Originally published as JCO Early Release 10.1200/JCO.2004.08.067 on June 1 2004

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XPD and XRCC1 Genetic Polymorphisms Are Prognostic Factors in Advanced Non—Small-Cell Lung Cancer Patients Treated With Platinum Chemotherapy

From the Departments of Medicine and Surgery, Massachusetts General Hospital; the Departments of Environmental Health, Epidemiology, and Biostatistics, Harvard School of Public Health; and the Dana-Farber/Harvard Cancer Center, Boston, MA

Address reprint requests to David C. Christiani, MD, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115; e-mail: dchristi{at}hsph.harvard.edu

	ABSTRACT

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PURPOSE: Platinum agents cause DNA cross-linking and oxidative damage. Genetic polymorphisms of DNA repair genes are associated with differential DNA repair activity and may explain interindividual differences in overall survival after therapy with platinum agents for non–small-cell lung cancer (NSCLC).

METHODS: We used polymerase chain reaction–restriction fragment length polymorphism to evaluate genetic polymorphisms of the XPD (Asp312Asn) and XRCC1 (Arg399Gln) DNA repair genes in 103 patients with stage III (54%) and IV (46%) NSCLC treated with platinum-based chemotherapy.

RESULTS: Median age was 58 years (range, 32 to 77 years), 49% were females, and there were 86 deaths. Median follow-up period was 61.9 months. Median survival time (MST) was 14.9 months; by stage, MST was 28.6 months (IIIA), 16.0 months (IIIB), and 9.3 months (IV). Genotypes were not associated with stage. Increasing numbers of either XPD or XRCC1 variant alleles were associated with shorter overall survival (P = .003 and P = .07, respectively, by log-rank test). Similarly, when we compared combinations of variant alleles across both polymorphisms, we found that a greater number of variant alleles was associated with decreasing overall survival (P = .009, log-rank test). These polymorphisms independently predicted overall survival even after taking into account stage, performance status, and chemotherapy regimen.

CONCLUSION: Genetic polymorphisms in XPD and XRCC1 may be important prognostic factors in platinum-treated patients with advanced NSCLC.

	INTRODUCTION

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Five-year survival rates for non–small-cell lung cancer (NSCLC) remain less than 15%.^1-4 Adverse clinical prognostic factors in NSCLC include advanced disease stage and poor performance status. Although a number of molecular markers have shown prognostic significance, as measured by overall survival, none has come into clinical use.^5,6 As a potential prognostic factor, the concept of suboptimal DNA repair capacity is appealing. Several studies have found associations between inefficient DNA repair and cancer risk.^7-11 It is also possible that the same factors that promote the development of cancer also can be adverse prognostic factors once the cancer has developed. Inefficient DNA repair may lead to additional genomic instability and more aggressive tumors. In this setting, suboptimal DNA repair may be an adverse prognostic factor in NSCLC.

Chemotherapy has been the mainstay of treatment for advanced NSCLC.^12,13 Of the various types of chemotherapy regimens available, platinum-based doublets have been shown to improve overall survival.^12-15 However, response rates to platinum-based regimens are less than 30% in NSCLC patients, compared with greater than 70% in ovarian, testicular, and head and neck cancer patients.^16,17 Although molecular predictors of treatment response to platinum have been studied, none has been established in the clinical setting.

Platinum compounds such as cisplatin form both intra- and interstrand DNA adducts that result in bulky distortion of DNA, destabilization of the double helix, and inhibition of DNA replication.¹⁸ These adducts are responsible for the cytotoxicity of the drug, and clinical outcome seems to be correlated with the level of platinum-DNA adducts in the circulation.^17-23 Therefore, an alternative hypothesis regarding DNA repair capacity and NSCLC outcome is that suboptimal DNA repair within the tumor actually may lead to the decreased removal of platinum-DNA adducts and therefore, increased clinical response to platinum therapy.^17,24 According to this line of reasoning, suboptimal DNA repair may predict better response to platinum chemotherapy and may be a prognostic factor for improved survival in advanced NSCLC.

