Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: Impact on adjuvant therapy

Creutzberg, Carien L.; León‐Castillo, Alicia; Boer, Stephanie M. de; Powell, Melanie; Mileshkin, Linda; Mackay, Helen; Leary, Alexandra; Nijman, HW; Singh, Naresh Pal; Pollock, Pamela M.; Fyles, Anthony; Haie-Méder, Christine; Smit, Vincent T.H.B.M.; Edmondson, RJ; Putter, Hein; Kitchener, H.; Crosbie, Emma J.; Bruyn, Marco de; Nout, R.; Bosse, Tjalling

doi:10.1093/annonc/mdz394.060

Cited by 18 publications

(29 citation statements)

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“…It has been suggested that POLE mut EC are immunogenic due to their high mutational load, which may be a more plausible explanation for the unusually low chance of recurrences observed in these patients . Importantly, in addition to the excellent prognosis of intermediate‐risk POLE mut EC, similar survival rates have now been reported for patients with high‐risk POLE mut EC . This consistent finding of excellent clinical outcomes in POLE mut ECs raises the question of whether these patients may be unnecessarily exposed to unwanted side‐effects of radio‐ and/or chemotherapy .…”

Section: Polemut High‐grade Endometrial Carcinomamentioning

confidence: 64%

“…The results of the ongoing PORTEC4a will show if this is a valid approach for patients with intermediate‐risk POLE mut EC. For high‐risk POLE mut EC, the recently presented molecular characterisation of the PORTEC‐3 trial has been highly informative . Patients with POLE mut EC showed an excellent prognosis independent of the treatment arm (EBRT versus CTRT), supporting omitting the addition of chemotherapy for patients with high‐risk POLE mut EC.…”

Section: Polemut High‐grade Endometrial Carcinomamentioning

confidence: 99%

“…Histologically, MMRd EC show similarities to POLE mut EC in that these are also associated with higher‐grade, endometrioid‐type histology and abundance of tumour‐infiltrating lymphocytes (TILs) . MMRd EC, however, have an intermediate prognosis, which significantly differs from POLE mut EC . Long‐term analysis of the PORTEC‐2 trial – comparing adjuvant VBT with EBRT in high–intermediate risk (HIR) EC – found that VBT was equally effective in preventing pelvic lymph node recurrences in the absence of unfavourable risk factors (p53abn, L1CAM, substantial LVSI), thus including HIR MMRd ECs having a very low absolute risk .…”

Section: Mmrd Endometrioid Endometrial Cancermentioning

confidence: 99%

“…Long‐term analysis of the PORTEC‐2 trial – comparing adjuvant VBT with EBRT in high–intermediate risk (HIR) EC – found that VBT was equally effective in preventing pelvic lymph node recurrences in the absence of unfavourable risk factors (p53abn, L1CAM, substantial LVSI), thus including HIR MMRd ECs having a very low absolute risk . In addition, for patients with HR MMRd EC, EBRT provides good pelvic control, and additional chemotherapy does not seem to improve prognosis . An example illustrated in Figure depicts a case of a stage IB MMRd EEC with unequivocal lymphovascular space invasion (LVSI).…”

Section: Mmrd Endometrioid Endometrial Cancermentioning

confidence: 99%

“…The reported poor clinical outcomes have been the rationale to propose adjuvant treatment escalation from VBT to EBRT in the PORTEC‐4a trial for high–intermediate‐risk EC patients in the uncommon scenario of mutant‐like p53 immunostaining in these patients. For high‐risk patients with a p53mut EC, such as those enrolled in the PORTEC‐3 trial, further treatment escalation by additional chemotherapy significantly improves clinical outcomes (5‐year RFS with CTRT 61 versus 37% for RT) …”

Section: P53 Mutant Low‐grade Endometrioid Endometrial Carcinomamentioning

confidence: 99%

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Incorporation of molecular characteristics into endometrial cancer management

et al. 2019

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Histopathological evaluation including subtyping and grading is the current cornerstone for endometrial cancer (EC) classification. This provides clinicians with prognostic information and input for further treatment recommendations. Nonetheless, patients with histologically similar ECs may have very different outcomes, notably in patients with high‐grade endometrial carcinomas. For endometrial cancer, four molecular subgroups have undergone extensive studies in recent years: POLE ultramutated (POLEmut), mismatch repair‐deficient (MMRd), p53 mutant (p53abn) and those EC lacking any of these alterations, referred to as NSMP (non‐specific molecular profile). Several large studies confirm the prognostic relevance of these molecular subgroups. However, this ‘histomolecular’ approach has so far not been implemented in clinical routine. The ongoing PORTEC4a trial is the first clinical setting in which the added value of integrating molecular parameters in adjuvant treatment decisions will be determined. For diagnostics, the incorporation of the molecular parameters in EC classification will add a level of objectivity which will yield biologically more homogeneous subclasses. Here we illustrate how the management of individual EC patients may be impacted when applying the molecular EC classification. We describe our current approach to the integrated diagnoses of EC with a focus on scenarios with conflicting morphological and molecular findings. We also address several pitfalls accompanying the diagnostic implementation of molecular EC classification and give practical suggestions for diagnostic scenarios.

