HER3 expression was identified in 40 percent of evaluable tumors (8 of 20 stage IV small bowel adenocarcinomas), according to a recent study.
In a multicenter study evaluating 26 patients with stage IV small bowel adenocarcinoma (SBA), researchersat the University of Pavia assessed the expression of HER2, HER3, and mismatch repair (MMR) proteins using immunohistochemistry to identify biomarker prevalence and spatial heterogeneity. HER3 expression, defined as a score of 2+ or 3+, was present in 40 percent of evaluable tumors. HER2 positivity, determined by a score of 3+ or 2+ with gene amplification, was found in 8 percent of cases. MMR deficiency (MMRd) was identified in 12 percent of tumors, with one case exhibiting subclonal MSH6 loss. Minimal overlap among biomarkers was observed. The study did not assess HER2 or MMR gene mutations, focusing instead on protein expression.
In seven patients, both primary tumor and matched distant metastases were available for analysis. Among these, histologic grade remained concordant in six cases. One case showed a shift from grade 2 in the primary tumor to grade 3 in the peritoneal metastasis, along with conversion from MMR-proficient to MMRd status and from HER3-negative to HER3-positive expression. HER2 expression remained stable across primary and metastatic tissues. HER3 score conversions – either positive or negative – were identified in three of the seven matched cases (43 percent). No conversions were seen using binary HER2 classification (positive vs negative).
Compared with a cohort of 47 patients with stage III SBA, MMRd was more frequent in stage III cases (31.9 percent vs 11.5 percent). Stage IV SBAs were less commonly associated with predisposing conditions, including celiac disease, Crohn’s disease, and Lynch syndrome. HER2 and HER3 positivity rates were similar between stage III and IV groups. No HER2-positive tumors showed concurrent HER3 or MMRd positivity, and only one tumor was both HER3-positive and MMRd.
Among HER2-positive cases, amplification was confirmed by fluorescence in situ hybridization. HER3 expression was measured using an adapted scoring system based on gastric cancer criteria, and the median H-score for HER3-positive tumors was 127.5. In the subset of tumors from patients under 50 years of age, all were MMR-proficient and HER2-negative; two were HER3-positive.
These findings indicate that HER2, HER3, and MMRd are present in non-overlapping subsets of stage IV SBA, with HER3 being the most frequently observed marker. Analysis of metastatic lesions showed different patterns of biomarker expression compared with primary tumors.
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