IGF1R Protein Expression Is Not Associated with Differential Benefit to Concurrent Trastuzumab in Early-Stage HER2⁺ Breast Cancer from the North Central Cancer Treatment Group (Alliance) Adjuvant Trastuzumab Trial N9831.

Abstract

<b>Background:</b> Preclinical evidence indicates that increased insulin-like growth factor receptor-1 (IGF1R) signaling interferes with the action of trastuzumab suggesting a possible mechanism of trastuzumab resistance. Thus, we evaluated IGF1R prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the prospective phase III HER2⁺ adjuvant N9831 trial.<b>Experimental Design:</b> IGF1R protein expression was determined in tissue microarray sections (three cores per block; <i>N</i> = 1,197) or in whole tissue sections (WS; <i>N</i> = 537) using IHC (rabbit polyclonal antibody against IGF1R β-subunit). A tumor was considered positive (IGF1R⁺) if any core or WS had ≥1+ membrane staining in >0% invasive cells. Median follow-up was 8.5 years.<b>Results:</b> Of 1,734 patients, 708 (41%) had IGF1R⁺ breast tumors. IGF1R⁺ was associated with younger age (median 48 vs. 51, <i>P</i> = 0.007), estrogen receptor/progesterone receptor positivity (78% vs. 35%, <i>P</i> < 0.001), nodal positivity (89% vs. 83%, <i>P</i> < 0.001), well/intermediate grade (34% vs. 24%, <i>P</i> < 0.001), tumors ≥2 cm (72% vs. 67%, <i>P</i> = 0.02) but not associated with race or tumor histology. IGF1R did not affect DFS within arms. Between Arms A and C, patients with IGF1R⁺ and IGF1R^- tumors had DFS HRs of 0.48 (<i>P</i> ≤ 0.001) and 0.68 (<i>P</i> = 0.009), respectively (<i>P</i>_interaction = 0.17). Between Arms A and B, patients with IGF1R⁺ and IGF1R^- tumors had DFS HRs of 0.83 (<i>P</i> = 0.25) and 0.69 (<i>P</i> = 0.01), respectively (<i>P</i>_interaction = 0.42).<b>Conclusions:</b> In contrast to preclinical studies that suggest a decrease in trastuzumab sensitivity in IGF1R⁺ tumors, our adjuvant data show benefit of adding trastuzumab for patients with either IGF1R⁺ and IGF1R^- breast tumors. <i>Clin Cancer Res; 23(15); 4203-11. ©2016 AACR</i>.