Background

Mutations in DNA polymerases POLE and POLD1 are associated with tumor development and certain hereditary cancers characterized by hyper-mutated genomic phenotypes, leading to high DNA tumor mutation burden (TMB). Similar to mismatch repair instability (MSI), increased TMB confers significant prognostic benefits to immunotherapy due to higher immune tumor microenvironment activation. The current study utilizes Tempus’ multimodal, real-world database, encompassing molecular and clinical de-identified records, to evaluate the prevalence of POLE/POLD1 mutations and their predictive significance in immunotherapy response, providing a unique perspective for pre-clinical and clinical discovery.

Methods

De-identified records of approximately 93,000 patients with DNA and RNA sequencing data were analyzed. Records include clinical testing such as mismatch repair (MMR) immunohistochemistry (IHC) and detailed annotations for treatments and outcomes.

Results

In the overall cohort, 10.5% (N=9,750) of patients harbored mutations in POLE or POLD1 genes. The prevalence of pathogenic or likely-pathogenic (P/LP) mutations was 0.16%, while variants of unknown significance (VUS) accounted for 8.67%. Patients harboring P/LP or VUS POLE/POLD1 mutations (n=8,206) displayed significantly higher TMB, regardless of MMR IHC status. A higher presence of RNA-estimated CD8+ T-cells was observed in mutated patients compared to non-mutated, suggesting increased immune activation. Moreover, mutated patients showed increased expression in key genes in the replicative stress repair pathway (ATR-CHK1). Among patients treated with immunotherapy, 12.5% (n=1,084) had POLE/POLD1 mutations (P/LP or VUS), 45% of which were non-MSI and TMB-low. Notably, these patients showed improved real-world progression-free survival (rwPFS; HR=0.9, p=0.0025) and overall survival (rwOS; HR=0.9, p=0.004) when applying a Cox proportional hazards test while adjusting by cancer type.

Conclusions

Findings in this study highlight the potential of POLE/POLD1 mutations as pan-cancer predictive biomarkers to impact clinical decision-making processes. POLE/POLD1 mutations can stratify a subset of non-MSI and TMB-low patients likely to respond to immunotherapy. In fact, the response rate to immunotherapy among patients with POLE/POLD1 mutations parallels that observed in TMB-high patients, with up to a 20% increase in responders compared to the TMB-high fraction selection, potentially due to increased immune activation. These results reinforce the clinical relevance of POLE/POLD1 mutations as predictive biomarkers to enhance immunotherapy’s precision and guide more personalized treatment strategies.

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