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

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.

Programmed Cell Death Ligand 1 Pathologist Training in the Time of COVID-19: Our Experience using a Digital Solution.

The COVID-19 pandemic presented numerous challenges to the continuity of programmed cell death ligand 1 (PD-L1) assay training events conducted by our organization. Under typical conditions, these training events are face-to-face affairs, where participants are trained to assay algorithms on glass slides during multi-headed scope sessions. Social distancing measures undertaken to slow pandemic spread necessitated the adaptation of our training methods to facilitate assay training and subsequent continuation of clinical trials. The present report details the creation and use of the Roche pathology training portal (PTP) that allowed for remote training to diagnostic assay algorithms. The PTP is a web-based system comprised of a learning management system (LMS) coupled to an image management system (IMS). Whole slide images (WSIs) were produced using a DP200 instrument (Roche, Pleasanton, CA) and these scan files were then uploaded to an IMS. Courses were created on the LMS using annotated WSIs that were shared with enrolled pathologists worldwide during assay training events. These courses culminated in assay certification examinations, where pathologists evaluated test-case WSIs and evaluated these cases within the LMS. Trainee submissions were analyzed for pass/fail status by comparing user data entries with consensus scores on these test-case WSIs. To date, 47 pathologist trainings have occurred and of these, 44 have successfully passed the associated assay certification exam on the first attempt (93% 1st-try pass rate). The PTP allowed roche to continue training sites during the COVID-19 pandemic, and these early results demonstrate the capability of this digital solution regarding PD-L1 diagnostic assay training events.

Analysis of microsatellite mutations in buccal cells from a case-control study for lung cancer.

Exposure to tobacco carcinogens is the major cause of human lung cancer, but even heavy smokers have only about a 10% life-time risk of developing lung cancer. Currently used screening processes, based largely on age and exposure status, have proven to be of limited clinical utility in predicting cancer risk. More precise methods of assessing an individual's risk of developing lung cancer are needed. Because of their sensitivity to DNA damage, microsatellites are potentially useful for the assessment of somatic mutational load in normal cells. We assessed mutational load using hypermutable microsatellites in buccal cells obtained from lung carcinoma cases and controls to test if such a measure could be used to estimate lung cancer risk. There was no significant association between smoking status and mutation frequency with any of the markers tested. No significant association between case status and mutation frequency was observed. Age was significantly related to mutation frequency in the microsatellite marker D7S1482. These observations indicate that somatic mutational load, as measured using mutation frequency of microsatellites in buccal cells, increases with increasing age but that subjects who develop lung cancer have a similar mutational load as those who remain cancer free. This finding suggests that mutation frequency of microsatellite mutations in buccal cells may not be a promising biomarker for lung cancer risk.

Human papillomavirus in early laryngeal carcinoma.

OBJECTIVES/HYPOTHESIS: To examine the role of HPV status in the etiology, prognosis, and treatment of head and neck squamous cell carcinoma in early larynx malignancies. STUDY DESIGN: Retrospective. METHODS: Thirty-eight cases of T1 or carcinoma in situ (CIS) laryngeal lesions were examined for the presence of human papilloma virus (HPV) using an inclusive polymerase chain reaction (PCR)/hybridization technique capable of identifying 37 HPV subtypes. RESULTS: HPV DNA was detected in 6 (16%) of the 38 lesions, representing HPV types 16, 26, 31, 39, and 52, and p16 tumor suppressor protein expression was confirmed in 10 representative cases. This HPV prevalence is higher than that noted in many previous laryngeal cancer studies, possibly due to the relatively large panel of subtypes screened for in this study. Identification of HPV-26, which has been associated with uterine cervical cancer, in an early laryngeal cancer specimen represents the first evidence of this subtype in a laryngeal carcinoma. Consistent with reports focusing on head and neck squamous cell carcinoma (HNSCC) arising from other subsites within the upper aerodigestive tract, patients with HPV-positive laryngeal carcinomas were of younger age and were somewhat less likely to have a history of tobacco use, although the latter of the two findings did not reach statistical significance. CONCLUSIONS: Our findings emphasize the presence of a broad spectrum of HPV types in a relevant proportion of early laryngeal cancers, and together with evidence of an association of HPV tumor status with a more favorable clinical course, provide a rationale for the routine HPV testing of small larynx lesions.