Molecular risk stratification to direct therapy in endometrial cancer: ready for the clinic?
Authors: C.L. Creutzberg, T. Bosse
Journal: Annals of Oncology (2018)

The Cancer Genome Atlas (TGCA) studies have defined the molecular genetic landscape of endometrial cancer and highlighted the molecular genetic diversity of both endometrioid and non-endometroid cancers [1.Kandoth C. Schultz N. Cherniack A.D. et al.Integrated genomic characterization of endometrial carcinoma.Nature. 2013; 497: 67-73Crossref PubMed Scopus (3038) Google Scholar]. The TCGA established four distinct endometrial cancer subclasses based on the extent of mutational load and somatic copy number alterations. The first molecular subclass of ultramutated cancers is characterised by mutations in the exonuclease domain of DNA polymerase epsilon (POLE), which has evoked substantial interest and specific research, as these cancers have an exceptionally good prognosis with very few recurrences despite mostly being high grade [2.Church D.N. Stelloo E. Nout R.A. et al.Prognostic significance of POLE proofreading mutations in endometrial cancer.J Natl Cancer Inst. 2015; 107: 402Crossref PubMed Scopus (205) Google Scholar]. The second subclass is characterised by mismatch-repair deficiency (MMRD), mostly as a consequence of MLH1 promoter hypermethylation but also including cancers that arise in the context of germline mutations in one of the MMR-genes (Lynch syndrome). The third subclass is characterised by high copy number alterations and TP53 mutations and contains typically serous cancers but also grade 3 endometrioid cancers. The remaining subgroup, referred to as ‘copy number low’ group by TGCA, is molecularly heterogeneous with Wnt- and PI3/AKt-alterations, and includes most prototypical low grade endometrioid endometrial cancers [1.Kandoth C. Schultz N. Cherniack A.D. et al.Integrated genomic characterization of endometrial carcinoma.Nature. 2013; 497: 67-73Crossref PubMed Scopus (3038) Google Scholar]. As these four subclasses have distinct biological properties with specific clinical implications, the development of clinically available, reproducible and affordable tumour tests to identify these subclasses and confirm their prognostic significance have been priorities in subsequent research. Several international collaborative groups have shown that they could successfully determine the four TGCA subclasses on formalin-fixed, paraffin-embedded tissues with cheaper, reproducible, more rapid and clinically available techniques, and have confirmed their prognostic significance [3.Stelloo E. Nout R.A. Osse E.M. et al.Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC Cohorts.Clin Cancer Res. 2016; 22: 4215-4224Crossref PubMed Scopus (400) Google Scholar, 4.Talhouk A. McConechy M.K. Leung S. et al.A clinically applicable molecular-based classification for endometrial cancers.Br J Cancer. 2015; 113: 299-310Crossref PubMed Scopus (431) Google Scholar]. Recent studies have shown that the additional value of an integrated molecular classification is particularly strong in patients that would currently be regarded as intermediate risk, while data on low- and high-risk endometrial cancer are still limited [5.Stelloo E. Bosse T. Nout R.A. et al.Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative.Mod Pathol. 2015; 28: 836-844Crossref PubMed Scopus (278) Google Scholar]. In the current issue of Annals of Oncology, Kommoss et al. report on the final validation step in the development process of a molecular classifier for endometrial cancer [6.Kommoss S. McConechy M.K. Kommoss F. et al.Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series.Ann Oncol. 2018; 29: 1180-1188Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar]. Their so-called Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE) has been shown to identify the four TCGA subclasses and to be applicable on both diagnostic and definitive specimens in previous studies [7.Talhouk A. Hoang L.N. McConechy M.K. et al.Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: earlier prognostic information to guide treatment.Gynecol Oncol. 2016; 143: 46-53Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 8.Talhouk A. McConechy M.K. Leung S. et al.Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer.Cancer. 