4671 - Clinicopathological and molecular criteria assessment for the screening of hypermutated proficient mismatch repair (pMMR) colorectal cancers (CRC) with exonucleasic domain POLE (edPOLE) mutations (mt).

Background

MMR Deficiency (dMMR) and edPOLE mutations (mt) are responsible for hypermutated tumoral phenotype. Immunotherapy have shown efficacy in dMMR/high mutation burden patients (pts). One of the French AcSé Nivolumab trial cohorts aims to assess Nivolumab in advanced edPOLE mt tumors. These mt occur in 1-2% of Colorectal Cancer (CRC). We aimed to define the most relevant criterias in CRC to facilitate the screening for inclusion in the AcSé Nivolumab edPOLE cohort.

Methods

edPOLE mutational status was evaluated in a cohort of locally advanced/metastatic (LA/M) CRC cancers enriched for BRAF mt, RAS mt, and unusual BRAF/RAS mt using High Resolution Melting PCR on the three hotspots described in the literature (codons 286, 411 and 459). Patients harboring edPOLE mt were then analyzed using FoundationOne genomic testing including tumor mutational burden (TMB).

Results

386 CRC pts were analysed between 2012 and 2018 (208 with atypical RAS or BRAF mutation, 119 with classical RAS or BRAF mutation, 59 RAS/BRAF wild type): 11 edPOLE mutated tumors were identified, most frequently in young male pts (Sex ratio 4,5, mean age: 54 years), pMMR (91%, 10/11), with left-sided tumors (73%, 8/11). The prevalence of edPOLE mt in atypical KRAS/BRAF mutated tumor was 5.3% (11/208) vs 0% (0/178) in other cases (p = 0.02). Among the 11 edPOLE mt cases, 2 had a low TMB ( < 12mt/Mb) 3 were hypermutated (TMB≥12- < 100 mt/Mb) and 6 ultramutated (TMB≥100mt/Mb). High TMB (mean 172 mt/Mb) was observed in 8 pMMR cases: 7 mt in hotspots (4, 2 and 1 respectively in codons 286, 411 and 459); 1 mt outside hotspots (codon 461). Codons 464 and 425 pMMR edPOLE mt cases had a low TMB (4 mt/Mb) and one was hypermutated dMMR case had a silent POLE codon 464 mt.

Conclusions

A screening strategy based on clinicopathological (male gender, young age, left-sided tumors), and molecular criterias (pMMR, unusual BRAF/KRAS mutations) may help to identify pathogenic edPOLE mt (codons 286, 411, 459 and 461) associated with a high TMB in LA/M CRC. The use of these criterias could help to select patients for POLE mt screening and facilitate their access to immunotherapy.

Clinical trial identification

NCT03012581.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Roche.

Disclosure

B.J. Rousseau: Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: Novartis. All other authors have declared no conflicts of interest.