Association between SLC genotypes and toxicity
One of the current research goals was to look into the emergence of toxicity in lung carcinoma patients given platinum-based doublet chemotherapy with docetaxel, pemetrexed, irinotecan, and paclitaxel. The odds ratio (OR) and 95 % confidence interval (CI) for obtaining different toxicity grades following therapy in participants with each genotype were calculated using univariate logistic regression analysis. The adjusted ORs were also evaluated using a multivariate regression model with the toxicity grades as the dependent variable. Age, gender, regimen, and performance status, were all included in the multivariate model and were evaluated for their interactions or confounding effects. We utilized three possible analysis methods to see how SLC polymorphisms affected different toxicity levels. We compared patients with any toxicity grade (grades 1-4) to no toxicity (grade 0) in the initial assessment, individuals with intermediate/severe toxicity (grades 2-4) to those with no/low-grade (grade 0-1) toxicity were compared in the second analysis and the third assessment, and high-grade toxicity (grades 3-4) versus no/low/intermediate toxicity (grades 0-2) to see if the SLC polymorphisms were linked to severe toxicity. In this manner, cases were categorized into different toxicity levels.
All chemotherapy-related adverse effects (AEs) were recorded for each treatment cycle. In hematological toxicities, we evaluated anemia, leukopenia, absolute neutropenia, and thrombocytopenia. In anemia, a total of 406 patients’ toxicity data was available (Table 6a) . The table depicts that 25.1% of patients were categorized in grade 0 toxicity, and74.8% individuals were categorized in grade 1-4 toxicity. As observed for SLCO1B1 T521C polymorphism, 7.14% of individuals harbored single copy mutant allele (TC ).Supplementary Table 8 shows that subjects with the heterozygous genotype (TC ) had a reduced risk of developing anemia (OR=0.44, 95% CI=0.20-0.96); p=0.04 ) when compared to the patients with a wild type genotype (TT ). For SLC19A1 G80A polymorphism, on comparing individuals with severe toxicity (grades 3-4) versus no/low-grade (grade 0-2) toxicity, we observed that 26.6% of patients in grade 3-4 anemia harboring heterozygous (GA ) genotype showed a reduced risk of anemia (OR=0.35, 95% CI=0.14-1.74; p=0.02 ) as compared to the wild type genotype (GG ). We did not find any association between the SLC polymorphisms other hematological toxicities such as leukopenia and other AEs due to chemotherapy (Supplementary Table 7 ).
For analysis of absolute neutrophil count (ANC), we compared intermediate/severe toxicity (grades 2-4) versus no/low-grade (grades 0-1) toxicity as shown in Supplementary Table 9 . A total of 367 patients’ toxicity data was available for ANC. For SLCO1B1 A388G polymorphism, 16% (3) patients harbored the mutant genotype (GG ). Supplementary Table 9 depicts subjects with mutant genotype (GG ) ofA388G had a reduced risk of developing neutropenia toxicity (OR=0.42, 95% CI=0.10-1.76, log-rank-p=0.23) when compared to the individuals with wild type genotype (AA ). After adjusting with confounding, factors like age, gender, regimen, and performance status, the decreased risk was consistent in mutant genotype (GG ) as compared to wild-type genotype (AA ) (AOR=0.17, 95% CI=0.02-1.04; p=0.05 ).
Chemotherapy-induced thrombocytopenia is a potentially lethal consequence resulting in chemotherapy dosage delays, reductions, or discontinuance. Keeping this complication in view, we have analyzed the impact of SLC variants in causing thrombocytopenia. As shown inTable 7, we compared low/intermediate/severe toxicity (grades 1-3) versus no grade (grade 0) toxicity. For thrombocytopenia, there were 367 patients with available toxicity data, of which 32.1% (18) patients with SLCO1B1 A388G polymorphism harboring a single copy of mutant allele (AG ) was associated with a lower incidence of thrombocytopenia when compared to the patients carrying wild type alleles (AA ) (OR=0.41, 95% CI=0.20-0.82; p=0.01 ). After adjusting for confounding variables such as age, gender, regimen, and performance status, the reduced risk in heterozygous genotype (AG ) for causing thrombocytopenia was consistent when compared to wild-type genotype (AA ) (AOR=0.35, 95% CI=0.14-0.85; p=0.02 ).
Renal functions are assessed during chemotherapy as chemotherapeutic drugs are eliminated via the kidneys and nephrotoxic. We have evaluated chemotherapy-induced nephrotoxicity by comparing intermediate/severe toxicity (grades 3-5) versus no/low grade (grades 1-2) toxicity. As shown in table 6a , data of 366 patients were available to assess the associationbetween the SLC polymorphisms and nephrotoxicity.Lung carcinoma patients with heterozygous (AG ) genotype forA1683-5676G polymorphism showed a lower incidence of nephrotoxicity when compared to the patients with wild type genotype (AA ) (OR=0.35, 95% CI=0.17-0.72; p=0.002) . When confounding characteristics such as age, gender, regimen, and performance status were taken into account, the reduced risk of nephrotoxicity in heterozygous and mutant genotype (AG+GG ) was consistent when compared to wild-type genotype (AA ) (AOR=0.38, 95% CI=0.15-0.98; p=0.04 ) as shown in table 7 .
Additionally, we investigated gastrointestinal (GI) toxicity by comparing patients with low toxicity (grade 1) grade to individuals with intermediate-high toxicity (grade 2). We evaluated diarrhea, anorexia, constipation, and nausea-vomiting (Table 6b). Lung cancer patient with the heterozygous genotype (AG ) for SLC19A1 A388G polymorphism has a reduced risk of having constipation as compared to the patients harboring wild-type genotype (AA ) (AOR=0.17, 95% CI=0.03-0.87, p=0.03 ) as shown inTable 8 . The reduced risk was consistent when we compared the combined heterozygous and mutant (AG+GG ) genotype with the wild type (AA ) genotype (AOR=0.22, 95% CI=0.05-0.97; p=0.04 ). For SLCO1B1 A388G , lung cancer patients with heterozygous genotype (AG) revealed a 3.87-fold increased risk of having constipation (AOR=3.87, 95% CI=0.91-16.48; p=0.04 ) as compared to the patients with wild type genotype (AA ).
In nausea/vomiting, the comparison was made between intermediate/ severe toxicity (grades 2-3) versus low-grade (grade 1) toxicity. Among 116 patients, 54.3% experienced grade 2-3 nausea/vomiting. ForSLCO1B1 A388G polymorphism, a lower incidence of nausea/vomiting was observed in patients with mutant genotype (GG ) as compared to patients with wild-type genotype (AA ) (AOR= 0.22; 95%CI=0.05-1.03, p=0.05 ( Table 8) . We did not find any association between the SLC polymorphisms, other gastrointestinal toxicities such as diarrhea and anorexia, and other AEs due to chemotherapy (Supplementary Table 10 ).