Clinical Cancer Research Bridging the Lab and the Clinic in Cancer Medicine Infection and Cancer: Biology, Therapeutics, and Prevention
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chang, J. Y.
Right arrow Articles by Wu, X.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chang, J. Y.
Right arrow Articles by Wu, X.
Clinical Cancer Research Vol. 11, 2894-2898, April 15, 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

High Mutagen Sensitivity in Peripheral Blood Lymphocytes Predicts Poor Overall and Disease-Specific Survival in Patients with Stage III Non–Small Cell Lung Cancer Treated with Radiotherapy and Chemotherapy

Joe Y. Chang1, Ritsuko Komaki1, Ryohei Sasaki1, Zhongxing Liao1, Craig W. Stevens1, Charles Lu3, Frank V. Fossella3, Pamela K. Allen1, James D. Cox1, Margaret R. Spitz2 and Xifeng Wu2

Authors' Affiliations: Departments of 1 Radiation Oncology, 2 Epidemiology, and 3 Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Joe Y. Chang, Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-2300; Fax: 713-563-2331; E-mail: jychang{at}mdanderson.org.


   Abstract
Top
 Abstract
Experimental Design
 Results
 Discussion
 References
 
Purpose: To investigate whether the bleomycin sensitivity assay, an in vitro peripheral blood lymphocyte assay, can predict outcome in patients with inoperable stage III non–small-cell lung cancer (NSCLC) treated with definitive radiotherapy and chemotherapy.

Experimental Design: We identified 102 patients with inoperable stage III NSCLC cell lung cancer treated with definitive radiotherapy and chemotherapy. The patients' pretreatment peripheral blood lymphocyte cultures were treated with the radiomimetic mutagen bleomycin. An index of bleomycin sensitivity was determined by counting the number of chromatid breaks in 50 metaphases. The correlation between bleomycin sensitivity (expressed as mean breaks per cell) and clinical outcome was analyzed.

Results: High bleomycin sensitivity (defined as a mean of >1.02 chromatid breaks/cell, representing the third quartile of bleomycin sensitivity) predicted poor disease-specific survival and overall survival. The 6-year disease-specific survival was 27% in patients with high bleomycin sensitivity compared with 46% in patients without such sensitivity (P = 0.0094). The association remained statistically significant when adjusted for smoking status, age, and radiation dose. The 6-year overall survival was 19% for patients with high bleomycin sensitivity and 29% for those without (P = 0.0193). There was a trend toward worse local regional control and worse disease-free survival among patients with high bleomycin sensitivity. There was no difference between the two groups in distant metastasis-free survival or radiation treatment-related complications.

Conclusions: High bleomycin sensitivity correlated with poor overall survival and disease-specific survival in these patients with stage III NSCLC treated with radiotherapy and chemotherapy. Bleomycin sensitivity may function as a biomarker for poor clinical outcome for this group of patients.

Key Words: Mutagen sensitivity • clinical predictor • non–small-cell lung cancer • chemoradiotherapy

Lung cancer remains the leading cause of cancer death in both men and women, with non–small-cell lung cancer (NSCLC) accounting for 80% of all cases. About 50% of patients with NSCLC present with locally advanced disease (stage III) and require multimodality management. With modern concurrent chemoradiotherapy, median survival times for such patients were only 15 to 17 months, with 5-year survival rates of 13% to 16% (1). In light of the dismal outcome following current treatment and the significant treatment-related toxicities in lung cancer, we urgently need markers to help individualize patient management.

Diminished capacity to repair DNA damage has been implicated as a risk factor for a variety of cancers (2). Cytogenetic assays in peripheral blood lymphocytes have been extensively used to survey exposure and response to genotoxic agents. The mutagen sensitivity assay was developed to measure indirectly an individual's DNA repair capacity from cellular damage remaining after an in vitro mutagenic exposure and recovery. This assay likely reflects general and nonspecific impairment of the DNA repair machinery and host genomic stability (2).

Our previous data showed that in vitro sensitivity of peripheral blood lymphocytes to bleomycin, a radiomimetic agent, is associated with the risk of oral premalignant lesions (3) and cancer recurrence in patients with cancer of the upper aerodigestive tract (4). Bleomycin-induced chromosome breaks in peripheral blood lymphocytes are also statistically significantly higher in lung cancer cases compared with controls (5).

