HER2 Expression in Endometrial Cancers Diagnosed as Clear Cell Carcinoma

Abstract

There is increasing evidence that many endometrial cancers (EC) diagnosed as clear cell carcinoma (CCC) have substantial overlap with both serous carcinoma (SC) and endometrioid carcinoma (EmC), not only in terms of morphology and immunophenotype but also by molecular characterization. Now with use of HER2-based therapy in SC, a CCC diagnosis in serous-like tumors has the potential to exclude patients from receiving beneficial therapy. To assess HER2 in CCC in relation to other characteristics, a tissue microarray of archived CCC, EmC, and SC was stained for HER2 alongside a battery of immunostains used in EC. Cases with equivocal HER2 IHC were also assessed by in situ hybridization. HER2 status was assessed in 229 cases (23 CCC, 74 SC, 132 EmC). HER2 was positive in 48% of cases diagnosed as CCC, 19% of SC, and 0% of EmC. Rigorous morphologic and immunophenotypic review by 5 gynecologic pathologists revealed diagnostic disagreement in 8/11 HER2+ cases diagnosed as CCC, with SC as the other major diagnostic consideration. All HER2+ (n = 25) cases were MMR-intact and most HER2+ EC had aberrant p53 staining (22/25, 88%); the 3 cases with a wild type pattern for p53 (12%) were all negative for ER. Based on these findings, patients with a diagnosis of CCC should be included in future clinical trials of HER2-targeted therapy. Moreover, given the diagnostic difficulty surrounding CCC, immunohistochemistry-based algorithms that include aberrant p53 and/or the absence of ER expression may provide a more objective means of establishing eligibility criteria than is currently possible using traditional histologic classification.

New Pathological and Clinical Insights in Endometrial Cancer in View of the Updated ESGO/ESTRO/ESP Guidelines

“…In the p53abn group, HER-2 amplification has been described in a subset of SEC [ 92 ]; anti-HER-2 targeted therapy with trastuzumab has shown promising results in these tumors [ 93 ]. Since HER-2 overexpression has also been described in UCS (which is p53abn in most cases) and in p53abn CCEC, it is possible that these tumors may be sensitive to anti-HER-2 targeted therapy [ 94 , 95 ]. Furthermore, a subset of p53abn carcinomas shows high DNA damage and high PARP-1 expression, offering the possibility of using PARP-inhibitors to treat these cases [ 96 ].…”

HER2 evaluation for clinical decision making in human solid tumours: pearls and pitfalls

“…These findings have prompted discussion about triaging all p53-abnormal "serous-like" tumours for HER2 analysis, instead of using a morphology approach based on identification of serous morphology, which is subject to interobserver bias, and may potentially exclude patients who might otherwise qualify for HER2-targeted therapies. 82,[86][87][88][89] HER2-positivity rates are much lower in ovarian high-grade serous carcinoma than in USC, with overexpression/amplification seen in only 2%-4% of cases, and low response rates in those treated with targeted therapy. [91][92][93] Limited data also suggest low HER2positivity rates in ovarian carcinosarcoma, at less than 10%.…”

“…82 For instance, similar rates of HER2 overexpression to that seen in USC has been reported in other high-grade endometrial cancers, with one study (N = 790) demonstrating HER2 overexpression in 30% of clear cell carcinomas, 23% of carcinosarcomas, and 21% of high-grade endometrioid carcinomas, compared to 11% of low-grade endometrioid carcinomas. 85 The recent literature has identified a strong association of TP53 mutations with HER2-amplified endometrial carcinomas with high-grade histology (USC, clear cell carcinoma, carcinosarcomas, and high-grade endometrioid carcinomas), 82,[85][86][87][88][89][90] with coexisting TP53 mutations in as high as 95% of HER2-positive cases. These findings have prompted discussion about triaging all p53-abnormal "serous-like" tumours for HER2 analysis, instead of using a morphology approach based on identification of serous morphology, which is subject to interobserver bias, and may potentially exclude patients who might otherwise qualify for HER2-targeted therapies.…”

The role of TCGA molecular classification in clear cell endometrial carcinoma

“…Furthermore, since HER-2 overexpression has been described in the p53abn CCEC, it is possible that the subgroup may be sensitive to anti-HER-2 targeted therapy ( 27 , 44 ). Additionally, a subset of p53abn ECs (including CCECs) shows high DNA damage and high PARP-1 expression, offering the possibility of using PARP-inhibitors to treat these cases ( 27 , 45 ).…”