Abstract 4671
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.
Resources from the same session
4097 - Targeting NRG1-fusions in multiple tumour types: Afatinib as a novel potential treatment option
Presenter: Stephen V Liu
Session: Poster Display session 3
Resources:
Abstract
1129 - Aspirin and Ticagrelor for the prevention of tumour cell induced platelet aggregation
Presenter: Meera Chauhan
Session: Poster Display session 3
Resources:
Abstract
4514 - Pharmacokinetic/ pharmacodynamic (PK/PD) exposure-response characterization of GSK3359609 (GSK609) from INDUCE-1, a phase I open-label study
Presenter: Michele Maio
Session: Poster Display session 3
Resources:
Abstract
5169 - In vitro functional interrogation of viable Circulating Tumor Associated Cells (C-TACs) for evaluating Platin resistance.
Presenter: Stefan Schuster
Session: Poster Display session 3
Resources:
Abstract
5827 - Targeting ARG2 as a novel therapeutic approach for cancer
Presenter: Marcin Grzybowski
Session: Poster Display session 3
Resources:
Abstract
3129 - MPS1 and PLK1 as new therapy targets in TP53 mutated solid tumors
Presenter: Balazs Gyorffy
Session: Poster Display session 3
Resources:
Abstract
2129 - The Tumor Static Exposure (TSE) concept & utility: application to combination treatment of radiation and radiosensitizing agent in tumor xenograft experiments
Presenter: Samer El Bawab
Session: Poster Display session 3
Resources:
Abstract
1814 - General Methodology to Optimize Tumor Treating Fields Delivery Utilizing Numerical Simulations
Presenter: Noa Urman
Session: Poster Display session 3
Resources:
Abstract
3010 - The Australian Exceptional Responders Program: a National collaboration
Presenter: Megan Barnet
Session: Poster Display session 3
Resources:
Abstract
4489 - A Window of Opportunity Trial of Atorvastatin Targeting p53 Mutant Malignancies
Presenter: Joaquina Baranda
Session: Poster Display session 3
Resources:
Abstract