Prognostic impact of HER family expressions for metastatic colorectal cancer (mCRC): SCRUM-Japan MONSTAR-SCREEN-2 and CALGB/SWOG 80405 trial (Alliance) international collaboration.
Authors: Hashimoto Tadayoshi , Nakamura Yoshiaki , Yang Yan , Battaglin Francesca , Innocenti Federico , Venook Alan P. , Makiyama Akitaka , Boku Shogen , Machida Nozomu , Takahashi Naoki , Kadowaki Shigenori , Komatsu Yoshito , Kudo Toshihiro , Oki Eiji , Kato Takeshi , Kagawa Yoshinori , Fujisawa Takao , Bando Hideaki , Lenz Heinz-Josef , Yoshino Takayuki 
Published: June 2024

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Background: Human epidermal growth factor receptor (HER) family plays a critical role in cancer pathogenesis. In the CALGB/SWOG 80405 trial, high HER2 expression was significantly good prognostic factor in patients with mCRC, and cetuximab improved overall survival (OS) in those with high HER2 expression compared to bevacizumab (Battaglin et al. ASCO2020; abstr 4086). Our study aimed to evaluate the prognostic impact of HER1/3/4 in the CALGB/SWOG 80405 and to corroborate it, including HER2, in the MONSTAR-SCREEN-2 in patients with mCRC, utilizing transcriptome expression data from both studies. Methods: In the CALGB/SWOG 80405 cohort, we assessed the prognostic potential of mRNA expressions of HER1, HER3, and HER4 from patients with KRAS exon 2 wild-type mCRC. Tumor tissue from 925 patients was tested for NanoString gene expression using an 800-gene panel. The results were validated through 398 mCRC patients according to RAS mutational status in the MONSTAR-SCREEN-2 cohort, employing whole-transcriptome sequencing with Caris MI profile. HER family expressions were classified into two or three groups, using the median or tertile expression values. The log-rank test was utilized to discern disparities in overall survival (OS). Results: In the CALGB/SWOG 80405 cohort, high HER3 expression significantly correlated with better OS (P=0.044), a trend particularly evident in patients undergoing cetuximab therapy (P=0.0048). HER1 and HER4 expression exhibited no significant association with OS, irrespective of treatment modality. In the corroborative analysis using the MONSTAR-SCREEN-2 cohort, high HER2expression demonstrated a significantly improved OS in the RAS wild-type population (hazard ratio [HR], 0.21; 95%CI, 0.06-0.71; P=0.0056), but no difference in OS compared to low HER2 expression in the RAS-mutant (HR, 1.11; 95%CI, 0.57-2.16; P=0.75). Elevated expressions of HER1 and HER3 were also significantly associated with better OS in RAS wild-type disease (HR, 0.22; 95%CI, 0.07-0.67; P=0.0034; and HR, 0.23; 95%CI, 0.07-0.70; P=0.0048, respectively), although there was no significant difference in RAS-mutant (HR, 0.83; 95%CI, 0.41-1.67; P=0.60; and HR, 0.76; 95%CI, 0.39-1.48; P=0.43, respectively). HER4expression exhibited no significant association with OS, irrespective of RAS mutational status. Conclusions: Our findings highlight the prognostic significance of HER1-3 gene expressions in RAS wild-type mCRC patients in the MONSTAR-SCREEN-2 cohort. These insights may contribute to the development of more efficacious treatment methodologies according to HER family transcriptome expression profiles. ClinicalTrials.gov Identifier: NCT00265850.