I-SPY2 is a neoadjuvant trial evaluating experimental therapies in combination with cytotoxic chemotherapy in breast cancer compared to chemotherapy alone with the primary endpoint of pathologic complete response (pCR). Abundant preclinical evidence suggested the type I insulin-like growth factor receptor (IGF-1R) regulated breast cancer growth, although multiple clinical trials did not show benefit. We were the first to report the results of a monoclonal IGF-1R antibody ganitumab (G) in combination with chemotherapy. PGM followed by doxorubicin/cyclophosphamide (AC) did not result in substantial increases in pCR when compared to P followed by AC. In this report, we examined several potential predictive biomarkers.
IGF-1R inhibitors inducehyperglycemia wemeasured hemoglobin A1C (HgbA1c) as a measure of glucose control in patients before and after PGM therapy. 106 patients received PGM and 104 patients had baseline HgbA1c with a median of 5.4%. However, 27% (28/104) had levels greater than 5.7% the upper limit of normal as defined by the NIDDK. 4 of 104 had HgbA1c greater than 6.5%,a level associated with type 2 diabetes. pCR rates are similarbetween patients with baseline HgbA1c ≤5.7% (21%) vs. >5.7% (25%) (Fisher test p=0.79). 72 of these patients had an additional HgbA1c during the course of PGM therapy. For patients with HgbA1c ≤5.7%, 27% (14/52) hadsubsequentelevation above 5.7%after PGM. For patients with a baseline HgbA1c >5.7%, all 20 patients continued to have elevated levels through PGM.
We also examined pre-treatment tumor gene expression profiles derived from custom Agilent44K full-genome microarrays. We studied 11 genes associated with the IGF-1R signaling (IGF1, IGF2, IGF1R, INSR, IGFBP2, IRS1, IRS2, IGFBP3, IGFBP4, IGFBP5, CDH1),the IGFBP5/IGFBP4 ratio, and twoIGFR expression signatures(Creighton, et al. J Clin Oncol 26:4078 2008 PMID: 18757322; Mu, et al. Breast Cancer Res Treat 133:321 2012 PMID: 22297468). The 2 signatures evaluated: the IGF1 ligand score and the IGF1-R signature are anti-correlated (Rp= -0.79). In the population as a whole, lower levels of IRS1 and IGFBP5 significantly associated with response to PGM (likelihood ratio test (LR)p< 0.05), as do lower levels of the IGF1 ligand score and higher levels of the IGF-1R signature. However, levels of IRS1 and the two expression signatures also trend toward or are significantly associated with response in the control arm; and treatment interactions for all four biomarkers are non-significant (LR p>0.05). Therefore, none of these biomarkers qualify as specific predictors of response to PGM. Similarly, high MammaPrint scores (MP2) were associated with higher pCR scores in both PGM and Control arms.Previous gene expression profiles were divided into tertiles (low, intermediate, high).Similar to the continuous case, IGF1Rsig-class associates with pCR in both the PGM and control arms (Fisher test p=0.033 and 0.044, respectively), and thus also fails as a specific predictor of response to PGM.
We conclude that PGM therapy results in worsening of glucose control and likely increases serum insulin levels. While IGF gene expression profiling associated with treatment response, they were not specific for PGM. Further, biomarker analysis and strategies to control glucose will be needed to optimize anti-IGF-1R therapies.