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Preoperative Plasma Levels of Transforming Growth Factor Beta₁ (TGF-ß₁) Strongly Predict Progression in Patients Undergoing Radical Prostatectomy

From the Matsunaga-Conte Prostate Cancer Research Center, Scott Department of Urology, and Department of Pathology, Baylor College of Medicine, and The Methodist Hospital, Houston, TX; and Departments of Urology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Kevin Mark Slawin, MD, Scott Department of Urology, Baylor College of Medicine, 6560 Fannin St, Suite 2100, Houston, TX 77030; email: kslawin{at}www.urol.bcm.tmc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Elevated local and circulating levels of transforming growth factor beta₁ (TGF-ß₁) have been associated with prostate cancer invasion and metastasis. We tested the hypothesis that preoperative plasma TGF-ß₁ levels would independently predict cancer stage and prognosis in patients who undergo radical prostatectomy.

PATIENTS AND METHODS: The study group consisted of 120 consecutive patients who underwent radical prostatectomy for clinically localized prostate cancer (median follow-up, 53.8 months). Preoperative plasma levels of TGF-ß₁ were measured and correlated with pathologic parameters and clinical outcomes. TGF-ß₁ levels also were measured in 44 healthy men without cancer, in 19 men with prostate cancer metastatic to regional lymph nodes, and in 10 men with prostate cancer metastatic to bone.

RESULTS: Plasma TGF-ß₁ levels in patients with lymph node metastases (14.2 ± 2.6 ng/mL) and bone metastases (15.5 ± 2.4 ng/mL) were higher than those in radical prostatectomy patients (5.2 ± 1.3 ng/mL) and healthy subjects (4.5 ± 1.2 ng/mL) (P < .001). In a preoperative analysis, preoperative plasma TGF-ß₁ level and biopsy Gleason sum both were predictors of organ-confined disease (P = .006 and P = .006, respectively) and PSA progression (P < .001 and P = .021, respectively). In a postoperative multivariate analysis, preoperative plasma TGF-ß₁ level, pathologic Gleason sum, and surgical margin status were predictors of PSA progression (P = .020,P = .020, and P = .022, respectively). In patients who progressed, preoperative plasma TGF-ß₁ levels were higher in those with presumed distant compared with local-only failure (P = .019).

CONCLUSION: Plasma TGF-ß₁ levels are markedly elevated in men with prostate cancer metastatic to regional lymph nodes and bone. In men without clinical or pathologic evidence of metastases, the preoperative plasma TGF-ß₁ level is a strong predictor of biochemical progression after surgery, presumably because of an association with occult metastatic disease present at the time of radical prostatectomy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THROUGH THE widespread use of prostate-specific antigen (PSA)-based screening, the number of men diagnosed and treated for clinically localized prostate cancer during the past decade has increased dramatically.¹ Concomitantly, the incidence of clinical metastatic disease at the time of initial diagnosis has dropped considerably, in concert with an overall decrease in prostate cancer mortality.² Despite the significant rate of long-term cancer control afforded patients with clinically localized prostate cancer who are treated with radical prostatectomy or radiation therapy (XRT), treatment fails in approximately 30% of these patients. This treatment failure is evidenced by a detectable and increasing PSA, which often is caused by early dissemination of microscopic metastatic disease before primary therapy.³ Because of their poor performance in the detection of early, low-volume metastases, conventional staging modalities such as bone scan, computed tomographic scan, and magnetic resonance imaging have a limited role in staging patients with clinically localized prostate cancer.^4,5 Preoperative nomograms that incorporate established markers such as PSA, clinical stage, and biopsy Gleason sum can provide an estimate of the risk of nodal metastasis or disease recurrence, but they are still imperfect for the determination of pathologic stage or prognosis in individual patients.^6,7 Improved preoperative identification of patients with occult metastatic disease, who have a high probability of disease progression despite effective local therapy, would be helpful in the effort to spare men the morbidity of a radical prostatectomy or XRT that would be ineffective, and in the selection of patients best suited for clinical trials of neoadjuvant or adjuvant therapy.