Because chemotherapy and radiotherapy both damage DNA, we hypothesized that this assay of genetic instability unmasked by in vitro exposure of lymphocytes to a radiomimetic mutagen challenge may likewise serve as a biomarker for clinical outcome in lung cancer. We therefore investigated how well bleomycin sensitivity, assessed before initiation of any treatment, predicted response and outcome in patients with inoperable stage III NSCLC treated with definitive radiotherapy and chemotherapy.


   Experimental Design
Top
 Abstract
 Experimental Design
Results
 Discussion
 References
 
Patient selection. The patients were treated at The University of Texas M.D. Anderson Cancer Center between 1995 and 2001. They were identified from an ongoing case control study of susceptibility markers for lung cancer, and blood samples were drawn before any therapy had been instituted. All patients with newly diagnosed, histopathologically confirmed lung cancer (stage I to stage IV) were eligible for the case control study but only patients with inoperable stage III NSCLC (total of 102 patients) were selected for the current analysis because they had received definitive radiotherapy (50-66 Gy with a daily fraction of 1.8 or 2 Gy, or 69.6 Gy with 1.2 Gy per fraction given twice daily) and chemotherapy. About 20% of the patients received sequential chemotherapy/radiotherapy and 80% received concurrent or induction followed by concurrent chemotherapy/radiotherapy. According to the standard of care at our cancer center, patients are followed every 3 months for 2 years, then every 6 months for 3 years, and then annually. The range of the follow up was 8 years (from 1996 to 2003). The median follow-up was 21 months after completion of definitive treatment.

Survival time was calculated from the date of diagnosis to the date of last follow-up or death. Patients who were alive at the end of the study were censored at the date of last contact. Disease-specific survival is defined as the percentage of patients who have survived NSCLC since diagnosis. Only deaths from NSCLC are counted. Overall survival is defined as the percentage of patients who have survived since NSCLC diagnosis and all deaths are counted.

Mutagen sensitivity assays. Fresh whole blood samples (1 mL each) were added to 9 mL of RPMI 1640 (Life Technologies, Inc., Grand Island, NY) supplemented with 20% fetal bovine serum as described previously (3, 4). After the samples were incubated at 37°C with 5% CO2 for 72 hours, bleomycin (Nippon Kayaku Co., Ltd., Tokyo, Japan) was added to the blood cultures to a final concentration of 0.03 units/mL, and the cultures were incubated for an additional 5 hours. During the last hour of incubation with bleomycin, 0.04 µg/mL colcemid was added to the cells to arrest them in mitosis. The cells were then harvested and stained with Giesma. For each sample, the chromosome breaks in 50 metaphases were counted because a previous study (6) showed that the conventional method of scoring 50 metaphases was adequate. The mean number of chromatid breaks per cell was used to represent the chromosome breaks of each sample. Chromatid gaps or attenuated regions were disregarded; only frank chromatid breaks or exchanges were recorded. The slides were coded to ensure blinded evaluation. High bleomycin sensitivity was defined as a mean of >1.02 chromatid breaks/cell, representing the third quartile of bleomycin sensitivity (designated as bleomycin sensitive).

Statistical analyses. Wilcoxon's rank-sum test was used to test difference of mutagen sensitivity by histology and tumor grade. The {chi}2 test was used to assess patient characteristics by mutagen sensitivity phenotype and to compare high value of bleomycin sensitivity with low value of bleomycin sensitivity. The results were also stratified into quartiles based on the overall distribution of the number of breaks per cell. An individual was considered sensitive to bleomycin if the number of chromatid breaks was ≥1.02 per cell. Crude and adjusted odds ratios and 95% confidence intervals were calculated by univariate and multivariable logistic regression analyses, respectively. All statistical tests were two sided. The data were analyzed using the Kaplan-Meier survival function with S-plus 6.1 statistical software. The log-rank test was used to compare survival between the two groups (bleomycin-induced chromatid break per cell, <1.02 versus ≥1.02). The Spearman correlation test was used to analyze the correlation between bleomycin sensitivity and complications. S-plus6.1 and SAS 8.02 were used to perform statistical analyses.


