HER2 Intratumoral Heterogeneity in Salivary Duct Carcinoma: Association With Treatment Response and Comparison Between Primary and Metastatic Lesions.

Abstract

Salivary duct carcinoma (SDC) is a rare and aggressive malignancy, with up to half of cases being HER2-positive. Trastuzumab combined with docetaxel (Tmab + DTX) is a key therapeutic regimen for unresectable HER2-positive SDC; however, robust predictors of the treatment response in this patient population remain undefined. Although HER2 intratumoral heterogeneity (ITH) and the degree of HER2 amplification are known to correlate with the response to HER2-targeted agents in breast and gastric cancers, their predictive relevance in SDC remains unclear. To address this issue, we retrospectively analyzed 98 patients with unresectable HER2-positive SDC treated with Tmab + DTX. In this study, HER2 ITH was defined based on the 2023 ASCO/CAP breast cancer guidelines as the presence of spatially distinct HER2-positive and HER2-negative regions, each comprising ≥10% of the tumor area, evaluated using both immunohistochemistry (IHC) and dual-color in situ hybridization (DISH). HER2 ITH was identified in 11 of the 98 cases (11.2%). The results of IHC and DISH demonstrated strong concordance, with the exception of 1 sarcomatoid case. HER2 ITH was identified only in resected primary tumor specimens. In HER2 ITH-positive cases, no HER2 ITH was observed in any available synchronous or metachronous metastatic lesions, and the HER2 status was concordant across metastatic lesions within each patient, with most lesions being HER2-positive. The cohort exhibited an objective response rate of 80.6%, with median progression-free survival and overall survival of 9.9 and 43.8 months, respectively. No significant associations were observed between HER2 ITH or other HER2 parameters (HER2 IHC score, HER2 copy number, or HER2/CEP17 ratio) and any clinical outcome measures. The predominance of HER2-positive metastatic lesions may explain the lack of association between HER2 ITH in primary tumors and treatment efficacy. In this largest cohort of HER2-positive SDC patients treated with Tmab + DTX, HER2 ITH was present in a clinically relevant subset of cases. In contrast to breast and gastric cancers, neither HER2 ITH nor HER2 amplification levels were associated with the therapeutic response. Our findings suggest that the presence of HER2 ITH may not preclude the use of HER2-targeted therapy in SDC.