Irinotecan is a semi-synthetic derivative of natural camptothecin, and has been widely used in the treatment of solid tumors such as gastric cancer, colorectal cancer (CRC), lung cancer, etc. A combination of irinotecan and fluorouracil is a standard first-line regimen for advanced CRC, especially advanced CRC with rapid progression, with an efficacy rate of up to 40% (10~12). However, this regimen has two major adverse reactions of delayed-onset diarrhea and neutropenia, where the incidences of grade 3~4 neutropenia and severe diarrhea are 45% and 20~40% (13), respectively, which limits its clinical application and exhibits inter-individual variations.
Irinotecan is hydrolyzed in vivo by carboxylesterase (CE) into an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). The latter is a topoisomerase I inhibitor that inhibits repair of broken single-stranded DNA, disrupts DNA replication and transcription, and exerts cytotoxic effects. SN-38 is inactivated by UGT1A1 as glucuronic acid product SN-38G, which is excreted into the intestine through the bile and is transformed into SN-38 by the intestinal bacterial β-glucuronidase, thereby inducing mucosal injury and delayed-onset diarrhea. UGT1A1 enzyme in the intestine can re-catalyze SN-38 for SN-38G detoxification. Therefore, the adverse reactions of irinotecan are related to its main drug-metabolizing enzyme UGT1A1, whose activity is affected by polymorphism. UGT1A1*28 polymorphism and irinotecan-related adverse reactions have been reported in many studies, but the correlation between UGT1A1*6 polymorphism and adverse reactions of irinotecan remains unclear. Several studies, with conflicting results, have indicated that the UGT1A1 polymorphism has insufficient sensitivity and specificity in predicting the adverse effects of irinotecan. The results of different ethnic groups in the same race are rarely reported. In addition, the role of UGT1A1 polymorphism in predicting the toxicity in patients receiving different doses of irinotecan is clinically controversial.
Due to differences in genetic background, different UGT1A1 mutation sites exist among various ethnic groups, which is responsible for different incidences of toxicity between different populations in eastern and western countries receiving irinotecan treatment. Studies on the distribution of UGT1A1 *28 and *6 polymorphisms have demonstrated that UGT1A1 * 28 homozygous mutant TA7/7 accounts for 10–15% and 12–27% in the Caucasian and African populations, respectively (14, 15), while its mutation rate is only 1.2–4.7% in Asian population (16, 17). Nakaura et al. (18) showed that the wild-type UGT1A1*28 accounted for 46% and 76% in the Caucasian and Asian populations, respectively, indicating significant inter-ethnic differences. Etienne-Grimald et al. (19) concluded that UGT1A1*28 had the highest expression frequency in Americans and Caucasians, accounting for 38–45% and 29–39%, respectively, while a mutation frequency of about 15–18% in Asians, of which the homozygous mutation type accounted for 3%. Zhang et al. (20) investigated the distribution of UGTlAl*28 polymorphism in 517 Han patients, and found that UGTlAl*28 TA6/6, TA7/6 and TA7/7 accounted for 77.2%, 22% and 0.8%, respectively. In this study, the distribution frequencies of wild-type and heterozygous-type UGTlAl*28 were 69.8% and 30.2%, respectively, in 86 patients in Guangxi Zhuang, with no homozygous-type case, which indicated that the homozygous mutation rate was further reduced as compared to the Asian Han ethnicity.
UGT1A1*6 is a unique UGT1A1 mutation type in Asian populations. The frequencies of UTG lAl*6 homozygous mutant A/A in Koreans and Japanese were reported to be 7% and 4%, respectively, while the frequencies of UGTlAl*6 G/G, G/A and A/A in Han Chinese were 66.9%, 29.3% and 3.8%, respectively (20). This study revealed that the frequencies of wild-type, heterozygous-type and homozygous-type UGT1A1*6 in Guangxi Zhuang were 76.7%, 20.9% and 2.3%, respectively, which differed from the reported distribution frequencies of genetic polymorphisms in Europeans and Americans, wherein the mutation rate was slightly lower than that in Chinese Han and other Asians. However, this may be due to a small sample size. Equilibrium test of UGT1A1*28 and UGT1A1*6 allelic frequencies in this study revealed that the samples were in accordance with the Hardy-Weinberg equilibrium, derived from a larger and randomized marriage-balanced population, and was representative.
