Gradishar et al. Page 301

Insulin and insulin-like growth factor (IGF) signaling pathways may be associated with resistance to antiestrogen therapies that commonly develops in hormone receptor-positive breast cancer. This randomized, open-label, phase 2 trial evaluated the efficacy and safety of cixutumumab, a monoclonal antibody specific for human IGF-receptor 1 (IGF-1R), in patients with hormone receptor-positive, metastatic breast cancer refractory to antiestrogen therapy. Although the primary endpoint was not met, Gradishar and colleagues demonstrated an inverse correlation between improved survival and insulin receptor expression in tumor tissue. This trial addresses an unmet need for the development of biomarkers for IGF-1R targeted therapies.

Callari et al. Page 337

Defining early breast cancer (EBC) patients who relapse in spite of standard systemic treatments represents an unmet medical need. By evaluating gene-expression profiles of 3847 EBC patients, Callari and colleagues developed subtype specific metagene-based predictors which identify those patients at lower and higher risk. In particular, for triple-negative breast cancer they developed a T-cell related metagene which defines a group with low immune infiltration with poor baseline prognosis and minimal benefit of chemotherapy, resulting in a dismal outcome despite chemotherapy administration. This group should be prioritized for inclusion in clinical trial.

Turksma et al. Page 346

New immunotherapeutic approaches for the treatment of cancer are on the rise. Despite clinical efficacy in a subset of patients, many patients do not have a good clinical outcome and, instead. just suffer from side effects. This calls for a personalized approach. Turksma and colleagues performed a retrospective study on tumor-infiltrating lymphocytes detected in primary colon cancers from patients with stage II or stage III disease, who previously participated in an Active Specific Immunotherapy (ASI) trial. The numbers of CD3 and CD8 positive T cells in the stroma and the epithelium were correlated with clinical outcome for controls and ASI-treated patients. In line with previous data, prognostic value was attributed to epithelial CD8 T cells. More importantly, prognostic as well as predictive value was attributed to stromal CD3 T cells. Compared with controls, patients with high numbers of stromal CD3 T cells benefitted from ASI treatment measured as disease-specific survival as well as recurrence-free survival. No differences in clinical outcome were found for patients with low numbers of stromal CD3 T cells. Although validation in future clinical trials is awaited, the biomarkers CD3 and CD8 in combination with T cell numbers and location may aid oncologists in determining which patient is likely to benefit most from immunotherapeutic approaches.

Shor et al. Page 383

Antibody-drug conjugates (ADCs) are emerging as a promising therapeutic modality for cancer treatment. In this study, Shor and colleagues evaluated most promising combination regimens of auristatin-based ADCs in vitro and in vivo and showed substantially greater antitumor effects when a tool ADC (5T4-ADC) was combined with PI3K/mTOR inhibitor or with taxanes. The results revealed unique reprogramming of mRNA translation with ADC or auristatin, an effect which is greatly amplified by the addition of PF-384. The data suggested that the mechanisms underlying the synergy may be attributed to cellular effects of the auristatin payload. These findings could be applicable to other auristatin-based ADCs in clinical trials.