HER2, HER3, and Mismatch Repair Protein Expression in Stage IV Small Bowel Adenocarcinoma: Results From a Multicenter Series
Bibliographic record
Abstract
Small bowel adenocarcinoma (SBA) is a rare and aggressive malignancy. One-third of SBA cases are diagnosed at an advanced stage, often with limited treatment options. Recent clinical trials have underscored the importance of testing predictive biomarkers for therapy response in advanced solid tumors, particularly with respect to antibody-drug conjugates and immunotherapy. However, few studies have investigated the expression of mismatch repair (MMR) proteins, HER2, and HER3 in metastatic SBA. In this study, the immunohistochemical expression of MMR proteins, HER2 (using gastric cancer scoring criteria), and HER3 was assessed in a multicentric series of 26 stage IV SBAs. In 7 cases, tissues from both the primary tumor and paired distant metastasis were tested for all biomarkers, and any discordance in biomarker expression (ie, spatial heterogeneity) was recorded. For comparison, a cohort of 47 stage III SBA patients was also evaluated. MMR deficiency (MMRd), HER2 positivity (score 3+ or 2+ with gene amplification), and HER3 positivity were identified in 11.5%, 7.7%, and 40% of stage IV SBAs, respectively, with limited overlap among the biomarkers. One stage IV SBA showed heterogeneous MMR status, with a distinct subclone lacking MSH6 expression. When stage III SBAs were compared with stage IV SBAs, MMRd was more frequent (31.9%) among stage III SBAs. In 1 case (14%), the primary tumor was MMR-proficient, HER2-negative, and HER3-negative, whereas the metachronous distant metastasis was MMR-deficient, HER2-negative, and HER3-positive. The percentage of MMRd and HER2 positivity observed in stage IV SBAs highlights the need to assess HER2 and MMR status in these rare tumors. Our findings also suggest that evaluating the response of SBAs to anti-HER3 therapies should be considered in future clinical trials. Additionally, evidence of spatial heterogeneity in biomarker expression emphasizes the importance of assessing biomarkers in metastatic tissue to identify actionable alterations that may not be present in the primary tumor.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".