Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups

Abstract

Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroups: p53 abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96 y). Federation Internationale de Gynecologie et d'Obstetrique stages (2009) were as follows: IA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0 y). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OS: hazard ratio [HR], 0.36 [95% confidence interval, 0.18-0.70]; P=0.003; RFS: HR, 0.17 [0.05-0.54]; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 [1.09-2.74]; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as follows: POLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five-year RFS rates were as follows: POLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et d'Obstetrique stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications.

Clinicopathological and molecular characterisation of ‘multiple‐classifier’ endometrial carcinomas

“…We obtained patient data and tumour tissue from ECs with more than one classifying feature (a pathogenic POLE exonuclease domain variant, MMR protein loss of expression or p53 abnormal expression) from previously published datasets [1,10,12,13,16,17]. A total of 2988 ECs had been molecularly classified in previous studies [10,12,13,16,17], in which MMR and p53 status were determined by immunohistochemistry (IHC) and POLE variants by Sanger sequencing or NGS of the complete exonuclease domain (exons [9][10][11][12][13][14] or targeted sequencing of exons 9, 13, and 14. For this current study, all POLE variants were reviewed and tumours were excluded when the POLE variant was not considered pathogenic following the recommended approach presented by León-Castillo et al [18].…”

Incorporation of molecular characteristics into endometrial cancer management

“…Although substantial LVSI has been described in all molecular EC groups, an association between the presence of substantial LVSI and MMRd has been noted, with a reported prevalence of substantial LVSI in up to 8.9% of MMRd EC ( P = 0.002) . This association may explain the fact that a relatively large proportion of high‐stage EC fall within the MMRd subgroup . How MMRd leads to LVSI in EC is not well understood, but it may be the result of frequent epithelial‐to‐mesenchymal transition in MMRd EC …”

“…A paradoxical scenario occurs when a morphological low‐grade endometrioid EC shows molecular characteristics associated with aggressive clinical behaviour, such as abnormal mutant‐type p53 staining. This is a rare finding in low‐grade EEC, as it is reported in 2–15% of glandular EEC with low nuclear grade, whereas it is a more common finding (10–15%) in high‐grade EECs . Two examples of low‐grade EEC with TP53 mutations and abnormal p53‐IHC are shown in Figure .…”

“…5,35 This association may explain the fact that a relatively large proportion of high-stage EC fall within the MMRd subgroup. 36 How MMRd leads to LVSI in EC is not well understood, but it may be the result of frequent epithelial-to-mesenchymal transition in MMRd EC. 37…”

“…This is a rare finding in low-grade EEC, as it is reported in 2-15% of glandular EEC with low nuclear grade, 5,6,21,29,44,45 whereas it is a more common finding (10-15%) in high-grade EECs. 36 Two examples of low-grade EEC with TP53 mutations and abnormal p53-IHC are shown in Figure 4. Both these tumours were diffusely positive for hormone receptors and showed loss of PTEN immunostaining, supporting the 'endometrioid' classification.…”