Affiliation of authors: The University of Texas M. D. Anderson Cancer Center, Houston, TX.
Correspondence to: M. R. Spitz, M.D., M.P.H., Department of Epidemiology, Box 189, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009 (e-mail: mspitz{at}mdanderson.org).
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ABSTRACT |
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INTRODUCTION |
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One determinant of the level of Plt-DNA adducts in the tissue of patients treated with platinum-containing drugs is the rate of DNA repair. Individuals vary considerably in their capacity to remove DNA adducts (7), and tumor cell lines demonstrating in vitro resistance to cisplatin rapidly clear Plt-DNA adducts from the cells (8). Nucleotide excision repair (NER), the major mechanism for repairing Plt-DNA adducts (9), involves the coordinated activity of more than 20 enzymes that remove a segment of DNA containing a bulky adduct and then restore that segment of DNA by replicating the intact complementary strand (10). In ovarian cancer cell lines, both decreased levels of Plt-DNA adducts (11) and resistance to cisplatin (11,12) have been associated with elevated expression of a major NER enzyme, excision repair cross-complementing group 1 (ERCC1). Conversely, inhibition of ERCC1 expression by antisense oligonucleotides reduces repair of cisplatin-induced Plt-DNA adducts (13). It is thought that effective NER in tumor tissue may impair clinical response by promoting the removal of DNA-bound chemotherapeutic agents (14). The finding that a 42-base-pair (bp) deletion of the ERCC1 gene is associated with high levels of ERCC1 mRNA (15) suggests that changes in the effectiveness of DNA repair have a genetic basis.
We hypothesized that patients with genetically determined effective DNA repair activity would be more likely to effectively repair Plt-DNA adducts in tumor tissue than would patients with genetically determined suboptimal DNA repair. To test this hypothesis, we evaluated the association between survival and the systemic ability to repair DNA adducts in patients with NSCLC. Because we also predicted an interaction between DNA repair and chemotherapy, a separate analysis was performed on patients stratified by treatment modality. Even though we were ultimately interested in identifying genetic determinants of survival in patients with NSCLC, for this analysis we used a functional assay of DNA repair capacity (DRC)the ability to repair benzo[a]pyrene diol epoxide (BPDE)-induced DNA adductsto screen for abnormalities in the very complex NER system. Because DRC was measured in peripheral lymphocytes rather than in tumors, our findings reflect systemic differences in DRC between individual patients and are not a reflection of somatic mutations within the tumors.
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PATIENTS AND METHODS |
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Patients were accrued for an ongoing, hospital-based, casecontrol study (16) of epidemiologic and genetic risk factors for the development of lung cancer. The capacity to repair BPDE-induced DNA adducts was one of the risk factors assessed in that study. A total of 375 patients were enrolled between July 1, 1995, and December 31, 1999, all of whom had pathologically confirmed NSCLC diagnosed within 4 months before enrollment. Follow-up was completed on October 1, 2001. All patients were enrolled through the University of Texas M. D. Anderson Cancer Center, Houston, TX. On entry into the study, each of the 375 patients had a personal interview in which they were asked to provide information about demographic variables, changes in body weight, and smoking history, using a standardized questionnaire. Each patient also had a 30-mL sample of blood drawn that was cryopreserved to maintain lymphocyte viability. All patients gave written informed consent, and the protocol was approved by the M. D. Anderson Cancer Center Institutional Review Board. The American Joint Committee on Cancer clinical stage (17) and information about treatment, the date of the last treatment at M. D. Anderson, and the date of death were obtained from the patient's medical record. If vital status was not available in the medical record, the date of death was sought from M. D. Anderson's tumor registry and/or from the National Death Index, which was accessed via the World Wide Web (www.ancestry.com) (18). Date of death for a patient was taken from the Death Index only if the patient's name, date of birth, and social security number were all in agreement with their medical record. If written confirmation was obtained through the tumor registry that the patient was alive after he/she had terminated care at M. D. Anderson and there was no entry in the Death Index, then that patient was censored at the date of last written contact. Of the 375 patients originally enrolled in the study, 70 were seen only for diagnosis or for a second opinion and, therefore, there was no information on follow-up or treatment for these patients. Another 30 patients did not have information on weight loss, leaving 275 patients with complete follow-up information.
