo Di Leo
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 24 Pg. 3908-15 (Aug 20 2009) ISSN: 1527-7755 [Electronic] United States
• PMID: 19620495 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Quinazolines
• Receptors, Estrogen
• Receptors, Progesterone
• Lapatinib
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Paclitaxel

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Breast Neoplasms (chemistry, drug therapy, genetics)
• ErbB Receptors (analysis)
• Female
• Gene Amplification
• Humans
• Immunohistochemistry
• In Situ Hybridization, Fluorescence
• Lapatinib
• Paclitaxel (administration & dosage)
• Quinazolines (administration & dosage)
• Receptor, ErbB-2 (genetics)
• Receptors, Estrogen (analysis)
• Receptors, Progesterone (analysis)