Abstract 2203
Background
Clonal heterogeneity in cancer contributes to resistance to therapy. The comparison of the genetic profile of primary tumours with that of metastases will inform clinical decision-making for advanced colorectal cancer patients.
Methods
Formalin-fixed paraffin-embedded colorectal adenocarcinoma from primary tumours (CRCp) and metastases (CRCm) from 82 patients managed according to HeCOG protocols were assessed. Next Generation Sequencing (Ion PROTON) was applied for mutational profiling of 51 cancer-related genes and 6 non-coding RNAs (444 amplicons, 48000 bases, median reading depth > 1300x). 57 patients had synchronous and 25 metachronous metastases. Intervening lines of therapy between primary tumour to resection of metastases were administered in 46 patients.
Results
The most frequently mutated genes in CRCp were TP53 45%, KRAS 32%, APC 27%, IGF1R 8.5%, CDH1 8.5%, whereas in CRCm TP53 48%, APC 30%, KRAS 27%, IGF1R 9.8%, PIK3CA 9.8%. Concordance rates between paired CRCp and CRCm were high (77-96%) for the commonly mutated genes. A trend for increasing discordance of the mutational status was observed in metachronous as compared to synchronous metastases.Higher mutational discordance was observed when therapy intervened between CRCp and CRCm. We observed co-existence of mutational discordance in genes related to several functional groups, suggesting clonal divergence affecting the genome diffusely. We will present more data on mutated allele frequencies in shared as well as in private mutations in CRCp and CRCm and analyse the impact on patient outcome.
%Mutational discordance CRCp vs CRCm by time and exposure to therapy
| GENE | Metachronous | Synchronous | Not exposed to tx | Exposed to tx |
|---|---|---|---|---|
| p53 | 31 | 18 | 15 | 28 |
| APC | 24 | 12 | 10 | 20 |
| KRAS | 9 | 4 | 2 | 6 |
| IGF1R | 8 | 4 | 0 | 10 |
| CDH1 | 10 | 8 | 0 | 14 |
| HER4 | 12 | 2 | 0 | 11 |
| SMAD4 | 12 | 4 | 1 | 11 |
| BRAF | 8 | 2 | 0 | 6 |
| NRAS | 5 | 2 | 0 | 4 |
Conclusions
Although a high concordance rate for frequently mutated genes was seen in CRCp versus CRCm, a trend was observed for increasing discordance with metachronous appearance of metastases and with prior exposure to antineoplastic therapy.
Clinical trial identification
Legal entity responsible for the study
Hellenic Cooperative Oncology Group
Funding
Hellenic Cooperative Oncology Group
Disclosure
All authors have declared no conflicts of interest.