Clinical outcomes of patients with POLE-mutated endometrioid endometrial cancer

Stasenko, Marina; Tunnage, I; Ashley, Charles; Rubinstein, Maria M.; Mueller, J.J.; Leitao, Mario M.; Makker, Vicky; Friedman, Claire F.; Soslow, R.A.; Hyman, DM; Latham, Alicia; Weigelt, Britta; Aghajanian, Carol; Abu-Rustum, N.R.; Cadoo, Karen A.

doi:10.1016/j.ygyno.2019.04.079

Cited by 6 publications

(8 citation statements)

References 35 publications

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“…Can we withhold adjuvant treatment of any kind (radiation, chemotherapy, or targeted) from women with POLE ‐mutated ECs, regardless of clinicopathological features and traditional risk group assignment? Because of the dramatically high salvage rates observed in the small proportion of POLE mut ECs with recurrence events (followed 5‐14 years without further evidence of a disease/death event) both in our series and in others, 14 reserving treatment (conventional and/or targeted) for these rare recurrence events may be the most reasonable approach.…”

Section: Discussionmentioning

confidence: 72%

“…The Cancer Genome Atlas (TCGA) 9 identified a novel subgroup of ECs with mutations in DNA polymerase epsilon ( POLE ) that are responsible for DNA replication and lead to exceedingly high somatic mutation frequencies (“ultramutated”: >100 mutations per megabase) 9 . It is now recognized that approximately 5% to 10% of all ECs harbor POLE mutations 10‐16 . Pragmatic molecular classification systems have moved to identify this subgroup simply by testing for pathogenic mutations within the exonuclease domain (EDM) of POLE, termed POLE mut 11,13,17‐19 .…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta‐analysis

McAlpine

Chiu

Nout

et al. 2021

Cancer

100

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BACKGROUND Endometrial cancers (ECs) with somatic mutations in DNA polymerase epsilon (POLE) are characterized by unfavorable pathological features, which prompt adjuvant treatment. Paradoxically, women with POLE‐mutated EC have outstanding clinical outcomes, and this raises concerns of overtreatment. The authors investigated whether favorable outcomes were independent of treatment. METHODS A PubMed search for POLE and endometrial was restricted to articles published between March 1, 2012, and March 1, 2018, that provided individual patient data (IPD), adjuvant treatment, and survival. Following the Preferred Reporting Items for Systematic Review and Meta‐Analysis (PRISMA) reporting guidelines for IPD, the authors used univariate and multivariate one‐stage meta‐analyses with mixed effects Cox models (random effects for study cohorts) to infer the associations of treatment, traditional prognostic factors, and outcome, which was defined as the time from first diagnosis to any adverse event (progression/recurrence or death from EC). RESULTS Three hundred fifty‐nine women with POLE‐mutated EC were identified; 294 (82%) had pathogenic mutations. Worse outcomes were demonstrated in patients with nonpathogenic POLE mutations (hazard ratio, 3.42; 95% confidence interval, 1.47‐7.58; log‐rank P < .01). Except for stage (P < .01), traditional prognosticators were not associated with progression/recurrence or death from disease. Adverse events were rare (11 progressions/recurrences and 3 disease‐specific deaths). Salvage rates in patients who experienced recurrence were high and sustained, with 8 of 11 alive without evidence of disease (range, 5.5‐14.2 years). Adjuvant treatment was not associated with outcome. CONCLUSIONS Clinical outcomes for ECs with pathogenic POLE mutations are not associated with most traditional risk parameters, and patients do not appear to benefit from adjuvant therapy. The observed low rates of recurrence/progression and the high and sustained salvage rates raise the possibility of safely de‐escalating treatment for these patients. LAY SUMMARY Ten percent of all endometrial cancers have mutations in the DNA repair gene DNA polymerase epsilon (POLE). Women who have endometrial cancers with true POLE mutations experience almost no recurrences or deaths from their cancer even when their tumors appear to have very unfavorable characteristics. Additional therapy (radiation and chemotherapy) does not appear to improve outcomes for women with POLE‐mutated endometrial cancer, and this supports the move to less therapy and less associated toxicity. Diligent classification of endometrial cancers by molecular features provides valuable information to inform prognosis and to direct treatment/no treatment.