Patient Categorization
Patients were categorized as having had chemotherapy if they had received at least one complete course of therapy. Resectional surgery was defined as a wedge resection, lobectomy, or pneumonectomy. Definitive radiotherapy was delivered in doses of 4569 Gy to the chest. Patients who received radiotherapy for palliation of pain or to relieve obstruction only were not categorized as having received radiotherapy. The distribution of treatment modalities across the 275 patients with complete follow-up information was as follows: supportive care, 43; chemotherapy alone, 86; surgery alone, 36; radiotherapy alone, 12; chemotherapy and surgery, 22; chemotherapy and radiotherapy, 54; surgery and radiotherapy, 13; and surgery plus chemotherapy plus radiotherapy, 9. Treatment for 171 (62%) of the patients with complete follow-up included chemotherapy at some time during their follow-up, and 104 (38%) received treatment that did not include any chemotherapy. Chemotherapy was given as the first-line treatment to 146 (85%) of the 171 chemotherapy patients, most of whom had stage III (49%) or stage IV (41%) disease [staging was in accordance with the American Joint Committee on Cancer clinical stages (17)] (Table 1). Of these 146 patients, 116 (79%) received a platinin (cisplatin or carboplatin), and 69 of the 116 (47%) received a platinin in combination with a taxane (docetaxel or paclitaxel). An additional nine patients (6%) received a taxane without a platinin (eight in combination with navelbine and one with gemcitabine). Two patients received chemotherapy that was not further categorized, and the remaining 19 were treated with seven different single agents or combinations of gemcitabine, navelbine topotecan, or bisfanide. All 146 patients received between one and 18 cycles of the first therapeutic regimen, and 42 of the 146 patients received second-line therapy with other drug combinations. Tumors were histologically classified as adenocarcinoma, squamous cell carcinoma, or NSCLC. The NSCLC category included carcinomas that could not be otherwise categorized and large-cell undifferentiated tumors as well as tumors that were called NSCLC by the pathologist.
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DRC was measured by the host cell reactivation (HCR) assay described by Athas et al. (19). Briefly, purified plasmid harboring a reporter gene, chloramphenicol acetyl transferase (CAT), was dissolved in TrisEDTA buffer (pH 7.8) at a concentration of 500 µg/mL. Aliquots of plasmid solution (1 mL) were placed in microcentrifuge tubes, dissolved BPDE was added to each tube to a final concentration of 60 µM, and the mixtures were incubated for 3 hours in the dark. Plasmids were then precipitated three times with 70% ethanol to remove any remaining free BPDE, dissolved in TrisEDTA buffer at a final concentration of 50 µg/mL, and stored in aliquots at 20 °C. Previous studies (7,16,19,20) have shown that these experimental conditions produce at least one BPDEDNA adduct per plasmid, such that transcription of the CAT reporter gene is completely blocked without inducing conformational changes in the DNA. This is important because conformational change of the plasmid could reduce the transfection rate.
Each patient's frozen lymphocytes were thawed and processed as described previously (21). Briefly, the cells in each cryogenic vial (1.5 mL) were quickly thawed by mixing with 8.5 mL of thawing medium (50% fetal bovine serum, 40% RPMI-1640 medium, and 10% dextrose), which ensured a cellular viability of more than 80%, as tested by the 0.4% trypan blue dye (GIBCO BRL, Grand Island, NY) exclusion test (22). The cells were washed one time with the thawing medium and then stimulated so that they would take up the plasmids (18) by incubating them at 37 °C for 72 hours in RPMI-1640 medium supplemented with 20% fetal bovine serum and 56.25 µg/mL phytohemagglutin (Murex Diagnostics, Norcross, GA). The number of viable, large lymphoblasts in the culture for each sample was counted to calculate the blastogenic rate ([number of lymphoblasts/number of lymphocytes stimulated] x 100). The stimulated lymphoblasts from each patient were then divided into four aliquots, each containing approximately 2 x 106 cells, for duplicate transfections with either untreated plasmids or BPDE-treated plasmids. The transfections were performed by the diethylamino-ethyl-dextran (Pharmacia Biotech Inc., Piscataway, NJ) method (23).