   Results
Top
 Abstract
 Experimental Design
 Results
Discussion
 References
 
Table 1 summarizes select patient characteristics for the 102 patients with stage III NSCLC treated with radiotherapy and chemotherapy. The median number of chromatid breaks per cell was 0.72, with a mean value of 0.8 (SD = 0.47) and a range of 0.06 to 3.04. The bleomycin sensitivity quartiles based on chromatid breaks per cell were <0.5, 0.5-0.71, 0.72-1.01, and ≥1.02. High bleomycin sensitivity was defined as a mean of ≥1.02 chromatid breaks/cell, representing the third quartile of bleomycin sensitivity. Patients were dichotomized based on their bleomycin sensitivity score (group 1: ≥1.02 chromatid breaks/cell, 25 patients; group 2: <1.02 chromatid breaks/cell, 77 patients). There was no significant difference between these two groups in sex, age, ethnicity, smoking status, or total radiation dose (P values of 0.496, 0.81, 0.815, 0.966, and 0.515, respectively).


View this table:
[in this window]
[in a new window]
  		Table 1. Characteristics for 102 patients with stage III lung cancer

 
High bleomycin sensitivity predicted poor disease-specific survival and overall survival (Figs. 1 and 2). The 6-year disease-specific survival was 27% in patients with bleomycin sensitivity compared with 46% in patients deemed not mutagen sensitive (P = 0.0094). The median disease-specific survival was 18.1 months in patients with bleomycin sensitivity compared with 49.9 months in patients who were not mutagen sensitive. The P value remained significant when adjusted (subgroup analysis) for smoking status, age (dichotomized at 60 years), and radiation dose (50-55, 55-65, and >65 Gy). The 6-year overall survival was 19% for patients with bleomycin sensitivity and 29% for patients who did not exhibit the sensitive phenotype (Fig. 2, P = 0.0193). The median overall survival was 12 months in bleomycin-sensitive patients compared with 23.6 months in nonsensitive patients. There was a trend toward worse local regional control and worse disease-free survival among bleomycin-sensitive patients (P = 0.0972 and P = 0.1813, respectively). However, there was no difference between the two groups in distant metastasis-free survival (P = 0.7695).



View larger version (12K):
[in this window]
[in a new window]
  		Fig. 1. High bleomycin sensitivity predicted poor disease-specific survival in patients with stage III NSCLC. Patients were divided based on the bleomycin sensitivity (solid line, <1.02 chromatid breaks/cell, 77 patients; dashed line, ≥1.02 chromatid breaks/cell, 25 patients). The data were analyzed using the Kaplan-Meier survival function, and the log-rank test was used to compare different survivals. P = 0.0094.

 


View larger version (12K):
[in this window]
[in a new window]
  		Fig. 2. High bleomycin sensitivity predicted poor overall survival in patients with stage III NSCLC. Patients were divided based on the bleomycin sensitivity as described in Fig. 1. P = 0.0193.

 
To explore the predictive value of bleomycin sensitivity in treatment-related complications, we analyzed the association between bleomycin sensitivity values and common radiation treatment-related complications, including esophagitis, pneumonitis, and lung fibrosis. The correlation coefficient between bleomycin sensitivity and the total number of complications was 0.078 (P = 0.431). Again, the association analysis showed no significant association between bleomycin sensitivity and treatment-related complications when the side effects were analyzed individually or combined. A logistic model was used to analyze patient variables (age, sex, bleomycin sensitivity, smoking status, and total radiation dose) to predict complications (Table 2). The results showed that only the total radiation dose had predicative value, and only for lung fibrosis (P = 0.0004). Other variables, including bleomycin sensitivity, did not predict radiation treatment-related complications.


View this table:
[in this window]
[in a new window]
  		Table 2. Use of the logistic model to predict treatment complications

 

   Discussion
Top
 Abstract
 Experimental Design
 Results
 Discussion
References
 
In current clinical practice, the significant prognostic factors for patients with NSCLC are based on clinical features such as clinical stage, performance status, and weight loss. Molecular marker studies of lung cancer prognosis have focused on somatic aberrations or protein expression (7). A recent report showed that specific mutations in the epidermal growth factor receptor in primary tumors from patients with NSCLC correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib (8). In the clinical setting, however, most cases of locally advanced lung cancer offer limited cancer tissue samples for molecular analysis because diagnosis is made by fine needle aspiration. In such patients, tumors are either not resected or are resected after induction chemotherapy or chemoradiotherapy. Therefore, it will not always be practical in routine clinical practice to use tumor tissue to add further prognostic information.

