Back to Journals » Pharmacogenomics and Personalized Medicine » Volume 13

Genetic Polymorphisms and the Efficacy of Platinum-Based Chemotherapy: Review

Authors Afifah NN , Diantini A , Intania R, Abdulah R , Barliana MI 

Received 13 June 2020

Accepted for publication 7 September 2020

Published 8 October 2020 Volume 2020:13 Pages 427—444

DOI https://doi.org/10.2147/PGPM.S267625

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Dr Martin H Bluth



Nadiya Nurul Afifah,1 Ajeng Diantini,1,2 Ruri Intania,3 Rizky Abdulah,1,2 Melisa I Barliana2,4

1Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, Indonesia; 2Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Bandung, Indonesia; 3Dr. H.A. Rotinsulu Lung Hospital, Bandung, Indonesia; 4Department of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, Indonesia

Correspondence: Melisa I Barliana
Department of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung Sumedang KM. 21, Jatinangor 45363, Indonesia
Email [email protected]

Abstract: Previous studies have indicated that genetic variations in individuals may result in changes in gene expression and amino acids. The effect of these changes may lead to different responses to platinum-based chemotherapy. A vast response rate interval and a short survival rate indicate that the efficacy and efficiency of the selection of chemotherapy have not been optimized. This article aims to illustrate the potential relationship of various genetic polymorphisms in response to platinum-based chemotherapy for several types of cancer. This review was conducted using articles from the last three- and five-year periods (2014– 2019) that use gene polymorphism and its relationship to the efficacy of platinum-based chemotherapy as their theme. A total of 26 out of 488 relevant articles were included based on specific criteria. Through various mechanisms, genes, including ERCC1, ERCC2/XPD, XPC, XPA, XRCC1, APE-1, PARP1, OGG1, ABCC2, MRP, GSTP1, GSTM1, GSTT1, MATE1, and OCT2, have been associated with patient response to platinum-based chemotherapy. We conclude that genetic polymorphism analysis is recommended for the management of cancer so that each patient can be administered therapy based on his or her genetic profile to achieve an effective and efficient outcome.

Keywords: genetic polymorphism, platinum-based chemotherapy, DNA repair, drug accumulation, drug detoxification

Introduction

Platinum, in the form of cisplatin, was first approved by the FDA as a therapy for cancer in 1978. That has led to an interest in platinum or other metal-containing compounds as potential anticancer drugs.13 The platinum-based chemotherapy (PBC) drugs currently prescribed include cisplatin, carboplatin, and oxaliplatin.4 PBC has been shown to inhibit cell division in various types of cancer.5 At sufficient intracellular levels, the drug becomes reactive and then binds to peptides and proteins containing sulfur residues such as cysteine, methionine, and especially glutathione. However, the most important therapeutic target of PBC is the DNA within the cell nucleus.6 Platinum reacts with guanine and adenosine residues and forms a bulky-adducts. With platinum bound to the DNA, it forms a lesion and DNA crosslink. As a result, DNA transcription and replication are inhibited, resulting in the apoptosis of the cancer cells.7 But that bulky-adducts can be recognized and repaired by the NER pathway, which requires many proteins. NER pathway causing the DNA to unwind, and platinum becomes detached. That mechanism leads to chemotherapy resistance.

Resistance is the most significant challenge to PBC’s success as it can reduce or even eliminate the effectiveness of chemotherapy. Resistance occurs through several mechanisms such as increased degradation and inactivation of the drug before reaching its therapeutic target (nuclear DNA), decreased drug uptake into cells or increased drug efflux, increased DNA repair activity; which also includes one mechanism of DNA damage tolerance; caused by the formation of DNA adducts such as platinum–DNA adducts, and epithelial–mesenchymal transition, as well as how inherent tumor cell heterogeneity plays a role in drug resistance.79 For every cellular process, there is a potential for genetic variability (individual genetics), especially in tumor somatic cells.10 Thus, genetic changes can alter the cell phenotype and vary the response of individuals to PBC. In this review, we will discuss the mechanisms of PBC resistance associated with genetic polymorphisms.

Materials and Methods

This review summarizes the results of several studies related to the effects of polymorphisms on platinum-based chemotherapy. It includes studies from the PubMed database identified using the keywords “polymorphism,” “platinum,” “response,” and “resistance.” Articles written in a non-English language and not including PBC therapy were excluded. Moreover, manuscripts, research communications, reviews, expert opinions, and unrelated studies not associated with PBC’s effectiveness were excluded (Figure 1).

Figure 1 Flowchart depicting the literature search process.

A total of 488 articles were identified through the PubMed database and then limited to publications from the last three years for articles involving response and the last five years for resistance. We also filtered the list to include articles, including the term “human.” As a result, the total number of articles included was 26. The majority of the articles discussed the effect of gene polymorphisms on the therapeutic outcome (side effects, effectiveness, resistance, and survival rates) from platinum-based chemotherapy in various types of cancer.

Pharmacogenetics and Its Importance

Pharmacogenetics is the study of the variability of therapeutic/drug response between individuals due to genetic variations in heredity, whereas pharmacogenomics was born as a more comprehensive study. Pharmacogenomics maps all the genetic variations, in the form of polymorphisms or mutations that have a clinical significance on therapeutic drug response, toxicity levels, or the incidence of resistance. Increasing our understanding of genes and completion of the Human Genome Project introduced the term of pharmacogenomics is more widely used to encompass the role of genetics in drug response.1113

A mutation is a change in DNA sequences. At the same time, the term polymorphism is used to define natural variants exist for traits for which no clearly normal type can be defined and that co-exist in a population at relatively high frequencies (>1%).14

Pharmacogenomics is a rapidly growing field that aims to trace the interindividual-genetic differences in drug response. That study has been applied to many anticancer drugs to identify relevant inherited or acquired genetic variations that may predict patient response to chemotherapy and targeted therapies. Some of anticancer has presented variations in therapeutic response, such as in PBC, this can be seen from the overall response rate of 26–63% these variations in therapeutic response means that some of the tumors are sensitive to platinum-based, some are hypersensitive, other tumors conversely have a potentially intrinsic resistance.15,16

Although the efficacy of chemotherapy can be affected by many factors, genetic variation as polymorphism plays a significant role in drug response. The location or site of the polymorphism will determine the effect, like polymorphism present within a coding sequence and leading to an amino acid change (referred to as a non-synonymous SNP or mutation) can modify the protein’s activity or function. If the mutation is synonymous, then translation rates or mRNA half-life may be affected. If the mutation causes a premature stop codon, this can lead to the production of a truncated protein product or nonsense-mediated decay phenotype.17,18 So, due to differences or changes at the genetic level, causing modifications in cellular phenotype could explain some of the variability in response or toxicity.19

Platinum-Based Chemotherapy Resistance

Platinum-based anticancer drugs are heavily applied in chemotherapy regimens. Nevertheless, the intrinsic or acquired resistance severely limit the clinical application of platinum-based treatment. Chemotherapy resistance is the innate and/or acquired ability of cancer cells to evade chemotherapeutics’ effects, and that is one of the causes of individual variation in PBC response.20