Repair of DNA damage is a complex process and is carried out by an array of DNA repair pathways, including the nucleotide excision and base excision repair pathways. The XPD (also known as ERCC2) gene encodes for a DNA helicase, which is a member of the multistep nucleotide excision repair pathway. Nucleotide excision repair accounts for the majority of platinum-DNA adduct repair and consists of the removal of a DNA segment with its associated bulky adduct, followed by the restoration of that DNA segment.^17,25-29 The XRCC1 gene is a member of the base excision repair pathway, a much more specific pathway that consists of multiple enzyme systems, each of which is specific for a particular type of base damage.

Both XPD and XRCC1 contain polymorphisms that may confer differential activity. For example, the XPD Asp312Asn polymorphism in exon 10, resulting from a GA substitution, has been highly conserved throughout evolution, suggesting that it bears functional significance.³⁰ Various assays have been developed to quantify DNA repair activity, including the Comet assay and the host cell reactivation assay.³¹ Despite some inconsistencies in the literature, the balance of information suggests that the wild-type and variant genotypes are likely associated with different levels of DNA repair activity.^27,30 In this manner, XPD and XRCC1 polymorphisms may contribute to interindividual DNA damage repair variability in the general population.

In theory, DNA repair gene polymorphisms could affect NSCLC outcome in two opposing ways. Polymorphisms conferring suboptimal DNA repair in the tumor could lead to more biologically aggressive tumors; conversely, these same polymorphisms could favorably influence response to platinum agents through inefficient removal of platinum-DNA adducts. Unlike many of the molecular markers assessed for prognostic potential, evaluation of germline genetic polymorphisms involves little more than a blood sample and standard polymerase chain reaction (PCR)–based reactions, making these tests potentially useful in the clinical setting. Thus, we hypothesized that specific genotypes of the DNA repair genes, XPD and XRCC1, may alter overall survival in patients with advanced NSCLC who are treated with platinum agents, but did not specify whether these variant genotypes might improve or worsen survival.

	METHODS

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Patient Selection
More than 1,000 patients with histologically confirmed NSCLC of all stages were recruited prospectively at Massachusetts General Hospital (MGH; Boston, MA) between 1992 and 2003. These individuals participated in a larger ongoing molecular epidemiologic study in which demographic and patient characteristic information (age, sex, race, smoking status, family history of cancer, and exposures were recorded using questionnaires) and patients' blood samples were collected for genotyping at the time of study entry.

For this analysis, we identified 251 patients with advanced NSCLC (stages IIIA to IV), enrolled between the years 1992 and 1999. We chose 1999 as the last year of eligibility with the goal of having adequate follow-up of individual participants. A review of medical records revealed that none of these patients had recurrences of prior earlier stage cancers, but instead had advanced disease at the time of diagnosis. Before 1997, only early-stage NSCLC patients were recruited, explaining the large difference between the sample size for the underlying epidemiologic study and the number of advanced NSCLC cases. Not all patients were treated at MGH; information about patients treated elsewhere was often sparse, and sometimes patients treated outside of MGH were not given standard treatments or observed in standard fashions.

Of the 251 advanced NSCLC patients, we identified a subset of 112 NSCLC patients whose histologic diagnoses were confirmed at MGH and who were treated at MGH with platinum agents (cisplatin or carboplatin), either first or second line. One of our priorities was to have complete data regarding diagnosis date, tumor stage, and chemotherapy administered. As a result, our study was limited to these 112 patients who were treated fully at MGH and who had available complete outpatient records. The patients not included in this subset either were treated at outside facilities or did not have available MGH outpatient charts. The demographics and characteristics of the patients not included in our study were similar to those of the included patients.

Finally, within this group of 112, there were 103 patients who had complete data for the XPD and XRCC1 genotypes. The other nine individuals did not have available DNA for genotyping. Thus, 103 patients were included in this study.