After 40 hours of incubation of the transfected cells, cell extracts were prepared for analysis of CAT activity (16). CAT was assayed by adding chloramphenicol and [3H]acetyl coenzyme A and measuring the production of [3H]monoacetylated and [3H]diacetylated chloramphenicols. The radiolabeled products were extracted with ethyl acetate, and the radioactivity was measured with a scintillation counter. DRC is reported as the ratio of the radioactivity of cells transfected with BPDE-treated plasmids to that of cells transfected with untreated plasmids. Assuming that the transfection efficiencies of BPDE-treated and untreated plasmids are equal (24), this ratio reflects the percentage of damaged CAT reporter genes repaired in test lymphocytes transfected with BPDE-treated plasmids. The laboratory personnel performing the HCR assay had no knowledge of the patients' clinical status or length of survival.
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STATISTICAL METHODS |
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In a preliminary analysis, a linear regression was performed between DRC and a number of clinical variables. DRC was statistically significantly associated with age (P = .031), sex (P = .001), date of enrollment in the study (P<.001), and pack-years of smoking (P = .05) (data not shown). DRC was predicted by the equation DRC = 24.2104 + 0.0335 x age 0.9419 x female 0.0013 x date of enrollment + 0.0086 x pack-years smoked. The decrease in DRC with date of enrollment in the study is probably related to alteration in the BPDE-treated plasmids over time, because only a single lot of such plasmids was used for all of the analyses. Because of their statistically significant associations with DRC, age, sex, date of enrollment in the study, and pack-years of smoking were included as covariates in the survival analysis.
Because enrollment occurred over a 4.5-year period, we adjusted the survival analyses for possible temporal changes in patient management and any effect from long-term storage of the patient's lymphocytes by including the date of enrollment in the study as a covariate. To test for the effect of exposure to ultraviolet light on DRC, the date of enrollment was also used to assign each patient to the season in which his or her blood sample was drawn: summer (JuneAugust), fall (SeptemberNovember), winter (DecemberFebruary), and spring (MarchMay). Clinical performance status was not available for all of the patients, so we used self-reported weight loss from the questionnaire as a surrogate for general health status. Weight loss was defined as the difference between the responses to the two questions: "What is your usual weight?" and "What is your current weight?" In the survival analyses, weight loss was entered as a binary variable (present or absent).
We performed survival analysis using Cox proportional hazards models. We assessed the fit of the hazard models by plotting the cumulative hazard of death against the CoxSnell residuals (25). To assess the proportionality of the hazard models, we tested the hypothesis that the slope of the regression of scaled Schoenfeld residuals on survival time equaled zero. In none of the final hazard models could the assumption of proportionality be rejected (the P values ranged from .11 to .65). We assessed the appropriateness of the linear fit of each covariate by plotting Martingale residuals against covariate values. We assessed the statistical significance of the relative risk (RR) of death associated with DRC with a Wald test, for which we analyzed DRC as a continuous variable. In addition, we assessed the effect of DRC on the RR of death using DRC quartiles (5.8%, 5.9%7.6%, 7.7%9.2%, and >9.2%). To assess survival differences in patients with complete and incomplete follow-up information, we used a Wilcoxon rank sum test. The purpose of the quartile analysis was to provide an easily interpretable estimate of the effect of DRC on survival. All statistical tests were two-sided. All calculations were performed with Stata software, version 6.0 (26).
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RESULTS |
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As can be seen in Table 6, there was no effect of DRC on the RR of death in patients who were treated without chemotherapy (RR = 1.02, 95% CI = 0.94 to 1.11, P = .60 for unadjusted analysis, and RR = 0.98, 95% CI = 0.88 to 1.09, P = .66 for adjusted analysis). However, patients who were treated with any combination of chemotherapy (including those who also received surgery and/or radiotherapy at some time during their course of treatment) had an RR of 1.09 (95% CI = 1.01 to 1.17; P = .02) per unit (percentage) increase in DRC in the adjusted analysis. The RR of death did not increase when only the 146 patients who received chemotherapy as first-line treatment were analyzed (RR = 1.08, 95% CI = 1.01 to 1.16; P = .03 for adjusted analysis). However, when the 86 patients who received chemotherapy only were analyzed separately, the RR increased to 1.11 (95% CI = 1.02 to 1.21; P = .01) per unit (percentage) increase in DRC in the adjusted analysis.