Previous studies on variability responses to platinum-based chemotherapy suggest that it is affected by the mechanism of how platinum is processed in the body, including pharmacokinetics and pharmacodynamics. In general, efforts have delivered evidence regarding DNA repair systems of tumor cells, and drug metabolization systems cause these variabilities in PBC response.20,21 Chemotherapy resistance can occur through many mechanisms such as; damage in the drug delivery system, increased efflux and/or decreased drug influx, increased detoxification rate, alteration of the target site, increased damaged-DNA repair activity manifested in tolerance of DNA damage, increased anti-apoptotic factors and/or decreased pro-apoptotic factors, as well as changes in cell cycle/transcription factors.9

Pharmacokinetic mechanisms include a reduction in drug levels at the target site due to reduced uptake and/or increased efflux by Adenosine triphosphate-binding cassette (ABC) transporters, drug detoxication by glutathione S-transferases (GSTs), and drug elimination by Organic Cation Transporter (OCT) along with Multidrug Toxin Extrusion (MATE). It is clear that reduced drug levels at the target site will affect the formation of platinum–DNA adducts and decreases the efficacy, while alteration of elimination rate will be affected to level and severity of toxicity.2229 The pharmacodynamics mechanism includes increased damaged-DNA repair activity. The DNA repair mechanism’s increased activity will result in failure to form DNA damage induced by platinum.21 In contrast, tumor heterogeneity includes alteration of the target site, cell cycle stage changes, stochastic variations between tumor cells, or hierarchical organization of cells. Tumor heterogeneity is included in the intrinsic resistance factor of the tumor cells themselves.10

For each pharmacokinetic and pharmacodynamic mechanism, there exists the potential for genetic variabilities, such as the occurrence of polymorphisms or mutations in genes that play a role in these mechanisms. Genetic polymorphisms can modify the cell phenotype, which could explain some variabilities in the response or resistance to platinum-based chemotherapy.21

Nucleotide Excision Repair

Nucleotide Excision Repair (NER) is a mechanism that is directly and specifically activated when platinum-based chemotherapy is given to patients. NER mechanism is typically activated when DNA damage occurs by UV lights, environmental mutagens, and active chemotherapy substances, which cause the addition of molecules to DNA (DNA adducts), one of which is platinum-based chemotherapy. DNA damage due to the addition of platinum is referred to as bulky lesions, while the BER repair mechanism repairs non-bulky lesions. NER is the primary mechanism of PBC resistance and is responsible for removing platinum that has been attached to the DNA of cancer cells. As a result, the repaired DNA damage prevents apoptosis from occurring (Figure 2).31,32 The repair of DNA lesions by NER is a multistep process. It includes (a) recognizing lesions, (b) unwinding the DNA strands, (c) incision of the lesion by endonuclease activity, and (d) DNA synthesis and ligation (Figure 3). Recognition of DNA lesions may be divided into two processes: global genome repair (GGR) and transcription-coupled repair (TCR) (Figure 3). Several proteins are involved in this mechanism that affects the response to PBC (Figure 3).

Figure 2 Principles of platinum-based chemotherapy.

Figure 3 Nucleotide excision repair.

Recognition of Lesion Sites

The global genomic repair (GGR) process detects lesions throughout the genome, regardless of whether a specific sequence is transcribed or not. In contrast, Transcription-Coupled Repair (TCR) is only initiated when lesions block RNA polymerases on the template of the DNA strand. Thus, these lesions are only removed from transcribed DNA sequences33,34 (Figure 3).

Several studies have indicated that the protein responsible for initial damage recognition during GGR is xeroderma pigmentosum complementation group C (XPC).35 This protein forms a complex with damaged DNA binding 1 and 2 (DDB1 and DDB2/XPE).3638 After XPC and its complex recognize the damaged site, a more stable and rigid XPC–DNA complex is formed. This complex then recruits other NER factors to the damaged site. The other NER factor that is responsible for the next step, which is the verification of the damaged DNA, is the transcription factor II H (TFIIH) complex in concert with xeroderma pigmentosum complementation group A (XPA)39,40 (Figure 3). Verification is an essential process since XPC can only bind to DNA sites containing mismatched bases, but devoid of any lesion. To avoid an error, this process is designed to verify that a relevant lesion indeed exists. TFIIH is a complex that contains two ATPase/helicase subunits, namely, xeroderma pigmentosum complementation group B (XPB) and xeroderma pigmentosum complementation group D (XPD), and it is essential for the subsequent NER step.41

In TCR, the protein that plays this role is RNA polymerase II, which binds to Excision Repair Cross-Complementation group 8 (ERCC8/CSA) and Excision Repair Cross-Complementation group 6 (ERCC6/CSB) to form a complex42 (Figure 3). A small number of mutations that occur in somatic cells can activate TCR.4345

Polymorphisms that occur within genes that encode the proteins involved in the recognition step of NER, TCR, and GGR affect PBC response. A recent meta-analysis study suggests that changes in the level of XPC gene expression genetically predispose tumors to various PBC outcomes46 (Table 1). Another study suggested that a polymorphism in ERCC6 could be a predictor for the clinical outcome of the platinum-based chemotherapy in Non-Small-Cell Lung Cancer (NSCLC)47 (Table 1).

Table 1 Summary of the Association of Genetic Polymorphisms to Platinum-Based Clinical Outcomes

DNA Unwinding

As mentioned previously, XPD is a component of the TFIIH complex, which has a role in the DNA-unwinding process of NER.48 Together with excision repair cross-complementation group 1 (ERCC1), the mRNA expression levels of XPD could be a predictive factor for platinum response in several types of cancer.49 Moreover, XPB and XPA are part of the TFIIH complex. The XPA protein binds to damaged sites that have been “marked” by XPE and XPC and then unwinds the DNA in conjunction with the TFIIH complex50,51 (Figure 3). XPA is one of the platinum efficacy predictors52 (Table 1). Other meta-analysis studies have concluded that XPD is one of the proteins that has a significant association with PBC outcome53 (Table 1).

Incision of the Lesion

ERCC1 is a protein that plays a major role in platinum resistance in recent years.49 ERCC1 forms heterodimers with XPF and is involved in the process of DNA incision54 (Figure 3). In vitro studies have indicated that a decrease in regulation or double knockdown of the XPF-ERCC1 complex increases the efficacy of cisplatin.55 Results from Phase II clinical studies indicate that the level of ERCC1 mRNA expression of ERCC1 is a predictor of PBC response.56 The International Adjuvant Lung Cancer Trial Biologic Program (IALT-Bio) states that ERCC1 is a biomarker for determining chemotherapy selection.57 In other types of cancer, the role of ERCC1 as a predictive factor remains unclear. Another protein that plays a role in the incision step and has a significant association with PBC outcome is XPG/ERCC553 (Table 1). The final step in the NER process is gap filling and ligation, which is conducted by several proteins, including DNA polymerase, PCNA, and DNA ligase (Figure 3).