Genomic instability can be unmasked by an in vitro mutagen challenge. The mutagen sensitivity assay, a phenotypic assay of host intrinsic DNA stability, was developed by Hsu et al. (9) using peripheral blood lymphocytes. Bleomycin, one of the mutagen challenges used, is a clastogenic agent that mimics the effects of radiation. It can form a complex with DNA, ferrous ions, and oxygen, generating free radicals that can cause DNA single- and double-strand breaks. Most of the DNA breaks are repaired by base excision repair and double-strand break repair. We have shown that the mutagen sensitivity determined by using this assay can predict the risk of lung cancer (10) and of recurrence in early-stage head and neck cancer (3, 4).

In the current study, high bleomycin sensitivity correlated with poor overall survival and poor disease-specific survival in patients with stage III NSCLC treated with radiotherapy and chemotherapy. There was also a trend indicating poor local regional control and poor disease-free survival in patients with the sensitive phenotype. There was no significant correlation between bleomycin sensitivity and treatment-related complications. There was also no significant correlation between bleomycin sensitivity and tumor grades (divided into well, moderate, and poor differentiation) and cancer histology based on analysis in these 102 patients (data not shown). Mutagen sensitivity may indicate a genetic instability that contributes to a high genetic heterogeneity, resulting in poor clinical outcomes. Bleomycin sensitivity may function as a biomarker for poor clinical outcome for this group of patients. Because this study is based on a case control analysis, we can only establish the correlation and/or association but not the causality between bleomycin sensitivity and clinical outcome.

DNA repair is critical in repairing the DNA damage induced by carcinogens. Equally, it plays an important role in repairing treatment-induced DNA damage. Decreased DNA repair capacity may increase the risk of developing cancer (carcinogenesis) and genomic instability that could lead to more biologically aggressive tumors and decreased survival. On the other hand, compromised DNA repair capacity may reduce the ability of cancer cells to repair DNA damage after chemotherapy and/or radiotherapy, resulting in better treatment response and more favorable clinical outcome, albeit with a greater likelihood of toxicity. Therefore, the effect on clinical outcome will be determined based on all these factors. In a previous study (11), DNA repair capacity in the peripheral lymphocytes from patients with NSCLC was analyzed using the host cell reactivation assay by transfecting plasmids damaged by exposure to the tobacco aromatic hydrocarbon, benzopyrene. Efficient DNA repair capacity was associated with a greater risk of death in patients with NSCLC who were treated with platinum-based chemotherapy. Interestingly, in this previous study effective DNA repair capacity was not associated with poorer survival in patients who were not treated with chemotherapy. The association between effective DNA repair capacity and poor survival was most evident in patients who were treated with platinum-based chemotherapy alone. There are several differences between the current analysis and our previous study using the host cell reactivation assay. The host cell reactivation assay measures the DNA repair capacity for bulky adducts, including those induced by the tobacco carcinogen benzo-[1]-pyrene and by platinum-based therapy. Bleomycin sensitivity indirectly measures repair capacity for bleomycin induced single- and double-strand DNA breaks. Therefore, the host cell reactivation assay may have better predictive value for patients who undergo platinum-based chemotherapy. In the current study, all patients had stage III NSCLC and were treated by radiotherapy and chemotherapy. By comparison, in the previous analysis (using the host cell reactivation assay), 37.6% of the patients had stage III NSCLC, 37.6% had stage IV, and only 29.7% received radiotherapy. For patients with stage IV disease, platinum-based chemotherapy plays a major role in survival. For patients with stage III disease, radiotherapy is critical for both local control and survival. Finally, in the current bleomycin sensitivity study, we used the third quartile as our cutoff value for defining bleomycin sensitivity. This may select a group of patients with significant genomic instability that causes biologically aggressive disease. In the current study, there was no association between the bleomycin sensitivity and radiation-induced toxicities identified. More patient data in a prospective study are needed to confirm this conclusion.

