Temporal Heterogeneity of HER2 Expression and Spatial Heterogeneity of (18)F-FDG Uptake Predicts Treatment Outcome of Pyrotinib in Patients with HER2-Positive Metastatic Breast Cancer

SIMPLE SUMMARY: Tumor heterogeneity plays an important role in malignant behaviors and treatment responses. This study aimed to evaluate the temporal and spatial heterogeneity in clinical practice and investigate its impact on the treatment outcome of pyrotinib in patients with HER2-positive metastatic breast cancer. Temporal heterogeneity was evaluated by the discordance between primary and metastatic immunohistochemistry results. (18)F-FDG uptake heterogeneity on baseline PET/CT scan was assessed to reflect spatial tumor heterogeneity among metastases. Our results showed that heterogeneous HER2 status between primary and metastatic lesions and spatial (18)F-FDG uptake heterogeneity were predictive of poorer outcomes of pyrotinib treatment. The best method to evaluate tumor heterogeneity in clinical practice still needs to be identified. Temporal heterogeneity of HER2 expression and spatial heterogeneity of (18)F-FDG uptake provided practically applicable methods to assess tumor heterogeneity and potential guidance for treatment decisions. ABSTRACT: Background: This study aimed to evaluate tumor heterogeneity of metastatic breast cancer (MBC) and investigate its impact on the efficacy of pyrotinib in patients with HER2-positive MBC. Methods: MBC patients who underwent (18)F-FDG PET/CT before pyrotinib treatment were included. Temporal and spatial tumor heterogeneity was evaluated by the discordance between primary and metastatic immunohistochemistry (IHC) results and baseline (18)F-FDG uptake heterogeneity (intertumoral and intratumoral heterogeneity indexes: HI-inter and HI-intra), respectively. Progression-free survival (PFS) was estimated by the Kaplan–Meier method and compared by a log-rank test. Results: A total of 572 patients were screened and 51 patients were included. In 36 patients with matched IHC results, 25% of them had HER2 status conversion. Patients with homogenous HER2 positivity had the longest PFS, followed by patients with gained HER2 positivity, while patients with HER2 negative conversion could not benefit from pyrotinib (16.8 vs. 13.7 vs. 3.6 months, p < 0.0001). In terms of spatial heterogeneity, patients with high HI-intra and HI-inter had significantly worse PFS compared to those with low heterogeneity (10.6 vs. 25.3 months, p = 0.023; 11.2 vs. 25.3 months, p = 0.040). Conclusions: Temporal heterogeneity of HER2 status and spatial heterogeneity of (18)F-FDG uptake could predict the treatment outcome of pyrotinib in patients with HER2-positive MBC, which provide practically applicable methods to assess tumor heterogeneity and guidance for treatment decisions.