Base Excision Repair

Base excision repair (BER) plays a role in removing non-helical-distorting bases or non-bulky DNA lesions from the genome that arise from alkylation, deamination, or oxidation. Some of the alkylating agents are exogenous agents contained in food; such as nitrosamines (cigarettes and food with intensive thermal treatment),58,59 alkylating agents found in the environment from industry and agriculture; such as vinyl chloride, which is used as a raw material in the plastics industry, bromomethane fumigants from the agricultural industry, and chloromethane, which is used as a coolant.6063 Several other alkylating agents, including cyclophosphamide, melphalan, busulfan, and temozolomide, are widely used in chemotherapy.64,65 The deamination of a DNA base can occur spontaneously66,67 because of inflammation, which results in oxidative deamination, or can be produced enzymatically.6870 Whereas base oxidations occurwhen DNA bases interact with reactive oxygen species (ROS) formed by ionizing radiation or produced under physiological conditions.

There are two types of BER in mammals. Short-Patch (SP) is a mechanism for single-nucleotide replacement, and Long-Patch (LP) replaces 2 to 13 nucleotides. The protein component of these BER mechanisms includes glycosylase, endonuclease, DNA polymerase, and DNA ligase (Figure 4). Therefore, the genes that express those proteins are considered as a predictor of chemo-sensitivity.71

Figure 4 Base excision repair.

As listed in Table 1, the ERCC1 polymorphisms, namely, Arg194Trp and Arg399Gln, are considered predictors of chemotherapeutic drug sensitivity. In studies of an Asian population, a relationship between increased PBC sensitivity in patients with these polymorphisms was evident.72,73 Moreover, other studies have reported that the XRCC1 rs25487 polymorphism results in a worse overall survival in a Caucasian patient cohort. Although the PFS in the Asian population was longer, the XRCC1 rs1799782 polymorphism produces a worse objective response.74 In addition to XRCC1, the other genes that play a role in the BER mechanism include APE-1, PARP1, and OGG1. These three genes are associated with PBC’s clinical outcomes and decreased PFS in patients who express variant alleles.75

Pharmacokinetic Mechanism

One mechanism of PBC resistance is decreased intracellular drug accumulation, which prevents the drug from reaching its target.76 The causes of the decreased drug accumulation include inhibition of drug uptake, increased drug efflux, or a combination of both. Another mechanism at this pharmacokinetic stage is the process of drug detoxication. The proteins which are critical players in the metabolism of many chemotherapeutic agents and play a role in the mechanism of reducing drug accumulation include the Adenosine triphosphate-binding cassette transporter family and proteins that play a role in the detoxication process, such as glutathione S-transferase, organic cation transporter, and multidrug toxin extrusion.25,28,29,77,78

Adenosine Triphosphate-Binding Cassette Transporter Family

Adenosine triphosphate-binding cassette (ABC) transporters, including ABCB, ABCC, and ABCG, represent general biological defenses against environmental toxicants. ABC transporters are an example of ATP-dependent pumps, and they can move substrates in (influx) or out (efflux) of cells. For example, such proteins play a role in increasing the efflux of hydrophobic cytotoxic drugs. These proteins utilize the energy derived from ATP hydrolysis to transport both endogenous and exogenous substances through the cell membrane.19,79 ABCC2 is a protein known to play a role in the transport of glutathione-conjugated platinum out of cells. ABCC2 was shown in in vitro studies to represent a mechanism leading to platinum-based chemotherapy resistance.19,25,80 As listed in Table 1, an ABCC2 polymorphism is associated with the overall survival of patients with advanced-stage NSCLC.29 A polymorphism in ABCC2 (rs717620) resulting from an alteration of C to T is known to be related to neoadjuvant chemotherapy’s pathological response. Another study has indicated that this protein is related to the tumor regression grade (TRG) value.81

ABCG2 htSNP rs2725264 may be independently associated with OS in unresectable NSCLC patients treated with first-line platinum-based chemotherapy.82 A study of the rs4148416 polymorphism of ABCC3, another member of the multidrug resistance protein (MRP) family, showed that this polymorphism was associated with a low survival rate.83

Detoxication Process

Platinum-containing drugs can be deactivated by glutathione S-transferases (GSTs). These enzymes, categorized as phase II metabolic enzymes, GSTs catalyze the conjugation of glutathione (GSH) to platinum. The formation of platinum–glutathione inactivates the drug by increasing its solubility that leading to excretion.84 Variations in GSTs have implications for cellular resistance to PBC. When GST enzyme activity decreases, the drug concentration within the tumor tissue increases and causes an increased risk of platinum toxicity.26 There are two families of GST enzymes involved in cisplatin detoxification; GSTP1 and GSTM.24,27 Besides GSTs, several other proteins affect the detoxication process.

Glutathione S-transferase P1 (GSTP1) is expressed in epithelial cells. Polymorphisms in the GSTP1 gene, such as the A to G base change in rs1695, cause the conversion of isoleucine to valine. This polymorphism results in the reduced activity of the GSTP1 enzyme and loss of this gene’s alleles causes the complete loss of enzymatic activity.85,86 Other studies suggest that polymorphisms at these sites are associated more with changes in PBC toxicity, such as granulocytopenia and peripheral neuropathy induced by platinum.86,87 Several recent studies showed that the GSTP1 polymorphism represents a predictive factor for the outcome of NSCLC patients treated with PBC88 (Table 1). Data from a meta-analysis showed that the Asian GSTP1 genotype, IIe105Val IIe/Val and Val/Val, exhibited a better response compared with IIe/IIe89 (Table 1). Furthermore, the GSTM1 polymorphism with a “null” phenotype is associated with a better response to PBC in Asian lung cancer patients. A meta-analysis regarding glutathione indicated that the GSTP1 polymorphism, IIe105Val, as well as the GSTM1 and GSTT1 null variants, may be useful predictors for the effectiveness of PBC89 (Table 1).

Elimination Process

Besides GSTs enzymes, summarized in Table 1, some transporters can affect the detoxification rate and implicated to the clinical outcome of PBC, include organic cation transporter 2 (OCT2) and multidrug toxin extrusion 1 (MATE1).

Platinum is eliminated through the proximal tubule of the kidney.90 OCT proteins are expressed in the kidney. Thus, they have an essential role in the regulation of platinum distribution and excretion.28,91 At the same time, MATE1 is an H+-coupled organic cation exporter expressed on the luminal membrane and renal duct.77,78 It is involved in excretion, specifically in the renal tubules.92 Both proteins are related to the disposition of platinum.30 The results of one study indicated that the polymorphisms, namely, OCT2 r316019 and MATE1 rs2289669, OCT2 rs316019, were associated with hepatotoxicity (P = 0.026) and hematological toxicity (P = 0.039), and MATE1 rs2289669 was associated with hematological toxicity induced by platinum (P = 0.016). Both of OCT2 and MATE1 are potential clinical markers for the toxicity of PBC in NSCLC.93

Discussion

This study aims to review several studies related to the correlation of gene polymorphisms to the efficacy of platinum-based chemotherapy in several types of cancer. The majority of studies were subjects with lung cancer (especially NSCLC), cervical, gastric, and ovarian cancer. From a total of 26 articles (original research and meta-analysis) included in the inclusion, there is the variability of the study results. The variation in the results of each study referred to the statistical significance of the results, the value and interpretation of the correlation, and the incidence rate of the polymorphism itself.