The effect on clinical outcome can be difficult to predict based on a single assay of DNA repair. Different cancer clinical stages and different treatments, including surgery, radiotherapy, and chemotherapy, may necessitate different assays to predict outcome. Polymorphisms of DNA repair genes such as XPD and XRCC1 are thought to result in suboptimal DNA repair (12–14). Our previous study (12) showed that DNA repair gene XPD polymorphisms (Lys751Gln and Asp312Asn) were associated with lower DNA repair capacity in lung cancer patients (as measured by the host cell reactivation assay). There is an expanding body of literature on the role of DNA repair genotypes modulating DNA repair capacity and on the clinical predictive value of decreased DNA repair capacity. However, all such studies have focused on chemotherapy, with no study investigating the association between DNA repair capacity and clinical outcome following radiotherapy for lung cancer. A recent report (15) showed that XPD (Asp312Asn) and XRCC1 (Arg399Gln) gene polymorphisms independently predicted shorter survival in patients with advanced NSCLC who were treated with platinum-based chemotherapy. Excision repair cross-complementation group 1 (ERCC1) is essential for nucleotide excision repair and genomic stability, as shown in ERCC1-deficient cells or knockout mice (16). ERCC1 C8092A but not codon 118 C/T polymorphism predicted poor survival in the same group of patients (17). Interestingly, the effect of the ERCC1 C8092A polymorphism on survival was observed only in patients with stage III NSCLC and not in those with stage IV disease. In another study, however, polymorphisms of ERCC1 codon 118 (C/T) but not XPD (Asp312Asn and Lys751Gln) predicted better survival in patients with NSCLC treated with cisplatin combination chemotherapy (18). Overexpression of ERCC1 was found to correlate with a lower response to cisplatin chemotherapy, and low expression of ERCC1 expression was found to correlate with prolonged survival in patients with NSCLC treated with cisplatin/gemcitabine chemotherapy (19, 20). A clinical trial of individualized chemotherapy based on ERCC-1 expression level is ongoing in Europe (21). In another study (22), XPD Lys751Gln polymorphism was associated with better progression-free survival in NSCLC patients treated with gemcitabine/cisplatin chemotherapy but with worse survival in patients receiving cisplatin/vinorelbine chemotherapy. When docetaxel was added to the gemcitabine/cisplatin chemotherapy, XPD Lys751Gln polymorphism was then associated with poor survival rather than better survival. Together, these results indicate that it may be possible in the future to tailor patient treatment based on genotype or repair phenotype. Prospective studies of DNA repair genotypes and phenotypes and their association with clinical response (including tumor local control, survival, and toxicities) will provide more accurate and validated data to guide patient management and eventually resolve the controversy related to DNA repair capacity and clinical outcome. For patients with aggressive cancer, as indicated by genotype evaluation, more aggressive treatment such as concurrent chemoradiotherapy plus more adjuvant full-dose chemotherapy and/or radiation dose escalation/accelerated radiotherapy may be warranted.


   Acknowledgments
 
We thank Susan Honn for patient recruitment, Qiong Dong for her assistance in statistical analysis, and the Department of Scientific Publications and Barbara E. Lewis for their assistance in the preparation of this article.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: R. Sasaki is currently at Division of Radiology, Kobe Graduate School of Medicine, Hyogo, Japan.

Received 10/26/04; revised 1/10/05; accepted 1/12/05.


