Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series

Kommoss, Stefan; McConechy, Melissa K.; Kommoss, Friedrich; Leung, Samuel; Bunz, Anne-Kathrin; Magrill, Jamie; Britton, Heidi; Grevenkamp, Friederike; Karnezis, Anthony N.; Yang, Winnie; Lum, Amy; Krämer, B.; Taran, Florin Andrei; Staebler, Annette; Lax, Sigurd; Brucker, Sara; Huntsman, David G.; Gilks, C Blake; McAlpine, Jessica N.; Talhouk, Aline

doi:10.1093/annonc/mdy058

Cited by 448 publications

(454 citation statements)

References 24 publications

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“…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 .…”

Section: P53 Mutant Low‐grade Endometrioid Endometrial Carcinomamentioning

confidence: 92%

“…MMR deficiency is frequent in EC (25–30%) and defined by the loss of nuclear expression of one or more MMR proteins (MLH1, PMS2, MSH6 and PMS2) by the tumour cells . Reflex testing for MMR status is increasingly recommended by (inter)national guidelines for the identification of patients (and families) who are at high risk of having Lynch syndrome .…”

Section: Mmrd Endometrioid Endometrial Cancermentioning

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: P53 Mutant Low‐grade Endometrioid Endometrial Carcinomamentioning

confidence: 92%

Section: Mmrd Endometrioid Endometrial Cancermentioning

confidence: 99%

Incorporation of molecular characteristics into endometrial cancer management

et al. 2019

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“…The 2 systems differ with respect to the order in which component assays are performed as well as the assay technologies used to for categorization (ie, P53 status based on IHC vs mutational analyses). The PRoMise molecular classifier has recently been validated in a larger, population‐based case series with good results …”

Section: Prognostic Factorsmentioning

confidence: 99%

Current recommendations and recent progress in endometrial cancer

Brooks

Fleming

Lastra

et al. 2019

CA A Cancer J Clinicians

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Endometrial cancer is the most common gynecologic cancer in the United States, and its incidence is rising. Although there have been significant recent advances in our understanding of endometrial cancer biology, many aspects of treatment remain mired in controversy, including the role of surgical lymph node assessment and the selection of patients for adjuvant radiation or chemotherapy. For the subset of women with microsatellite‐instable, metastatic disease, anti– programmed cell death protein 1 immunotherapy (pembrolizumab) is now approved by the US Food and Drug Administration, and numerous trials are attempting to build on this early success.

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“…Recently, The Cancer Genome Atlas (TCGA) identified four distinct subgroups based on genomic background, including an “ultramutated” subgroup associated with mutations in the exonuclease domain of polymerase‐ε ( POLE ); a microsatellite‐instable subgroup, with deficiency of one or more mismatch repair proteins; a copy number‐high subgroup with frequent p53 mutations; and a copy number‐low subgroup . These molecular subgroups categorize patients with distinct prognoses, but so far TCGA classification has not been studied in relation to the risk estimation of LNM . Several guidelines, including the European Society of Medical Oncology, European Society of Gynecological Oncology, European Society for Radiotherapy and Oncology (ESMO‐ESGO‐ESTRO) consensus conference guideline, incorporate measurement of cancer antigen 125 (Ca‐125) and/or assessment of lymphadenopathy by imaging as part of preoperative workup .…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Accuracy of Clinical Biomarkers for Preoperative Prediction of Lymph Node Metastasis in Endometrial Carcinoma: A Systematic Review and Meta-Analysis

et al. 2019

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Background In endometrial carcinoma (EC), preoperative classification is based on histopathological criteria, with only moderate diagnostic performance for the risk of lymph node metastasis (LNM). So far, existing molecular classification systems have not been evaluated for prediction of LNM. Optimized use of clinical biomarkers as recommended by international guidelines might be a first step to improve tailored treatment, awaiting future molecular biomarkers. Aim To determine the diagnostic accuracy of preoperative clinical biomarkers for the prediction of LNM in endometrial cancer. Methods A systematic review was performed according to the Meta‐analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Studies identified in MEDLINE and EMBASE were selected by two independent reviewers. Included biomarkers were based on recommended guidelines (cancer antigen 125 [Ca‐125], lymphadenopathy on magnetic resonance imaging, computed tomography, and 18F‐fluorodeoxyglucose positron emission tomography/computed tomography [18FDG PET‐CT]) or obtained by physical examination (body mass index, cervical cytology, blood cell counts). Pooled sensitivity, specificity, area under the curve (AUC), and likelihood ratios were calculated with bivariate random‐effects meta‐analysis. Likelihood ratios were classified into small (0.5–1.0 or 1–2.0), moderate (0.2–0.5 or 2.0–5.0) or large (0.1–0.2 or ≥ 5.0) impact. Results Eighty‐three studies, comprising 18,205 patients, were included. Elevated Ca‐125 and thrombocytosis were associated with a moderate increase in risk of LNM; lymphadenopathy on imaging with a large increase. Normal Ca‐125, cytology, and no lymphadenopathy on 18FDG PET‐CT were associated with a moderate decrease. AUCs were above 0.75 for these biomarkers. Other biomarkers had an AUC <0.75 and incurred only small impact. Conclusion Ca‐125, thrombocytosis, and imaging had a large and moderate impact on risk of LNM and could improve preoperative risk stratification. Implications for Practice Routine lymphadenectomy in clinical early‐stage endometrial carcinoma does not improve outcome and is associated with 15%–20% surgery‐related morbidity, underlining the need for improved preoperative risk stratification. New molecular classification systems are emerging but have not yet been evaluated for the prediction of lymph node metastasis. This article provides a robust overview of diagnostic performance of all clinical biomarkers recommended by international guidelines. Based on these, at least measurement of cancer antigen 125 serum level, assessment of thrombocytosis, and imaging focused on lymphadenopathy should complement current preoperative risk stratification in order to better stratify these patients by risk.

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Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series

Cited by 448 publications

References 24 publications

Incorporation of molecular characteristics into endometrial cancer management

Incorporation of molecular characteristics into endometrial cancer management

Current recommendations and recent progress in endometrial cancer

Diagnostic Accuracy of Clinical Biomarkers for Preoperative Prediction of Lymph Node Metastasis in Endometrial Carcinoma: A Systematic Review and Meta-Analysis

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