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Section: Polemut High‐grade Endometrial Carcinomamentioning

confidence: 64%

Section: Polemut High‐grade Endometrial Carcinomamentioning

confidence: 99%

Section: Mmrd Endometrioid Endometrial Cancermentioning

confidence: 99%

Section: Mmrd Endometrioid Endometrial Cancermentioning

confidence: 99%

Section: P53 Mutant Low‐grade Endometrioid Endometrial Carcinomamentioning

confidence: 99%

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Incorporation of molecular characteristics into endometrial cancer management

et al. 2019

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Molecular subtypes of endometrial cancer: Implications for adjuvant treatment strategies

Yang

Bao

2023

Intl J Gynecology & Obste

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BackgroundWhen determining adjuvant treatment for endometrial cancer, the decision typically relies on factors such as cancer stage, histologic grade, subtype, and a few histopathologic markers. The Cancer Genome Atlas revealed molecular subtyping of endometrial cancer, which can provide more accurate prognostic information and guide personalized treatment plans.ObjectiveTo summarize the expression and molecular basis of the main biomarkers of endometrial cancer.Search StrategyPubMed was searched from January 2000 to March 2023.Selection CriteriaStudies evaluating molecular subtypes of endometrial cancer and implications for adjuvant treatment strategies.Data Collection and AnalysisThree authors independently performed a comprehensive literature search, collected and extracted data, and assessed the methodological quality of the included studies.Main ResultsWe summarized the molecular subtyping of endometrial cancer, including mismatch repair deficient, high microsatellite instability, polymerase epsilon (POLE) exonuclease domain mutated, TP53 gene mutation, and non‐specific molecular spectrum. We also summarized planned and ongoing clinical trials and common therapy methods in endometrial cancer. POLE mutated endometrial cancer consistently exhibits favorable patient outcomes, regardless of adjuvant therapy. Genomic similarities between p53 abnormality endometrial cancer and high‐grade serous ovarian cancer suggested possible overlapping treatment strategies. High levels of immune checkpoint molecules, such as programmed cell death 1 and programmed cell death 1 ligand 1 can counterbalance mismatch repair deficient endometrial cancer immune phenotype. Hormonal treatment is an appealing option for high‐risk non‐specific molecular spectrum endometrial cancers, which are typically endometrioid and hormone receptor positive. Combining clinical and pathologic characteristics to guide treatment decisions for patients, including concurrent radiochemotherapy, chemotherapy, inhibitor therapy, endocrine therapy, and immunotherapy, might improve the management of endometrial cancer and provide more effective treatment options for patients.ConclusionsWe have characterized the molecular subtypes of endometrial cancer and discuss their value in terms of a patient‐tailored therapy in order to prevent significant under‐ or overtreatment.

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The impact of wait times on oncological outcome in high‐risk patients with endometrial cancer

Mitric

Matanes

Wissing

et al. 2020

Journal of Surgical Oncology

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Objective To evaluate the impact of surgical wait times on outcome of patients with grade 3 endometrial cancer. Methods All consecutive patients surgically treated for grade 3 endometrial cancer between 2007 and 2015 were included. Patients were divided into two groups based on the time interval between endometrial biopsy and surgery: wait time from biopsy to surgery ≤12 weeks (84 days) vs more than 12 weeks. Survival analyses were conducted using log‐rank tests and Cox proportional hazards models. Results A total of 136 patients with grade 3 endometrial cancer were followed for a median of 5.6 years. Fifty‐one women (37.5%) waited more than 12 weeks for surgery. Prolonged surgical wait times were not associated with advanced stage at surgery, positive lymph nodes, increased lymphovascular space invasion, and tumor size (P = .8, P = 1.0, P = .2, P = .9, respectively). In multivariable analysis adjusted for clinical and pathological factors, wait times did not significantly affect disease‐specific survival (adjusted hazard ratio [HR]: 1.2, 95% confidence interval [CI], 0.6‐2.5, P = .6), overall survival (HR: 1.1, 95% CI, 0.6‐2.1, P = .7), or progression‐free survival (HR: 0.9, 95% CI, 0.5‐1.7, P = .8). Conclusion Prolonged surgical wait time for poorly differentiated endometrial cancer seemed to have a limited impact on clinical outcomes compared to biological factors.

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Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: Impact on adjuvant therapy

Cited by 18 publications

References 0 publications

Incorporation of molecular characteristics into endometrial cancer management

Incorporation of molecular characteristics into endometrial cancer management

Molecular subtypes of endometrial cancer: Implications for adjuvant treatment strategies

The impact of wait times on oncological outcome in high‐risk patients with endometrial cancer

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