The existing prognosis is based on the clinicopathological stage of the tumor – TMN stage, some clinicopathological indicators: such as the degree of tumor differentiation, the presence of intestinal obstruction or perforation, the patient’s physical status score and serum CEA level. Recent studies have found that mutations in some molecules on the epidermal growth factor receptor (EGFR) signaling pathway are associated with the efficacy of anti-EGFR therapy, genomic instability is associated with prognosis, and a close relationship exists between pharmacogenomics and the efficacy of chemotherapy for colorectal cancer.
I. K-RAS and BRAF : Predictive molecules of anti-EGFR therapy efficacy in colorectal cancer
Genetic models of colorectal carcinogenesis suggest that KRAS mutations are associated with colorectal carcinogenesis, and in addition KRAS mutations are associated with colorectal cancer recurrence. Because of the role of KRAS in the EGFR signaling pathway and tumorigenesis, it is suggested that KRAS mutations may be potential prognostic factors and predictors of anti-EGFR therapy efficacy markers.
Studies in the early years found that patients with KRAS mutations in colorectal cancer had a poor prognosis, especially in patients with stage III colorectal cancer with base substitution mutations in exon 12 of the KRAS gene. However, in recent years, more studies have found that KRAS mutations are not an independent prognostic factor for colorectal cancer.
As the use of anti-EGFR-targeted therapeutics continues, studies to predict the efficacy of anti-EGFR therapy are becoming more advanced. 2008 ASCO meeting reported the results of several studies analyzing clinical trials (CRYSTAL trial, OPUS trial and EVEREST trial). These studies all showed that in metastatic colorectal cancer, the presence or absence of KRAS mutations clearly correlated with the efficacy of cetuximab, with KRAS wild-type patients benefiting more from cetuximab in combination with chemotherapy, with improved efficiency and median progression-free time compared to the chemotherapy alone group; while KRAS mutant patients did not benefit from combination chemotherapy, there was no There was no significant difference in adverse effects between KRAS wild-type and mutant patients. The predictive effect of KRAS was also confirmed in clinical studies using panitumumab for advanced colorectal cancer. Therefore, K-RAS became the first important efficacy-predicting molecular marker for targeted therapies in colorectal cancer.
BRAF is a downstream molecule of KRAS, and KRAS and BRAF gene mutations are mutually exclusive. It has been shown that patients with BRAF mutations have lower efficiency in receiving anti-EGFR therapy. Moreover, about 10% of patients with KRAS wild type are BRAF mutant, and this group of patients has poorer efficiency, median progression-free survival and overall survival when treated with cetuximab.
PTEN (Phosphatase homologue to tensin): a possible predictor of the efficacy of anti-EGFR therapy
PTEN is an oncogene that regulates the PI3K/AKT signaling pathway. deletion of PTEN is associated with activation of the AKT pathway, which can lead to differentiation and growth of tumor cells. It has been shown that patients with PTEN deletion treated with cetuximab and irinotecan have poorer efficiency and median progression-free survival than patients with normal PTEN expression. It is suggested that PTEN may be a predictor of the efficacy of anti-EGFR therapy.
III. Genomic instability.
Genomic instability plays an important role in the pathogenesis of colorectal cancer. Genomic instability includes chromosomal instability (CI) and microsatellite instability (MSI). Chromosomal instability refers to an accelerated increase or decrease in the number of all chromosomes. Microsatellite instability refers to the addition or loss of simple repeats due to replication error (RER).
Chromosomal instability and microsatellite instability can be found in approximately 65-70% and 15% of colorectal cancer patients. Traditional theory suggests an inverse correlation between CI and MSI. Currently, two Meta-analyses have confirmed the value of chromosomal instability and microsatellite instability on the prognosis of colorectal cancer patients: patients with CI have a poor prognosis; while patients with MSI have a better prognosis. However, in a study combining multifactorial analysis of the prognostic role of CI and MSI in colorectal cancer, MSI was not found to be an independent prognostic factor. the PETACC 3 study reported at the 2009 ASCO meeting showed that MSI was an independent prognostic factor in patients with stage II and III colon cancer receiving adjuvant chemotherapy with 5-FU. patients with high MSI expression had a better prognosis, especially in The prognosis of patients with high MSI expression was better, especially in stage II colon cancer patients.
IV. Pharmacogenomics and individualized treatment of colorectal cancer
Currently, Single Nucleotide Polymorphisms (SNPs) are the main content of pharmacogenomic research, which not only elucidates the relationship between drug metabolism, drug transport, genetic polymorphisms of drug target molecules and drug effects including efficacy and toxic side effects, but also closely relates to tumor genesis, development and prognosis. (1) Thymidylate synthase
(1) Thymidylate Synthetase (TS)
TS is a key enzyme in the metabolism of fluorouracil, and is closely related to the prognosis, sensitivity to chemotherapy, and toxicity of chemotherapy in colorectal cancer, as shown in the Metal analysis of colorectal cancer by Popat S et al. Similarly, it has been shown that plasma TS mRNA is derived from tumor tissue, that tumor tissue TS mRNA levels are significantly higher than normal tissue, and that their expression levels correlate with the presence or absence of lymph node metastasis and stage. Patients with high plasma TS mRNA levels had a poor prognosis. a study by Lecomte et al. predicting 5-FU-based chemotherapy toxicities according to TS genotype showed that survival was 27, 15 and 21 months for 2R/2R, 2R/3R and 3R/3R genotypes, respectively. However, they had 43%, 18% and 3% probability of toxic reactions of degree III or IV, respectively , especially haploid 2R/-6bp and 5-FU were significantly associated with toxic reactions.
