Discordant HER2 expression and response to neoadjuvant chemoradiotherapy in esophagogastric adenocarcinoma

Background: Targeting human epidermal growth factor receptor 2 (HER2) with trastuzumab in metastatic esophagogastric adenocarcinoma (EGA) improves survival. The impact of HER2 inhibition in combination with chemoradiotherapy (CRT) in early stage EGA is under investigation. This study analyzed the pattern of HER2 overexpression in matched-pair tumor samples of patients who underwent neoadjuvant CRT followed by surgery.

Methods: All patients with EGA who underwent standard neoadjuvant CRT followed by esophagectomy at the University of Florida were included. Demographics, risk factors, tumor features, and outcome data were analyzed. Descriptive statistics, Chi-square exact test, uni- and multivariate analyses, and Kaplan Meier method were used. HER2 expression determined by immunohistochemical (IHC) was scored as negative (0, 1+), indeterminate (2+) or positive (3+).

Results: Among 49 sequential patients (41 M/8 F) with matched-pair tumor samples, 9/49 patients (18%) had pathologic complete response (pCR), 10/49 had near pCR or not enough tumor (NET) to examine in the post- treatment samples. Patients with initial HER2 negativity demonstrated conversion to HER2 positivity after neoadjuvant CRT (7/30 cases; 23%). Baseline HER2 overexpression was more common in lower stage/node negative patients (67% in stages I, IIA vs. 33% in stages IIB, III) and did not correlate with treatment response or survival.

Conclusions: Although limited by a relatively small sample size, our study failed to demonstrate that baseline HER2 protein over-expression in EGA predicts response to standard CRT. However, our data suggested that HER2 was up regulated by CRT resulting in unreliable concordance between pre-treatment (pre-tx) and post-treatment (post-tx) samples. Pre-therapy HER2 expression may not reliably reflect the HER2 status of persistent or recurrent disease.