Firstly, present study provided and highlighted the real-world evidence regarding the prognostic data of patients with CRC who were treated with surgical resection and capecitabine-based adjuvant chemotherapy in real-world. Simultaneously, the prognostic association analysis suggested that TYMP gene polymorphism rs11479 might involve in the prognosis of postoperative patients with CRC who received capecitabine based adjuvant chemotherapy through the mediation TYMP mRNA expression.
To the best of our knowledge, CRC was established to be a highly heterogeneous digestive system malignancy. Comparatively limited research progresses that could strikingly improve the prognosis of the patients with CRC were observed in recent years. At present, PD-1/PD-L1 blockades were reported to be effective for considerable patients with advanced stage of cancer which provided significant survival benefit to some extent. Nevertheless, the availability of PD-1/PD-L1 blockades in advanced CRC was scanty, which indicated that only patients with dMMR might benefit from PD-1 blockade according to Keynote 177 clinical trial. As a result, traditional chemotherapy still played an important role in the treatment for CRC. However, it should be noticed that ORR of chemotherapy was relatively limited, which exhibited the urgent exploration of potential biomarkers that could predict the efficacy of traditional chemotherapy was an important research direction. At present, biomarkers that might predict the effectiveness to traditional chemotherapy were predominately focused on genetic polymorphisms, ctDNA and somatic gene mutations. Specifically, a recently reported polymorphism study initiated by JS Su and colleagues indicated that PD-L1 gene polymorphism 901T>C could be used as a potential biomarker to involve in the prognosis of patients with CRC receiving capecitabine-based adjuvant chemotherapy through mediation of the mRNA expression of PD-L1. Furthermore, another study initiated by JT and colleagues investigated the clinical significance of ctDNA for guiding the prognosis of patients with high-risk stage Ⅲ colon cancer, which indicated that the monitoring of ctDNA might be useful to predict the prognosis of patients with high-risk stage Ⅲ colon cancer. Additionally, AJ Li and colleagues performed a study to explore the predictive association between PIK3CA and TP53 somatic mutations status and OS for patients with stage Ⅱ and Ⅲ CRC. And the results suggested that patients with PIK3CA and TP53 double mutations were correlated with worse OS. Collectively, all the above findings demonstrated that genome DNA status of colon cancer or rectal cancer might predict the prognosis of patients with CRC who were treated with conventional chemotherapy to some extent.
Although present study was designed as a retrospective analysis, we still carried out the prognostic analysis of the 218 patients with CRC who received capecitabine-based adjuvant chemotherapy. And the results exhibited that the median DFS of the 218 patients was 4.6 years (95%CI: 3.80-5.40) and the median OS of the 218-patient cohort was 5.8 years (95%CI: 5.12-6.48). The DFS and OS data in our study seemed to be lower than that in NO16968 clinical trial which was implemented to identify the feasibility of oxaliplatin combined with capecitabine as adjuvant therapy for stage Ⅲ CRC. The discrepancy between the two study could be attributed to the following explanation: our study included more patients with an ECOG performance status of 2 score than that in the NO16968 study and the results of the Cox analysis in our study indicated that patients with ECOG of 2 score conferred a worse prognosis, which was consistent with the previous study. Besides, it should be noted that this study was designed as a retrospective analysis. Management of the patients in retrospective study was not sufficient and normative compared with well-designed phase Ⅲ clinical trial, which was also reflected in the fact that the actual completion of capecitabine monotherapy regimen in this study was only 5 cycles, and the CAPEOX regimen was only 4 cycles. The insufficient adjuvant chemotherapy might stand a good chance to compromise the survival of the patients.
Considerable previous studies indicated that genetic variation of drug metabolism gene might contribute to the effectiveness of a variety of drugs. To our knowledge, our study might be the first exploration disclosed that the carriers of the T allele at rs11479 of TYMP gene could be sensitive to capecitabine administration and benefit from capecitabine adjuvant chemotherapy in Chinese patients with CRC who received capecitabine based adjuvant chemotherapy by influencing the mRNA expression of TYMP. Interestingly, a previous study initiated by YB Du and colleagues was reported. A total of 235 patients with CRC underwent surgical treatment were included in their study retrospectively and they investigated the influence of TYMP genetic variation on clinical outcomes of patients with CRC. The conclusion in their study suggested that 5633C>T of TYMP might impact the prognosis of the patients, which was consistent with the design and results of our study. However, the heterogeneous adjuvant chemotherapy regimens might compromise the clinical significance of 5633C>T of TYMP in their study. Another recent study initiated by WC Chen and colleagues performed the implication of TYMP genetic variation on the clinical outcome of gastric cancer patients received capecitabine based adjuvant chemotherapy. A total of 198 patients with gastric cancer were participated in the study and clinical significance of TYMP genetic variation was implemented. Furthermore, the conclusion exhibited that rs11479 of TYMP had favorable influence on the clinical outcomes of gastric cancer patients received capecitabine based adjuvant chemotherapy, which was in concert with our study even the tumors in the two studies were different. On other hand, another study initiated by H Liu and colleagues investigated the relevance of TYMP genetic variation to the survival of gastrointestinal cancer patients treating by fluoropyrimidines. A total of 141 metastatic GIC patients received 5-FU based first-line chemotherapy were included and the results suggested that T allele gene carriers were associated with higher TYMP gene expression, which was consistent with the mRNA expression results in our study. However, they failed to identify the positive association of the polymorphism with OS mainly own to the relatively limited sample size. Furthermore, a previous study initiated by BA Jennings and colleagues found that T allele gene carriers of rs11479 were correlated with higher incidence of adverse reaction among patients with CRC receiving capecitabine therapy, which was partly in line with the results of our study, highlighting the possibility that T allele carriers of rs11479 might be more sensitive to capecitabine administration.
Interestingly, the relationship between the expression level of TYMP gene and the prognosis of CRC remains controversial in recent study . Our study preliminarily sugested that patients with higher mRNA expression of TYMP might be likely to benefit from capecitabine administration, thus conferring a superior prognosis, which was consistent with the results of the previous study initiated by M Lu and colleagues. A total of 57 patients with advanced gastric cancer who received capecitabine-based regimen were included and identified that the mRNA expression of TYMP was positively associated with overall response and OS. Nevertheless, on the other hand, considerable studies had found that TYMP gene was an important factor promoting tumor angiogenesis, which demonstrated that higher expression of TYMP gene was usually accompanied by a higher tumor burden, which generated the tendency that the tumor was easy to recurrence and metastasis, thus contributing to the worse prognosis . Collectively, TYMP gene played a dual role in vivo. On the one hand, it stimulated angiogenesis of tumor cells to promote tumor growth. On the other hand, TYMP was an important metabolic gene of capecitabine and a key gene for 5-FU chemotherapy drugs to play a cytotoxic role and kill tumor cells. In a word, the conclusion in our study was needed to be confirmed in large-scale clinical trials subsequently.
The limitations of this study were as follows: firstly, the sample size of the study was relatively small, and the clinical significance of TYMP polymorphism in patient with CRC was still needed to be evaluated in a in a larger population. Secondly, present study was designed as a retrospective analysis and some bias could not be avoided. However, the clinical significance of TYMP rs11479 was fully evaluated, we thought our study was of clinical significance for the prognostic evaluation of patients with CRC who received surgical resection and capecitabine-based adjuvant chemotherapy.