From the Guidelines
The most important gene responsible for colonic cancer recurrence is KRAS. Mutations in the KRAS gene are strongly associated with colorectal cancer recurrence after treatment, as they are a downstream target of epidermal growth factor receptor (EGFR) signaling and activating mutations in codon 12 or 13 of this gene are present in approximately 30% to 40% of colorectal cancers 1. The evidence shows with great consistency that patients whose tumors harbor a mutation in the KRAS gene do not benefit from cetuximab or panitumumab, whether in monotherapy or in combination with chemotherapy, whereas those whose tumors are wild-type have significantly higher response rates and longer survival 1. In the context of real-life clinical medicine, the KRAS gene mutation status is crucial in guiding treatment decisions, particularly in the use of EGFR-targeted therapy, and recent guidelines recommend RAS and BRAF gene mutation testing for patients with colorectal cancer 1. Some key points to consider include:
- KRAS mutations are found in approximately 30-40% of colorectal cancers 1
- KRAS mutation status is a predictive factor for non-response to EGFR-targeted therapy 1
- RAS and BRAF gene mutation testing can be performed using DNA direct sequencing or amplification-refractory mutation system (ARMS) method 1
- The use of anti-human epidermal growth factor receptor (HER)-2 therapy, neurotrophic tyrosine receptor kinase (NTRK) inhibitors, and immune checkpoint inhibitors is increasingly emphasized in the treatment of colorectal cancer, and testing for these genes may be considered in patients who fail standard treatment 1. Overall, understanding a patient's KRAS mutation status can help guide treatment decisions and improve outcomes in colorectal cancer.
From the Research
Colonic Cancer Recurrence Genes
The most important gene responsible for colonic cancer recurrence is a subject of ongoing research. Based on available studies, the following genes have been identified as significant:
- KRAS: mutations in this gene have been recognized as a critical determinant of the therapeutic response of colorectal cancer 2, 3, 4
- TP53: combined mutation with KRAS enhances chemoresistance, promoting postoperative recurrence and metastasis 5
- Other genes such as APC and PIK3CA are also frequently mutated in advanced colorectal cancer patients, but their correlation with therapeutic effects remains elusive 5
KRAS Gene
The KRAS gene is a member of the RAS family and is one of the most dominant mutations in colorectal cancer 3. Studies have shown that KRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor (EGFR) targeting antibodies 4. The impact of KRAS mutations on the prognosis and survival of CRC patients drives many research studies to explore potential therapeutics or target therapy for the KRAS mutant CRC 3.
Therapeutic Response
The therapeutic response of colorectal cancer is tightly correlated with genomic variation, and the precise correlation between these mutations and the therapeutic effects of chemotherapy remains elusive 5. However, studies have shown that patients with KRAS wild-type metastatic colorectal cancer (mCRC) may benefit from cetuximab plus FOLFIRI treatment 6. In contrast, patients with combined KRAS and TP53 mutations have a dismal objective response rate to standard first-line chemotherapy and are predisposed to recurrence and metastasis 5.