Abstract A019: IGF-1R protein pathway activation is associated with pathologic complete response to an anti-IGF-1R regimen (paclitaxel, ganitumab, and metformin) in the I-SPY2 neoadjuvant breast cancer trial
Authors: Emanuel F. Petricoin, Denise M. Wolf, Christina Yau, Julia Wulfkuhle, Laura van ‘t Veer, Rosa I. Gallagher, Gillian L. Hirst, Lamorna Brown-Swigart, Laura J. Esserman, Douglas Yee
Journal: Cancer Research (2024)

Abstract BACKGROUND: The addition of PGM followed by doxorubicin/cyclophosphamide versus control was evaluated as neoadjuvant therapy. Here IGF-1R pathway based protein and phosphoprotein (p) biomarkers were examined for their predictive utility. METHODS: Reverse phase protein array evaluated 102 pretreatment PGM and 169 control HER2- specimens. 32 pre-specified biomarker candidates were examined. A logistic regression model adjusted for hormone receptor (HR) status. The Benjamini-Hochberg (BH) method adjusted for multiple hypothesis testing. ROC analysis identified dichotomizing thresholds for select biomarkers. RESULTS: In the entire PGM population in a model adjusting for HR status, higher levels of pIGF-1R (Y1135/Y1136)/IR (Y1150/Y1151) (OR=2.13 p&amp;lt;0.002; BH p&amp;lt;0.05) and lower levels of p27 T187 (OR= 0.41 p&amp;lt;0.002; BH p&amp;lt;0.05) were significantly associated with pCR. Downstream IGF-1R signaling proteins were nominally associated with pCR (IRS-1 S612, p90 RSK S380, FOXO1 T24/FOXO3a T32). In HR+ tumors (n=58), pIGF-1R retained its significant positive association with pCR (OR=4.08 P&amp;lt;0.002; LR p&amp;lt;0.05), with an AUC of 0.79 [95% CI: 0.56-1]. Using an optimal dichotomizing threshold, 16% (9/58) of HR+HER2- were classified pIGF-1R.IR-High; and 56% (5/9) of these patients achieved pCR vs. 6% (3/49) in the pIGF1R.IR-Low subset. In TN patients (n=44), pIGF-1R did not associate with response. However, lower pp27 remained nominally associated with higher pCR rates for PGM treatment (OR=0.42 p&amp;lt;0.009; BH p&amp;gt;0.05) with an AUC of 0.74 [95% CI: 0.58-0.89]; and when optimally dichotomized, 52% (13/25) of pp27 Low TN patients achieved pCR vs. 12% (2/17) in the pp27 High group. None of these PGM-response-predictive biomarkers associated with response in the control arm. Total receptor levels did not associate with response. CONCLUSION: We are the first to show that pre-treatment levels of IGF-1R protein pathway activation-based signaling phosphoproteins, including levels of pIGF-1R, the drug target for ganitumab, may be predictive biomarkers for drugs targeting this receptor especially in the HR+ subset. Citation Format: Emanuel F. Petricoin, Denise M. Wolf, Christina Yau, Julia Wulfkuhle, Laura van ‘t Veer, Rosa I. Gallagher, Gillian L. Hirst, Lamorna Brown-Swigart, Laura J. Esserman, Douglas Yee. IGF-1R protein pathway activation is associated with pathologic complete response to an anti-IGF-1R regimen (paclitaxel, ganitumab, and metformin) in the I-SPY2 neoadjuvant breast cancer trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A019.