Discussion
SLC transporters mediate the flow of chemotherapeutic drugs across
biological membranes in various organs, and the various single
nucleotide polymorphisms alter this inflow of drugs. Genetic
polymorphisms can cause individual variations in the metabolism and
pharmacotherapy of these transporters, which may create
population-specific disparities in drug transport. In a population,
heterogeneity in the pharmacokinetic profile of chemotherapeutic drugs
results from multiple interactions between genetic, environmental, and
physiological factors. In the past, many theories have been put forth to
explain the observed discrepancies regarding several therapeutic
drugs that may increase or inhibit the function or expression of solute
carrier protein, thus altering the phenotypic activity of the SLC
transporters. Given the effect of these polymorphisms on SLC transporter
activity, it is essential to look into their role in lung cancer, as
their expression levels could control the extent and duration of
chemotherapeutic drug inflow, affecting patients’ responses. Hence,
understanding and minimizing inter-individual variation in drug
responsiveness, toxicity, and sensitivity and its critical role in
identifying the efficient treatment option for lung carcinoma patients
is therefore imperative and clinically meaningful.
We have attempted to investigate the significance of SLC polymorphisms
in influencing survival rates and their correlation with toxicity in
lung cancer patients undergoing platinum-based chemotherapy treatment.
Our results from North Indian lung carcinoma patients suggest that
mutant genotype (AA ) of SLC19A1G80Apolymorphism is correlated with increased survival. Our results align
with Collin et al., who found no correlation ofG80A polymorphism in recessive, dominant, or
additive models in prostate cancer.21 A study by Liuet al . did not find any significant association forRFCvG80A polymorphism with lung cancer
susceptibility.22 However, we can explain the
increased survival trend in lung cancer patients with mutant genotype
(AA ) of SLC19A1G80A polymorphism. TheA allele of G80A might have a greater
influx propensity for the substrates, resulting in improved
bioavailability and chemotherapeutic drug intake,23thereby leading to better survival outcomes in the individuals with the
mutant genotype (AA ). On the contrary to our outcomes, Jabeenet al. has reported better survival in the patients with
wild-type genotype (GG ) in comparison to the mutant genotype
(AA ) of SLC19A1 G80Apolymorphism.24 These incongruent results could be
attributed to the differences in clinical characteristics and ethnicity
of patients.
In patients with SLCO1B1A388G polymorphism, our
results demonstrated that the patients with mutant genotype (GG )
had the same median survival time as the wild-type genotype (AA) .
Our results are in concordance with Lee et al., who put forth
that SLCO1B1 A388G is associated with an
unaltered transport function, so there would be no modification in the
drug influx, which could be the likely cause for no difference in median
survival time between mutant (GG) and wild type genotypes(AA) .25 On the contrary, Sissung et al.stated that A388G polymorphism is correlated
with the altered SLCO1B1 transport function, leading to modifications in
the transmembrane domain structure.26 While
Liutkevicie et al. put forth that the G allele ofA388G is associated with the increased SLCO1B1
function, proposing increased functional activity of the
transporter.27 SLCO1B1 polymorphism has been
reported by numerous researchers, who have linked theA388G mutation to an increase, decrease, or no
effect on the transporter activity.28 These disparate
results could be ascribed to ethnicity and clinical characteristics of
patients, such as the methodology used to detect the expression of SLC
and heterogeneity in tumor histology, all of which could play a decisive
role.
Our results for SLCO1B1 T521C polymorphism
showed reduced survival in patients with mutant genotype (CC ) as
compared to both homozygous (TT ) and heterozygous genotype
(TC ), though the substantial significance betweenT521C polymorphism and overall survival was not
achieved. Studies in the past have shown that the C allele ofT521C is correlated with decreased activity of
SLCO1B1.29 Due to this reduced activity of the
transporter, patients harboring the variant allele (C ) ofT521C polymorphismmay have reduced inflow of
drugs, which can explain the lower survival in lung cancer patients. On
the contrary, Feng et al. has shown better survival in gastric
cancer patients having mutant (CC) and heterozygous (TC)genotype.30
We have also assessed the impact of SLC polymorphism on overall survival
based on histology. Our findings demonstrated that ADCC patients with
the mutant genotype (AA) of the SLC19A1
G80A polymorphism had a better prognosis
(p=0.04 ). Mechanistically, the RFC1 protein is encoded by the
main influx transporter SLC19A1. I t mediates folate uptake in the
cell and transports antifolate chemotherapeutic agents. RFC1 is
substantially expressed in lung cancer patients.31 It
has been reported that in adenocarcinoma cells, RFC1 proteins are
overexpressed.32
Furthermore, studies have linked downregulation of the RFC1 protein to
impaired drug transport, developing resistance.24,33The overexpression of RFC1 in ADCC patients explains our results with
better survival in the mutant genotype (AA) of SLC19A1
G80A polymorphism. Even though SLC19A1 is the
most common antifolate uptake transporter, our results did not show any
association of G80A polymorphism with the
survival of the patients undergoing pemetrexed and cisplatin/carboplatin
treatment. Our results align with the various studies on
NSCLC.34-36 Our findings also revealed that patients
with SCLC who had the mutant genotype (AA) of SLC19A1
G80A polymorphism had a better prognosis (p=0.04). To
the best of our knowledge, none of the previous studies have looked at
the role of the SLC19A G80A polymorphism in
SCLC, as most of the research has focused on its impact on NSCLC. Based
on our findings, we believe that the SLC19A1
G80A polymorphism may improve overall survival in
SCLC patients.
