Evaluation of endometrial carcinoma prognostic immunohistochemistry markers in the context of molecular classification

Karnezis, Anthony N.; Leung, Samuel; Magrill, Jamie; McConechy, Melissa K.; Yang, Winnie; Chow, Christine; Köbel, Martin; Lee, Cheng‐Han; Huntsman, David G.; Talhouk, Aline; Kommoss, F; Gilks, C Blake; McAlpine, Jessica N.

doi:10.1002/cjp2.82

Cited by 88 publications

(86 citation statements)

References 45 publications

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“…The Cancer Genome Atlas (TCGA) identified four molecular subtypes of EC based on genomic alterations: (1) ultramutated/DNA polymerase ε mutated (POLEmut); (2) hypermutated/microsatellite instability; (3) low copy number abnormalities (CNlow); and (4) high copy number abnormalities (CN-high) [7]. Pathogenic variants in the exonuclease domain of POLE are used as a surrogate marker for the ultramutated group, while abnormal expression of mismatch repair proteins, recognised through loss of expression on immunostaining (DNA mismatch repair-deficient or MMRd), is a widely used clinical marker of the hypermutated/microsatellite instability group [9][10][11][12][13][14][15][16][17]. The presence of TP53 mutation characterises the CN-high group.…”

Section: Introductionmentioning

confidence: 99%

p53 immunohistochemistry is an accurate surrogate for TP53 mutational analysis in endometrial carcinoma biopsies

Singh

Piskorz

Bosse

et al. 2020

The Journal of Pathology

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TP53 mutations are considered a surrogate biomarker of the serous‐like ‘copy number high’ molecular subtype of endometrial carcinoma (EC). In ovarian carcinoma, p53 immunohistochemistry (IHC) accurately reflects mutational status with almost 100% specificity but its performance in EC has not been established. This study tested whether p53 IHC reliably predicts TP53 mutations identified by next‐generation sequencing (NGS) in EC biopsy samples for all ECs and as part of a molecular classification algorithm after exclusion of cases harbouring mismatch repair defects (MMRd) or pathogenic DNA polymerase epsilon exonuclease domain mutations (POLEmut). A secondary aim assessed inter‐laboratory variability in p53 IHC. From a total of 207 cases from five centres (37–49 cases per centre), p53 IHC carried out at a central reference laboratory was compared with local IHC (n = 164) and curated tagged‐amplicon NGS TP53 sequencing results (n = 177). Following consensus review, local and central p53 IHC results were concordant in 156/164 (95.1%) tumours. Discordant results were attributable to both interpretive and technical differences in staining between the local and central laboratories. When results were considered as any mutant pattern versus wild‐type pattern staining, however, there was disagreement between local and central review in only one case. The concordance between p53 IHC and TP53 mutation was 155/168 (92.3%) overall, and 117/123 (95.1%) after excluding MMRd and POLEmut EC. Three (3/6) discordant results were in serous carcinomas with complete absence of p53 staining but no detectable TP53 mutation. Subclonal mutant p53 IHC expression was observed in 9/177 (5.1%) cases, of which four were either MMRd or POLEmut. Mutant pattern p53 IHC was observed in 63/63 (100%) serous carcinomas that were MMR‐proficient/POLE exonuclease domain wild‐type. Optimised p53 IHC performs well as a surrogate test for TP53 mutation in EC biopsies, demonstrates excellent inter‐laboratory reproducibility, and has high clinical utility for molecular classification algorithms in EC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Introductionmentioning

confidence: 99%

p53 immunohistochemistry is an accurate surrogate for TP53 mutational analysis in endometrial carcinoma biopsies

Singh

Piskorz

Bosse

et al. 2020

The Journal of Pathology

Self Cite

216

189

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“…First, the CIN signature should be optimized on the basis of CIN25 and CIN70. Different adjuvant radiotherapy subgroups in the guidelines have different clinicopathological and molecular features ( (45), such as L1CAM, ER and PR, remain to be explored. It is unclear whether these features are still independent prognostic factors in our integrated model.…”

