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Originally published as JCO Early Release 10.1200/JCO.2007.15.4336 on April 28 2008 © 2008 American Society of Clinical Oncology. Serum TIMP-1 and Response to the Aromatase Inhibitor Letrozole Versus Tamoxifen in Metastatic Breast Cancer
From the Penn State University, Hershey Medical Center, Hershey; Lebanon VAMC, Lebanon, PA; Oncogene Science Biomarker Group/Siemens Medical Solutions Diagnostics, Cambridge, MA; Oncology Business Unit, Novartis Pharma AG; and Oncology Research, Novartis Institutes for BioMedical Research Basel, Basel, Switzerland Corresponding author: Allen Lipton, MD, Penn State University, Hershey Medical Center, Hematology/Oncology, 500 University Dr, Hershey, PA, United States, 17033; e-mail: alipton{at}psu.edu
Purpose To determine the effect of elevated serum TIMP-1 on the response of patients with metastatic breast cancer to an aromatase inhibitor versus tamoxifen. Patients and Methods Five hundred twenty-two patients estrogen receptor–positive metastatic breast cancer were randomly assigned to receive first-line hormone therapy with letrozole or tamoxifen. Serum tissue inhibitor of metalloproteinases-1 (TIMP-1) levels were measured using an enzyme-linked immunosorbent assay. Results Pretreatment serum TIMP-1 was elevated in 120 (23%) of 522 patients. Patients with elevated serum TIMP-1 had a significantly reduced objective response rate (19.2% v 30.6%; odds ratio, 0.54; P = .01), duration of response (median, 15.5 v 26.2 months; P = .001), time to treatment progression (TTP; median, 4.5 v 9.2 months; HR, 1.78; P = .0001), time to treatment failure (median, 3.5 v 9.0 months; HR, 1.77; P = .0001), and overall survival (median, 20.3 v 35.8 months; HR, 1.77; P = .0001) compared with patients with normal pretreatment TIMP-1 levels. Letrozole was superior to tamoxifen in both the normal serum TIMP-1 group (median TTP, 11.8 v 8.6 months; P = .003) and in the elevated serum TIMP-1 group (median, 6.1 v 3.2 months; P = .03) In multivariate analysis, elevated serum TIMP-1 remained an independent predictor of both shorter TTP (HR, 1.46; P = .002) and survival (HR, 1.44; P = .002), as did serum HER-2. Combined analysis of both serum TIMP-1 and HER-2/neu conferred additional ability to predict significantly different clinical outcomes compared to using either biomarker alone. Conclusion Patients with elevated pretreatment serum TIMP-1 had a significantly reduced response and survival. Serum TIMP-1 was an independent predictive and prognostic factor. Blockade of TIMP-1 and HER-2/neu activity may be beneficial in a subset of patients with breast cancer.
Despite the presence of the estrogen receptor (ER), only one half of patients with breast cancer will respond to endocrine therapy. A possible explanation for hormone resistance is that these tumors have developed other autocrine or paracrine pathways to facilitate their growth. We have previously shown that patients with breast cancer who have elevated serum levels of HER-2/neu are relatively resistant to hormone therapy with either letrozole or tamoxifen.1 Matrix metalloproteinases (MMPs) play a key role in invasion and metastasis of cancer cells. MMPs are able to degrade extracellular matrix and aid formation of new blood vessels, thus supporting metastatic tumor growth and angiogenesis.2-4 The MMP family can be regulated by their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs), which bind MMPs noncovalently.5-7 The rate of extracellular matrix turnover is regulated by the balance between activated MMP levels and free TIMP levels.8 Four TIMPs have been identified (TIMP 1 to 4).9 Although both TIMP-1 and TIMP-2 inhibit the activity of most MMPs, TIMP-1 preferentially forms a 1:1 complex with activated MMP-1, MMP-2, and MMP-3 and forms a complex with pro-MMP-9 that block its activation by stromelysins.7 Initially described as inhibitors of the catalytic activity of MMPs, TIMPs also possess pro-tumorigenic and metastatic activities, including growth factor activity. TIMP-1 promotes the growth of human keratinocytes and several other cell types,10,11 inhibits apoptosis,12-14 promotes growth,11,15 and regulates angiogenesis, including enhancement of vascular endothelial growth factor expression in breast cancer.16-17 Elevated TIMP-1 expression been observed in gastric, colon, breast, lung, and carcinoma of unknown primary.18-23 TIMP-1 overexpression was an independent prognostic predictor of worse survival in patients with non–small-cell lung cancer.21 Elevated TIMP-1 levels in primary breast cancer are associated with a decreased time to recurrence and overall survival.24 High preoperative plasma TIMP-1 levels are also associated with short survival in patients with colorectal cancer.25 In second-line metastatic breast cancer, we have previously demonstrated that the chance of a patient achieving clinical benefit, time to progression, and overall survival were all significantly shorter in patients with elevated plasma TIMP-1 levels.26 The purpose of this study was to determine serum TIMP-1 levels in patients with metastatic breast cancer receiving first-line hormone therapy, and to compare the response rate of the aromatase inhibitor letrozole to the antiestrogen tamoxifen in patients with elevated TIMP-1 levels.