DNA Extraction and Genotyping
Whole blood was collected from patients at the time of enrollment, and DNA was extracted from these samples using the Puregene DNA Isolation kit (Gentra Systems, Minneapolis, MN). The XPD Asp312Asn polymorphism was detected using modified PCR–restriction fragment length polymorphism methods, with primer sequences that have been described previously.²⁷ DpnII and MspI digestions (New England BioLabs, Beverly, MA) were used for the restriction fragment analyses.

The XRCC1 Arg399Gln polymorphism was detected using modified PCR–restriction fragment length polymorphism methods as well, using published primer sequences.³² Briefly, a 242-base pair PCR product including the Arg/Gln (AC) allele in exon 10 (codon 399) was amplified, and then digested using the MspI enzyme (New England BioLabs). For quality control, a random 5% of the samples were repeated. Two authors independently reviewed all of the agarose gels, data entry, and statistical analyses.

Survival Measurements
Our end point was overall survival from the time of histologic diagnosis. Dates of death were obtained and cross-checked using at least one of the following four methods: Social Security Death Index, inpatient and outpatient medical records, MGH tumor registry, and confirmation with the patient's primary care physician and/or family. Date of death was obtained most often through the Social Security Death Index, but in unusual instances in which the patient's date of death was not reported there (either due to death within 3 months of the data collection or some other reason), date of death was obtained through at least one of the other measures listed. Patients who were not deceased were censored at the last date they were known to be alive based on the date of last contact. This date was verified by inpatient and outpatient medical records, and/or confirmation with the patient's primary care physician and/or family.

Statistical Methods
Demographic and clinical information was compared across genotype, using Pearson ² tests (for categoric variables) and one-way analysis of variance (for continuous variables), where appropriate. The distribution of XPD and XRCC1 genotypes was represented in a two-way contingency table. The association between the two polymorphisms was tested using Fisher's exact test. For the analysis of the combination of XPD and XRCC1 polymorphisms, individuals were placed into categories indicating the number of variant alleles present from both polymorphisms. The association between overall survival and the genetic polymorphisms (or the total number of variant alleles from both polymorphisms) was estimated using the method of Kaplan and Meier and assessed using the log-rank test. Median follow-up time was computed among censored observations only. Cox proportional hazards models were also used to adjust for stage, performance status, and chemotherapy regimen, with number of variant alleles represented by indicator variables. All statistical testing was conducted at the .05 level and SAS software version 8 (SAS Institute, Cary, NC) was used.

	RESULTS

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Patient, Treatment, and Follow-Up Characteristics
Patient characteristics are listed in Table 1. The median age was 58 years (range, 32 to 77 years). Forty-nine percent of the patients were women. Of a total of 103 patients, 25% had stage IIIA, 29% had stage IIIB, and 46% had stage IV disease at the time of diagnosis.

The median follow-up time was 61.9 months (range, 4.9 to 118.6 months). There were 86 deaths. Overall, the median survival time (MST) was 14.9 months. By stage, MST ranged from 9.3 months in the stage IV patients to 28.6 months in the stage IIIA group. Stage IIIB patients had an intermediate MST of 16.0 months.

Allele Frequencies
Genotype frequencies for both XPD and XRCC1 polymorphisms were found to be in Hardy-Weinberg equilibrium. The variant allele frequency for the XPD polymorphism was 31.6%; for the XRCC1 polymorphism, the variant allele frequency was 30.0%. No associations were detected between genotype and age, sex, or performance status. None of the evaluated genotypes was associated with disease stage (² test, P = .75 for XPD10; P = .37 for XRCC1). The numbers of variant alleles for XPD and XRCC1 were not associated with one another (Fisher's exact test, P = .40; Table 2).

View larger version (19K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curves of (A) XPD Asp312Asn polymorphism (P = .003, log-rank test); (B) XRCC1 Arg399Gln polymorphism (P = .07, log-rank test); and (C) number of variant alleles from both polymorphisms (P = .009, log-rank test). The graphs present 5 years of follow-up. The log-rank test was based on the full data.

