Does Specimen Type Have an Impact on HER2 Status in Endometrial Serous Carcinoma? Discordant HER2 Status of Paired Endometrial Biopsy and Hysterectomy Specimens in the Presence of Frequent Intratumoral Heterogeneity

Abstract

A recent clinical trial showed prolonged progression-free survival in human epidermal growth factor receptor 2 (HER2)-positive advanced stage and recurrent endometrial serous carcinomas when trastuzumab was added to traditional chemotherapy. Approximately one third of these tumors are HER2-positive and have been described to show unique characteristics of HER2 protein expression and gene amplification, including significant intratumoral heterogeneity, in recent studies. However, currently, there are no standard protocols for the selection of optimal specimen type or algorithm for HER2 testing in endometrial serous carcinomas. The current study aimed to evaluate the concordance of HER2 status between endometrial biopsy/curettage and subsequent hysterectomy specimens in endometrial serous carcinoma. A total of 57 patients with endometrial serous carcinoma with available HER2 status were identified during the study period, 14 of which (14/57, 25%) were HER2-positive by immunohistochemistry and/or fluorescent in situ hybridization (FISH). The final study cohort consisted of 40 paired endometrial biopsies/curettings and hysterectomies to include all 14 HER2-positive tumors and 26 selected HER2-negative tumors to represent an equal distribution of HER2 immunohistochemical scores. HER2 FISH was performed on all tumors with an immunohistochemical score of 2+. HER2 immunohistochemical scores, heterogeneity of HER2 expression, FISH results, and the overall HER2 status were compared between the 2 specimen types. HER2 status was successfully assigned in both specimen types in 37 cases, as three specimens showed inadequate FISH signals. Concordant HER2 status was observed in 84% of cases (31/37), with identical HER2 immunohistochemical scores in 65% (26/40) of tumors. Among the 6 tumors with a discordant HER2 status, 2 were HER2 negative in the biopsy and positive in the hysterectomy, and 4 were HER2-positive in the biopsy and negative in the hysterectomy. The false-negative rate would be 15.4% and 26.7% if only the biopsy or only the hysterectomy would be the basis for the result, respectively. Intratumoral heterogeneity of HER2 protein expression was present in 22 tumors (55%), including all cases with a discordant HER2 status. The concordance rate of HER2 status between paired endometrial biopsies/curettings and hysterectomies of endometrial serous carcinoma is lower than the reported rates of breast cancer, and comparable to those of gastric carcinomas. Frequent heterogeneity of HER2 protein expression combined with the possibility of a spatially more heterogenous sampling of endometrial cavity in biopsies and curettings, and the potential differences in specimen handling/fixation between the 2 specimen types may explain our findings. HER2 testing of multiple specimens may help identify a greater proportion of patients eligible for targeted trastuzumab therapy and should be taken into account in future efforts of developing endometrial cancer-specific HER2 testing algorithm.

HER2 Expression in Endometrial Cancers Diagnosed as Clear Cell Carcinoma

“…Such a result raises the issue of what threshold should be used to reflex to ISH testing. That both of our cases that had a score of 1+ on the TMA were ultimately 2+ on whole sections underscores the potential that heterogeneity can have on sampling bias, as has been shown previously; it is important to remember, however, that even though biopsies have limited material, they may have the most well preserved tissue for testing, and we support testing of both the biopsy and the hysterectomy specimen for the highest yield (28). It is currently unclear if tumors with less extensive HER2 expression will respond to HER2-targeted therapy in the same manner as those with higher expression and this requires further investigation.…”

HER2 Overexpression and Amplification in Uterine Carcinosarcomas With Serous Morphology

“…25 Temporal heterogeneity of HER2 expression between the initial biopsy and hysterectomy specimen has also been recently reported, which emphasizes the need for repeat HER2 testing on subsequent specimens. 24 It is worth mentioning that recently recommendations for HER2 grading of endometrial tumors have been up for discussion. Initially, the HER2 scoring systems were based off of the ASCO/CAP recommendations for breast carcinoma; however, as reflex HER2 testing has become standard of care for a variety of tumor types from various organ systems over the past few years, it has become evident that application of one tumor scoring system cannot be broadly applied to others.…”

Current Prognostic and Predictive Biomarkers for Endometrial Cancer in Clinical Practice: Recommendations/Proposal from the Italian Study Group

“…Recently, discordant HER2 status has also been observed between primary and metastatic endometrial tumors, in particular in heterogeneous cancers (142,143).…”