PD03-10: Gene Modules and Response to Neoadjuvant Chemotherapy in Breast Cancer: A Meta-Analysis.
Authors: Ignatiadis M , Singhal SK , Desmedt C , Haibe-Kains B , Criscitiello C , Loi S , Andre F , Piccart M , Michiels S , Sotiriou C 
Published: June 2012

Abstract
Background: We and others have shown that high expression of proliferation and immune related genes are associated with pathological complete response (pCR) after neoadjuvant chemotherapy in breast cancer (BC). Here, we performed a meta-analysis to validate these findings and to interrogate the association between pCR and several other gene expression modules beyond standard clinico-pathological characteristics in BC subtypes.
Methods: We searched for publicly available gene expression studies evaluating anthracycline ± taxane-based neoadjuvant chemotherapy. We identified 7 studies with complete genomic and clinico-pathological data including pCR totaling 788 patients. Relapse-free survival (RFS) data were available for 427 patients. We used gene expression data generated from pretreatment biopsies and computed 17 gene modules corresponding to proliferation-driven signatures, immune response, stroma activation, phosphatase and tensin homolog (PTEN) loss, chromosomal instability, and several other oncogenic pathways. We calculated odds ratios (OR) for pCR for one-unit increases in scaled modules, all adjusting for pretreatment clinico-pathological characteristics. Moreover, we tested for interactions between gene modules and ER or HER2 status for their association with pCR after adjusting for clinicopathological characteristics. We used the false discovery rate (FDR) to adjust for multiple testing.
Results: We observed pCR in 178(22.6%) of 788 patients: 112(30.1%) of 372 with ER−/HER2− BC, 41(36%) of 113 with HER2+ BC, and 25(8.2%) of 303 with ER+/HER2− BC. High values of the proliferation-driven modules were associated with increased pCR rates in ER−/HER2− (e.g. Gene70 OR=2.34, 95%CI 1.22−4.59, p=0.01, FDR=0.10) and ER+/HER2− (e.g. Gene70 OR=3.26, CI 1.13−9.60, p=0.03, FDR=0.16), but not in the HER2+ subtype (e.g. Gene70 OR=0.82, CI 0.23−2.67, p=0.74, FDR=0.86). There was a trend for interaction between proliferation-driven modules (e.g. Gene70) and HER2 status (p=0.08, FDR=0.23). Interestingly, we demonstrated a strong association between high values of immune module and increased pCR rates in the HER2+ (OR=6.58, CI 2.20−23.40, p&lt;0.01, FDR=0.03) and ER−/HER2− (OR=1.75, CI 1.12−2.76, p=0.02, FDR=0.10) but not in the ER+/HER2− subtype (OR=1.50, CI 0.63−3.42, p=0.35, FDR=0.49). Moreover, high values of AKT activation module were associated with decreased pCR rates in HER2+ (OR=0.38, CI 0.14−0.98, p=0.05, FDR=0.29) but not in the ER−/HER2− (OR=0.87, CI 0.56−1.37, p=0.56, FDR=0.68) or ER+/HER2− (OR=1.81, CI 0.65−5.30, p=0.27, FDR=0.47) subtype. Interactions between immune module and HER2 status and between AKT module and HER2 status were nominally significant (p=0.04 and p=0.05, respectively), but came with an FDR of 0.23. Of interest after a median follow-up of 3.47 years, (95% CI 3.18−3.70 years) patients with pCR had significantly longer RFS irrespective of BC subtypes (HR=0.20, 95% CI 0.08 to 0.50, p&lt;0.001).
Conclusion: Different biological processes namely proliferation, immune response and AKT activation are associated with pCR in different BC subtypes. Our results suggest that new drugs that modulate immune responses in ER−/HER2− and HER2+ BC and target AKT activation in HER2+ BC might be evaluated in these subtypes.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD03-10.