Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039).

Abstract

PURPOSE:

Not all breast cancers respond to lapatinib. A change in Ki67 after short-term exposure may elucidate a biomarker profile for responsive versus nonresponsive tumors.

EXPERIMENTAL DESIGN:

Women with primary breast cancer were randomized (3:1) to 10 to 14 days of preoperative lapatinib or placebo in a multicenter phase II trial (ISRCTN68509377). Biopsies pre-/posttreatment were analyzed for Ki67, apoptosis, HER2, EGFR, ER, PgR, pAKT, pERK, and stathmin by IHC. Further markers were measured by RT-PCR. Primary endpoint was change in Ki67. HER2(+) was defined as 2+/3+ by IHC and FISH(+).

RESULTS:

One hundred twenty-one patients (lapatinib, 94; placebo, 27) were randomized; of these, 21% were HER2(+), 78% were HER2(-) nonamplified, 26% were EGFR(+). Paired samples containing tumor were obtained for 98% (118 of 121). Ki67 fell significantly with lapatinib (-31%; P < 0.001), but not with placebo (-3%). Whereas Ki67 reduction with lapatinib was greatest in HER2(+) breast cancer (-46%; P = 0.003), there was a significant Ki67 decrease in HER2(-) breast cancer (-27%; P = 0.017) with 14% of HER2(-) breast cancer demonstrating ≥50% Ki67 reduction with lapatinib. Among HER2(+) patients, the only biomarker predictive of Ki67 response was the EGFR/HER4 ligand epiregulin (EREG) (rho = -0.7; P = 0.002). Among HER2(-) tumors, only HER3 mRNA levels were significantly associated with Ki67 response on multivariate analysis (P = 0.01). In HER2(-) breast cancer, HER2 and HER3 mRNA levels were highly correlated (rho = 0.67, P < 0.001), with all Ki67 responders having elevated HER3 and HER2 expression.

CONCLUSIONS:

Lapatinib has antiproliferative effects in a subgroup of HER2(-) nonamplified tumors characterized by high HER3 expression. The possible role of high HER2:HER3 heterodimers in predicting response to lapatinib merits investigation in HER2(-) tumors.

• Authors: Alexandra Leary, Abigail Evans, Stephen R D Johnston, Roger A'Hern, Judith M Bliss, Rashmita Sahoo, Simone Detre, Benjamin P Haynes, Margaret Hills, Catherine Harper-Wynne, Nigel Bundred, Gill Coombes, Ian Smith, Mitch Dowsett
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 13 Pg. 2932-40 (Jul 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25398453 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Quinazolines
• Lapatinib
• ERBB2 protein, human
• ERBB3 protein, human
• Receptor, ErbB-2
• Receptor, ErbB-3

Topics

• Adult
• Aged
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Carcinoma, Ductal, Breast (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Chemotherapy, Adjuvant
• Double-Blind Method
• Female
• Humans
• Lapatinib
• Middle Aged
• Preoperative Period
• Quinazolines (pharmacology, therapeutic use)
• Receptor, ErbB-2 (metabolism)
• Receptor, ErbB-3 (metabolism)
• Treatment Outcome