Patient Population Nine hundred seven postmenopausal locally advanced or metastatic ER- and/or progesterone (PgR)-positive patients were randomly assigned to letrozole (453 patients) or tamoxifen (454 patients). The patient inclusion-exclusion criteria, and clinical, radiologic, and efficacy assessments for this trial have been reported.27 In this study, pretreatment serum samples obtained within 14 days before initiation of therapy were available from 522 patients (mainly European sites). No patients received trastuzumab. This project was approved by the institutional review board of the Penn State/Hershey Medical Center (Hershey, PA).
Efficacy Assessments
TIMP-1 and HER-2/neu Enzyme-Linked Immunosorbent Assay
Statistical Methods
This study was derived from an international, multicenter, double-blind, double-dummy, randomized, two-arm, phase III clinical trial comparing letrozole with tamoxifen as first-line treatment for postmenopausal women with advanced breast cancer.27 In our current study, pretreatment serum TIMP-1 was evaluated as a predictive factor for response to hormone therapy. Pretreatment serum samples were available from 522 of 907 patients. Serum was available from 57.6% of patients in the letrozole arm (261 of 453 patients) and 57.4% of the patients in the tamoxifen arm (261 of 454 patients). There were no significant differences in clinical characteristics of all ITT patients (n = 907) when compared with patients with available serum (n = 522), except for a higher percentage of patients with bone metastasis in the available serum group (Table A1, online only).
Pretreatment Serum TIMP-1
Response According to Serum TIMP-1 Status We next examined ORR to either letrozole or tamoxifen according to pretreatment serum TIMP-1 level. ORR (CR + PR) to letrozole was 35.9% (71 of 198) in patients with normal serum TIMP-1, while it was 23.8% (15 of 63) in patients with elevated serum TIMP-1. Response to tamoxifen was 25.5% (52 of 204) in patients with normal serum TIMP-1 and was only 14% (eight of 57) in patients with elevated serum TIMP-1. Although the response rate was higher with letrozole than with tamoxifen, regardless of serum TIMP-1, the difference was statistically significant only in patients with normal expression of serum TIMP-1 (P = .025). The median duration of response was longer for both letrozole and tamoxifen in patients with normal serum TIMP-1 (24.8 months for letrozole, and 26.2 months for tamoxifen) compared with patients with elevated serum TIMP-1 (16.9 months for letrozole, and 13.0 months for tamoxifen).
TTP When analyzed by treatment arm, median TTP for patients with normal pretreatment serum TIMP-1 receiving letrozole was 11.8 months versus 8.6 months for tamoxifen (P = .003). The median TTP for patients with elevated baseline TIMP-1 was 6.1 months for letrozole versus 3.2 months for patients receiving tamoxifen (P = .03). In summary, treatment with letrozole was associated with a significantly lower risk of progression and longer TTP compared with treatment with tamoxifen, regardless of serum TIMP-1 expression.