2017; 123: 802-813Crossref PubMed Scopus (389) Google Scholar]. In their current study, an unselected retrospective German cohort of endometrial cancers has been used for independent validation, and the authors conclude that the classifier is now fully validated and ready for clinical evaluation. Strengths of their study are the comprehensive analysis and validation process according to the Institute of Medicine Guidelines, the confirmation of the concordance in diagnostic and surgical specimens, and the evaluation of the ProMisE classifier with other clinical and pathological variables. However, the validation study is still relatively small, as among the 452 evaluable cases, 62% had grade 1 and only 21% grade 3 tumours; 61% had very early disease stage (IA), and only 6% and 13% had stage II and III disease, respectively. This may be one of the reasons why the molecular classifier was significantly associated with progression-free survival, but not with overall survival. Just over 50% of their cohort were copy number low tumours (called p53wt by Kommoss), for which no additional prognostic information is obtained with the molecular classifier. Another important limitation is the lack of central pathology review [9.Manion E. Cohen M.B. Weydert J. Mandatory second opinion in surgical pathology referral material: clinical consequences of major disagreements.Am J Surg Pathol. 2008; 32: 732-737Crossref PubMed Scopus (112) Google Scholar]. The question remains how representative this low-risk validation group is for the women with high-risk endometrial cancers who would benefit most of the prognostic information and potential predictive role for molecular driven adjuvant therapies. Finally, a small subset of EC (1.8% in the study by Kommoss, 3%–4% in other studies) [3.Stelloo E. Nout R.A. Osse E.M. et al.Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC Cohorts.Clin Cancer Res. 2016; 22: 4215-4224Crossref PubMed Scopus (400) Google Scholar, 10.Bosse T. Nout R.A. McAlpine J.N. et al.Molecular classification of grade 3 endometrioid endometrial cancers identifies distinct prognostic subgroups.Am J Surg Pathol. 2018; (Mar 2 [Epub ahead of print] doi 101097/PAS0000000000001020)Crossref Scopus (152) Google Scholar] remains unclassifiable due to multiple mutations (e.g. POLE and TP53 mutation). This warrants further investigation, as the proposed ProMisE decision tree that dictates the order in which tumours are assigned to a specific type seems not to be based on specific data. Is this the final step and should molecular classification of endometrial cancer now be considered standard to inform and determine patient management? Due to the retrospective nature of the studies, the molecular classifiers can be used to refine prognosis in women with intermediate-risk endometrial cancer, but data for those with high-risk, non-endometrioid (e.g. clear cell) cancers or with advanced stage of disease are still limited [10.Bosse T. Nout R.A. McAlpine J.N. et al.Molecular classification of grade 3 endometrioid endometrial cancers identifies distinct prognostic subgroups.Am J Surg Pathol. 2018; (Mar 2 [Epub ahead of print] doi 101097/PAS0000000000001020)Crossref Scopus (152) Google Scholar]. An additional concern is which prognostic parameters other than the four molecular subclasses should be taken into account in clinical patient management [3.Stelloo E. Nout R.A. Osse E.M. et al.Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC Cohorts.Clin Cancer Res. 2016; 22: 4215-4224Crossref PubMed Scopus (400) Google Scholar, 11.Karnezis A.N. Leung S. Magrill J. et al.Evaluation of endometrial carcinoma prognostic immunohistochemistry markers in the context of molecular classification.J Pathol Clin Res. 2017; 3: 279-293Crossref PubMed Scopus (56) Google Scholar]. This is particularly relevant for the 50% of cases that ProMisE could not classify as they were ‘p53 wildtype’. Overexpression of L1 cell adhesion molecule (L1CAM) and mutations in exon3 of CTNNB1 have been shown in multiple studies to have significant impact on the risk of recurrence and endometrial cancer-related death [12.Zeimet A.G. Reimer D. Huszar M. et al.L1CAM in early-stage type I endometrial cancer: results of a large multicenter evaluation.J Natl Cancer Inst. 2013; 105: 1142-1150Crossref PubMed Scopus (165) Google Scholar, 13.Bosse T. Nout R.A. Stelloo E. et al.L1 cell adhesion molecule is a strong predictor for distant recurrence and overall survival in early stage endometrial cancer: pooled PORTEC trial results.Eur J Cancer. 