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Epidemiology and Prevention |
Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029 [C. B. A.]; Division of Epidemiology, University of Minnesota, Minneapolis, Minnesota 55454 [C. S.]; National Center for Toxicological Research, Division of Molecular Epidemiology, Jefferson, Arkansas 72079 [B. F. C., G. Y. M., M. Y. F., A. S., F. F. K.]; Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 [S. K., L. F. H.]; and University of Texas M D Anderson Cancer Center, Department of Epidemiology, Houston, Texas 77030 [P. A. T.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Both radiation therapy and chemotherapy largely exert their antineoplastic effects by generating ROS3 and their byproducts (1 , 2) . In a population including patients receiving radiation therapy and those administered chemotherapy, marked increases in ROS levels were noted with spectrophotometric detection following treatment in both groups (3) . Interestingly, no significant differences were observed between patients who received radiation or chemotherapy, indicating that both treatment regimens are equally effective in generating ROS. Because in many cases ROS are the proximate cause of tumor cell death, the amount of reactive species that reach tumor cells and have either direct cytotoxic effects or trigger intracellular apoptotic pathways is likely to have initial and immediate impact on treatment efficacy. Thus, interindividual variability in enzymes that will affect ROS levels is likely to impact patient prognosis after treatment.
The GSTs are induced under conditions of oxidative stress, and 
-, 
-, µ-, and 
-class GSTs are active in detoxification of numerous products resulting from reactive oxidant damage to DNA and lipids, such as organic epoxides, hydroperoxides, and unsaturated aldehydes (4)
. GST-catalyzed reduction of these molecules prevents further oxidant damage within cells. GSTs M1 and T1 have been shown to have activity toward lipid hydroperoxides (5)
,4
and individuals lacking each of these enzymes may have reduced removal of secondary organic oxidation products produced by cancer therapy and, thus, may have better prognoses. In this retrospective analysis of women who were treated for breast cancer, we evaluated the role of genetic polymorphisms in GSTM1 and GSTT1 on disease-free and overall survival after treatment.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Laboratory Analysis.
For genotyping for deletions in GSTM1 and GSTT1, normal tissue was obtained from archival specimens. The majority of specimens (50-µm slices) were derived from normal lymph nodes (76%), with skin and breast tissue used when nodes were not available. Tissue slices were deparaffinized, and the DNA was extracted by a commercial kit (Qiagen, Chatworth, CA). Multiplex PCR was used to simultaneously amplify GSTM1 and GSTT1 (7)
, with albumin as a control gene. For GSTM1, primers 5'-GAACTCCCTGAAAAGCTAAAGC-3' and 5'-GTTGGGCTCAAATATACGGTGG-3' were used; for GSTT1, primers T1 (5'-TTCCTTACTGGTCCTCACATCTC-3') and T2 (5'-TCACCGGATCATGGCCAGCA-3') were used. The absence of amplified GSTM1 or GSTT1 product (in the presence of the albumin PCR product) indicated the respective null genotype for each.
Because the GSTT1 PCR assay produces a relatively long product, there is a chance of false null GSTT1 genotypes when archival specimens are used because of fragmented DNA from the fixed tissue samples. We therefore confirmed GSTT1-null results by a second assay, with forward primer 5'-CATCCCTGCCCTCACAACCA-3' and reverse primer 5'-CTTCTGCTTTATGGTGGGGTCTG-3' amplifying a 214-bp section of the GSTT1 gene, with concurrent amplification of the albumin gene. The reliability of the 214-bp GSTT1 PCR assay had been tested with DNA extracted from blood samples from a case-control study. Concordance of results from the conventional multiplex assay and the short-product GSTT1 assay for 96 DNA samples from blood was 100%. For DNA samples extracted from paraffin blocks for the present study, the short-product GSTT1 assay was run for all 75 samples that had null GSTT1 results from the multiplex assay and for a randomly selected group of samples with GSTT1-present results. Laboratory personnel were blinded to previous results. Three samples with GSTT1-null results from the multiplex assay, i.e., no 480-bp product, did produce a 214-bp GSTT1 PCR product, and results from these specimens were excluded from the analyses.
Statistical Analysis.