TTF When analyzed by treatment arm, median TTF for patients with normal pretreatment serum TIMP-1 receiving letrozole was 9.7 months versus 6.3 months for tamoxifen (P = .005). Median TTF for patients with elevated pretreatment serum TIMP-1 was 5.7 months for letrozole versus 3.2 months for patients receiving tamoxifen (P = .04). In summary, using the defined cutoff of 454 ng/mL to differentiate normal versus elevated levels of serum TIMP-1, letrozole was associated with a significantly lower risk of treatment failure and longer TTF compared with tamoxifen, irrespective of serum TIMP-1 level.
Overall Survival
Multivariate Analysis Multivariate analyses were conducted fitting 21 pretreatment clinical and biochemical covariates in the model without selection (Table A2, online only). TTP was significantly affected by seven covariates (Table 1). Elevated pretreatment serum TIMP-1 level remained an adverse predictive factor for TTP (HR, 1.46; P = .002). The risk for disease progression was also significantly increased in the presence of elevated serum HER-2/neu, adjuvant tamoxifen, liver metastases, Karnofsky performance score (KPS) of 80 or lower, disease-free interval (DFI) fewer than 2 years, and treatment with tamoxifen.
In multivariate analysis of overall survival, elevated serum TIMP-1 level (HR, 1.44; P = .002) was among five covariates that also remained significant independent prognostic factors (Table 2). The risk of death was also significantly increased in the presence of elevated serum HER-2/neu, soft tissue metastases, liver metastases, and KPS of 80 or lower.
Combined Analysis of Pretreatment Serum TIMP-1 and HER-2/neu We have previously reported that elevated pretreatment serum HER-2/neu was associated with a decreased response to hormone therapies.1 Because elevated pretreatment serum TIMP-1 level was also associated with a decreased response to hormone therapy (and independent of serum HER-2/neu), an analysis of the effect of both biomarkers on TTP was performed, as well as an analysis by treatment arm (letrozole v tamoxifen). Among patients with available pretreatment serum, 298 patients had normal pretreatment serum levels of both TIMP-1 and HER-2/neu (reference group), 72 patients had elevated serum TIMP-1 and normal serum HER-2/neu, 104 patients had normal serum TIMP-1 and elevated serum HER-2/neu levels, and 48 patients had elevated pretreatment serum levels of both TIMP-1 and HER-2/neu. Median TTP for all three patient groups with either or both serum biomarkers elevated was significantly reduced compared with that of the reference group (normal pretreatment serum levels of both TIMP-1 and HER-2/neu; P < .0001; Fig 2). Therefore, serum TIMP-1 assay detected a substantial subgroup of 72 patients (14%), with elevated TIMP-1/normal HER-2 who had a significantly reduced TTP to hormone therapy compared with the reference group (median 5.7 v 11.6 months). This important patient subgroup could not have been identified using pretreatment serum HER-2 alone.
In the analysis by treatment arm, patients with normal serum levels of both TIMP-1 and HER-2/neu, median TTP for letrozole was 14.4 months versus 9.2 months for tamoxifen (P = .01). In patients with elevated TIMP-1 and normal HER-2/neu, median TTP for letrozole was 9.2 months versus 3.7 months for tamoxifen (P = .02). In patients with normal TIMP-1 and elevated HER-2/neu, median TTP was 7.4 months for letrozole versus 4.6 months for tamoxifen (P = .13). Finally, in patients with elevation of both TIMP-1 and HER-2/neu, median TTP was 3.2 months for both letrozole and tamoxifen (P = .45). A forest plot of these results shows that letrozole is superior to tamoxifen in the overall population (HR, 0.71), and that all subgroups of serum TIMP-1 and HER-2 straddle this line, indicating that none of these patient subgroups yielded results significantly different from the overall population for the superior effect of letrozole (Fig 3). Within each subgroup, because of low power, the risk of progression was significantly lower with letrozole than with tamoxifen only in the two subgroups with normal serum HER-2 (Fig 3).
