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.