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.

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