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

Abstract

<h3>Objectives:</h3> 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. <h3>Methods:</h3> 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. <h3>Results:</h3> 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 (<i>p</i>=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 (<i>p</i>=0.471), race (<i>p</i>=0.323) or distribution of recurrence sites (<i>p</i>=0.813) between HER2 positive and negative tumors. Platinum sensitivity was significantly improved in HER negative (65%) vs. HER2 positive tumors (30%) (<i>p</i>=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 (<i>p</i>=0.229 and <i>p</i>=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 (<i>p</i><0.001) and HER2 (<i>p</i>=0.027) status were independent predictors of survival. Age, race, stage and histology did not independently alter survival outcomes. <h3>Conclusions:</h3> 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.