A Comprehensive Analysis of HER2 status Heterogeneity Using Matched Samples among Potential Beneficiaries of Trastuzumab Deruxtecan Therapy in Non-Small Cell Lung Cancer.

[BACKGROUND] HER2 overexpression is defined as immunohistochemistry (IHC) 2+/3+, and trastuzumab deruxtecan (T-DXd) is approved for treating unresectable or metastatic solid tumors with HER2 3+. HER2 spatiotemporal heterogeneity is crucial for identifying patients responsive to T-DXd. While extensively studied in gastric and breast cancers, research in non-small cell lung cancer (NSCLC) is limited. We aim to examine HER2 expression and their implications for optimizing specimen selection in potential T-DXd beneficiaries.

[MATERIALS AND METHODS] We retrospectively collected NSCLC cases from Peking University Cancer Hospital (2015-2024) with HER2 testing, matched specimens (resection vs. biopsy; primary vs. metastasis), at least 1 lesion with HER2 2+ or 3+. Two pathologists independently re-evaluated enrolled cases using gastric cancer criteria.

[RESULTS] A total of 5211 cases underwent HER2 testing, with 2+ expression in 773 (14.8%) and 3+ in 35 (0.7%) cases. Ultimately, 129 patients met inclusion criteria, comprising 88 surgical/biopsy and 102 primary/metastatic samples. Concordance between biopsy and resection was 51.4% (38/74) for HER2 2+ and 21.4% (3/14) for HER2 3+, with significantly higher concordance for 2+ (P = .040). Concordance was 39.4% (28/85) for HER2 2+ and 35.4% (5/14) for HER2 3+ in primary vs metastatic tumors, with no significant difference between lymph node and distant metastases. Both biopsy and metastatic samples underestimated HER2 2+ and 3+ expression.

[CONCLUSIONS] Our study demonstrates that in potential NSCLC beneficiaries of T-DXd therapy, HER2 expression is underestimated in biopsy samples and metastatic lesions compared to resected and primary sites. This heterogeneity holds great significance for guiding clinical sample selection.