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.

Fig 1.

Patient enrollment and movement through the study. SAE, serious adverse event.

Fig 2.

Hormone receptor status and response to lapatinib in human epidermal growth factor receptor 2 (HER2) –amplified breast cancer. (A) Lapatinib in patients with HER2 amplification. (B) Lapatinib in the subset that was either estrogen receptor positive or progesterone receptor positive. (C) Lapatinib in the HER2-amplified, hormone receptor–negative population. P, paclitaxel; MBC, metastatic breast cancer; 1stQ, first quartile; 3rdQ, third quartile; HR, hazard ratio.

Fig 3.

Estrogen receptor (ER) and progesterone receptor (PR) expression in patients with hormone receptor–positive, non–human epidermal growth factor receptor 2–amplified cancer. (A) Distribution of ER and PR in patients with hormone receptor–positive disease (ER or PR H-score > 0). ER: median, 110; mode, 180. PR: median, 90; mode, 0 (n = 246). (B) No relationship between ER and PR expression in this cohort.

Fig 4.

Hormone receptor status and response to lapatinib in women with human epidermal growth factor receptor 2 (HER2) –nonamplified cancer. Subgroup analysis of estrogen receptor–positive patients as a function of progesterone receptor (PR) status reveals a variable response based on PR expression. (A) PR strong, H-score more than 50, (B) PR weak, H-score 1 to 50, and (C) PR negative, H-score = 0. P, paclitaxel; MBC, metastatic breast cancer; 1stQ, first quartile; 3rdQ, third quartile; HR, hazard ratio.

Fig 5.

Lapatinib adds no benefit on estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2–negative breast cancer (“triple-negative”), n = 131. Abbreviations: P, paclitaxel; MBC, metastatic breast cancer; 1stQ, first quartile; 3rdQ, third quartile; HR, hazard ratio.

Fig 6.

Epidermal growth factor receptor (EGFR) expression does not affect response to lapatinib in a non–human epidermal growth factor receptor 2–amplified cohort. (A) EGFR = 0; (B) EGFR = 1, 2, or 3+. In patients with triple-negative breast cancer, EGFR expression does not predict for benefit in either the (C) paclitaxel (P) + lapatinib group or (D) P + placebo group. MBC, metastatic breast cancer; 1stQ, first quartile; 3rdQ, third quartile; HR, hazard ratio.