Clinical studies have shown that Caucasians with UGT1A1*28 gene mutants (TA6/7 and TA7/7) have a higher risk of severe granulocytopenia and diarrhea than those with wild-type UGT1A1*28 (TA6 /6) after receiving irinotecan (21). In our study, Guangxi Zhuang patients with UGT1A1*28 mutations showed a higher risk of 3~4 grade delayed-onset diarrhea as compared to those with wild-type UGT1A1*28 (30.8% vs. 11.7%, p=0.044), but did not have a higher risk of 3~4 grade neutropenia (34.6% vs. 15.0%, p=0.112), which was consistent with other domestic reports (22). Moreover, Guangxi Zhuang patients with UGT1A1*6 mutations had a higher risk of 3~4 grade delayed-onset diarrhea after receiving irinotecan (45% vs. 9.1%, p=0.001), and an increased risk of 3~4 grade neutropenia (40% vs. 15.2%, p=0.017), which was consistent with numerous clinical studies in Japan (23~25). The correlation between UGT1A1 genotype and adverse reactions of irinotecan remains controversial. For the effect of UGT1A1* 28 mutant on delayed-onset diarrhea and 3~4 grade granulocytopenia, only one adverse reaction was mentioned in some studies. For example, Miyata et al. only compared the risk of neutropenia, but not the risk of delayed-onset diarrhea (26). Also, the predictive effects were refuted in some studies, but supported in other studies. Some studies supported the predictive effect on 3~4 grade neutropenia but refuted the risk of delayed-onset diarrhea (17), while others supported the occurrence of delayed-onset diarrhea but refuted the risk of 3~4 grade neutropenia (22). In addition to the racial differences, we believe it is also related to the dose of irinotecan. In many studies, Caucasians were enrolled and a larger initial dose of irinotecan may have been selected, but the dose of irinotecan was not investigated. Previous studies revealed that UGT1A1*28 and UGT1A1*6 have a predictive effect on the adverse reactions of intermediate or high dose of irinotecan, but not on a low dose of irinotecan (27). In this study, the homozygous and heterozygous mutations of UGT1A1 showed a predictive effect when the dose of irinotecan was reduced. For UGT1A1*28 and UGT1A1*6, the incidence of 3~4 grade neutropenia and 3~4 grade diarrhea significantly declined in both the dose reduction and non-reduction groups.
The correlation between UGT1A1 gene polymorphism and efficacy of irinotecan chemotherapy remains inconclusive. Toffoli et al. (28) believed that the efficacy was better in patients with mutant UGT1A1*28 as compared to those with wild-type UGT1A1*28. However, others believed that the efficacy was better in wild-type patients as compared to mutant patients (29), or the UGT1A1 gene polymorphism was not correlated with the efficacy (30). The relationship between UGT1A1 gene polymorphism and adverse reactions of chemotherapy has been reported in several studies, while the efficacy of chemotherapy has been rarely studied. This study showed that the polymorphism of UGTIAI*28 and UGTIAI*6 genes in Guangxi Zhuang patients with CRC was not significantly correlated with the RR and median PFS of irinotecan chemotherapy. Nevertheless, the correlation between UGT1A1 polymorphism and efficacy of irinotecan chemotherapy needs further verification with a large sample size study.
The above results may be affected by differences in population, drug dose, and a small sample size. Whether the gene polymorphism distribution and inter-individual variations in response to irinotecan in Chinese Zhuang are different from that in Han as well as European and American populations remains unknown. The sample size should be increased and the follow-up survival should be analyzed based on the gene distribution characteristics of Chinese and combined with the drug dose, in order to achieve the goal of individualization.