Initial analyses included the assessment of patient and tumor characteristics by GSTM1 and GSTT1 genotypes, using 
2 analysis and Fisher’s exact test, when appropriate. The effects of genotype on both cancer recurrence and overall survival were evaluated by the Kaplan-Meier survival function, log-rank tests for survival differences, and Cox proportional hazards models (8)
, with an a priori hypothesis that women with gene deletions for GSTM1 and GSTT1 would have better survival. Thus, HRs represent relative risk of death among women with null genotypes compared with those with the GSTM1- or GSTT1-present alleles. They were calculated from the Cox model first by univariate analysis, then from a multivariate model with adjustment for prognostic factors. Adjusted models included age (four categories), stage, and node status at diagnosis as stratifying variables and race (Caucasian or African-American, excluding other or unknown) as covariate. Estrogen and progesterone receptor status were also evaluated as potential confounders, but did not alter HRs for GSTM1 and GSTT1 genotypes and were not included in the final models. For analysis of disease-free survival, time from disease-free date to recurrence, death, or last follow-up was calculated, and adjusted HRs were estimated from the Cox model, including prognostic factors as described for analysis of overall survival. To examine the combined effects of GSTM1 and GSTT1 on survival and recurrence, a dummy variable was created with three categories representing presence of alleles for the following: both GSTM1 and GSTT1; presence of one of the GST genes; and null status for both GSTM1 and GSTT1.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, the population was primarily Caucasian (80%) and ranged in age from 25 to 78 years. Women in this study (representative of the patient population at the Arkansas Cancer Research Center) were younger and had a more advanced stage at diagnosis than the observed distribution of breast cancer in most incident populations. Almost 75% of patients were under age 60, and >50% had nodal involvement. These characteristics could, in part, be attributable to the fact that the Arkansas Cancer Research Center is a tertiary care facility. When women were classified by genotype, 46% of Caucasians and 52% of African-Americans were GSTM1 null. For GSTT1, 26% of Caucasians had the null genotype, and 40% of African-Americans carried the deletion polymorphism. Table 1
also shows the proportion of demographic and pathological characteristics by genotype status for GSTM1 and GSTT1. As shown, there were no significant differences by genotype for any of these characteristics; however, allele distribution varied by race, and women with GSTM1- and GSTT1-present alleles were also more likely to be deceased (P = 0.06 and 0.09, respectively).
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Seventy-nine percent (n = 197) of the women in this study received chemotherapy, which in most cases was a combination of cyclophosphamide (95%), Adriamycin (76%), and 5-fluorouracil (80%), and 38% of those women also received radiation therapy. There was also a group (n = 54) who were treated only with radiation therapy. Disease recurrence was noted for 72 women, and 74 deaths were recorded. Median follow-up by the Tumor Registry of 177 women alive at last contact was 58 months. For women whose disease recurred (and with information on subsequent treatments), 60% received chemotherapy and 37% received radiotherapy after relapse.
Kaplan-Meier survival curves (Figs. 1
and 2
) showed unadjusted relationships between GSTM1 and GSTT1 genotypes and survival after treatment for breast cancer. As hypothesized, null alleles for both GSTM1 and GSTT1 were associated with better overall survival. Cox proportional hazards models were used to estimate hazard of death and are presented in Table 2
, both univariate estimates and ratios adjusted for other prognostic and possibly confounding factors. In crude models, there were nonsignificant reductions in hazard of death to 0.66 and 0.63 among women who were null for GSTM1 and GSTT1, respectively. However, when models were adjusted for age, race, and stage, estimates were further reduced and strengthened (GSTM1, HR = 0.59, 95% CI, 0.36–0.97; GSTT1, HR = 0.51, 95% CI, 0.29–0.90).
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. Adjusted models showed slightly more than half the hazard of death among those with either M1 or T1 present, and a two-thirds reduction in risk for those who were null for both genotypes (Table 2)
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. GSTM1- and GSTT1-null genotypes, considered separately or in combined categories, were again associated with less recurrence. HRs for recurrence-free survival were similar to those for overall survival, although relationships with GST genotype were somewhat attenuated, perhaps because women who were never disease-free had to be excluded from this analysis, thus reducing sample size.
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, there appeared to be some difference in relationships between genotype and disease-free survival depending on stage at diagnosis, although the numbers were small and the confidence intervals wide, so it is likely that the estimates were unstable. However, for GSTM1, it appeared that the relationship was important only among women with stage 1 and 2 disease. Perhaps in women with more advanced, aggressive disease, the impact of variability in response to treatment agents may have been too subtle and the disease severity outweighed any modifying impact of genotype. However, in relation to GSTT1 genotype, the effect was greatest among women with advanced disease, although there were only five women with the null genotype who did not survive. Although treatment given (chemotherapy or radiation therapy) did not appear to alter relationships between GSTT1 and genotype, among women who received only radiation therapy, there were no deaths for those with GSTM1-null genotypes, whereas 21% of those with GSTM1 present did not survive.
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DISCUSSION |
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The majority of women in this study were treated with a combination of cyclophosphamide, Adriamycin, and 5-fluorouracil, and a large proportion of them also received radiation therapy, either alone or in combination with chemotherapy.