View larger version (16K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curves of XPD Asp312Asn genotypes by stage. (A) Stages IIIA and IIIB (P = .004, log-rank test); and (B) stage IV (P = .51, log-rank test). The graphs present 5 years of follow-up. The log-rank test was based on the full data.

In this analysis, we found that with an increasing number of variant alleles, the MST decreased in a stepwise manner. In the double homozygote group (ie, 0 variant alleles), the MST was 20.4 months. As the number of variant alleles increased, the MST decreased to 16.6, 11.0, and 6.8 months, respectively, and the corresponding log-rank test was highly statistically significant (P = .009; Table 5). The HR for death in the poorest prognosis group of three variant alleles was 2.75 (95% CI, 1.33 to 5.70; P = .007). Of note, there were no individuals with four variant alleles. Similar to Figures 1A and 1B, Figure 1C shows the separation in curves among the four groups. Again, the effect was more striking in the stage III patients (log-rank test, P = .004; Table 5) than in the stage IV patients (log-rank test, P = .18). Patients with stage III disease with 0 variant alleles lived for a median of 35.0 months, and this MST decreased to 25.9, 15.2, and 6.3 months, respectively, as the number of variant alleles increased (Table 5). In general, we found no significant differences in the magnitude of effect according to the source of the variant alleles (XPD or XRCC1, data not shown). However, our statistical ability to identify a predominant source of such an effect was limited.

	DISCUSSION

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Factors such as disease stage and performance status provide a crude discrimination of prognosis in NSCLC. These clinical prognostic factors represent surrogate markers of tumor behavior. Molecular markers of lung cancer prognosis have focused thus far on somatic aberrations and gene or protein expression.^5,6 Although these molecular markers are useful in identifying and confirming biologic processes, they have not translated well into the clinical setting. There are two major limitations to this approach: the handling of tumor material can be challenging, and specialized laboratories often are needed to measure these factors. Furthermore, in the setting of advanced disease, diagnoses are made from small needle biopsy samples; tumors are either not resected, or are resected after neoadjuvant therapy. Therefore, using tumor tissue to add further prognostic information or to predict response may be difficult to adopt in the routine clinical setting. On the contrary, assessing germline genetic polymorphisms as either prognostic or predictive markers has much appeal, especially in the advanced cancer setting.

In this study, we evaluated the role of two DNA repair gene polymorphisms in the survival of advanced-stage NSCLC patients treated with platinum agents. We demonstrated that the XPD and XRCC1 variant genotypes, both alone and in combination, are associated with decreased overall survival in this patient population.

Survival differences in this study were most apparent in individuals with stage III disease. There are several explanations for this finding. First, it may be that individuals with stage IV disease already have too many somatic mutations driving tumor growth or treatment resistance, such that any subtle capacity of genotypes to alter DNA repair capacity is overwhelmed. Second, the survival differences may reflect a radiation-related outcome, given that most stage III individuals received radiation to the primary tumor, whereas only a minority of stage IV individuals was radiated as part of the primary treatment. This latter explanation does not explain the common occurrence of relapsed metastatic disease outside the field of radiation.

We selected DNA repair genes as the focus of this study because of their pivotal role in carcinogenesis and in platinum function. However, DNA repair has been termed a double-edged sword because decreased DNA repair may increase the risk of developing cancer, although it might simultaneously improve survival in patients already diagnosed with cancer, when treated with platinum agents.^10,33 Interpretation of our results is complicated by controversies regarding which genotypes confer decreased DNA repair activity; therefore, definitive conclusions are premature. One strategy to evaluate whether DNA repair genes are affecting tumor aggressiveness or platinum function is to study nonplatinum-treated patients. In our population, we did not have an adequate number of patients treated with a nonplatinum doublet regimen; as a result, these analyses could not be performed. Finally, these polymorphisms may not be functional but instead could be markers of specific haplotypes of this section of chromosome 19, where many of the DNA repair genes reside. These haplotypes may be associated with differential activity because of variations in many DNA repair genes. Additional directions for research may include measuring haplotypes rather than single nucleotide polymorphisms.

