Abstract 924: Predictive biomarker identification for combined anti-mTOR and anti-IGF-1R treatment in luminal B breast cancer
Authors: Rivas Martin A. , Ibrahim Yasir H. , Rodríguez Olga , Antón Pilar , Cozar Patricia , Gómez-Pardo Patricia , Aura Claudia , Haines Brian B. , Sathyanarayanan Sriram , Zhang Theresa , Serra Violeta , Baselga José 
Published: May 2015

Abstract
Luminal B breast cancer is one of the most aggressive subtypes of breast cancer for which effective treatments are needed. Recently, a phase I clinical study revealed that blockade of mTOR and IGF-1R has potential clinical activity in this cancer subtype. However, biomarkers to predict patient's response to the combination are still needed. Previous exploratory studies in ovarian cancer have associated low RAS-pathway activity, as determined by a RAS gene expression signature score, and high levels of IGF-1R axis genes with response to this combination therapy. In the present study we evaluated low RAS signature/high IGF-1/high IGF-1R as potential predictive biomarkers for anti-mTOR and anti-IGF-1R combination therapy in luminal B breast cancer patient-derived xenografts (PDX) treated with the allosteric mTOR inhibitor ridaforolimus and the monoclonal antibody against IGF-1R, dalotuzumab. Expression array analysis revealed that our 6 luminal B PDXs exhibited a low RAS signature score, compared to 6 HER2 and triple negative PDXs. Overall, luminal B PDXs expressed higher IGF-1R as compared to the other breast cancer subtypes with some variability among the different luminal models. Low expression of human IGF-pathway ligands IGF-1 and IGF-2 among the luminal PDXs, compared to luminal B breast cancers, suggested to us the need of exogenous IGF-1 ligand supplementation to derive IGF-1R feedback activation and combinatorial antitumor response. Accordingly, three high IGF-1R-PDXs treated with the anti-mTOR and anti-IGF-1R combination therapy supplemented with recombinant human IGF-1 exhibited statistically significant anti-tumor response as compared to single agents, whereas two low IGF-1R-expressing PDXs did not. As anticipated, ridaforolimus induced the IGF-1R-axis by increasing the levels of the adapter protein IRS-1, which potentiated Akt signaling. Hence, in vitro knockdown of IRS-1 promoted the antiproliferative activity of ridaforolimus in patient-derived tumor cells. In conclusion, our results demonstrate that baseline IGF-pathway expression, namely IGF-1, IGF-1R and IRS-1, predict benefit to combined anti-mTOR and anti-IGF-1R treatment in breast cancer and supports further exploration in luminal B breast cancers that derived benefit from this combination.
Citation Format: Martin A. Rivas, Yasir H. Ibrahim, Olga Rodríguez, Pilar Antón, Patricia Cozar, Patricia Gómez-Pardo, Claudia Aura, Brian B. Haines, Sriram Sathyanarayanan, Theresa Zhang, Violeta Serra, José Baselga. Predictive biomarker identification for combined anti-mTOR and anti-IGF-1R treatment in luminal B breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 924. doi:10.1158/1538-7445.AM2014-924