Adjuvant treatment for POLE proofreading domain-mutant cancers: sensitivity to radiotherapy, chemotherapy, and nucleoside analogs

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 (ECs) in the observation arm of the randomized PORTEC-1 EC trial (N=245 patients with stage I EC for analysis). Sensitivity to radiotherapy and selected chemotherapeutics was compared between Pole-mutant mouse 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 ECs (N=16) had an improved recurrence-free survival (10yr RFS 100% vs 80.1% for POLE-wild-type; HR=0.143, 95% CI=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 (IC50 Pole P286R-mutant vs wild-type: 0.05 vs 0.17 μM for cytarabine, 4.62 vs 11.1 μM 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 analogs, suggesting the use of these compounds as a potentially effective targeted treatment for advanced-stage POLE-mutant cancers.

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