The DNA repair genes that we studied exhibit other potentially functional polymorphisms. For example, we evaluated the XPD Lys751Gln polymorphism in place of the XPD Asp312Asn polymorphism and found similar trends in our results (data not shown). Because of the strong linkage disequilibrium between these two XPD polymorphisms, we reported only the XPD Asp312Asn polymorphism in our analyses because it had the stronger association with overall survival.

The choice of these DNA repair genes, XPD and XRCC1, was driven by their prior evaluation in numerous risk-association studies. Although a number of other DNA repair genes would be interesting to evaluate in NSCLC, these genes have specific roles in DNA repair: XPD is involved in nucleotide excision repair and basal transcription, and XRCC1 is an important component of the base excision repair pathway. The polymorphisms chosen for this study also have been shown to have functional significance.

In the retrospective setting, evaluation of clinical response and time to progression is often imprecise; thus, we chose to concentrate on overall survival, the most objective outcome. However, measuring clinical response and time to progression may be critical to elucidate further the mechanism by which DNA repair affects outcome. These parameters can distinguish whether DNA repair gene polymorphisms are predictive of treatment response, or are prognostic by determining outcome. Ideally, prospective validation studies should be carried out to measure these additional end points. On the basis of the expected outcome of the patient, both predictive and prognostic factors may be important in the choice of chemotherapy drugs. The data presented here are, therefore, prognostic factors because the primary end point was survival rather than clinical response.

The predictive and prognostic role of DNA repair gene and other functional gene polymorphisms in clinical outcomes is the subject of a growing body of literature in pharmacogenomics.^34-37 For example, in advanced colorectal cancer patients treated with oxaliplatin, associations between ERCC1 codon 118 and XPD Lys751Gln polymorphisms and survival have been described.^38,39 With regard to lung cancer, one group has evaluated XPD Asp312Asn and Lys751Gln polymorphisms in locally advanced NSCLC patients treated with gemcitabine plus cisplatin combination therapy and has found a nonsignificant trend toward association between the XPD Asp312Asn variant genotype and treatment response.⁴⁰ This last study is an example of the predictive role of genetic polymorphisms in lung cancer treatment response.

The goal of all these studies is to generate the necessary data to move toward an era in which chemotherapy is individualized on the basis of genetic constitution. As such, a prospective study is ongoing in Europe in which treatment of NSCLC patients is assigned on the basis of ERCC1 gene expression.⁴¹ In the future, careful consideration of other pathways involved in the metabolism of commonly used chemotherapy drugs will be critical, given that the basis for treatment of advanced NSCLC involves combinations of cytotoxic agents. Ultimately, through additional studies in this field, we will develop a much clearer understanding of genetic variations among individuals and their role in determining treatment tolerance and response as well as overall outcome. Even in the context of a prognostic marker, a simple blood test that can discriminate beyond performance status and disease stage will be useful in identifying patients for clinical trials involving novel agents for first- or second-line therapy.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: David C. Christiani, Gentra Corporation. Received more than $2,000 a year from a company for either of the last 2 years: David C. Christiani, Gentra Corporation.

	Acknowledgment

 
We thank all the physicians and surgeons at the Massachusetts General Hospital Cancer Center, and the HSPH/MGH Lung Cancer Susceptibility Group. We also thank Dr Panos Fidias and Dr Bruce A. Chabner for their generous support of our work.

	NOTES

 
D.C.C. was supported by National Institutes of Health (NIH) grants CA092824, CA74386, and CA90578; S.G. was supported by an NIH grant (5T32 CA71345-07) in Cancer Biology; G.L. was supported by a Doris Duke C.S. Award and a DF/HCC Lung Cancer Clinician Scientist Development Award.

This study was initially presented in the Pharmacogenomics and Cancer Therapy oral presentation session at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted August 11, 2003; accepted March 19, 2004.

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