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Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta‐analysis

McAlpine

Chiu

Nout

et al. 2021

Cancer

100

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“…FIGO grade 3 endometrioid carcinomas are highly represented in group 1, some of which resemble serous carcinomas. Irrespective of grade, group 1 tumors have an excellent prognosis, although this is not confirmed in all of the recent literature (4,(202)(203)(204). Group 2 and group 3 show similar progression-free survival rates that are intermediate between groups 1 and 4.…”

Section: Tcga-based Molecular Classification Of Endometrial Carcinomasmentioning

confidence: 84%

Data Set for the Reporting of Endometrial Cancer: Recommendations From the International Collaboration on Cancer Reporting (ICCR)

Matías‐Guiu

Selinger

Anderson

et al. 2022

International Journal of Gynecological Pathology

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Endometrial cancer is one of the most common cancers among women. The International Collaboration on Cancer Reporting (ICCR) developed a standardized endometrial cancer data set in 2011, which provided detailed recommendations for the reporting of resection specimens of these neoplasms. A new data set has been developed, which incorporates the updated 2020 World Health Organization Classification of Female Genital Tumors, the Cancer Genome Atlas (TCGA) molecular classification of endometrial cancers, and other major advances in endometrial cancer reporting, all of which necessitated a major revision of the data set. This updated data set has been produced by a panel of expert pathologists and an expert clinician and has been subject to international open consultation. The data set includes core elements which are unanimously agreed upon as essential for cancer diagnosis, clinical management, staging, or prognosis and noncore elements which are clinically important, but not essential. Explanatory notes are provided for each element. Adoption of this updated data set will result in improvements in endometrial cancer patient care.

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“…They may show intratumoral morphological heterogeneity and ambiguous morphology, with features of both endometrioid and serous histotypes. Women with POLE mut ECs tend to be younger, with a normal BMI, and are associated with a favorable prognosis despite often having high‐risk pathologic features such as high tumor grade and extensive lymphovascular space invasion (LVSI) (>96% 5‐year survival, confirmed across multiple studies) [40–43].…”

Section: Figurementioning

confidence: 99%

Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis

Huvila

Pors

Thompson

et al. 2021

The Journal of Pathology

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Endometrial carcinoma (EC) is classified into a wide range of morphological variants; this list has expanded over the past decade with the inclusion of mesonephric‐like and dedifferentiated carcinoma as EC variants in the fifth edition of the WHO Classification of Female Genital Tumours, and recognition that carcinosarcoma is a biphasic carcinoma rather than a sarcoma. Each EC variant has distinct molecular abnormalities, including TCGA‐based molecular subtypes, allowing further subclassification and adding complexity. In contrast to this rapid progress in understanding EC, there are only two recognized EC precursor lesions: endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia (EAH/EIN) and serous intraepithelial carcinoma, a situation that has not changed for many years. Diagnosis of EC precursors is a cornerstone of surgical pathology practice, with early diagnosis contributing to the relatively favorable prognosis of EC. In this review we relate the precursor lesions to each of the EC morphological variants and molecular subtypes, discuss how successful early diagnosis is for each variant/molecular subtype and how it might be improved, and identify knowledge gaps where there is insufficient understanding of EC histogenesis. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Clinical outcomes of patients with POLE-mutated endometrioid endometrial cancer

Cited by 6 publications

References 35 publications

Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta‐analysis

Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta‐analysis

Data Set for the Reporting of Endometrial Cancer: Recommendations From the International Collaboration on Cancer Reporting (ICCR)

Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis

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