LowIGFBP7expression identifies a subset of breast cancers with favorable prognosis and sensitivity to IGF-1 receptor targeting with ganitumab: Data from I-SPY2 and SCAN-B

Abstract

AbstractTo date, no IGF-1R targeting agent has shown clinical benefit in patients despite promising preclinical data. We hypothesized that Insulin-like growth factor binding protein-7 (IGFBP7)expression predicts response to Insulin-like growth factor-1 receptor (IGF-1R) targeting agents, for which there are no biomarkers predictive of efficacy. High IGFBP7 expression was previously associated with breast cancer progression. Therefore, the predictive value ofIGFBP7expression was interrogated in I-SPY2 (NCT01042379) for pathological complete response (pCR) to neoadjuvant treatment and in SCAN-B (NCT02306096) for clinical outcome. In I-SPY2,IGFBP7expression was examined as a predictor of pCR to neoadjuvant chemotherapy alone and separately to the combination of chemotherapy plus ganitumab (anti-IGF-1R antibody) and metformin. Odds ratios (OR) and hazard ratios (HR) with 95% confidence interval (CI) were calculated with logistic and Cox regression, respectively. HigherIGFBP7expression conferred lower odds of achieving pCR in the ganitumab/metformin plus chemotherapy arm, ORadj0.38 (95% CI 0.17–0.80) but not in the chemotherapy-alone arm, adjusted OR 1.23 (95% CI 0.63–2.45;Pinteraction=0.016). In the ganitumab/metformin plus chemotherapy arm, 46.9% of patients with tumors in the lowest quartile ofIGFBP7expression achieved pCR compared to compared to only 5.6% in the highest quartile. In SCAN-B, higherIGFBP7expression was associated with distant metastasis risk HRadj1.41 (95% CI 1.16–1.73). In conclusion, lowIGFBP7gene expression identifies a subset of breast cancer patients for whom the addition of ganitumab and metformin to chemotherapy results in a significantly improved pCR rate compared to neoadjuvant chemotherapy alone. Furthermore, we add to prior evidence that highIGFBP7expression is predictive of poor outcome.SummaryThere has been a long-standing interest in targeting the Insulin-like growth factor-1 receptor (IGF-1R) signaling system in breast cancer due to its key role in growth, proliferation, and survival. To date, no IGF-1R targeting agent has shown substantial clinical benefit in controlled trials despite promising preclinical data. Treatment predictive biomarkers for IGF-1R targeting agents are lacking. IGFBP7 is an atypical insulin-like growth factor binding protein as it associates with the IGF-1R, reducing its capacity to bind IGF-1 or IGF-2. We report that lowIGFBP7gene expression identified a subset of breast cancers for which the addition of ganitumab (an anti-IGF-1R monoclonal antibody) with metformin to chemotherapy substantially improved the pathological complete response rate compared to neoadjuvant chemotherapy alone. Furthermore, highIGFBP7expression predicted increased distant metastasis risk.IGFBP7expression deserves further evaluation as a predictor of therapeutic benefit of IGF-1R targeting agents and of breast cancer prognosis.