Prevalence And Influence On Outcome Of Neuregulin- (Nrg1), Her2/Neu- And Her3-Expression In Patients With Metastatic Colorectal Cancer (Mcrc) Treated With Irinotecan-Based First-Line Regimens (Fufiri Vs. Mirox) In The Fire 1-Trial.

e14609 Background: The epidermal growth factor receptor is frequently expressed in colorectal carcinoma and acts as therapeutic target in RAS wild-type mCRC. Although HER2/neu- and HER3-targeted agents are available, little is known about the role of these receptors in mCRC. Hence, we set out to explore the impact of HER2/neu- and HER3- receptor as well as their ligand’s neuregulin (NRG1) expression in patients with mCRC. Methods: NRG1, HER2 and HER3 expression was detected by immunostaining in 208 available tumors of patients with mCRC receiving 5-FU/LV plus irinotecan (FUFIRI) or irinotecan plus oxaliplatin (mIROX) as first-line treatment within a randomized trial (FIRE1). For NRG1-, HER2/neu and HER3-expression, Rüschoff-score for immunohistochemistry (IHC) was used (i.e. +++ and ++ vs. + and 0) (Rüschoff et al.: HER2 testing in gastric cancer: a practical approach. Modern Pathology, 25, 637-650. 2012.). Expression of NRG1, HER2/neu and HER3 was correlated with response, median progression-free survival (PFS) and median overall survival (OS). Results: NRG1 (low: 192 vs high: 16), HER2/neu (low: 178 vs high: 30) and HER3 (low: 69 vs high: 139) expression was assessed in all 208 patients. High vs low HER3 expression did not influence outcome (PFS: 7.1 vs 8.8 months, HR: 1.11 [95% CI: 0.82 – 1.50], p = 0.50; OS: 19.8 vs 21.1 months, HR: 0.95 [95% CI: 0.70 – 1.30], p = 0.75), neither did high compared to low HER2/neu expression (PFS: 7.7 vs 8.0 months, HR: 1.07 [95% CI: 0.71 – 1.60], p = 0.75; OS: 16.6 vs 21.1 months, HR: 1.13 [95% CI: 0.75 – 1.71], p = 0.57). High vs low NRG1 expression affected PFS (4.7 vs 8.2 months, HR: 2.45 [95% CI: 1.45 – 4.13], p = 0.001), but not OS (15.5 vs 20.7 months, HR: 1.33 [95% CI: 0.76 – 2.35], p = 0.32). Conclusions: High IHC-expression of NRG1, HER2/neu and HER3 was detected in 8%, 14% and 67% of tumors respectively. High NRG1-expression was associated with inferior PFS, while HER2/neu and HER3 did not correlate with outcome. Further research is required to identify diagnostic algorithms and to explore if HER2/neu- and HER3-receptors represent potential targets in the treatment of mCRC.