HER2 immunoreactivity in advanced non-p53abn endometrial carcinoma: Association with clinical features, prognosis, and molecular characteristics
Human epidermal growth factor receptor 2 (HER2) is an emerging therapeutic target in endometrial carcinoma (EC). Current guidelines recommend routine HER2 testing for p53 abnormal (p53abn) tumors, potentially underestimating its value in non-p53abn cases. This study aimed to assess the incidence and clinical relevance of HER2 immunoreactivity in advanced non-p53abn EC. HER2 immunohistochemistry and next-generation sequencing were performed in 128 advanced EC patients. Clinicopathological features, survival, and molecular alterations were compared according to HER2 immunoreactivity. Of all patients, 18.8 % were HER2 2 + /3 + , 28.9 % were HER2 1 + , and 52.3 % were HER2 0. Molecular classification included 1.6 % POLE mutant, 35.2 % mismatch repair-deficient/ microsatellite instability-high, 29.7 % p53abn, and 33.6 % no specific molecular profile (NSMP). In the non-p53abn group, HER2 3 + was less frequent than in the p53abn group, whereas the frequencies of HER2 2 + and 1 + did not differ significantly between the two groups. In non-p53abn patients, HER2 2 + /3 + occurred most frequently in clear cell carcinoma (CCC, 6/11, 54.5 %) and was associated with adnexal metastasis (2 +/3 + vs. 1 +, 66.7 % vs. 15.4 %, P < 0.05). No survival differences were observed among non-p53abn patients by HER2 immunoreactivity, however, within the NSMP subgroup, both overall and progression-free survival were worse in HER2 2 + /3 + compared with 1 + (log-rank P < 0.05). In non-p53abn ECs, KRAS mutations were significantly less frequent in HER2 2 + /3 + group (2 +/3 + vs. 1 +, 6.7 % vs. 46.2 %, P < 0.05). HER2 2 + /3 + immunoreactivity was detected in 16.7 % of advanced non-p53abn EC, particularly enriched in CCC. These findings highlight the potential clinical significance of HER2 testing in non-p53abn patients.