Application of the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) to patients conservatively treated: Outcomes from an institutional series

Falcone, Francesca; Normanno, Nicola; Losito, Nunzia Simona; Scognamiglio, Giosuè; Abate, Riziero Esposito; Chicchinelli, Nicoletta; Casella, G.; Laurelli, Giuseppe; Scaffa, Cono; Greggi, Stefano

doi:10.1016/j.ejogrb.2019.07.013

Cited by 31 publications

(26 citation statements)

References 26 publications

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“…Marked inter-tumor and intra-tumor molecular heterogeneity have been reported in lowgrade endometrial tumors (57)(58)(59) . Intra-tumor heterogeneity may vary between molecular markers as one study reported >95% concordance between three tumor blocks for POLE and CTNNB1 mutation status and MMR protein expression, whilst concordance for p53 and L1CAM (L1 cell adhesion molecule) protein expression was 91-94%, supporting the use of select biomarkers in clinical decision-making (60) .…”

Section: Classification Of Endometrial Cancer and Its Limitationsmentioning

confidence: 99%

Improving response to progestin treatment of low-grade endometrial cancer

Baxter

Brennan

McAlpine

et al. 2020

Int J Gynecol Cancer

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ObjectivesThis review examines how response rates to progestin treatment of low-grade endometrial cancer can be improved. In addition to providing a brief overview of the pathogenesis of low-grade endometrial cancer, we discuss limitations in the current classification of endometrial cancer and how stratification may be refined using molecular markers to reproducibly identify ‘low-risk’ cancers which may represent the best candidates for progestin therapy. We also discuss constraints in current approaches to progestin treatment of low-grade endometrial cancer and perform a systematic review of predictive biomarkers.MethodsPubMed, ClinicalTrials.gov, and Cochrane Library were searched for studies reporting pre-treatment biomarkers associated with outcome in women with low-grade endometrial cancer or endometrial hyperplasia with an intact uterus who received progestin treatment. Studies of fewer than 50 women were excluded. The study protocol was registered in PROSPERO (ID 152374). A descriptive synthesis of pre-treatment predictive biomarkers reported in the included studies was conducted.ResultsOf 1908 records reviewed, 19 studies were included. Clinical features such as age or body mass index cannot predict progestin response. Lesions defined as ‘low-risk’ by FIGO criteria (stage 1A, grade 1) can respond well; however, the reproducibility and prognostic ability of the current histopathological classification system is suboptimal. Molecular markers can be reproducibly assessed, have been validated as prognostic biomarkers, and may inform patient selection for progestin treatment. DNA polymerase epsilon (POLE)-ultramutated tumors and a subset of p53 wild-type or DNA mismatch repair (MMR)-deficient tumors with ‘low-risk’ features (eg, progesterone and estrogen receptor-positive) may have improved response rates, though this needs to be validated.DiscussionMolecular markers can identify cases which may be candidates for progestin treatment. More work is needed to validate these biomarkers and potentially identify new ones. Predictive biomarkers are anticipated to inform future research into progestin treatment of low-grade endometrial cancer and ultimately improve patient outcomes.

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Section: Classification Of Endometrial Cancer and Its Limitationsmentioning

confidence: 99%

Improving response to progestin treatment of low-grade endometrial cancer

Baxter

Brennan

McAlpine

et al. 2020

Int J Gynecol Cancer

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“…International guidelines have introduced the microsatellite instability and/or MMR immunohistochemistry (IHC) screening in all patients with EC, especially in those younger than 50 years of age, with approximately 90% concordance between germline analysis and IHC [ 1 ]. Moreover, it has been reported that these molecular analyses work successfully also on resectoscopic specimens of EC patients candidate for conservative treatment, allowing a reliable and early hereditary cancer risk assessment [ 39 ]. In spite of the considerations above, genetic analyses (MMR IHC with or without germline LS testing) were performed in only one-fourth of our patients, with a positive rate for germline mutations in one out of five.…”

Section: Discussionmentioning

confidence: 99%

“…This is a study limitation and is mostly due to the relatively long time of enrolment. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has been recently reported in a small series of G1 EC conservatively treated suggesting a potential role for a more reliable prognostic information [39]. The application of ProMisE could be even more appropriate in G2 EC.…”

