HER2‐low heterogeneity between primary and paired recurrent/metastatic breast cancer: Implications in treatment and prognosis

Abstract Background With the largest sample size to date, the authors’ objective was to investigate the incidence of primary‐to‐metastatic human epidermal growth factor 2 (HER2) conversion and the predictors for such conversion. Moreover, no previous studies have evaluated the prognosis of patients who have negative HER2 expression (HER2‐0) versus low HER2 expression (HER2‐low) when HER2 status was assessed based on all recurrent/metastatic lesions. Methods The authors included 1299 patients who had available HER2 status of primary breast tumors and paired recurrent/metastatic lesions at Fudan University Shanghai Cancer Center and West China Hospital. Results In total, 370 patients (28.5%) experienced primary‐to‐metastatic HER2 conversion. Intrapatient intermetastasis spatial heterogeneity and temporal heterogeneity of HER2 were detected. When assessing HER2 based on recurrent/metastatic tumors, patients who had HER2‐0 tumors had significantly shorter overall survival than those who had HER2‐low tumors in the overall population and in the estrogen receptor (ER)‐negative subgroup. However, when assessing HER2 based on primary tumors, there was no difference in overall survival between patients who had HER2‐0 versus HER2‐low tumors. Moreover, patients who had tumors that converted from HER2‐0 to HER2‐low had longer overall survival than those who had consistent HER2‐0 status in the ER‐negative subgroup. By combining four predictors (ER status, Ki67 index, biopsy site, and disease‐free interval), the authors established the first prediction tool to estimate the probability of HER2‐0 tumors converting to HER2‐low/positive tumors. Conclusions Intrapatient primary‐to‐metastatic and intermetastatic HER2 heterogeneity were observed in this large‐scale cohort study. When evaluating HER2 based on recurrent/metastatic tumors, an overall survival difference was observed between patients who had HER2‐0 versus HER2‐low, recurrent/metastatic breast tumors. The developed prediction tool might help clinicians screen out patients with primary HER2‐0 tumors that have a high probability of HER2 status conversion and recommend them for re‐biopsy, thus helping to screen out candidate patients for trastuzumab deruxtecan treatment.