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HER2 Expression, Test Deviations, and Their Impact on Survival in Metastatic Gastric Cancer: Results From the
Ivonne Haffner1, Katrin Schierle2, Elba Raimúndez3,4
1University Cancer Center Leipzig (UCCL), Leipzig University Medical Center, Leipzig, Germany.
Purpose:
Trastuzumab is the only approved targeted drug for first-line treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic gastric cancer (mGC). However, not all patients respond and most eventually progress. The multicenter VARIANZ study aimed to investigate the background of response and resistance to trastuzumab in mGC.
Methods:
Patients receiving medical treatment for mGC were prospectively recruited in 35 German sites and followed for up to 48 months. HER2 status was assessed centrally by immunohistochemistry and chromogenic in situ hybridization. In addition, HER2 gene expression was assessed using qPCR.
Results:
Five hundred forty-eight patients were enrolled, and 77 had HER2+ mGC by central assessment (14.1%). A high deviation rate of 22.7% between central and local test results was seen. Patients who received trastuzumab for centrally confirmed HER2+ mGC (central HER2+/local HER2+) lived significantly longer as compared with patients who received trastuzumab for local HER2+ but central HER2- mGC (20.5 months, n = 60 v 10.9 months, n = 65; hazard ratio, 0.42; 95% CI, 8.2 to 14.4; P < .001). In the centrally confirmed cohort, significantly more tumor cells stained HER2+ than in the unconfirmed cohort, and the HER2 amplification ratio was significantly higher. A minimum of 40% HER2+ tumor cells and a HER2 amplification ratio of ≥ 3.0 were calculated as optimized thresholds for predicting benefit from trastuzumab.
Conclusion:
Significant discrepancies in HER2 assessment of mGC were found in tumor specimens with intermediate HER2 expression. Borderline HER2 positivity and heterogeneity of HER2 expression should be considered as resistance factors for HER2-targeting treatment of mGC. HER2 thresholds should be reconsidered. Detailed reports with quantification of HER2 expression and amplification levels may improve selection of patients for HER2-directed treatment.
Insights
Accurate human epidermal growth factor receptor 2 (HER2) testing is crucial for effective trastuzumab treatment in metastatic gastric cancer. Optimized HER2 thresholds improve patient selection for HER2-targeted therapies.
Area of Science:
- Oncology
- Gastroenterology
- Pharmacology
Background:
- Trastuzumab is the sole approved first-line targeted therapy for HER2-positive (HER2+) metastatic gastric cancer (mGC).
- Treatment response and resistance to trastuzumab in mGC remain areas requiring further investigation.
- The VARIANZ study was designed to explore factors influencing response and resistance to trastuzumab in mGC.
Purpose of the Study:
- To investigate the background of response and resistance to trastuzumab in metastatic gastric cancer.
- To identify factors influencing patient outcomes in HER2+ mGC treated with trastuzumab.
- To evaluate the impact of HER2 assessment discrepancies on treatment efficacy.
Main Methods:
- Prospective recruitment of mGC patients across 35 German sites with up to 48 months follow-up.
- Centralized HER2 status assessment using immunohistochemistry and chromogenic in situ hybridization, alongside qPCR for HER2 gene expression.
- Comparison of treatment outcomes based on central and local HER2 assessment results.
Main Results:
- Out of 548 enrolled patients, 77 (14.1%) had centrally confirmed HER2+ mGC.
- A significant discrepancy rate (22.7%) was observed between central and local HER2 testing.
- Patients with centrally confirmed HER2+ mGC receiving trastuzumab demonstrated significantly longer survival (20.5 months) compared to those with locally positive but centrally negative HER2 status (10.9 months).
- Optimized thresholds of ≥40% HER2+ tumor cells and a HER2 amplification ratio of ≥3.0 were identified for predicting trastuzumab benefit.
Conclusions:
- Discrepancies in HER2 assessment, particularly with intermediate or borderline expression, significantly impact treatment outcomes in mGC.
- Borderline HER2 positivity and intratumoral heterogeneity are potential resistance factors to HER2-targeted therapy.
- Revising HER2 testing thresholds and providing detailed quantification of HER2 expression and amplification can enhance patient selection for trastuzumab therapy.
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