Immune and Growth Factor Signaling Pathways Are Associated with Pathologic Complete Response to an Anti–Type I Insulin-like Growth Factor Receptor Regimen in Patients with Breast Cancer

Abstract Purpose: Pretreatment specimens from patients treated on the I-SPY2 neoadjuvant breast cancer trial were studied to identify prespecified biomarkers associated with response to the regimen of paclitaxel, the anti–type I insulin-like growth factor receptor (IGF-1R) antibody ganitumab, and metformin (PGM) followed by doxorubicin and cyclophosphamide (AC) compared with control therapy (paclitaxel followed by AC). The primary endpoint of this trial is pathologic complete response (pCR). Experimental Design: One hundred six patients treated with PGM and 119 contemporary controls were evaluated using laser capture microdissection and reverse-phase protein array to evaluate 32 prespecified potential predictive biomarkers in the IGF-1R pathway and 109 additional exploratory endpoints. Results: Total levels of IGF-1R were poorly correlated with phosphorylated IGF-1R/insulin receptor (IR). Higher levels of phosphorylated IGF-1R/IR were associated with an increased likelihood of obtaining pCR, especially in the hormone receptor (HR)–positive subgroup. Markers of immune response also showed an association with pCR but differed between HR+ and HR− subgroups. In HR− tumors, phospho-STAT1 Y701 and low levels of phospho-p27 associated with pCR. These relationships were not observed in patients treated with control chemotherapy. Conclusions: Activation status of IGF-1R/IR associated with increased pCR to PGM in HR+ breast cancers. Immune activation markers were also associated with response in HR+ and HR− subgroups. Thus, IGF-1R may directly regulate tumor biology and associate with immune response to therapy.