Figure 4 shows the overall survival for the four biomarker subgroups. Elevated versus normal serum TIMP-1 was associated with a significantly increased risk of death, both within the normal serum HER-2 subgroup (median survival, 26 v 42 months; P = .0006), and within the elevated serum HER-2 subgroup (median survival, 15 v 25 months; P = .01). Patients with elevated serum levels of both TIMP-1 and HER-2 had the worst prognosis, which was significantly shorter compared with all other subgroups (median survival, 15 months; P < .0001 v reference group, and P = .01 for both remaining subgroups).
The response rate (CR + PR + stable disease) to endocrine therapy in patients with ER-positive metastatic breast cancer is 50% to 60%. One third to one half of patients will not benefit from treatments that block the ER or inhibit estrogen biosynthesis. A possible explanation for hormone resistance is that these cancers have developed other autocrine or paracrine pathways to facilitate their growth. Increased expression of TIMP-1 has been associated with an unfavorable prognosis in several tumor types. The overexpression of TIMP-1 is an independent prognostic marker in patients with non–small-cell lung cancer, and evaluating TIMP-1 may be important in identifying patients with greater risk of recurrence.21 In primary breast cancer, tumor tissue levels of TIMP-1 are associated with prognosis.22,24,29 Patients with higher levels of TIMP-1 had a shorter recurrence-free survival, decreased overall survival, and in multivariate analysis, TIMP-1 remained significantly associated with shorter relapse-free survival.24 Our recent report concluded that elevated plasma TIMP-1 predicted poorer response and survival to second-line hormone therapy in a phase III metastatic breast cancer trial of 251 patients.26 Also, high plasma TIMP-1 levels in the pre- to postoperative setting predicted patient survival in a 280-patient colorectal cancer study.30 Most recently, another report concluded that plasma TIMP-1 was significantly and independently associated with objective response, TTP, and survival in 90 patients with metastatic colorectal cancer receiving combination chemotherapy; and TIMP-1 was superior to carcinoembryonic antigen.31 This study was performed using serum from 522 patients with metastatic breast cancer treated with first-line hormone therapy, and is the largest phase III clinical trial result evaluating serum TIMP-1. Pretreatment serum was analyzed for TIMP-1 levels using the Oncogene Science/Siemens enzyme-linked immunosorbent assay. The odds of a patient achieving an objective response (CR + PR) from first-line endocrine therapy was much lower (19.2% v 30.6%) if serum TIMP-1 was elevated (OR, 0.54; P = .02). Time to progression (HR, 1.78; P = .0001) and overall survival (HR, 1.77; P = .0001) were also significantly shorter in patients with elevated serum TIMP-1 levels. In multivariate analysis, elevated serum TIMP-1 remained an independent predictor of both TTP (HR, 1.46; P = .002) and survival (HR, 1.44; P = .002), as did serum HER-2/neu. Combined analysis of both serum TIMP-1 and HER-2/neu conferred additional ability to predict subgroups of patients with significantly different clinical outcomes as compared to using either biomarker alone. The serum TIMP-1 assay detected a substantial subgroup of 72 patients (14%) with elevated TIMP-1/normal HER-2 who had a significantly reduced TTP to hormone therapy compared with the group with normal TIMP-1/normal HER-2 (median, 5.7 v 11.6 months). This important patient subgroup could not have been identified using pretreatment serum HER-2 alone, and selection of this cohort to evaluate response to targeted anti-TIMP-1 therapy may be critical. When TTP was analyzed by treatment arm, letrozole was superior to tamoxifen in both the normal serum TIMP-1 group (P = .003) and in the elevated serum TIMP-1 group (P = .03). Similarly, for TTF letrozole was again superior to tamoxifen in both the normal serum TIMP-1 group (P = .005) and in the elevated serum TIMP-1 group (P = .05). Therefore, irrespective of serum TIMP-1 level, TTP and TTF were significantly longer in patients treated with letrozole; and irrespective of treatment arm, patients with elevated serum TIMP-1 had significantly reduced TTP and TTF. We previously reported that cancers that have elevated serum levels of HER-2/neu are relatively resistant to hormone therapies.1 It would also appear from our results that ER-positive breast cancers may not be inhibited by endocrine therapy alone if TIMP-1 is overexpressed. The oncogenic activity of TIMP-1 may allow for cancer cells to overcome blockade of the estrogen receptor pathway. Our results further suggest that there are subgroups of ER-positive patients who do not express HER-2/neu or TIMP-1, some cancers that express one or the other, and finally some ER-positive cancers can activate both pathways and respond poorly to all hormone therapies. Future treatments may require targeting the HER-2/neu or TIMP-1 pathways or both in addition to traditional endocrine therapy.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Hilary A. Chaudri-Ross, Novartis (C); Dean B. Evans, Novartis (C); Peter Hamer, OSBD/Siemens (C); Sheryl Brown-Shimer, OSBD/Siemens (C); Karen Pierce, Siemens (C); Victor Gaur, Siemens (C); Walter Carney, Siemens (C) Consultant or Advisory Role: Allan Lipton, Novartis (C) Stock Ownership: Hilary A. Chaudri-Ross, Novartis; Dean B. Evans, Novartis; Peter Hamer, OSBG/Siemens Honoraria: Allan Lipton, Novartis-; Kim Leitzel, Siemens Research Funding: Allan Lipton, Novartis, Siemens; Kim Leitzel, Novartis, Siemens Expert Testimony: None Other Remuneration: None
Conception and design: Allan Lipton, Kim Leitzel, Hilary A. Chaudri-Ross, Dean B. Evans, Suhail M. Ali, Walter Carney Financial support: Dean B. Evans Provision of study materials or patients: Allan Lipton, Hilary A. Chaudri-Ross, Dean B. Evans, Peter Hamer, Victor Gaur, Walter Carney Collection and assembly of data: Kim Leitzel, Hilary A. Chaudri-Ross, Dean B. Evans, Peter Hamer, Sheryl Brown-Shimer, Karen Pierce, Victor Gaur, Walter Carney Data analysis and interpretation: Allan Lipton, Kim Leitzel, Hilary A. Chaudri-Ross, Dean B. Evans, Suhail M. Ali, Laurence Demers, Peter Hamer, Sheryl Brown-Shimer, Karen Pierce, Victor Gaur, Walter Carney Manuscript writing: Allan Lipton Final approval of manuscript: Allan Lipton, Kim Leitzel, Hilary A. Chaudri-Ross, Dean B. Evans, Suhail M. Ali, Laurence Demers, Peter Hamer, Sheryl Brown-Shimer, Karen Pierce, Victor Gaur, Walter Carney
published online ahead of print at www.jco.org on April 28, 2008 Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Lipton A, Ali SM, Leitzel K, et al: Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen. J Clin Oncol 21:1967-1972, 2003 2. Chambers AF, Matrisian LM: Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89:1260-1270, 1997 3. Remacle AG, Noel A, Duggan, C, et al: Assay of matrix metalloproteinases types 1,2,3 and 9 in breast cancer. Br J Cancer 77:926-931, 1998[Medline] 4. Rha SY, Yang WI, Kim, JH, et al: Different expression patterns of MMP-2 and MMP-9 in breast cancer. Oncol Rep 5:875-879, 1998[Medline] 5. Ray JM, Stetler-Stevenson WG: The role of matrix metalloproteinases and their inhibitors in tumor invasion, metastasis, and angiogenesis. Eur Respir J 7:2062-2072, 1994[Abstract] 6. Apte SS, Olsen BR, Murphy G: The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J Bio Chem 270:14313-14318, 1995 7. Goldberg GI, Strongin A, Collier IE, et al: Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase and activation of the proenzyme with stromelysin. J Biol Chem 267:4583-4591, 1992 8. Cox G, Steward WP, O'Bryne KJ: The plasmin cascade and matrix metalloproteinases in nonsmall cell lung cancer. Thorax 54:169-179, 1999 9. Brew K, Dinakarpandian D, Nagase N: Tissue inhibitors of metalloproteinases: Evolution, structure and function. Biochem Biophys Acta 1477:267-283, 2000[CrossRef][Medline] 10. Bertaux B, Hornebeck W, Eisen AZ, et al: Growth stimulation of human keratinocytes by tissue inhibitor of metalloproteinases. J Invest Dermatol 97:679-685, 1991[CrossRef][Medline] 11. Hayakawa T, Yamashita K, Tanzawa, K, et al: Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells: A possible new growth factor in serum. 