It is known that the mechanism of cytotoxicity with radiation therapy is through the generation of ROS (2) . Radiation therapy may eradicate cancer cells either directly through effects on the target molecules or indirectly through intermediate radiation products (2) . When water, the most abundant intra- and extracellular material, is exposed to ionizing radiation, decomposition occurs, through which a variety of ROS, including superoxide radicals, hydrogen peroxide, and hydroxyl radicals, are generated (9) . These reactive species can damage cells, proteins, and DNA or interact with other cellular molecules, producing secondary oxidation products, reactive molecules that contribute to cytotoxicity through the same mechanisms.
Generation of ROS is part of the cytotoxic activity of chemotherapy agents as well. Numerous clinical studies have shown that patients treated with a wide range of cytotoxic agents have marked increases in lipid peroxidation products (10, 11, 12, 13) . Decreases in vitamin E concentrations were also noted after treatment (13) . In the population in this study, women were treated primarily with cyclophosphamide, Adriamycin, and 5-fluorouracil. There are data that all of the agents used, but particularly cyclophosphamide and Adriamycin, result in lipid peroxidation and generation of ROS. Numerous studies have noted that administration of cyclophosphamide or its metabolite, acrolein, to rats results in an increase in lipid peroxidation products, such as malondialdehyde (14, 15, 16) . Cyclophosphamide exposure also results in concomitant decreases in glutathione (17) and the endogenous antioxidants superoxide dismutase and glutathione peroxidase (16) . The mechanism of by which cyclophosphamide kills tumor cell through ROS is further demonstrated by rodent data showing that the lung injury associated with treatment with cyclophosphamide is attributable to its ability to generate free radicals (15 , 18) . Exposure to Adriamycin, an antineoplastic antibiotic widely used in breast cancer treatment, like other anthracyclines can result in the formation of quinone-mediated free radicals (19) . Adriamycin-generated free radicals have the capacity to cause oxidative damage and cytotoxicity (20) . Lipid peroxides resulting from doxorubicin can break down to yield hydroxyalkenals, which are substrates for glutathione-conjugating isozymes (21) . The fact that its tumor cell-killing mechanism is through oxidative stress is demonstrated by data showing that Adriamycin’s cardiotoxicity is a result of the production of ROS (22 , 23) , which are presumably acting on tumor cells as well. As stated above, both GSTM1 and GSTT1 have been shown to have activity toward lipid hydroperoxides, and clearly their activity in the removal of lipid hydroperoxides may be key to DNA damage and cytotoxicity.
There have been few studies of GST genetic polymorphisms and survival. For the most part, prior studies of treatment efficacy and the GSTs have been based on studies of phenotype in tumor tissue, and these have primarily been in relation to GST . GST and µ are reported present in normal and tumor breast tissue (24
, 25)
, and we have noted that GSTT1 is expressed in breast tumor tissue as well.5
However, the impact of GST genotype may also be important for hepatic detoxification and/or systemic effects via the presence of the GSTs in lymphocytes and erythrocytes (26)
. In fact, studies relating levels of GSTs in peripheral blood to response to therapy support this notion (27
, 28)
.
Two studies of similar size investigated associations between GST genetic polymorphisms and survival with ovarian cancer. In one study (29) , there was no effect for GSTM1 or GSTT1 genotype alone, but the combined null genotypes for GSTM1 and GSTT1 were associated with poorer survival. A recent study, however, reported no association between GSTM1 genotype and ovarian cancer survival (30) . In studies of hematopoietic cancers, reduced risk of disease recurrence was noted among children with acute lymphoblastic leukemia who had alleles encoding no or lower activity for GSTM1, -P1, and -T1 (31) . Davies et al. (32) reported increased therapy-related toxicity among the GSTT1-null patients with acute myelocytic leukemia. These findings support the hypothesis that patients with GSTT1-null genotypes have reduced detoxification of therapeutic agents and, in the case of high-dose therapy for acute myelocytic leukemia, worse outcomes. We believe that, in the present study of primary breast cancer patients, the better outcomes that were observed among GSTT1-null patients who were not treated with high-dose therapy can be explained by the increased efficacy of treatment. We recently found that women with the less active variant for GSTP1 had improved survival after breast cancer treatment (6) , possibly because of the role of GSTP1 in metabolism of cyclophosphamide. Contrary to observations reported here, a hospital-based study (33) reported reduced survival among breast cancer patients with the GSTM1-null genotype. However, whether patients received adjuvant therapy was not reported, and HRs were not adjusted for other prognostic factors.
