Dr. Starr on the Characterization of POLE/POLD1 Mutations in Colorectal Adenocarcinoma

Jason Starr, DO, medical oncologist, the Department of Internal Medicine, the Mayo Clinic, discusses the characterization of POLE/POLD1 mutations in colorectal adenocarcinoma.

Investigators conducted a real-world study of a large cohort of patients with colorectal cancer (CRC) to further examine the association between POLE/POLD1 mutations and susceptibility to immunotherapy. Data were pooled from 9,136 patients. Of these patients, 217 harbored POLE/POLD1 mutations, including 203 patients with POLE mutations, 13 patients with POLD1mutations, and 1 patient with both. Although germline POLE/POLD1 mutations are a possibility in CRC, no instances of these germline mutations were observed in this study. 

Once investigators identified patients with POLE/POLD1 mutations, they focused on classifying the alteration types, such as frameshift mutations, point mutations, or copy number alterations. Notably, 58.5% of POLE/POLD1 alterations were POLE copy number loss, 4.6% were POLD1copy number loss, and 0.5% were both POLE and POLD1 copy number loss, where the gene was not being transcribed, leading to instability of the DNA, Starr notes.

Historically, patients with microsatellite instability–high (MSI-H) CRC benefit from immunotherapy. However, among evaluable patients with POLE/POLD1 wild-type disease (n = 8865), 6.1% had MSI-H disease, and only 1.8% of patients with POLE/POLD1 mutations were MSI-H. The mechanism of the immunotherapy working is not mismatch repair deficiency or MSI-H in the majority of patients; rather, this hypermutated genotype is creating neoantigens that stimulate the immune system, Starr says.

Additionally, 22% of patients harboring POLE/POLD1 mutations had a high tumor mutational burden, defined as greater than 10 mut/Mb. Among patients with POLE/POLD1 wild-type tumors, 9.9% had a high tumor mutational burden. These findings suggested that POLE/POLD1 mutations are not synonymous with a high tumor mutational burden, which was disappointing for investigators, who hoped to identify more patients that could benefit from immunotherapy, Starr concludes.