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Abstract
Purpose: Pathogenic POLE proofreading domain mutations are found in many malignancies where they are associated with ultramutation and favorable prognosis. The extent to which this prognosis depends on their sensitivity to adjuvant treatment is unknown, as is the optimal therapy for advanced-staged or recurrent POLE-mutant cancers.Experimental Design: We examined the recurrence-free survival of women with POLE-mutant and POLE-wild-type endometrial cancers (EC) in the observation arm of the randomized PORTEC-1 endometrial cancer trial (N = 245 patients with stage I endometrial cancer for analysis). Sensitivity to radiotherapy and selected chemotherapeutics was compared between Pole-mutant mouse-derived embryonic stem (mES) cells, generated using CRISPR-Cas9 (Pole mutations D275A/E275A, and cancer-associated P286R, S297F, V411L) and isogenic wild-type cell lines.Results: In the observation arm of the PORTEC-1 trial (N = 245), women with POLE-mutant endometrial cancers (N = 16) had an improved recurrence-free survival (10-year recurrence-free survival 100% vs. 80.1% for POLE-wild-type; HR, 0.143; 95% confidence interval, 0.001-0.996; P = 0.049). Pole mutations did not increase sensitivity to radiotherapy nor to chemotherapeutics in mES cells. In contrast, Pole-mutant cells displayed significantly increased sensitivity to cytarabine and fludarabine (IC50Pole P286R-mutant vs. wild-type: 0.05 vs. 0.17 μmol/L for cytarabine, 4.62 vs. 11.1 μmol/L for fludarabine; P < 0.001 for both comparisons).Conclusions: The favorable prognosis of POLE-mutant cancers cannot be explained by increased sensitivity to currently used adjuvant treatments. These results support studies exploring minimization of adjuvant therapy for early-stage POLE-mutant cancers, including endometrial and colorectal cancers. Conversely, POLE mutations result in hypersensitivity to nucleoside analogues, suggesting the use of these compounds as a potentially effective targeted treatment for advanced-stage POLE-mutant cancers.

Author information

Van Gool IC1, Rayner E2, Osse EM1, Nout RA3, Creutzberg CL3, Tomlinson IPM2,4, Church DN2,5, Smit VTHBM1, de Wind N6, Bosse T7, Drost M8.
1
Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
2
Molecular and Population Genetics Laboratory, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
3
Department of Clinical and Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands.
4
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
5
Oxford Cancer Centre, Churchill Hospital, Oxford, United Kingdom.
6
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands. T.Bosse@lumc.nl N.de_Wind@lumc.nl.
7
Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. T.Bosse@lumc.nl N.de_Wind@lumc.nl.
8
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.