HER2 as a limited predictor of the therapeutic response to neoadjuvant therapy in locally advanced rectal cancer

Human epidermal growth factor 2 (HER2) is a candidate therapeutic and prognostic marker for rectal cancer treated with neoadjuvant chemoradiotherapy. The specific frequency and prognostic role of HER2 protein expression and HER2 gene amplification in those rectal cancers has not been fully investigated. Pretreatment biopsied and surgically resected formalin-fixed paraffin-embedded tissues from 74 patients were retrospectively evaluated for HER2 protein expression and HER2 gene copy number using immunohistochemistry (IHC) and silver in situ hybridization (SISH), respectively. The tumor response to chemoradiation was evaluated with TNM staging and tumor regression grading (TRG) systems. Good response to chemoradiation therapy (TRG3), poor response (22 TRG1 and 19 TRG2), and TNM downstaging achieved in 33 (44.6%), 41 (55.4%), and 42 (56.8%) patients, respectively. The frequency of HER2 positivity is 17.6%, all of which were low-level HER2 gene amplification with 2.2 of median gene copy number ratio, detected in IHC0 (3/39), IHC1+ (2/18), IHC2+ (5/14) and IHC3+ (2/3). There was no association of HER2 positivity with clinicopathological parameters or survival. However, older age (≥61 years) and HER2 positivity were the independent predictive factors for non-down staging, while poorly differentiation and the papillary pattern were predictors for poor response. In multivariate analysis, good response proved as an only independent favorable prognostic factor affecting survivals. In conclusion, HER2 positivity may be predictive for a high-risk therapeutic resistance in rectal cancers. The discrepancy between IHC and gene amplification may result from the low-level amplification, which may explain lack of prognostic impact of HER2 positivity.