Diagnosis of Basal-Like Breast Cancer Using a FOXC1-Based Assay

• Published in: JNCI : Journal of the National Cancer Institute Vol. 107; no. 8; p. 1
• Main Authors: Jensen, Tor W, Ray, Tania, Wang, Jinhua, Li, Xiaodong, Naritoku, Wesley Y, Han, Bingchen, Bellafiore, Frank, Bagaria, Sanjay P, Qu, Annie, Cui, Xiaojiang, Taylor, Clive R, Ray, Partha S
• Format: Journal Article
• Language: English
• Published: United States Oxford Publishing Limited (England) 01.08.2015; Oxford University Press
• Subjects: Adult; Aged; Area Under Curve; Biomarkers; Biomarkers, Tumor - analysis; Brain Neoplasms - chemistry; Brain Neoplasms - diagnosis; Brain Neoplasms - secondary; Breast cancer; Breast Neoplasms - chemistry; Breast Neoplasms - diagnosis; Breast Neoplasms - pathology; Carcinoma, Basal Cell - chemistry; Carcinoma, Basal Cell - diagnosis; Chemotherapy; Female; Forkhead Transcription Factors - analysis; Formaldehyde; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Medical diagnosis; Metastasis; Middle Aged; Paraffin Embedding; Polymerase chain reaction; Predictive Value of Tests; Prognosis; Real-Time Polymerase Chain Reaction; Reproducibility of Results; ROC Curve; Sensitivity and Specificity; Tissue Fixation - methods; Up-Regulation
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djv148

Diagnosis of basal-like breast cancer (BLBC) remains a bottleneck to conducting effective clinical trials for this aggressive subtype. We postulated that elevated expression of Forkhead Box transcription factor C1 (FOXC1) is a simple and accurate diagnostic biomarker for BLBC. Accuracy of FOXC1 expression in identifying BLBC was compared with the PAM50 gene expression panel in gene expression microarray (GEM) (n = 1992) and quantitative real-time polymerase chain reaction (qRT-PCR) (n = 349) datasets. A FOXC1-based immunohistochemical (IHC) assay was developed and assessed in 96 archival formalin-fixed, paraffin-embedded (FFPE) breast cancer samples that also underwent PAM50 profiling. All statistical tests were two-sided. A FOXC1-based two-tier assay (IHC +/- qRT-PCR) accurately identified BLBC (AUC = 0.88) in an independent cohort of FFPE samples, validating the accuracy of FOXC1-defined BLBC in GEM (AUC = 0.90) and qRT-PCR (AUC = 0.88) studies, when compared with platform-specific PAM50-defined BLBC. The hazard ratio (HR) for disease-specific survival in patients having FOXC1-defined BLBC was 1.71 (95% CI = 1.31 to 2.23, P < .001), comparable to PAM50 assay-defined BLBC (HR = 1.74, 95% CI = 1.40 to 2.17, P < .001). FOXC1 expression also predicted the development of brain metastasis. Importantly, unlike triple-negative or Core Basal IHC definitions, a FOXC1-based definition is able to identify BLBC in both ER+ and HER2+ patients. A FOXC1-based two-tier assay, by virtue of being rapid, simple, accurate, and cost-effective may emerge as the diagnostic assay of choice for BLBC. Such a test could substantially improve clinical trial enrichment of BLBC patients and accelerate the identification of effective chemotherapeutic options for this aggressive disease.