Prognostic implications of HER2/neu on chemosensitivity and survival in uterine serous and clear cell carcinoma

Objectives: Uterine serous (USC) and clear cell carcinoma (CC) are aggressive variants of endometrial cancer (EC), comprising only 20% of all cases, but accounting for a disproportionately high number of EC related deaths. The molecular profile of USC and CC is distinct from that of other EC, displaying alternations in TP53 and HER2/neu. Human epidermal growth factor receptor 2/neu (HER2) is a key player in singling for cancer cell growth, survival and proliferation. Recent data demonstrates a survival benefit with the use of trastuzumab, a monoclonal antibody against HER2, in combination with chemotherapy for HER2 expressing USC. However, the clinical implications of HER2 status on prognosis remain unclear. Methods: A multicenter retrospective analysis of patients with USC and CC was conducted from 2000 - 2019. Inclusion criteria were patients who had undergone comprehensive surgical staging/tumor debulking with archival tissue available for HER2 assessment via immunohistochemistry (IHC). HER2 positive was defined as IHC score of 3+. Platinum sensitivity was defined as recurrence >6 months from last platinum-based therapy. Differences in the frequencies of stage, race, chemosensitivity and sites of disease recurrence were identified using Pearson's chi-square test. Progression free survival (PFS) and overall survival (OS) analysis was performed using Kaplan-Meier estimates. Multivariate analysis (MVA) was performed using Cox proportional hazards model. Results: HER2 status was evaluated in 56 patients. Histology included 44 (79%) USC, 9 (16%) CC and 3 (6%) mixed serous-clear cell. 11 (19.6%) were positive for HER2; 18.2% USC, 22.2% CC and 33.3% mixed histology. Of these 56 patients, 50 had follow-up information available for review and were included in final analysis. The mean age was 67-years and the majority of patients were African American (88%). Stage distribution included 38% stage I, 8% stage II, 18% stage III and 36% stage IV. 29 (58%) patients recurred during the study period, 7 (70%) of the HER2 positive and 22 (55%) of the HER2 negative cohort (p=0.390). The most common location of recurrence was the abdomen followed by the pelvis and extra-abdominopelvic sites. There was no difference in the stage (p=0.471), race (p=0.323) or distribution of recurrence sites (p=0.813) between HER2 positive and negative tumors. Platinum sensitivity was significantly improved in HER negative (65%) vs. HER2 positive tumors (30%) (p=0.044). For the entire cohort, the median PFS was 21 months and the median OS was 29 months. The median PFS and OS did not differ significantly based on HER2 status (p=0.229 and p=0.255, respectively). However, there was a clinically relevant trend towards improved PFS (26 vs. 7 months) and OS (35 vs. 14 months) in HER2 negative vs. positive tumors. On MVA, platinum sensitivity (p Download : Download high-res image (140KB) Download : Download full-size image Conclusions: In addition to being a tool to guide targeted therapy, HER2 is a valuable prognostic marker in USC and CC. Expression is associated with significantly lower platinum sensitivity and inferior survival compared to tumors not expressing HER2.