Section: Endometrial Cancer Conservative Managementmentioning

confidence: 99%

Fertility-sparing treatment for intramucous, moderately differentiated, endometrioid endometrial cancer: a Gynecologic Cancer Inter-Group (GCIG) study

et al. 2020

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Objective: 'The Endometrial Cancer Conservative Treatment (E.C.Co.). A multicentre archive' is a worldwide project endorsed by the Gynecologic Cancer Inter-Group, aimed at registering conservatively treated endometrial cancer (EC) patients. This paper reports the oncological and reproductive outcomes of intramucous, G2, endometrioid EC patients from this archive. Methods: Twenty-three patients (Stage IA, G2, endometrioid EC) were enrolled between January 2004 and March 2019. Primary and secondary endpoints were, respectively, complete regression (CR) and recurrence rates, and pregnancy and live birth rates. Results: A median follow-up of 35 months (9-148) was achieved. Hysteroscopic resection (HR) plus progestin was adopted in 74% (17/23) of cases. Seventeen patients showed CR (median time to CR, 6 months; 3-13). Among the 6 non-responders, one showed persistence and 5 progressed, all submitted to definitive surgery, with an unfavorauble outcome in one. The recurrence rate was 41.1%. Ten (58.8%) complete responders attempted to conceive, of whom 3 achieved at least one pregnancy with a live-birth. Two out of the 11 candidate patients underwent definitive surgery, while the remaining 9 have so far refused. To date, 22 patients show no evidence of disease, and one is still alive with disease. Conclusions: Fertility-sparing treatment seems to be feasible even in G2 EC, although caution should be kept considering the potential pathological undergrading or non-endometrioid

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“…ProMisE approximates TCGA categorizations, including survival curves, using single gene sequencing of POLE and protein expression analysis via immunohistochemistry, and it is a clinically feasible method to identify TCGA groups [ 21 , 22 , 23 ]. To date, molecular classification has been applied to endometrial cancer patients receiving standard-of-care therapy with hysterectomy and used to describe the frequency of molecular alterations in hormonally treated endometrial cancers [ 24 , 25 ]. This molecular classification has not been previously applied to patients with EIN.…”

Section: Introductionmentioning

confidence: 99%

Molecular Classification to Prognosticate Response in Medically Managed Endometrial Cancers and Endometrial Intraepithelial Neoplasia

Puechl

Spinosa

Berchuck

et al. 2021

Cancers

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Background: The aim of this study was to evaluate whether molecular classification prognosticates treatment response in women with endometrial cancers and endometrial intraepithelial neoplasia (EIN) treated with levonorgestrel intrauterine system (LNG-IUS). Methods: Patients treated with LNG-IUS for endometrial cancer or EIN from 2013 to 2018 were evaluated. Using immunohistochemistry and single gene sequencing of POLE, patients were classified into four groups as per the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE): POLE-mutated, mismatch repair-deficient (MMRd), p53 wild type (p53wt), and p53-abnormal (p53abn). Groups were assessed relative to the primary outcome of progression or receipt of definitive treatment. Results: Fifty-eight subjects with endometrioid endometrial cancer or EIN treated with LNG-IUS were included. Of these, 22 subjects (37.9%) had endometrial cancer and 36 subjects (62.1%) had EIN. Per the ProMisE algorithm, 44 patients (75.9%) were classified as p53wt, 6 (10.3%) as MMRd, 4 (6.9%) as p53abn, and 4 (6.9%) as POLE-mutated. Of the 58 patients, 11 (19.0%) progressed or opted for definitive therapy. Median time to progression or definitive therapy was 7.5 months, with p53abn tumors having the shortest time to progression or definitive therapy. Conclusions: Molecular classification of endometrial cancer and EIN prior to management with LNG-IUS is feasible and may predict patients at risk of progression.

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Application of the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) to patients conservatively treated: Outcomes from an institutional series

Cited by 31 publications

References 26 publications

Improving response to progestin treatment of low-grade endometrial cancer

Improving response to progestin treatment of low-grade endometrial cancer

Fertility-sparing treatment for intramucous, moderately differentiated, endometrioid endometrial cancer: a Gynecologic Cancer Inter-Group (GCIG) study

Molecular Classification to Prognosticate Response in Medically Managed Endometrial Cancers and Endometrial Intraepithelial Neoplasia

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