Four-Year Disease-Free Remission in a Patient With POLE Mutation–Associated Colorectal Cancer Treated Using Anti–PD-1 Therapy

Abstract

The stability of the human genome depends upon a delicate balance between replication by high- and low-fidelity DNA polymerases. Aberrant replication by error-prone polymerases or loss of function of high-fidelity polymerases predisposes to genetic instability and, in turn, cancer. DNA polymerase epsilon (Pol ε) is a high-fidelity, processive polymerase that is responsible for the majority of leading strand synthesis, and mutations in Pol ε have been increasingly associated with various human malignancies. The clinical significance of Pol ε mutations, including how and whether they should influence management decisions, remains poorly understood. In this report, we describe a 24-year-old man with an aggressive stage IV high-grade, poorly differentiated colon carcinoma who experienced a dramatic response to single-agent checkpoint inhibitor immunotherapy after rapidly progressing on standard chemotherapy. His response was complete and durable and has been maintained for more than 48 months. Genetic testing revealed a P286R mutation in the endonuclease domain of POLE and an elevated tumor mutational burden of 126 mutations per megabase, both of which have been previously associated with response to immunotherapy. Interestingly, tumor staining for PD-L1 was negative. This case study highlights the importance of genetic profiling of both early and late-stage cancers, the clinical significance of POLE mutations, and how the interplay between genetic instability and immune-checkpoint blockade can impact clinical decision-making.

Case report: POLE (P286R) mutation in a case of recurrent intestinal leakage and its treatment

“…A combination of ipilimumab and nivolumab has also been approved for metastatic colorectal cancer with high MSI or mismatch repair defects. Patients with a POLE gene mutation have been reported to benefit from immunotherapy, suggesting that the POLE gene may be a potential marker for CRC treatment (18,19).B.J-C. Rousseau et al (20) reported the first clinical trial to evaluate PD1 in MMR tumors with POLE mutation and found that nivolumab activity appeared in pathogenic mutations of the POLE, such as P286R, V4111L. The POLE mutation site in our case is P286R, which is consistent with the literature, indicating its sensitivity to immunotherapy.…”

Metastatic sites and lesion numbers cooperated to predict efficacy of PD‐1 inhibitor‐based combination therapy for patients with metastatic colorectal cancer

“…Hitherto, limited studies reported the efficacy of immunotherapy for those with POLE mutation in mCRC. Michael recently presented a case who had POLE P286R mutation and was treated with pembrolizumab monotherapy obtaining complete remission and a striking four‐year disease‐free survival 24 . In another study assessing the efficacy of immune treatment in POLE mutations across all tumors, pathogenic POLE mutations, were associated with significant clinical benefits to immunotherapy with DCB reaching 82.4% 6 .…”

“…Michael recently presented a case who had POLE P286R mutation and was treated with pembrolizumab monotherapy obtaining complete remission and a striking four‐year disease‐free survival. 24 In another study assessing the efficacy of immune treatment in POLE mutations across all tumors, pathogenic POLE mutations, were associated with significant clinical benefits to immunotherapy with DCB reaching 82.4%. 6 Of three patients with POLE P286R mutation in our study, two received regorafenib and one received capecitabine and bevacizumab as combined regimens when progressed on standard chemotherapy.…”