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

Background: 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. Experimental Design: IGF1R protein expression was determined in tissue microarray sections (three cores per block; N = 1,197) or in whole tissue sections (WS; N = 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. Results: Of 1,734 patients, 708 (41%) had IGF1R⁺ breast tumors. IGF1R⁺ was associated with younger age (median 48 vs 51, P = 0.007), estrogen receptor/progesterone receptor positivit (78% vs. 35%, P < 0.001), nodal positivity (89% vs. 83%, P < 0.001), well/intermediate grade (34% vs. 24%, P < 0.001), tumors ≥2 cm (72% vs. 67%, P = 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 (P ≤ 0.001) and 0.68 (P = 0.009), respectively (P_interaction = 0.17). Between Arms A and B, patients with IGF1R⁺ and IGF1R⁻ tumors had DFS HRs of 0.83 (P = 0.25) and 0.69 (P = 0.01), respectively (P_interaction = 0.42). Conclusions: 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.