As per our results, patients who were given docetaxel along with
cisplatin/ carboplatin and were heterozygous carriers (AG) for
the SLCO1B3 (A1683-5676G) polymorphism had a
significantly shorter survival time as compared to the wild type(AA) genotype. No supporting studies were found because the
pharmacogenetics of SLCO1B3 is little understood, and previousin vivo and in vitro studies gave inconsistent results
regarding the functional effects of the SLCO1B3 polymorphisms.
Chew et al. revealed that the SLCO1B3
(A1683-5676G) variant allele is related to altered
docetaxel disposition.37 However, our investigation
did not find any patients with mutant genotype (GG) forSLCO1B3 (A1683-5676G) polymorphism administered
docetaxel and cisplatin/carboplatin therapy, and we could not assess the
role of its variant genotype on the survival of lung cancer patients.
Chew et al. have mentioned that inter-individual variability in
docetaxel disposition is influenced by SLCO1B3pharmacogenetics.38 However, more research is needed
to investigate the functional characterization ofSLCO1B3 -associated docetaxel transport, which may help
researchers better understand the molecular basis for docetaxel disposal
disposition.
We have also evaluated whether SLC polymorphisms were associated
with toxicity among platinum-based chemotherapy-treated lung cancer
patients. Our results showed that patients with at least one mutant
allele (AG) in SLCO1B1 A388G had a
significantly lower risk of developing thrombocytopenia. Leiri et
al. have reported that the presence of the G allele at the codon
388 can modulate the activity of SLCO1B1.39 The
systemic concentration of the chemotherapeutic drug is strongly
dependent on the activity of SLCO1B1. An increase in the SLCO1B1
activity and subsequent increase in the hepatic clearance of the
chemotherapeutic drug may lead to reduced systemic exposure and hence
less toxicity.40 This may explain the reduced risk of
developing thrombocytopenia in the heterozygous (AG) genotype ofA388G, as the occurrence of
chemotherapy-induced thrombocytopenia varies according to the treatment
used. Our findings showed a significant association of SLC19A1
G80A polymorphism with a reduced risk of anemia. The
heterozygous genotype (GA) of G80Apolymorphism showed a substantial protective effect from hematological
toxicity-anemia. Generally, folate is required for RBC production and is
a typical target of chemotherapeutic agents.41 These
drugs impede folate metabolism, and a deficiency of folate causes DNA
synthesis abnormalities, which leads to genomic instability leading to
the hypothesis that a lack of folic acid inhibits RBC maturation,
resulting in anemia. However, our results suggest that the heterozygous
genotype (GA) of G80A polymorphism is
associated with a reduced risk of developing anemia in lung cancer
patients.
Our results showed a reduced risk of developing nephrotoxicity in
patients harboring heterozygous genotype (AG ) on comparing severe
toxicity (grade 3-5) with the absence of any/ intermediate toxicity
(grade 1-2). Mechanistically, the kidney is the main organ involved in
eliminating platinum-based chemotherapeutic drugs.42Many drugs, particularly those with a propensity for nephrotoxicity, are
eliminated in the urine by active tubular secretion in addition to
glomerular filtration.43 In vitro studies have
shown that OATP1B1 and OATP1B3 transport cisplatin and
carboplatin, and the toxicity of these drugs in human tumor cells was
enhanced with increased OATP1B3 mRNA
expression.4 Hilgendorf et al., have reported
low mRNA expression of SLCO1B3 in the kidney.44Also, it has been reported that the A1683-5676Gvariant may lead to the reduced activity of SLCO1B3 that might
vary the therapeutic efficacy.18 These findings
explain that SLCO1B3 has reduced expression in the kidney,
leading to reduced drug uptake and thereby showing a reduced risk of
causing nephrotoxicity.
Gastrointestinal (GI) toxicity is a typical adverse effect of
chemotherapy treatments in lung cancer patients. We observed that
heterozygous genotype of SLC19A1 G80A andSLCO1B1 A388G polymorphisms were associated
with protective effects from gastrointestinal toxicity.Due to a scarcity
of research, determining the actual incidence rate of
chemotherapy-induced constipation across all cancer patients is
challenging. Some studies state that SLCO1B1 polymorphisms are
correlated with the increased risk of gastrointestinal toxicity in acute
lymphoblastic leukemia.45 In the case ofSLC19A1 , Lima et al. found that G carriers ofG80A polymorphism were linked to
chemotherapy-associated gastrointestinal toxicity 10,
whereas various other studies did not find any correlations with the
toxicity.46,47 Several factors, including the
patient’s characteristics, dose schedule, the type of chemotherapy, and
regimen employed, influence the severity and extent of
chemotherapy-induced toxicity. Therefore, these conflicting data ofSLC polymorphism and chemotherapy-related gastrointestinal
toxicity need to be clarified.
It is essential to mention that the present study has certain
limitations since carcinoma is often detected at a late stage; our study
only includes patients with advanced lung cancer. This could be because
of public awareness or its similarity to other diseases like
tuberculosis.Many patients who receive chemotherapy at an advanced stage
of cancer cannot achieve the treatment’s endpoint, weakening the
research’s scope on chemotherapy response.The majority of the people who
came to PGIMER for treatment were from rural areas in Northern
India.Since it was difficult for them to commute from their homes, many
patients in remote areas did not regularly visit the hospital. Some
patients left the clinic before or after six chemotherapy cycles, while
others did not.
Due to the shortage of clinical data could not conduct progression-free
survival analysis on the current study group.On the other hand, our
study has several advantages, including enrollingmany lung cancer
patients.Second, patients on platinum-based chemotherapy regimens were
included, and everyone was treated at the same hospital.Third, patients
were enrolled, and clinical parameter data was obtained separately,
regardless of the information of SLC polymorphism.