Mismatch Repair Deficiency (dMMR) and edPOLE mutations (mt) are responsible for hypermutated tumoral phenotype. Immunotherapy have shown efficacy in dMMR/high mutation burden patients (pts) and could be also active in edPOLEmt tumors. These mt occur in 6-12% of endometrial cancers (EC) and in 1-2% of Colorectal Cancer (CRC) and are likely infrequent in advanced setting. We aimed to define the most relevant clinicopathogical and molecular criterias to facilitate screening for edPOLE mt pts.
EdPOLE mutational status was evaluated in cohorts of pMMR CRC and EC using High Resolution Melting PCR on the hotspots described in literature (codons 286, 411 and 459). CRC subcohorts were enriched for BRAF mt, RAS mt, unusual BRAF/RAS mt and young pts (≤40 yrs). Pts harboring a mutated profile were confirmed by Sanger sequencing.
245 pts were screened: 49 EC and 196 CRC. Among CRC, 41 were BRAF mt (30 V600E, 11 non V600E), 79 were KRAS mt (30 on codon 12/13, 49 other mt), 20 were selected because of the presence of ≥ 2 simultaneous BRAF/KRAS/NRAS mt, 30 were BRAF/KRAS/NRAS wild type (wt) and 30 were ≤40 yrs. Using our method, 9 edPOLE mt tumors were identified (Table): 4 among EC and 5 among CRC. edPOLE mt EC were all endometrioid ADK. edPOLEmt CRC were all localized in the left colon or rectum with unusual molecular alterations: 1 BRAF (p.D594G), 3 KRAS mt (p.A59T p.A146T et p.N116H) and 1 with two NRAS mt (p.Q61R et p.T58A).Table: 109P
|Tumor subcohort||% of edPOLE mt (n/N)||Clinical and molecular profile of edPOLE mt pts|
|Whole cohort||3.6 (9/245)||pMMR: 100% (9/9)|
|EC Endometrioid adenocarcinomas Other histologies||8 (4/49) 13 (4/31) 0 (0/18)||3 codon 286 POLE 0 codon 411 POLE 1 codon 459 POLE|
|CRC BRAF/KRAS/NRAS wt p.V600E BRAF mt Non p.V600E BRAF mt Codons 12 or 13 KRAS mt Non codons 12 or 13 KRAS mt Multiple BRAF/KRAS/NRAS mt||2.6 (5/196) 0 (0/30) 0 (0/30) 9 (1/11) 0 (0/30) 6 (3/49) 5 (1/20)||Left colon or rectum: 100% (5/5) Age ≤ 40 years old: 20% (1/5) 2 codon 286 POLE 1 codon 411 POLE 2 codon 459 POLE|
Our screening strategy identified edPOLEmt in 13% of endometrioid ADK and 2.6% of CRC. Pts selection on clinicopathological (histology for EC, young age, left colon or rectum), and molecular criterias (pMMR, unusual BRAF/KRAS/NRAS mt) seem to increase the proportion of edPOLEmt. The use of these criteria in practice could help select patients for edPOLE screening. Additional clinicopathological and molecular data will be shown.
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All authors have declared no conflicts of interest.