Jessica N McAlpine1,2, Derek S Chiu3, Remi A Nout4, David N Church5, Pascal Schmidt1,6, Stephanie Lam1, Samuel Leung7, Stefania Bellone8, Adele Wong9, Sara Y Brucker10, Cheng Han Lee2,3, Blaise A Clarke11, David G Huntsman2,3, Marcus Q Bernardini12, Joanne Ngeow13, Alessandro D Santin8, Paul Goodfellow14, Douglas A Levine15, Martin Köbel16, Stefan Kommoss10, Tjalling Bosse17, C Blake Gilks2, Aline Talhouk1. 1. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada. 2. BC Cancer Agency, Vancouver, British Columbia, Canada. 3. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 4. Department of Clinical Oncology, Leiden University Medical Centre, Leiden, the Netherlands. 5. Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. 6. Department of Statistics, Simon Fraser University, Burnaby, British Columbia, Canada. 7. Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada. 8. Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut. 9. Department of Pathology and Laboratory Medicine, KK Women and Children's Hospital, Kallang, Singapore. 10. Department of Women's Health, University of Tübingen, Tübingen, Germany. 11. Toronto General Hospital, University Health Network, Toronto, Ontario, Canada. 12. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. 13. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. 14. Ohio State University Comprehensive Cancer Center, Columbus, Ohio. 15. Department of Obstetrics and Gynecology, New York University Grossman School of Medicine, New York City, New York. 16. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada. 17. Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands.
Abstract
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.
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.
Authors: Eun Young Kang; Nicholas Jp Wiebe; Christa Aubrey; Cheng-Han Lee; Michael S Anglesio; Derek Tilley; Prafull Ghatage; Gregg S Nelson; Sandra Lee; Martin Köbel Journal: J Pathol Clin Res Date: 2021-10-01
Authors: Stephanie R Barbari; Annette K Beach; Joel G Markgren; Vimal Parkash; Elizabeth A Moore; Erik Johansson; Polina V Shcherbakova Journal: Nucleic Acids Res Date: 2022-08-12 Impact factor: 19.160