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 ).