Adjuvant Treatment for POLE Proofreading Domain-Mutant Cancers: Sensitivity to Radiotherapy, Chemotherapy, and Nucleoside Analogues

Pathogenic 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 -mutant cancers. We examined the recurrence-free survival of women with -mutant and wild-type endometrial cancers (EC) in the observation arm of the randomized PORTEC-1 endometrial cancer trial ( = 245 patients with stage I endometrial cancer for analysis). Sensitivity to radiotherapy and selected chemotherapeutics was compared between -mutant mouse-derived embryonic stem (mES) cells, generated using CRISPR-Cas9 ( mutations D275A/E275A, and cancer-associated P286R, S297F, V411L) and isogenic wild-type cell lines. In the observation arm of the PORTEC-1 trial ( = 245), women with -mutant endometrial cancers ( = 16) had an improved recurrence-free survival (10-year recurrence-free survival 100% vs. 80.1% for wild-type; HR, 0.143; 95% confidence interval, 0.001-0.996; = 0.049). mutations did not increase sensitivity to radiotherapy nor to chemotherapeutics in mES cells. In contrast, -mutant cells displayed significantly increased sensitivity to cytarabine and fludarabine (IC P286R-mutant vs. wild-type: 0.05 vs. 0.17 μmol/L for cytarabine, 4.62 vs. 11.1 μmol/L for fludarabine; < 0.001 for both comparisons). The favorable prognosis of -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 -mutant cancers, including endometrial and colorectal cancers. Conversely, mutations result in hypersensitivity to nucleoside analogues, suggesting the use of these compounds as a potentially effective targeted treatment for advanced-stage -mutant cancers. .