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To summarize the association between DRC and survival, patients who were treated with chemotherapy only were divided into quartiles by DRC values (Table 7). Patients who were in the top DRC quartile of the group (DRC>9.2%) had a risk of death that was more than two times the risk of death of patients in the bottom quartile (DRC
5.8%) (RR = 2.72, 95% CI = 1.24 to 5.95; P = .01). The median survival was 8.9 months (interquartile range = 5.9 to 12.4 months) for patients whose DRC was in the top quartile compared with a median survival of 15.8 months (interquartile range = 9.0 to 26.4 months) for patients whose DRC was in the bottom quartile (P = 0.04 for the unadjusted difference in survival between the top and bottom quartile). The survival of patients in the midquartile range did not differ from the survival of patients in the bottom quartile (quartile 2 versus quartile 1, RR = 1.80, 95% CI = 0.95 to 3.51; P = .09; quartile 3 versus quartile 1, RR = 1.01, 95% CI = 0.45 to 2.27; P = .98) (Table 7
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DISCUSSION |
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Second, it was not a condition of enrollment in the study that the patients receive all of their medical treatment at M. D. Anderson. This inclusion criterion could have resulted in misclassification of patients who may have received additional treatment at another institution. However, neither the total duration of follow-up nor the time between last clinic visit and date of death or censoring differed between patients with effective DRC and those with suboptimal DRC, so misclassification is unlikely to explain our findings.
Third, the observational nature of our study and the small number of patients limited our ability to evaluate the effect of DRC by individual therapeutic agents or specific drug combinations. The majority of the 146 patients who received chemotherapy (79%; Table 1) were treated with platinins, whose association with DNA repair has been well studied (14). However, only eight patients received monotherapy (seven with gemcitabine and one with taxotere), and non-platinum-containing drugs may also affect DRC (28). For instance, the second most commonly used chemotherapeutic agents in the current report were taxanes (docetaxel or paclitaxel), and there is limited evidence that this class of drug interferes with DNA repair (28). Taxanes might potentiate the activity of platinins by decreasing their removal from DNA, thereby confounding the relationship between DRC, survival, and platinin therapy.
Potential limitations due to the HCR assay were accounted for through the study design. Because NER is inducible by alkylating agents and oxidants (27), we did not include patients who had received prior chemotherapy, and we included smoking history in the adjusted survival analyses. DRC was not related to clinical stage of disease or to recent weight loss, suggesting that the general health of the patients did not contribute to the variability in DRC. NER capacity may also be altered by lifestyle variables such as emotional stress (29) and caffeine consumption (30). We did not measure these variables in our patients, but there is little reason to think that they would be associated with survival after adjustment for clinical stage. Histone acylation (31), p53 activity (32), and the activity of mismatch repair enzymes (33) can affect the rate of removal of DNA adducts and are frequently altered in tumor tissue. However, these factors are unlikely to be altered in peripheral lymphocytes. In addition, we used BPDE-damaged plasmids in the HCR assay as a surrogate for cisplatin-damaged human DNA. BPDE induces adducts primarily at the N(2) position of guanine (34), and cisplatin induces N(7) adducts between guanines (14). Although the two types of adducts are not identical, they both result in bulky distortion of the DNA, and their repair requires the removal of more than one base pair. The rate of repair of these two types of DNA adducts may differ, but it is generally thought that the mechanism for repair (i.e., NER) is the same (35,36).
Despite the variety of factors that can influence the HCR assay, it has many strengths. Polymorphisms in genes that are important in NER have been shown to modulate DRC (21). For example, in a casecontrol study (21) using the same patient population and the same HCR assay as those used in the current study, patients carrying common polymorphisms in exon 10 and exon 23 of the gene that codes for XPD, one of the complementation groups of proteins included in NER, were found to have relatively poor DRC and increased risk of lung cancer. In addition, NER is a multistep process, and the use of a functional assay such as HCR allowed us to test the integrity of the entire system rather than that of a single step. Furthermore, when performing the HCR assay, the plasmid is damaged before introduction into the test lymphocytes, so the results reflect the host's DRC before receiving any therapy and before any in vitro manipulation of the lymphocytes. Finally, the assay was performed by laboratory personnel without knowledge of the patient's clinical status.