Polymorphism is defined as natural variants that exist for traits for which no clearly normal type can be defined and co-exist in a population at relatively high frequencies (>1%).14 In the human genome, any two randomly chosen DNA molecules are likely to differ at about one SNP site every 1000 base pair (bp) in noncoding DNA and at about one SNP site every 3000 bp in protein-coding DNA. SNPs are the most common form of genetic differences among people. About 3 million SNPs that are relatively common in the human population have been identified,94 and The effects of the variant form may be both beneficial and detrimental, depending on the circumstances.

SNPs not just responsible for the disease but also other clinical manifestations such as therapeutic outcomes or drug resistance that do not necessarily have to occur in coding regions. They could occur in any genetic region that can affect the expression, structure or form, or activity of the protein. SNPs in genetic regions like transcription factor binding domains, promoter regions, intron-exon boundaries, may cause defects in splicing or mRNA signal process.95

For a long time, it has been known that genetic variation, including SNPs, is influenced by many factors, one of which is race/ethnicity. The studies that were included in this review show a different result between Asian and Caucasian. However, it is known that even in the same races/population, the incidence of genetic variability between individuals also has a high probability.96 Therefore, genetic-related studies, even in the same race, may have different results. This is what underlies a systematic review, review studies, and meta-analysis of genetic polymorphism urgently needed.

As in this article, the result of polymorphism analysis against chemotherapy response studies in patients with different cancer types was linear. As in NSCLC, lung cancer in general, and gastric cancer, ERCC2 rs1799793, the mutant genotype will have worse chemotherapy efficacy with shorter survival. Whereas in NSCLC and gastric cancer, ABCC2 rs717620, the mutant genotype had better survival and response.

ERCC2 or XPD is a gene that encodes the XPD protein, which is a component of the transcription factor complex II H (TFIIH) and has ATP-Dependent Helicase activity. In other words, the XPD protein is included as a helicase enzyme and plays a vital role in the DNA repair mechanism.97,98 Amino acid changes due to A>C polymorphism (rs1799793) affect the alteration of activity and function of these proteins. The impact of these changes is related to the clinical outcome of chemotherapy’s effectiveness, such as decreased response and survival.99,100 In contrast to ABCC2, which is one of the MRP transporter families that encodes Multidrug Resistance-associated Protein 2, it functions as an organic anion transporter, playing a role in platinum-conjugated transport out of cells. C>T polymorphisms (rs717620) are associated with altered ABCC2 expression or function. Besides promoting the export of glutathione-conjugated platinum, upregulated ABCC2 expression also decreases the formation of platinum-DNA adducts and reduces G2-arrest in cisplatin-resistant cell lines. This polymorphism’s clinical manifestation is an increase in the response of platinum-based chemotherapy survival rates.101103

However, in this review, we found the contradictory result between the studies, as in XRCC1 rs1799782, where the mutant genotype is known to have low overall survival. In contrast, the results of other studies suggest that the mutant genotype has a better chemotherapy response. It is influenced by several factors, one of which is the amount of data (sample subjects or articles) that are different. Several studies, with a smaller number of data samples, become their limitations and affect reliability. Meanwhile, factors other than polymorphism also play an important role related to chemotherapy response, such as tumor heterogeneity, age, comorbidity and severity, treatment modality, previous therapy response, stage, serum albumin levels, the general condition of patients on Zubrod and Karnofsky scales, histology, and types of cancer, as well as chemotherapy side effects that occur in patients.104108

Age is related to physiology and comorbidities. A study stated that patients under 60 years old had a higher chance of survival with p = 0.016.104 Meanwhile, research in Japan concluded that the level of serum albumin and patient comorbidity (Charlson Comorbidity Index) are fundamental factors in the clinical response of elderly patients over 75 years.105 Other studies stated that comorbidity and their severity could affect the chemotherapy response. Studies conducted on breast cancer patients proved this with OR = 0.46; 95% (CI: 0.27–0.76) among patients with a Charlson score of 2 versus 0.107 In a meta-analysis study, it was stated that in general, the response to chemotherapy could differ between types of cancer and their histology. It is also greatly influenced by choice of chemotherapy regimen and stage.108

Conclusion and Prospects

Polymorphisms that occur in several genes related to DNA repair or a drug’s pharmacokinetic mechanism in cancer patients may involve the alteration of one base with or without a significant clinical impact. The effects of such changes are related to the gene coding instructions, such as at the level of gene expression, or the amount and type of amino acids produced. It is directly or indirectly results in a different response for each individual to platinum-based chemotherapy. Treatment management based on gene polymorphisms is not new, but it has been used thus far for metastatic cancer patients to identify gene polymorphisms related to targeted drug therapy.109 For several cancers, polymorphism detection is used as a preventive measurement, assessment, or risk factor for cancer.110112 Our review demonstrates that the examination of genetic profiles that influence the efficacy of chemotherapy is highly recommended. It will be beneficial as a consideration for the selection of the type of chemotherapy regimen to achieve cost-effective and efficient therapy.

Acknowledgments

This research was partially funded by the Indonesian Ministry of Research, Technology and Higher Education, under Post Graduate Research Scheme for AD; and the Indonesian Ministry of Research and Technology/National Agency for Research and Innovation, and Indonesian Ministry of Education and Culture, under World Class University Program managed by Institut Teknologi Bandung, for RA.

Disclosure

The authors report no conflicts of interest in this work.

References

1. Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007;7(8):573–584. doi:10.1038/nrc2167

2. Makovec T. Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy. Radiol Oncol. 2019;53(2):148–158. doi:10.2478/raon-2019-0018

3. Frezza M, Hindo S, Chen D, et al. Novel metals and metal complexes as platforms for cancer therapy. Curr Pharm Des. 2010;16(16):1813–1825. doi:10.2174/138161210791209009

4. Apps MG, Choi EHY, Wheate NJ. The state-of-play and future of platinum drugs. Endocr Relat Cancer. 2015;22(4):R219–R233. doi:10.1530/ERC-15-0237

5. Shaloam D, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364–378. doi:10.1016/j.ejphar.2014.07.025.Cisplatin

6. Johnstone TC, Suntharalingam K, Lippard SJ. The next generation of platinum drugs: targeted Pt(II) agents, nanoparticle delivery, and Pt(IV) prodrugs. Chem Rev. 2016;116(5):3436–3486. doi:10.1021/acs.chemrev.5b00597

7. Amable L. Cisplatin resistance and opportunities for precision medicine. Pharmacol Res. 2016;106:27–36. doi:10.1016/j.phrs.2016.01.001

8. Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: an overview. Cancers (Basel). 2014;6(3):1769–1792. doi:10.3390/cancers6031769

9. Stewart DJ. Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol. 2007;63(1):12–31. doi:10.1016/j.critrevonc.2007.02.001

10. Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The different mechanisms of cancer drug resistance: a brief review. Adv Pharm Bull. 2017;7(3):339–348. doi:10.15171/apb.2017.041

11. Scott SA. Personalizing medicine with clinical pharmacogenetics Stuart. Bone. 2011;23(1):1–7. doi:10.1038/jid.2014.371

12. Tavakolpour S, Darvishi M, Ghasemiadl M. Pharmacogenetics: a strategy for personalized medicine for autoimmune diseases. Clin Genet. 2018;93(3):481–497. doi:10.1111/cge.13186

13. Hicks JK, McLeod HL. Pharmacogenetics and Pharmacogenomics. Genomic Precis Med Prim Care. 2017;89–107. doi:10.1016/B978-0-12-800685-6.00004-7

14. Nickle T, Barrette-Ng I. Mutation and polymorphism; 2020. Available from: https://bio.libretexts.org/Bookshelves/Genetics/Book%3A_Online_Open_Genetics_(Nickle_and_Barrette-Ng)/04%3A_Mutation_and_Variation/4.1%3A_Mutation_and_Polymorphism.

15. Bahl A, Falk S. Meta-analysis of single agents in the chemotherapy of NSCLC: what do we want to know? Br J Cancer. 2001;84(9):1143–1145. doi:10.1054/bjoc.2000.1740

16. Petrelli F, Coinu A, Cabiddu M, Ghilardi M, Ardine M, Barni S. Platinum rechallenge in patients with advanced NSCLC: a pooled analysis. Lung Cancer. 2013;81(3):337–342. doi:10.1016/j.lungcan.2013.06.022

17. Mendell JT, Dietz HC. When the message goes awry: disease-producing mutations that influence mRNA content and performance. Cell. 2001;107(4):411–414. doi:10.1016/S0092-8674(01)00583-9

18. Nicholson P, Yepiskoposyan H, Metze S, et al. Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors. Cell Mol Life Sci. 2010;67(5):677–700. doi:10.1007/s00018-009-0177-1

19. Robert F, Pelletier J. Exploring the impact of single-nucleotide polymorphisms on translation. Front Genet. 2018;9:(October):1–11. doi:10.3389/fgene.2018.00507

20. Zhou J, Kang Y, Chen L, et al. The drug-resistance mechanisms of five platinum-based antitumor agents. Front Pharmacol. 2020;11:(March):1–17. doi:10.3389/fphar.2020.00343

21. Roco Ángela CJ, Contreras S, Stojanova J, Quiñones L. Can pharmacogenetics explain efficacy and safety of cisplatin pharmacotherapy? Front Genet. 2014;5(NOV):1–15. doi:10.3389/fgene.2014.00391

22. Stewart DJ.Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer. Crit Rev Oncol Hematol. 2010;75(3):173-234. doi:10.1016/j.critrevonc.2009.11.006

23. Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of efflux pumps in multidrug-resistant cancer. Nat Rev Cancer. 2018;18(7):452–464. doi:10.1038/s41568-018-0005-8.Revisiting

24. Pereira D, Assis J, Gomes M, Nogueira A, Medeiros R. Improvement of a predictive model in ovarian cancer patients submitted to platinum-based chemotherapy: implications of a GST activity profile. Eur J Clin Pharmacol. 2016;72(5):545–553. doi:10.1007/s00228-016-2015-3

25. Campa D, Müller P, Edler L, et al. A comprehensive study of polymorphisms in ABCB1, ABCC2 and ABCG2 and lung cancer chemotherapy response and prognosis. Int J Cancer. 2012;131(12):2920–2928. doi:10.1002/ijc.27567

26. De Luca A, Parker LJ, Ang WH, et al. A structure-based mechanism of cisplatin resistance mediated by glutathione transferase P1-1. Proc Natl Acad Sci U S A. 2019;116(28):13943–13951. doi:10.1073/pnas.1903297116

27. Sawers L, Ferguson MJ, Ihrig BR, et al. Glutathione S-transferase P1 (GSTP1) directly influences platinum drug chemosensitivity in ovarian tumour cell lines. Br J Cancer. 2014;111(6):1150–1158. doi:10.1038/bjc.2014.386

28. Rabik CA, Dolan ME. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. 2007;33(1):9–23. doi:10.1016/j.ctrv.2006.09.006

29. Cuffe S, Azad AK, Qiu X, et al. ABCC2 polymorphisms and survival in the Princess Margaret cohort study and the NCIC clinical trials group BR.24 trial of platinum-treated advanced stage non-small cell lung cancer patients. Cancer Epidemiol. 2016;41:50–56. doi:10.1016/j.canep.2015.12.012

30. Chen Y, Teranishi K, Li S, et al. Genetic variants in multidrug and toxic compound extrusion‐1, hMATE1, alter transport function. Pharmacogenomics J. 2010;9(2):127–136. DOI:10.1038/tpj.2008.19.Genetic

31. Ignatov AV, Bondarenko KA, Makarova AV. Non-bulky lesions in human DNA: the ways of formation, repair, and replication. Acta Naturae. 2017;9(3):12–26. doi:10.32607/20758251-2017-9-3-12-26

32. Hu J, Choi JH, Gaddameedhi S, Kemp MG, Reardon JT, Sancar A. Nucleotide excision repair in human cells: fate of the excised oligonucleotide carrying DNA damage in vivo. J Biol Chem. 2013;288(29):20918–20926. doi:10.1074/jbc.M113.482257

33. Atanassov B, Velkova A, Mladenov E, Anachkova B, Russev G. Comparison of the global genomic and transcription-coupled repair rates of different lesions in human cells. Zeitschrift fur Naturforsch - Sect C J Biosci. 2004;59(5–6):445–453. doi:10.1515/znc-2004-5-628

34. Okuda M, Nakazawa Y, Guo C, Ogi T, Nishimura Y. Common TFIIH recruitment mechanism in global genome and transcription-coupled repair subpathways. Nucleic Acids Res. 2017;45(22):13043–13055. doi:10.1093/nar/gkx970

35. Sugasawa K, Ng JMY, Masutani C, et al. Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. Mol Cell. 1998;2(2):223–232. doi:10.1016/S1097-2765(00)80132-X

36. Fitch ME, Cross IV, Turner SJ, et al. The DDB2 nucleotide excision repair gene product p48 enhances global genomic repair in p53 deficient human fibroblasts. DNA Repair (Amst). 2003;2(7):819–826. doi:10.1016/S1568-7864(03)00066-1

37. Moser J, Volker M, Kool H, et al. The UV-damaged DNA binding protein mediates efficient targeting of the nucleotide excision repair complex to UV-induced photo lesions. DNA Repair (Amst). 2005;4(5):571–582. doi:10.1016/j.dnarep.2005.01.001

38. Wang QE, Zhu Q, Wani G, Chen J, Wani AA. UV radiation-induced XPC translocation within chromatin is mediated by damaged-DNA binding protein, DDB2. Carcinogenesis. 2004;25(6):1033–1043. doi:10.1093/carcin/bgh085