In our data, the effect of the GSTM1- and GSTT1-null genotypes on survival after treatment for breast cancer was evident in the entire population. Stratification by stage at diagnosis and treatment received, however, appeared to alter associations, with a much stronger effect of the GSTM1-null genotype among women who received only radiation, although the association was still evident for those treated with chemotherapy. The effects of GSTM1 and GSTT1 also appeared to vary by stage at diagnosis; whereas the GSTT1-null genotype reduced the risk of death in women with advanced disease, the inverse associations with the null genotype for GSTM1 were apparent only with stage 1 and 2 disease. Interestingly, in a small study of women with advanced breast cancer who received chemotherapy (34) , GSTM1 genotype had no effect on survival, which is consistent with our findings when stratified by stage of diagnosis. However, the numbers in these stratified analyses were small, and risk estimates were likely to be unstable. Hence, these relationships should be further explored with specific emphasis on stage at diagnosis and treatment received.
The patient population was also heterogeneous in other well-established prognostic factors, including age and hormone receptor status. Relationships between genotype and prognosis were evaluated within these categories by stratified analyses, with no differences noted between groups (data not shown). Furthermore, in the absence of evidence of associations between genotype and other prognostic factors, it is likely that genotypes are randomly distributed (regardless of, e.g., tumor stage and grade and estrogen receptor and progesterone receptor status). This nondifferential distribution is also likely to apply to other tumor tissue characteristics that may have prognostic importance, such as p53, Bcl-2, and ErbB2 overexpression, as well as proteins associated with multidrug resistance. With evidence that genotype is independent of stage, grade, and hormone receptor status, there is little theoretical rationale to support the possibility that associations between genotype and survival would be differentially impacted by other prognostic factors, such as tumor tissue characteristics. There is also the possibility that women with GSTM1- and GSTT1-present genotypes, being more resistant to therapy, were likely to receive higher doses of chemotherapy and/or radiation. Unfortunately, we do not have sufficient data to address this question; however, if women with those genotypes received more intensive treatments than those with null alleles, the associations we observed would be attenuated, and true relationships would actually be stronger than those reported.
Distribution of the null genotype for both GSTM1 and GSTT1 was higher in our patient population than in most populations for controls, as well as for cases, particularly for African-Americans. For most studies of GSTM1 and GSTT1, the null allele is present in 
50% and 15–20% of Caucasians of European descent, respectively. In the Carolina Breast Study (35)
, 51 and 52% of Caucasian cases and controls had the GSTM1 deletion, and 15 and 16% were null for GSTT1. For African-Americans, 25 and 28% of cases and controls were null for GSTM1, and 20 and 17% were null for GSTT1. The high proportion of African-American women who are null for GSTM1 and GSTT1 may be attributable to chance, or it may indicate that this genotype increases risk of breast cancer in our study population. We are unable to explore this issue further, however, in the absence of an appropriate control group.
As stated above, most studies in the past have evaluated GST polymorphisms in relation to cancer risk, rather than prognosis. For the most part, studies have found no increased risk for breast cancer with null genotypes for GSTM1 and/or GSTT1 (reviewed in Ref. 36 ), although there have been some positive findings (37 , 38) . Nor does there appear to be any association between genotype and stage at diagnosis or risk of breast cancer according to disease stage (35 , 39) . However, one of the earlier studies of GSTM1 and breast cancer indicated that the null genotype could be related to survival because of its association with risk in women with prevalent, but not incident breast cancer (40) .
In summary, we found that genetic polymorphisms in GSTs M1 and T1, known to be involved in response to ROS and products of lipid peroxidation resulting from chemo- and radiation therapy, were associated with significantly reduced hazard of death and risk of recurrence following treatment for breast cancer. Women with null genotypes for both GSTM1 and GSTT1 had one-third the hazard of death than those with alleles for both genes present. It has been suggested that the use of genomics in therapeutic decision-making may play an important role in the clinic, with microarrays specific for metabolic treatment pathways used for individualized dosing in the future (41) . Findings such as ours, if corroborated, could be useful in tailoring therapeutic regimens based on patient genotypes predictive of increased efficacy and decreased toxicity among patients being treated for cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This research was supported by the Arkansas Breast Cancer Research Program. C. S. and G. Y. M. were supported by fellowships from the National Center for Toxicological Research/Oak Ridge Institute for Science and Engineering. 
2 To whom requests for reprints should be addressed, at Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, Box 1130, One Gustave L. Levy Place, New York, NY 10029. Phone: (212) 659-5552; Fax: (212) 849-2564; E-mail: christine.ambrosone{at}mssm.edu
3 The abbreviations used are: ROS, reactive oxygen species; GST, glutathione S-transferase; HR, hazard ratio; CI, confidence interval.
4 B. F. Coles, unpublished data.
5 B. F. Coles, C. Sweeney, L. Joseph, M. Y. Fares, and C. B. Ambrosone, unpublished data.
Received 3/ 7/01. Accepted 8/ 2/01.
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