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.
Michael L. Durando, Sanjay V. Menghani, Jessica L. Baumann, Danny G. Robles, Tovah A. Day, Cyrus Vaziri, and Aaron J. Scott
Featured Updates to the NCCN Guidelines
Chrysalyne D. Schmults, Rachel Blitzblau, Sumaira Z. Aasi, Murad Alam, James S. Andersen, Brian C. Baumann, Jeremy Bordeaux, Pei-Ling Chen, Robert Chin, Carlo M. Contreras, Dominick DiMaio, Jessica M. Donigan, Jeffrey M. Farma, Karthik Ghosh, Roy C. Grekin, Kelly Harms, Alan L. Ho, Ashley Holder, John Nicholas Lukens, Theresa Medina, Kishwer S. Nehal, Paul Nghiem, Soo Park, Tejesh Patel, Igor Puzanov, Jeffrey Scott, Aleksandar Sekulic, Ashok R. Shaha, Divya Srivastava, William Stebbins, Valencia Thomas, Yaohui G. Xu, Beth McCullough, Mary A. Dwyer, and Mai Q. Nguyen
The NCCN Guidelines for Squamous Cell Skin Cancer provide recommendations for diagnostic workup, clinical stage, and treatment options for patients with cutaneous squamous cell carcinoma. The NCCN panel meets annually to discuss updates to the guidelines based on comments from panel members and the Institutional Review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new surgical recommendation terminology (peripheral and deep en face margin assessment), as well as recent updates on topical prophylaxis, immunotherapy for regional and metastatic disease, and radiation therapy.