Section: Discussionmentioning

confidence: 99%

Integrating Pathology, Chromosomal Instability and Mutations for Risk Stratification in Early-stage Endometrioid Endometrial Carcinoma

Guo

et al. 2020

Preprint

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Background: Risk stratifications for endometrial carcinoma (EC) depend on histopathology and molecular pathology. Histopathological risk stratification lacks reproducibility, neglects heterogeneity and contributes little to surgical procedures. Existing molecular stratification is useless in patients with specific pathological or molecular characteristics and cannot guide postoperative adjuvant radiotherapies. Chromosomal instability (CIN), the numerical and structural alterations of chromosomes resulting from ongoing errors of chromosome segregation, is an intrinsic biological mechanism for the evolution of different prognostic factors of histopathology and molecular pathology and may be applicable to the risk stratification of EC.Results: By analyzing CIN25 and CIN70, two reliable gene expression signatures for CIN, we found that EC with unfavorable prognostic factors of histopathology or molecular pathology had serious CIN. However, the POLE mutant, as a favorable prognostic factor, had elevated CIN signatures, and the CTNNB1 mutant, as an unfavorable prognostic factor, had decreased CIN signatures. Only if these two mutations were excluded were CIN signatures strongly prognostic for outcomes in different adjuvant radiotherapy subgroups. Integrating pathology, CIN signatures and POLE/CTNNB1 mutation stratified stageⅠendometrioid EC into four groups with improved risk prognostication and treatment recommendations. Conclusions: We revealed the possibility of integrating histopathology and molecular pathology by CIN for risk stratification in early-stage EC. Our integrated risk model deserves further improvement and validation.

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“…They also provided detailed guidelines for adjuvant treatment and post treatment follow up. There is still place for immune therapy and targeted therapy in EC that will hopefully have positive impact on PFS and OS [34,35]. The next step should be an evaluation of patients treated for recurrence that were exposed to radiation and/or chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Adjuvant therapy for early endometrial cancer — who benefits the most from a radiation therapy?

et al. 2020

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Objectives: Since 1990s the number of patients diagnosed with endometrial cancer (EC) has doubled. The standard treatment method for treating early endometrial cancer is surgery. Some patients require a subsequent adjuvant therapy. In early endometrial cancers its application is limited to the populations with a high risk of recurrence. The aim of this study was to assess the effectiveness of early endometrial cancer treatment based on an analysis of 5-year follow up of EC patients. Material and methods:The analysis consisted in a retrospective non-randomized interventional study of patients treated for early endometrial cancer (FIGO stage IA, IB, II). Its end point was either local (small pelvis) or distant recurrence of the disease. Intervention involved an adjuvant treatment applied in selected patients according to the current guidelines for EC treatment. There was no randomization for adjuvant and non-adjuvant EC treatment. The study included a total of 419 patients treated for EC from 2010 to 2012.Results: The analysis revealed that 108 patients (25.8%) were diagnosed with the recurrent disease. Out of 112 patients treated for stage IA endometrial cancer 32 (28.6%) experienced recurrence. Out of 216 patients at FIGO Stage IB, recurrence was diagnosed in 38 (17.6%). In the group of 91 patients treated for FIGO stage II, EC the recurrence was diagnosed in 38 (41.2%) cases.conclusions: Early EC treatment results were unsatisfactory and should be improved. The best outcomes were achieved in patients with IA stage of EC who received a radiation therapy.

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Evaluation of endometrial carcinoma prognostic immunohistochemistry markers in the context of molecular classification

Cited by 88 publications

References 45 publications

p53 immunohistochemistry is an accurate surrogate for TP53 mutational analysis in endometrial carcinoma biopsies

p53 immunohistochemistry is an accurate surrogate for TP53 mutational analysis in endometrial carcinoma biopsies

Integrating Pathology, Chromosomal Instability and Mutations for Risk Stratification in Early-stage Endometrioid Endometrial Carcinoma

Adjuvant therapy for early endometrial cancer — who benefits the most from a radiation therapy?

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