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Int J Cancer 75:81-87, 1998[CrossRef][Medline] 17. Laleur MA, Handsley MM, Knauper V, et al: Endothelial tubulogenesis within fibrin gels specifically requires the activity of membrane-type matrix metalloproteinases (MT-MMPs). J Cell Sci 115:3427-3428, 2002 18. Karavasilis V, Malamou-Mitsi V, Briasoulis E, et al: Matrix metalloproteinases in carcinoma of unknown primary. Cancer 104:2282-2287, 2005[CrossRef][Medline] 19. Zeng ZS, Cohen AM, Zhang ZF, et al: Elevated tissue inhibitor of metalloproteinase I RNA in colorectal cancer stroma correlates with lymph node and distant metastases. Clin Cancer Res 1:899-906, 1995[Abstract] 20. Mimori K, Mori M, Shiraishi T, et al: Clinical significance of tissue inhibitor of metalloproteinase expression in gastric carcinoma. Br J Cancer 76:531-536, 1997[Medline] 21. Gouyer V, Conti M, Devos P, et al: Tissue inhibitor of metalloproteinase-1 is an independent predictor of prognosis in patients with non-small cell lung carcinoma who undergo resection with curative intent. Cancer 103:1676-1684, 2005[Medline] 22. Ree AH, Florenes VA, Berg JP, et al: High levels of messenger RNAs for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in primary breast carcinomas are associated with development of distant metastases. Clin Cancer Res 3:1623-1628, 1997[Abstract] 23. Guedez L, McMarlin AJ, Kingma DW, et al: Tissue inhibitor of metalloproteinase-1 alters the tumorigenicity of Burkitt's lymphoma via divergent effects of tumor growth and angiogenesis. Am J Pathol 158:1207-1215, 2001 24. Schroll A-S, Holten-Andersen MN, Peters HA, et al: Tumor tissue levels of tissue inhibitor of metalloproteinase-1 as a prognostic marker in primary breast cancer. Clin Ca Res 10:2289-2298, 2004[CrossRef] 25. Holten-Andersen MN, Stephens RW, Nielsen HJ, et al: High preoperative plasma tissue inhibitor of metalloproteinase-1 levels are associated with short survival of patients with colorectal cancer. Clin Ca Res 6:4292-4299, 2000 26. Lipton A, Ali SM, Leitzel K, et al: Elevated plasma TIMP-1 level predicts decreased response and survival in metastatic breast cancer. Cancer 109:1933-1939, 2007[Medline] 27. Mouridsen H, Gershanovich M, Sun Y, et al: Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: Results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 19:2596-2606, 2001 28. International Union Against Cancer: Manual of adult and pediatric medical oncology, in Monfardini S, Brunner K, Crowther D, et al (eds): Evaluation of the Cancer Patient and the Response to Treatment. Berlin, Germany, Springer, 1987, pp 22-38 29. Vizoso FJ, Gonzalez LO, Corte MD, et al: Study of matrix metalloproteinases and their inhibitors in breast cancer. Br J Cancer 96:903-911, 2007[CrossRef][Medline] 30. Holten-Anderson MN, Nikolaj M, Nielsen HJ, et al: Tissue inhibitor of metalloproteinases-1 in the post-operative monitoring of colorectal cancer. Eur J Cancer 42:1889-1896, 2006[CrossRef][Medline] 31. Sorensen MN, Bystrom P, Christensen IJ, et al: TIMP-1 is significantly associated with objective response and survival in metaststic colorectal cancer patients receiving combination of irinotecan, 5-fluorouracil, and folinic acid. Clin Cancer Res 13:4117-4122, 2007 Submitted December 5, 2007; accepted February 14, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