   References
Top
 Abstract
 Experimental Design
 Results
 Discussion
 References
 

  1. Curran WJ, Scott CB, Langer CJ, et al. Long-term benefit is observed in a phase III comparison of sequential vs. concurrent chemo-radiation for patients with unresected stage III NSCLC: RTOG 9410. Proc of ASCO 2003;22:621.
  2. Berwick M, Vineis P. Markers of DNA repair and susceptibility to cancer in humans: an epidemiologic review. J Natl Cancer Inst 2000;92:874–97.[Abstract/Free Full Text]
  3. Wu X, Lippman SM, Lee JJ, et al. Chromosome instability in lymphocytes: a potential indicator of predisposition to oral premalignant lesions. Cancer Res 2002;62:2813–8.[Abstract/Free Full Text]
  4. Spitz M, Lippman S, Jiang H, et al. Mutagen sensitivity as a predictor of tumor recurrence in patients with cancer of the upper aerodigestive tract. J Natl Cancer Inst 1998;90:243–5.[Free Full Text]
  5. Zheng Y-L, Loffredo CA, Yu Z, et al. Bleomycin-induced chromosome breaks as a risk marker for lung cancer: a case-control study with population and hospital controls. Carcinogenesis 2003;24:269–74.[Abstract/Free Full Text]
  6. Lee JJ, Trizna Z, Hsu TC, Spitz MR, Hong WK. A statistical analysis of the reliability and classification error in application of the mutagen sensitivity assay. Cancer Epidemiol Biomarkers Prev 1996;5:191–7.[Abstract]
  7. Salgia R, Skarin A. Molecular abnormalities in lung cancer. J Clin Oncol 1998;16:1207–17.[Abstract]
  8. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–39.[Abstract/Free Full Text]
  9. Hsu TC, Johnston DA, Cherry LM, et al. Sensitivity to genotoxic effects of bleomycin in humans: possible relationship to environmental carcinogenesis. Int J Cancer 1989;43:403–9.[Medline]
  10. Wu X, Zhao Y, Honn SE, et al. Benzo[a]pyrene diol epoxide-induced 3p21.3 aberrations and genetic predisposition to lung cancer. Cancer Res 1998;58:1605–8.[Abstract/Free Full Text]
  11. Bosken CH, Wei Q, Amos CI, Spitz MR. An analysis of DNA repair as a determinant of survival in patients with non-small cell lung cancer. J Natl Cancer Inst 2002;94:1091–9.[Abstract/Free Full Text]
  12. Spitz MR, Wu X, Wang Y, et al. Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res 2001;61:1354–7.[Abstract/Free Full Text]
  13. Lunn RM, Helzlsouer KJ, Parshad R, et al. XPD polymorphisms: effects on DNA repair proficiency. Carcinogenesis 2000;21:551–5.[Abstract/Free Full Text]
  14. Dianova II, Sleeth KM, Allinson SL, et al. XRCC1-DNA polymerase ß interaction is required for efficient base excision repair. Nucleic Acids Res 2004;32:2550–5.[Abstract/Free Full Text]
  15. Gurubhagavatula S, Liu G, Park S, et al. XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy. J Clin Oncol 2004;22:2594–601.[Abstract/Free Full Text]
  16. Melton D, Ketchen A, Nunez F, et al. Cells from ERCC1-deficient mice show increased genome instability and a reduced frequency of S-phase-dependent illegitimate chromosome exchange but a normal frequency of homologous recombination. J Cell Sci 1998;111:395–4.[Abstract]
  17. Zhou W, Gurubhagavatula S, Liu G, et al. Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res 2004;10:4939–43.[Abstract/Free Full Text]
  18. Ryu JS, Hong YC, Han HS, et al. Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy. Lung Cancer 2004;44:311–6.[CrossRef][Medline]
  19. Rosell R, Fossella F, Milas L, Group SLC. Molecular markers and targeted therapy with novel agents: prospects in the treatment of non-small cell lung cancer. Lung Cancer 2002;38:43–9.
  20. Lord RVN, Brabender J, Gandara D, et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res 2002;8:2286–91.[Abstract/Free Full Text]
  21. Rosell R, Taron M, Alberola V, Massuti B, Felip E. Genetic testing for chemotherapy in non-small cell lung cancer. Lung Cancer 2003;41:S97–102.
  22. Rosell R, Taron M, Camps C, Lopez-Vivanco G. Influence of genetic markers on survival in non–small-cell lung cancer. Drugs Today 2003;39:775–86.



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
X. Wu, J. Gu, Q. Dong, M. Huang, K.-A. Do, W. K. Hong, and M. R. Spitz
Joint Effect of Mutagen Sensitivity and Insulin-Like Growth Factors in Predicting the Risk of Developing Secondary Primary Tumors and Tumor Recurrence in Patients with Head and Neck Cancer
Clin. Cancer Res., December 1, 2006; 12(23): 7194 - 7201.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
D. L. Chao, C. C. Maley, X. Wu, D. C. Farrow, P. C. Galipeau, C. A. Sanchez, T. G. Paulson, P. S. Rabinovitch, B. J. Reid, M. R. Spitz, et al.
Mutagen Sensitivity and Neoplastic Progression in Patients with Barrett's Esophagus: A Prospective Analysis.
Cancer Epidemiol. Biomarkers Prev., October 1, 2006; 15(10): 1935 - 1940.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chang, J. Y.
Right arrow Articles by Wu, X.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chang, J. Y.
Right arrow Articles by Wu, X.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online