The treatment of gastric cancer is still a troublesome problem worldwide, and up to now there is not systematic standard regimen for gastric cancer. Over 50% patients couldn't respond to chemotherapy with the major obstacle is drug resistance. So how to improve the response and extend the life of patients is requested urgently. At present, the regimen of platinum (cisplatin, oxaliplatin, etc.) combined with fluorouracil (5-FU, capecitabine, etc.) is most used for gastric cancer in China. Capecitabine is a new type flurouracil carbamates antitumor agent and widespread used by tumor patients due to its convenient administration, well tolerance, definite effect and low side effect. Animal experiments have shown that many drugs, such as irinotecan, oxaliplatin, cisplatin and paclitaxel, had synergistic effect with capecitabine [32–34], and capecitabine plus paclitaxel or cisplatin regimens have been considered as desirable chemotherapy in clinical studies [13–15].
Based on our results, the response rate of capecitabine plus paclitaxel or cisplatin was 48.5% and 33.3%, respectively. However, although these regimens were effective in gastric cancer, over an half patients failed to respond due to drug resistance. So if we can find some predictive biomarkers for capecitabine plus paclitaxel to guide treatment of patients, there must be a very great improvement for response and survival. TP is a key enzyme in the metabolic pathway of capecitabine. TP enzyme, also called tumor related angiogenesis factor, is higher expressed in tumor tissues than in normal tissues, then the concentration of 5-FU in tumor tissues is raised followed by enhanced antitumor activity. In our results, the response rate, PFS and OS for TP positive patients are all higher than that in TP negative patients, which is similar with the results by other researchers [8–11]. According to above results, we analyzed TP expression in advanced gastric cancer and found the overall survival of TP positive patients was much better than that in TP negative patients. However, in different studies of colorectal cancer, data about the prognostic or predictive value of TP were conflicting: Meropol NJ et al  reported TP expression might be a predictive marker for capecitabine response, but Koopman et al  found TP expression didn't show a predictive or prognostic value for capecitabine combination chemotherapy.
Taxanes are a kind of antitumor drugs and mechanisms about its resistance have been studied for a long time. Microtubule is the target of paclitaxel which induces microtubule stabilization, inhibits microtubule dynamics and interrupts cell divisions. Studies showed that TUBB3 high expressed in paclitaxel-resistant cells  and after transfecting TUBB3 cDNA into mammalian cells, cells with TUBB3 expression displayed resistant to paclitaxel . Also in other studies about breast cancer, ovary cancer, head and neck neoplasms, there were relationship between TUBB3 expression and response or survival of paclitaxel. We studied the correlation in 33 samples treated with capecitabine plus paclitaxel, and found that the response rate for TUBB3 negative patients was 72.7%, but only 36.4% in TUBB3 positive patients. Moreover, in cohort 1, the prognosis of TUBB3 negative patients was much better than that of TUBB3 positive patients. Our results indicated there was not relationship between TUBB3 expression and response or survival in patients receiving capecitabine plus cisplatin, so TUBB3 expression could act as a predictor of paclitaxel efficacy.
TP could be upregulated after the treatment of taxane in preclinical trial , we analyzed the relationship between TP, TUBB3 expressions and the response or survival of patients. Interestingly, the response rate in TP positive & TUBB3 negative patients was 87.5%, but only 14.3% in TP negative & TUBB3 positive patients. This result will need to be further confirmed in future studies.
Recently, many studies put the sights into genomic polymorphisms in genes involved in drug metabolic pathway and correlated with the target of agents. Few genes have been used to guide clinical medication, such as K-RAS , C-KIT , EGFR , Her-2 , and so on, but for most drugs there were no predictive markers. According to our results, TP and TUBB3 may be prospective to be used to predict the response and survival of capecitabine and paclitaxel.
To summarize our results, our findings demonstrate it's possible that overexpression of TUBB3 is the major reason of paclitaxel resistance in gastric cancer, and positive TP & negative TUBB3 expressions might predict response and prognosis to capecitabine plus paclitaxel chemotherapy in AGC.