39. Li CL, Golebiowski FM, Onishi Y, Samara NL, Sugasawa K, Yang W. Tripartite DNA lesion recognition and verification by XPC, TFIIH, and XPA in nucleotide excision repair. Mol Cell. 2015;59(6):1025–1034. doi:10.1016/j.molcel.2015.08.012

40. Mathieu N, Kaczmarek N, Naegeli H. Strand- and site-specific DNA lesion demarcation by the xeroderma pigmentosum group D helicase. Proc Natl Acad Sci U S A. 2010;107(41):17545–17550. doi:10.1073/pnas.1004339107

41. Mathieu N, Kaczmarek N, Rüthemann P, Luch A, Naegeli H. DNA quality control by a lesion sensor pocket of the xeroderma pigmentosum group D helicase subunit of TFIIH. Curr Biol. 2013;23(3):204–212. doi:10.1016/j.cub.2012.12.032

42. Schwertman P, Lagarou A, Dekkers DHW, et al. UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair. Nat Genet. 2012;44(5):598–602. doi:10.1038/ng.2230

43. Pleasance ED, Stephens PJ, O’Meara S. A small cell lung cancer genome reports complex tobacco exposure signatures. Nature. 2010;463(7278):184–190. doi:10.1038/nature08629.A

44. Pleasance ED, Cheetham RK, Stephens PJ, et al. UKPMC Funders Group UKPMC Funders Group Author Manuscript a comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010;463(7278):191–196. doi:10.1038/nature08658.A

45. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–421. doi:10.1038/nature12477

46. Xie C, Zhao J, Hua W, et al. Effect of XPC polymorphisms on the response to platinum-based chemotherapy: a meta-analysis. Onco Targets Ther. 2019;12:3839–3848. doi:10.2147/OTT.S202617

47. Song X, Wang S, Hong X, et al. Single nucleotide polymorphisms of nucleotide excision repair pathway are significantly associated with outcomes of platinum-based chemotherapy in lung cancer. Sci Rep. 2017;7(1):1–11. doi:10.1038/s41598-017-08257-7

48. Singh A, Compe E, Le May N, Egly JM. TFIIH subunit alterations causing xeroderma pigmentosum and trichothiodystrophy specifically disturb several steps during transcription. Am J Hum Genet. 2015;96(2):194–207. doi:10.1016/j.ajhg.2014.12.012

49. Bowden NA. Nucleotide excision repair: why is it not used to predict response to platinum-based chemotherapy? Cancer Lett. 2014;346(2):163–171. doi:10.1016/j.canlet.2014.01.005

50. Cleaver JE. Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer. 2005;5(7):564–573. doi:10.1038/nrc1652

51. Spivak G. Transcription-coupled repair: an update graciela. Physiol Behav. 2017;176(3):139–148. doi:10.1016/j.physbeh.2017.03.040

52. Fu BH, Zhang Q, Li X, et al. Evaluation of prediction of polymorphisms of DNA repair genes on the efficacy of platinum-based chemotherapy in patients with non-small cell lung cancer: a network meta-analysis. J Cell Biochem. 2017;118(12):4782–4791. doi:10.1002/jcb.26147

53. Tan LM, Qiu CF, Zhu T, et al. Genetic polymorphisms and platinum-based chemotherapy treatment outcomes in patients with non-small cell lung cancer: a genetic epidemiology study based meta-analysis. Sci Rep. 2017;7(1):1–19. doi:10.1038/s41598-017-05642-0

54. Rosell R, Taron M, Barnadas A, Scagliotti G, Sarries C, Roig B. Nucleotide excision repair pathways involved in cisplatin resistance in non – small-cell lung cancer. Cancer Control. 2003;297–305. DOI:10.1177/107327480301000404

55. Arora S, Kothandapani A, Tillison K, Kalman-maltese V, Patrick SM. NIH public access. DNA Repair. 2015;9(7):745–753. doi:10.1016/j.dnarep.2010.03.010.Downregulation

56. Takemoto S, Nakamura Y, Gyoutoku H, Senju H, Ogawara D. Phase II trial of a non-platinum triplet for patients with advanced non-small cell lung carcinoma (NSCLC) overexpressing ERCC1 messenger RNA. Thorac Cancer. 2019;10:452–458. doi:10.1111/1759-7714.12958

57. Pirker R, Filipits M. Adjuvant therapy in patients with completely resected non–small-cell lung cancer: current status and perspectives. Clin Lung Cancer. 2018. doi:10.1016/j.cllc.2018.09.016

58. Chikan NA, Shabir N, Shaffi S, Mir MR, Trupti N. COMMENTARY N -nitrosodimethylamine in the Kashmiri diet and possible roles in the high incidence of gastrointestinal cancers. Asian Pac J Cancer Prev. 2012;13:1077–1079.

59. Sutandyo N. Nutritional carcinogenesis. Acta Med Indones. 2010;42(1):36–42.

60. Bolt HM, Gansewendt B. Mechanisms of carcinogenicity of methyl halides. Crit Rev Toxicol. 1993;23(3):237–253.

61. Bulathsinghala AT, Shaw IC. The toxic chemistry of methyl bromide. Hum Exp Toxicol. 2014;33(1):81–91. doi:10.1177/0960327113493299

62. Guengerich FP, Min KS, Persmark M, et al. Dihaloalkanes and polyhaloalkenes. IARC Sci Publ. 1994;125:57–72.

63. Chappell G, Pogribny IP, Guyton KZ, Rusyn I. Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: a systematic literature review. Mutat Res Rev Mutat Res. 2016;768:27–45. doi:10.1016/j.mrrev.2016.03.004

64. Cheung-ong K, Giaever G, Nislow C. Perspective DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology. Chem Biol. 2013;20(5):648–659. doi:10.1016/j.chembiol.2013.04.007

65. Colvin M. Holland-Frei cancer medicine. In: Kufe DW, Pollock RE, Weichselbaum RR, editors. Holland-Frei Cancer Medicine. 6 th. Hamilton: BC Decker; 2003.

66. Shen WMR, Jones PA. The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA. Nucleic Acids Res. 1994;22(6):972–976.

67. Singer B, Grunberger D. Molecular Biology of Mutagens and Carcinogens. New York: Plenum Press; 1983. doi:10.1007/978-1-4613-3772-0

68. Caulfield JL, Wishnok JS, Tannenbaum SR. Nitric oxide-induced deamination of cytosine and guanine in deoxynucleosides and oligonucleotides. J Biol Chem. 1998;273(21):12689–12695.

69. Nguyen T, Brunson D, Crespit CL, Penmant BW, Wishnok JS, Tannenbaum SR. DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc Natl Acad Sci. 1992;89(April):3030–3034.