In preliminary analyses, we found that women had lower DRCs and longer survival than men. Prolonged survival in females with lung cancer has previously been reported (37,38), and it is tempting to suggest that suboptimal DNA repair may be responsible for better survival in women. However, compared with male patients in our study, a lower percentage of female patients had stage IV disease, and they smoked less and reported less weight loss. In addition, progressively more women than men were enrolled as the study continued. All of these factors combined to confound the relationship between DRC, sex, and survival, resulting in no effect of sex in the multivariable models (Table 5).
Several lines of investigation (6,9,14,39,40) suggest that DNA repair is important in the response of patients with lung cancer to chemotherapy. In experiments using cell lines derived from NSCLC tumors (39), resistance to cisplatin was assessed by comparing the dose of cisplatin required to kill 50% of the cells (IC50) with the level of Plt-DNA adducts in the tumor tissue. The increased IC50 after in vitro treatment of cell lines with cisplatin has been associated both with increased DNA repair (39) and increased expression of enzymes important in NER, such as ERCC1 (12). Resistance to cisplatin has also been associated with increased conjugation of platinum with glutathione (40) and increased removal of cisplatinglutathione conjugates from cells (41). However, in comparing the level of resistance to cisplatin in various cell lines, it has been suggested that DNA repair is the predominant mechanism for the moderate levels of cisplatin resistance that are seen clinically (42). In addition, in experiments with cells derived from cisplatin-naive tumors, cisplatin-insensitive NSCLC cells had an IC50 that was higher than that of cisplatin-sensitive small-cell lung cancer cells (SCLC), and Plt-DNA adducts were removed faster in the NSCLC cells than in the SCLC cells (42). These findings suggest that the well-known difference in clinical response to chemotherapy between patients with SCLC and NSCLC may be, at least in part, due to differences in DNA repair. Other clinical studies also support the notion that DNA repair is a determinant of survival. For example, in 27 patients with stage III NSCLC who were treated with cisplatin and definitive radiotherapy, patients whose level of Plt-DNA adducts in the buccal mucosa were above the median level were at one tenth the risk of death of patients whose level of Plt-DNA adducts was below the median (6).
Few data have directly compared levels of Plt-DNA adducts (43,44) or functional NER (41) in peripheral tissues with those in tumor tissues. Oshita et al. (44) measured DNA repair in peripheral monocytes and adenocarcinoma cells from the pleural space of nine patients with primary lung cancer. The correlation coefficient between the peripheral monocyte cells and the tumor cells was 0.68. In the current study, we did not measure the DRC of the patient's tumor tissue, and we therefore cannot address this question.
The finding of a decreased RR of death with effective DRC in patients after surgical resection who never received chemotherapy is intriguing; however, the number of patients in this subgroup was small, and the estimated RR changed when adjustment factors were added. It is hazardous to draw firm conclusions on this small sample; however, this finding does lend support to the suggestion that the deleterious effects of effective DNA repair are caused by an interaction with chemotherapy.
In conclusion, drug resistance is a complicated process that has been associated with abnormalities of drug uptake and excretion (42,43), removal of Plt-DNA adducts from target tissues, abnormal DNA mismatch repair, and abnormal NER. Although we did not investigate mechanisms of DNA repair other than NER, our findings suggest that NER may be a clinically important determinant of survival in patients with NSCLC who have been treated with chemotherapy. Because we measured DRC in peripheral lymphocytes and because we found no association between DRC and tumor clinical stage, we believe that these findings reflect a systemic host response to DNA damage rather than changes caused by somatic mutation within the tumors. Additional research will be required to directly assess the genetic basis of our findings and to investigate the relationship between NER activity as measured in peripheral lymphocytes and that measured in tumor tissue. Moreover, investigation into the relationship between specific chemotherapy drug combinations and DNA repair could potentially lead to the development of drug regimens tailored to individual patients.
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NOTES |
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We thank Maureen Goode (Department of Scientific Publications, The University of Texas M. D. Anderson Cancer Center, Houston, TX) for editing the manuscript, Kim Ahn Do (Department of Biostatistics, M. D. Anderson Cancer Center) for suggestions about the analysis, Susan Honn for patient recruitment, Wayne Gosbee for data management, and Zhaozheng Guo and Yawei Qiao for performing the laboratory assays.
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Manuscript received November 19, 2001; revised May 1, 2002; accepted May 9, 2002.
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