(2) Dehydropyrimidine dehydrogenase (DPD)
DPD is the main rate-limiting enzyme for the catabolism of fluorouracil drugs. DPD is a major rate-limiting enzyme for the breakdown of fluorouracil. 3%-5% of patients are partially deficient in DPD, while 0.2% are completely deficient in DPD. A study in Thailand showed that 1627A>G, 967G>A, 1774C>T, and IVS14+G>A may be important causes of DPD deficiency in Thais, and several of these genetic polymorphisms are associated with severe toxicity produced by 5-FU. However, the relationship between DPD expression and the prognosis of colorectal cancer is unclear.
(3) Uridine diphosphate glucosyltransferase 1A (UDP-glucuronosyltransf-erase1A, UGT1A)
Irinotecan (CPT-11) is activated in vivo by carboxylesterase to SN-38, which exhibits anticancer activity by inhibiting topoisomerase I. Subsequently, SN-38 is glucosylated to SN-38 glucuronoside (SN-38G) catalyzed by the uridine diphosphate glucosyltransferase 1A (UGT1A) family (e.g., 1A1, 1A7, 1A9, 1A10), and UGT1A1 is the major enzyme catalyzing SN-38 glucosylation in this family. uGT1A1 polymorphism occurs most frequently in the TATA promoter region, which exhibits a variable TA repeat. The native promoter sequence has six TA repeats (TA)6, also known as UGT1A1*1, and three variable alleles with three TA repeats – (TA)5, (TA)7, and (TA)8 – respectively.(TA)7 polymorphism (also known as UGT1A1*28) is the most common, (TA) The 7/7 (UGT1A1*28/*28) genotype is the one with the highest risk of irinotecan toxicity. However, the UGT1A1 polymorphism differs among individuals of different races, with the UGT1A1*28 allele occurring more frequently in Caucasian cancer patients than in other races, and Caucasians with UGT1A1*28 being significantly associated with irinotecan toxicity, which is relatively uncommon in Asian populations. Han et al. further suggested that UGT1A1 211AA(*6/*6) is an important risk factor for the induction of neutropenia with irinotecan. However, the relationship between UGT1A and the prognosis of colorectal cancer is unclear.
(4) Excision repair cross – Comp lementing gene (ERCC)
Platinum drugs enter tumor cells and bind to DNA, forming platinum-DNA conjugates that cause inter- or intra-strand cross-stranding of DNA, causing impaired DNA replication and thus inhibiting tumor cell division. Resistance to platinum drugs arises through four main pathways: reduction of drug accumulation, removal of drug toxicity by conjugate binding, increased tolerance to DNA conjugates induced by platinum drugs, and improved DNA repair capacity. Among them, ERCC1 is one of the most prominent genes in the DNA repair pathway. single nucleotide polymorphism (SNP) of ERCC1 is significantly associated with platinum drug resistance, with a one-base variation from C to T on the asparagine codon at position 118 of the ERCC1 gene. the ERCC1-118AAC→AAT transition leads to down-regulation of ERCC1 translation and nucleic acid excision repair capacity decreases. The French National Institute of Sciences in 2005 retrospectively examined the ERCC1-118 SNP in 91 colorectal cancer patients who had received oxaliplatin chemotherapy (first or second line) and found that the C/C genotype was less efficient than those with the C/T genotype and the T/T genotype in patients treated with FOLFOX regimen chemotherapy. Another study also concluded that ERCC1-118SNP was associated with survival in patients with colorectal cancer.
(5) Glutathione-S-transferase (GST)
The GST family includes five isoforms: GSTA1, GSTP1, GSTPM1, GSTT1 and GSTZ1P. Among them, the conversion of the amino acid codon at position 105 of GSTP1 from isoleucine (Ile) to valine ( Val), which can lead to a decrease in GSTP1 enzyme activity.Stoehlmacher et al. retrospectively examined GSTP1-105SNP in 107 patients with metastatic colorectal cancer treated with 5-FU + oxaliplatin chemotherapy, and the median survival of Val-pure patients was significantly longer than that of Val heterozygous and Ile-pure patients. It has also been suggested that GSTP1-105SNP is associated with the neurotoxicity of oxaliplatin.
V. Conclusion
Using the theory and technology of molecular biology, pharmacogenetics and pharmacogenomics to guide the treatment of colorectal cancer is of great value in judging prognosis, predicting drug efficacy and reducing serious adverse drug reactions, and is the basis for achieving individualized treatment. At present, KRAS gene mutation detection has been more widely used in clinical practice, but the clinical application and promotion of other molecular indexes still need to accumulate more evidence. We believe that in the near future, our judgment of prognosis and prediction of medical treatment for colorectal cancer will become more and more accurate and the treatment level will become higher and higher.