70. Ohshima H, Tatemichi M, Rahaman M, Ohshima H, Tatemichi M, Sawa T. Chemical basis of inflammation-induced carcinogenesis. Arch Biochem Biophys. 2003;417:3–11. doi:10.1016/S0003-9861(03)00283-2

71. Xiong Y, Yin BHJ, Yin J-Y. Pharmacogenomics of platinum-based chemotherapy in non-small cell lung cancer: focusing on DNA repair systems. Med Oncol. 2017;34(4):1–16. doi:10.1007/s12032-017-0905-6

72. Li D, Zhou Q, Liu Y, Yang Y, Li Q. DNA repair gene polymorphism associated with sensitivity of lung cancer to therapy. Med Oncol. 2011;29:1622–1628. doi:10.1007/s12032-011-0033-7

73. Zhao W, Hu L, Xu J. Polymorphisms in the base excision repair pathway modulate prognosis of platinum-based chemotherapy in advanced non-small cell lung cancer. Cancer Chemother Pharm. 2013;1287–1295. DOI:10.1007/s00280-013-2127-8

74. Li DJ, Xiao D. Association between the XRCC1 polymorphisms and clinical outcomes of advanced NSCLC treated with platinum-based chemotherapy: a meta-analysis based on the PRISMA statement. BMC Cancer. 2017;17(1):1–13. doi:10.1186/s12885-017-3487-y

75. Peng Y, Li Z, Zhang S, et al. Association of DNA base excision repair genes (OGG1, APE1 and XRCC1) polymorphisms with outcome to platinum-based chemotherapy in advanced nonsmall-cell lung cancer patients. Int J Cancer. 2014;2696:2687–2696. doi:10.1002/ijc.28892

76. Kelland LR. New platinum antitumor complexes. Crit Rev Oncol Hematol. 1993;8428(93).

77. Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y. A human transporter protein that mediates the final. Proc Natl Acad Sci. 2005;102(50).

78. Tanihara Y, Masuda S, Sato T, Katsura T. Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H + -organic cation antiporters. Biochem Pharm. 2007;74:359–371. doi:10.1016/j.bcp.2007.04.010

79. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2(1):48–58. doi:10.1038/nrc706

80. Xie SM, Fang WY, Liu TF, Yao KT, Zhong XY. Association of ABCC2 and CDDP-resistance in two sublines resistant to CDDP derived from a human nasopharyngeal carcinoma cell line. J Oncol. 2010;2010:1–7. doi:10.1155/2010/915046

81. Li Z, Xing X, Shan F, et al. ABCC2-24C > T polymorphism is associated with the response to platinum/5-Fu-based neoadjuvant chemotherapy and better clinical outcomes in advanced gastric cancer patients. Oncotarget. 2016;7(34):55449–55457. doi:10.18632/oncotarget.10961

82. Kim SH, Kim MJ, Cho YJ, et al. Clinical significance of ABCG2 haplotype-tagging single nucleotide polymorphisms in patients with unresectable non-small cell lung cancer treated with first-line platinum-based chemotherapy. Am J Clin Oncol Cancer Clin Trials. 2015;38(3):294–299. doi:10.1097/COC.0b013e318297f333

83. Caronia D, Patino A, Perez A, et al. Effect of ABCB1 and ABCC3 polymorphisms on osteosarcoma survival after chemotherapy: a pharmacogenetic study. Plos One. 2011;6(10). doi:10.1371/journal.pone.0026091.

84. Sarin N, Engel F, Rothweiler F, et al. Key players of cisplatin resistance: towards a systems pharmacology approach. Int J Mol Sci. 2018;19(3):767. doi:10.3390/ijms19030767

85. Stoehlmacher J, Park DJ, Zhang W, et al. M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J Natl Cancer Institute. 2002;94(12).

86. Katayanagi S, Katsumata K, Mori Y, et al. GSTP1 as a potential predictive factor for adverse events associated with platinum-based antitumor agent-induced peripheral neuropathy. Oncol Lett. 2019;17(3):2897–2904. doi:10.3892/ol.2019.9907

87. Rednam S, Scheurer ME, Adesina A, Lau CC, Fatih Okcu M. NIH public access. Pediatr Blood Cancer. 2014;60(4):593–598. doi:10.1002/pbc.24366.Glutathione

88. Han ZG, Tao J, Yu TT, Shan L. Effect of GSTP1 and ABCC2 polymorphisms on treatment response in patients with advanced non-small cell lung cancer undergoing platinum-based chemotherapy: a study in a Chinese Uygur population. Med Sci Monit. 2017;23:1999–2006. doi:10.12659/MSM.904156

89. Ye H, Shao M, Shi X, et al. Predictive assessment in pharmacogenetics of Glutathione S-transferases genes on efficacy of platinum-based chemotherapy in non-small cell lung cancer patients. Sci Rep. 2017;7(1):1–13. doi:10.1038/s41598-017-02833-7

90. Tong Z, Yerramilli U, Surapaneni S, Kumar G. The interactions of lenalidomide with human uptake and efflux transporters and UDP ‑ glucuronosyltransferase 1A1: lack of potential for drug – drug interactions. Cancer Chemotherapy and Pharmacology. 2014;73(4):869–874. doi:10.1007/s00280-014-2415-y

91. Chen J, Wang Z, Zou T, et al. Pharmacogenomics of platinum-based chemotherapy response in NSCLC: a genotyping study and a pooled analysis. Oncotarget. 2016;7(34):55741–55756. doi:10.18632/oncotarget.9688

92. Terada T, Masuda S, Asaka J, Tsuda M, Katsura T. Short communication molecular cloning, functional characterization and tissue distribution of Rat H +/organic cation antiporter MATE1. Pharm Res. 2006;23(8):1696–1701. doi:10.1007/s11095-006-9016-3

93. Qian CY, Zheng Y, Wang Y, et al. Associations of genetic polymorphisms of the transporters organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), and ATP-binding cassette subfamily C member 2 (ABCC2) with platinum-based chemotherapy response and toxicity in non-sma. Chin J Cancer. 2016;35(1):85. doi:10.1186/s40880-016-0145-8

94. Ismail S, Essawi M. Genetic polymorphism studies in humans. Middle East J Med Genet. 2012;1(2):57–63. doi:10.1097/01.mxe.0000415225.85003.47

95. Artiga MJ, Sáez AI, Romero C, et al. A short mutational hot spot in the first intron of BCL-6 is associated with increased BCL-6 expression and with longer overall survival in large B-cell lymphomas. Am J Pathol. 2002;160(4):1371–1380. doi:10.1016/S0002-9440(10)62564-3

96. Jorde LB, Wooding SP. Genetic variation, classification and ‘race’. Nat Genet. 2004;36(11):1–6. doi:10.1034/ng1435

97. Fan L, Fuss JO, Cheng QJ, et al. XPD helicase structures and activities: insights into the cancer and aging phenotypes from XPD mutations. Cell. 2008;133(5):789–800. doi:10.1016/j.cell.2008.04.030

98. Boldrin E, Malacrida S, Rumiato E, et al. Association between ERCC1rs3212986 and ERCC2/XPDrs1799793 and OS in patients with advanced esophageal cancer. Front Oncol. 2019;9(FEB):1–9. doi:10.3389/fonc.2019.00085

