Discordance in HER2 expression in primary and recurrent/metastatic lesions of upper tract urothelial carcinoma: A study focusing on temporal heterogeneity.

839 Background: The promising performance of HER2 antibody–drug conjugates (ADC) in clinical trials suggested that HER2-targerted therapy, particularly ADCs, may be a suitable treatment option for metastatic UTUC. However, we have observed cases where ADCs were ineffectiveness for recurrent/metastatic lesions in patients with HER2-positive primary UTUC. Thus, we conducted a retrospective study of UTUC patients to investigate the specific HER2 expression in paired primary and recurrent/metastatic lesions. Methods: Data of 290 UTUC patients who underwent radical nephroureterectomy at West China Hospital of Sichuan University from Jan 2020 and Oct 2023 without neoadjuvant treatment were retrospectively included. The HER2 expression was independently evaluated through immunohistochemistry by our professional genitourinary pathologists. HER2 2+ and HER2 3+ were considered HER2-positive whereas others were considered HER2-negative. Results: A total of 249 patients had HER2 expression evaluation of their specimens, with 92 patients (39.36%) showing HER2-positivity (IHC HER2 2+ or 3+). During rigorous follow-up, 31 patients (12.45%) developed local recurrence or distant metastasis. The majority of those patients had locally advanced UTUC (pT ≥ 3) and high grade disease. We observed discordance in HER2 expression between primary and recurrent/metastatic lesions in 22 cases (70.97%), with 9 cases (29.03%) showing an increase in HER2 expression and 13 cases (41.94%) showing a loss of HER2 expression. The conversion from HER2 negative to positive or vice versa occured in 5 cases (16.13%) and 10 cases (32.26%), respectively. Notably, all primary lesions with HER2 0 expression obtained HER2 expression in recurrent/metastatic lesions (5/5, 100%). Conclusions: Our findings highlight the discordance in HER2 expression between primary and recurrent/metastatic lesions in UTUC, underscoring the need for further investigation and potential modifications in disease management.