Abstract 465P
Background
Increasing numbers of actionable alterations have emerged in colorectal cancer. Aside from anti-EGFR monoclonal antibody therapy for patients with KRAS, NRAS, and BRAF wild-type tumors, around 60% of patients could benefit from single or combined targeted therapies. To inform potential therapy options, a next-generation sequencing (NGS)-based comprehensive genomic profiling is essential prior treatment. In this study, we aim to identify rational targeted therapy options in colorectal cancer.
Methods
A total of 438 primary colorectal tumors were sequenced using ACTOnco® panel. Tumor mutational burden (TMB) was estimated by calculating the number of somatic nonsynonymous mutations per megabase (muts/Mb) of coding genes. Microsatellite instability (MSI) status was determined by a machine-learning (ML) algorithm that classified the features of microsatellite sequences into MSI-H or MSS and correlated with immunohistochemical (IHC) findings. Clinical actionability was assessed according to OncoKB database.
Results
For all 438 cases, thirteen percent were predicted as MSI-H by MSI ML algorithm and the remaining cases were classified as MSS. This result was 100% concordant with the mismatch repair deficiency status determined by IHC. Among MSI-H patients, the average TMB was 42.9 muts/Mb while the average TMB for MSS patients was 5.6 muts/Mb excluding two cases of POLE driver mutant. Overall, APC (67%) and TP53 (61%) were the most frequently mutated tumor suppressor genes and KRAS (40%), BRAF (24%), and PIK3CA (21%) were among the most commonly mutated oncogenes. Moreover, we found a significant enrichment of actionable mutations in BRAF, PIK3CA, and PTEN on right-sided tumors. Pathway analysis revealed over 80% of right-sided tumors and 60% of left-sided tumors had actionable alterations in RAS or PI3K pathway. Among patients with actionable alterations in RAS pathway, one-third of patients with right-sided tumors and one-fifth of patients with left-sided tumors could benefit from combined therapies that simultaneously target RAS and PI3K pathways.
Conclusions
This study demonstrated that comprehensive genomic profiling is essential for identifying rational targeted therapy options in colorectal cancer.
Legal entity responsible for the study
A.K. Lam.
Funding
This research project is kindly supported by Elite Research Grant from Hong Kong Science & Technology Park.
Disclosure
All authors have declared no conflicts of interest.