99. Liao WY, Ho CC, Tsai TH, Chen KY, Shih JY, Yu CJ. Combined effect of ERCC1 and ERCC2 polymorphisms on overall survival in non-squamous non-small-cell lung cancer patients treated with first-line pemetrexed/platinum. Lung Cancer. 2018;118(May2017):90–96. doi:10.1016/j.lungcan.2018.01.011

100. Li M, Zhao Y, Zhao E, Wang K, Lu W, Yuan L. Predictive value of two polymorphisms of ERCC2, rs13181 and rs1799793, in clinical outcomes of chemotherapy in gastric cancer patients: a meta-analysis. Dis Markers. 2018;2018:1–12. doi:10.1155/2018/3947626

101. Laechelt S, Turrini E, Ruehmkorf A, Siegmund W, Cascorbi I, Haenisch S. Impact of ABCC2 haplotypes on transcriptional and posttranscriptional gene regulation and function. Pharmacogenomics J. 2011;11(1):25–34. doi:10.1038/tpj.2010.20

102. Liedert B, Materna V, Schadendorf D, Thomale J, Lage H. Overexpression of cMOAT (MRP2/ABCC2) is associated with decreased formation of platinum-DNA adducts and decreased G2-arrest in melanoma cells resistant to cisplatin. J Invest Dermatol. 2003;121(1):172–176. doi:10.1046/j.1523-1747.2003.12313.x

103. Haenisch S, Zimmermann U, Dazert E, et al. Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex. Pharmacogenomics J. 2007;7(1):56–65. doi:10.1038/sj.tpj.6500403

104. Abbasi S, Badheeb A. Prognostic factors in advanced non-small-cell lung cancer patients: patient characteristics and type of chemotherapy. Lung Cancer Int. 2011;2011(January 2011):1–4. doi:10.4061/2011/152125

105. Ito S, Ito H, Sato N, et al. Clinical factors associated with the therapeutic outcome of chemotherapy in very elderly cancer patients. Int J Clin Oncol. 2019;24(5):596–601. doi:10.1007/s10147-018-01385-8

106. Audrina GW, Purwanto H, Statistika J, et al. Faktor-faktor yang mempengaruhi tingkat keberhasilan pemberian kemoterapi pada pasien penderita kanker payudara Di RSUD Dr. Soetomo Dengan Menggunakan regresi logistik ordinal. Jurnal Sains Dan Seni ITS. 2014;3(1):D36–D40.

107. Libby E, Hromas R. Dismounting the MDR horse. Blood. 2010;116(20):4037–4038. doi:10.1182/blood-2010-09-304311

108. Rodríguez-Vicente AE, Lumbreras E, Hernández JM, et al. Pharmacogenetics and pharmacogenomics as tools in cancer therapy. Drug Metab Pers Ther. 2016;31(1):25–34. doi:10.1515/dmpt-2015-0042

109. Ettinger DS, Aisner DL, Wood DE, et al. CE NCCN guidelines ® insights non – small cell lung cancer, featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2018;7. doi:10.6004/jnccn.2018.0062

110. Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;28(5). doi:10.1200/JCO.2009.27.0660

111. Riley BD, Culver JO, Skrzynia C, et al. Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns. 2012;151–161. doi:10.1007/s10897-011-9462-x

112. Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Development G. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17(1). doi:10.1038/gim.2014.147

113. Ge L, Yang Y, Sun Y, Xu W, Lu D, Su B. P73 G4C14-to-A4T14 polymorphism is associated with survival in advanced non-small cell lung cancer patients. Thorac Cancer. 2017;8(2):63–72. doi:10.1111/1759-7714.12397

114. Li X, Huang K, Zhang Q, et al. Genome-wide association study identifies four SNPs associated with response to platinum-based neoadjuvant chemotherapy for cervical cancer. Sci Rep. 2017;7(January):1–7. doi:10.1038/srep41103

115. Singh A, Singh N, Behera D, Sharma S. Polymorphism in XRCC1 gene modulates survival and clinical outcomes of advanced North Indian lung cancer patients treated with platinum-based doublet chemotherapy. Med Oncol. 2017;34(4):1–14. doi:10.1007/s12032-017-0923-4

116. Karageorgopoulou S, Kostakis ID, Gazouli M, et al. Prognostic and predictive factors in patients with metastatic or recurrent cervical cancer treated with platinum-based chemotherapy. BMC Cancer. 2017;17(1):1–10. doi:10.1186/s12885-017-3435-x

117. Lawania S, Singh N, Behera D, Sharma S. Xeroderma pigmentosum complementation group D polymorphism toward lung cancer susceptibility survival and response in patients treated with platinum chemotherapy. Future Oncol. 2017;13(29):2645–2665. doi:10.2217/fon-2017-0211

118. Xiang T, Kang X, Gong Z, Bai W, Chen C, Zhang W. XPG genetic polymorphisms and clinical outcome of patients with advanced non-small cell lung cancer under platinum-based treatment: a meta-analysis of 12 studies. Cancer Chemother Pharmacol. 2017;79(4):791–800. doi:10.1007/s00280-017-3280-2

119. Li P, Wang D, Cheng J, Chen JC, Ha MW. Association between polymorphisms of BAG-1 and XPD and chemotherapy sensitivity in advanced non-small-cell lung cancer patients treated with vinorelbine combined cisplatin regimen. Tumor Biol. 2015;36(12):9465–9473. doi:10.1007/s13277-015-3672-z

120. Tang N, Lyu D, Zhang Y, Liu H. Association between the ERCC1 polymorphism and platinum-based chemotherapy effectiveness in ovarian cancer: a meta-analysis. BMC Womens Health. 2017;17(1):1–8. doi:10.1186/s12905-017-0393-z

121. Dong J, Wang X, Yu Y, Yan X, Cui JW. Association of base excision repair gene polymorphisms with the response to chemotherapy in advanced non-small cell lung cancer. Chin Med J (Engl). 2018;131(16):1904–1908. doi:10.4103/0366-6999.238141

122. Fan X, Xiu Q. Effect of X-ray repair cross complementing group 1 polymorphisms on the efficacy of platinum-based chemotherapy in patients with nonsmall cell lung cancer. J Cancer Res Ther. 2015;11(3):571–574. doi:10.4103/0973-1482.159085

123. Peng Y, Wang L, Qing Y, et al. Polymorphisms of BCL2 and BAX genes associate with outcomes in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Sci Rep. 2015;5(1):1–11. doi:10.1038/srep17766

124. Alanee S, Delfino K, Wilber A, Robinson K, Brard L, Semaan A. Single nucleotide variant in Nucleoporin 107 may be predictive of sensitivity to chemotherapy in patients with ovarian cancer. Pharmacogenet Genomics. 2017;27(7):264–269. doi:10.1097/FPC.0000000000000288

125. Mlak R, Krawczyk P, Ciesielka M, et al. The relationship between RRM1 gene polymorphisms and effectiveness of gemcitabine-based first-line chemotherapy in advanced NSCLC patient. Clin Transl Oncol. 2016;18(9):915–924. doi:10.1007/s12094-015-1461-1

Creative Commons License © 2020 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.