2014; 50: 2602-2610Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 14.van der Putten L.J.M. Visser N.C.M. van de Vijver K. et al.Added value of estrogen receptor, progesterone receptor, and L1 cell adhesion molecule expression to histology-based endometrial carcinoma recurrence prediction models: an ENITEC Collaboration Study.Int J Gynecol Cancer. 2018; 28: 514-523Crossref PubMed Scopus (34) Google Scholar]. L1CAM overexpression is often associated with, but independent from TP53 mutation [15.Van Gool I.C. Stelloo E. Nout R.A. et al.Prognostic significance of L1CAM expression and its association with mutant p53 expression in high-risk endometrial cancer.Mod Pathol. 2016; 29: 174-181Crossref PubMed Scopus (52) Google Scholar]. TP53 wildtype EC with L1CAM positivity or with CTNNB1 mutations would need to be identified to avoid undertreatment. Finally, many of the traditional prognostic factors such as depth of invasion or histological grade, which are subject to interobserver variations in their assignment [9.Manion E. Cohen M.B. Weydert J. Mandatory second opinion in surgical pathology referral material: clinical consequences of major disagreements.Am J Surg Pathol. 2008; 32: 732-737Crossref PubMed Scopus (112) Google Scholar, 16.Gilks C.B. Oliva E. Soslow RA. Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma.Am J Surg Pathol. 2013; 37: 874-881Crossref PubMed Scopus (250) Google Scholar, 17.Scholten A.N. Smit V.T.H.B.M. Beerman H. et al.Prognostic significance and interobserver variability of histologic grading systems for endometrial carcinoma.Cancer. 2004; 100: 764-772Crossref PubMed Scopus (106) Google Scholar], may become less important in the presence of the new molecular integrated classification, but lymph-vascular space invasion has remained an independent and powerful prognostic parameter. It is associated with a higher risk of microscopic lymph node involvement, but also with up to fivefold risk of recurrence and reduced survival in absence of lymph node involvement, and quantification of LVSI has been shown to have clinical relevance [18.Briet J.M. Hollema H. Reesink N. et al.Lymphvascular space involvement: an independent prognostic factor in endometrial cancer.Gynecol Oncol. 2005; 96: 799-804Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 19.Bosse T. Peters E.E. Creutzberg C.L. et al.Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial cancer - a pooled analysis of PORTEC 1 and 2 trials.Eur J Cancer. 2015; 51: 1742-1750Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar]. Indeed Kommoss et al. reported that the ESMO 2016 risk group [20.Colombo N. Creutzberg C. Amant F. et al.ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow-up.Ann Oncol. 2016; 27: 16-41Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar] was more strongly associated with overall and disease-free survival than the ProMisE classifier alone, and that the C-index was further improved when the molecular classifier was augmented with other clinical parameters, which has also been reported by Stelloo et al. [3.Stelloo E. Nout R.A. Osse E.M. et al.Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC Cohorts.Clin Cancer Res. 2016; 22: 4215-4224Crossref PubMed Scopus (400) Google Scholar]. The results of the study by Kommoss et al. give compelling and urgent rationale for further well-designed clinical studies of the use of these new molecular markers to direct patient management. First small studies of targeted therapies, especially immunological treatment by checkpoint inhibition of patients with recurrent disease and POLE or MMRD phenotypes have shown promising results [21.Le D.T. Durham J.N. Smith K.N. et al.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science. 2017; 357: 409-413Crossref PubMed Scopus (3808) Google Scholar]. The first prospective randomised trial using molecular characteristics to determine adjuvant radiotherapy in women with early stage, intermediate risk endometrial cancer, the PORTEC-4a trial, is ongoing. Other studies are being designed by international groups, and would especially benefit from strong international collaboration as they should ideally address the role of the molecular integrated classifiers to inform and direct treatment of specific subgroups, both in treatment of primary and recurrent disease. No funding was received for the writing of this manuscript. Previous translational studies by our group were funded by a Dutch Cancer Society grant (UL2012-5719). Dr Bosse’s current translational work is supported by a Dutch Cancer Society Young Investigators Grant (31648).