Biomarker Analyses in CLEOPATRA: A Phase III, Placebo-Controlled Study of Pertuzumab in Human Epidermal Growth Factor Receptor 2–Positive, First-Line Metastatic Breast Cancer

Biomarker Analyses in CLEOPATRA: A Phase III, Placebo-Controlled Study of Pertuzumab in Human Epidermal Growth Factor Receptor 2–Positive, First-Line Metastatic Breast Cancer

1. José Baselga⇑, 
2. Javier Cortés, 
3. Seock-Ah Im, 
4. Emma Clark, 
5. Graham Ross,
6. Astrid Kiermaier and 
7. Sandra M. Swain

+Author Affiliations

1. José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; Javier Cortés, Vall d’Hebron University Hospital, Barcelona, Spain; Seock-Ah Im, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Emma Clark and Graham Ross, Roche Products, Welwyn Garden City, United Kingdom; Astrid Kiermaier, F. Hoffmann-La Roche, Basel, Switzerland; and Sandra M. Swain, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC.

1. Corresponding author: José Baselga, MD, PhD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; e-mail: baselgaj@mskcc.org.

Abstract

Purpose To explore the prognostic and/or predictive value of human epidermal growth factor receptor 2 (HER2) pathway–related biomarkers in the phase III CLEOPATRA study of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel as first-line treatment for patients with HER2-positive metastatic breast cancer.

Patients and Methods Mandatory tumor and serum samples were collected (N = 808; 58% to 99.8% were assessable), and amphiregulin, betacellulin, epidermal growth factor (EGF), transforming growth factor alpha, EGF receptor, HER2, HER3, insulin-like growth factor 1 receptor, PTEN, phosphorylated AKT, PIK3CA, CMYC, serum HER2 extracellular domain (sHER2), and FCγR were assessed using appropriate assays. Two types of correlations were investigated using univariable Cox regression: predictive effects (qualitative association of biomarkers with pertuzumab progression-free survival [PFS] benefit) and prognostic effects independent of treatment arm (relationship of each biomarker to clinical outcome in both arms pooled).

Results Pertuzumab consistently showed a PFS benefit, independent of biomarker subgroups (hazard ratio < 1.0), including estrogen receptor–negative and –positive subgroups. High HER2 protein, high HER2 and HER3 mRNA levels, wild-typePIK3CA, and low sHER2 showed a significantly better prognosis (P < .05). PIK3CAshowed the greatest prognostic effect, with longer median PFS for patients whose tumors expressed wild-type versus mutated PIK3CA in both the control (13.8 v 8.6 months) and pertuzumab groups (21.8 v 12.5 months).

Conclusion Through comprehensive prospective analyses, CLEOPATRA biomarker data demonstrate that HER2 is the only marker suited for patient selection for the trastuzumab plus pertuzumab–based regimen in HER2-positive metastatic breast cancer. HER2, HER3, and PIK3CA were relevant prognostic factors.