Transforming growth factor beta₁ (TGF-ß₁) is a pleiotropic growth factor that regulates cellular proliferation, chemotaxis, cellular differentiation, immune response, and angiogenesis. Loss of response to the inhibitory effect of TGF-ß₁ has been associated with the progression of cancer. TGF-ß₁ has been demonstrated to promote cell motility and metastasis in experimental prostate cancer models.^8,9 Increased local expression of TGF-ß₁ has been associated with tumor grade, pathologic stage, and lymph node metastasis in patients with prostate cancer.^10-14 Elevated circulating levels of TGF-ß₁ have been found in patients with many different types of tumors (Shariat et al, manuscript submitted for publication).^15-19 In some studies, higher circulating TGF-ß₁ levels have demonstrated an association with prostate cancer invasion²⁰ and metastasis,^20-22 although others have demonstrated no association.^23,24 We confirm a strong association between elevated plasma TGF-ß₁ level and prostate cancer metastases to regional lymph nodes and to bone. Furthermore, we hypothesized that men with clinically localized prostate cancer who harbor occult metastases also would have elevated levels of plasma TGF-ß₁ that would be associated with biochemical progression despite effective local control of disease. Therefore, to determine the relationship between preoperative plasma TGF-ß₁ levels and established markers of prostate cancer invasion, metastasis, and disease progression, we studied a large consecutive cohort of patients with clinically localized prostate cancer who underwent radical prostatectomy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
We assessed plasma TGF-ß₁ levels in 44 healthy patients without cancer, in 19 men with prostate cancer metastatic to regional lymph nodes, and in 10 patients with bone scan-proven, metastatic prostate cancer. Neither patients with metastatic lymph node disease nor patients with metastatic bone disease were treated with hormonal therapy or XRT before plasma collection. The healthy noncancer group was composed of three sets of consecutive patients who participated in the Baylor Prostate Center’s weekly prostate cancer screening program. They had no prior history of cancer or chronic disease, normal digital rectal examination results, and a PSA level less than 2.0 ng/mL, which is in the PSA range with an estimated prostate cancer detection probability of less than 1% in the first 4 years after screening.²⁵

We also studied 120 consecutive patients who underwent radical prostatectomy for clinically localized prostatic adenocarcinoma (clinical stage, T1 to T2) at The Methodist Hospital, Houston, TX, between December 1994 and November 1995. No patient was treated preoperatively with either hormonal therapy or XRT, and none had a secondary cancer. The clinical stage was assigned by the operative surgeon in accordance with the 1992 tumor-node-metastasis system. The mean patient age was 61.8 ± 7.2 years (median, 63.0 years; range, 40 to 76 years). Serum PSA was measured by the Hybritech Tandem-R assay (Hybritech, Inc, San Diego, CA).

TGF-ß₁ Measurements
Serum and plasma samples were collected on an ambulatory basis at least 4 weeks after transrectal guided-needle biopsy of the prostate, which typically was performed on the morning of the scheduled day of surgery after a preoperative overnight fast. Blood was collected into Vacutainer CPT MDSU 8-mL tubes (Becton Dickinson Vacutainer Systems, Franklin Lakes, NJ) that contained 0.1 mL of 1 molar sodium citrate anticoagulant; samples were then centrifuged at room temperature for 20 minutes at 1500 g. The top layer, which corresponded to plasma, was decanted by use of sterile transfer pipettes, frozen immediately, and stored at -80°C in Nalgene polypropylene cryopreservation vials (Nalge Nunc International, Rochester, NY). Before assessment, an additional centrifugation of the plasma was performed at room temperature for 10 minutes at 10,000 g for complete platelet removal. For quantitative measurements of plasma and serum TGF-ß₁ levels, we used the Quantikine human TGF-ß₁ enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, MN), a quantitative sandwich enzyme immunoassay that is specific for TGF-ß₁ and does not cross-react with TGF-ß₂ or TGF-ß₃. Recombinant TGF-ß₁ was used as the standard. Every sample was tested in duplicate, and the mean was used for data analysis. Differences between the two measurements were minimal, as demonstrated by the intra-assay precision coefficient of variation of only 4.73% ± 1.87%.

TGF-ß₁ Collection Formats
In a preliminary study, we assessed TGF-ß₁ levels from three synchronously drawn blood specimens from 10 of the 44 healthy screening patients. Plasma was separated using Vacutainer K₃ ethylenediaminetetra-acetic acid (EDTA) 5-mL tubes (Becton Dickinson Vacutainer Systems) that contained 0.057 mL of 15% K₃ EDTA solution and Vacutainer CPT MDSU 8-mL tubes that contained sodium citrate. Serum was separated by use of Vacutainer Brand SST (Becton Dickinson Vacutainer Systems) serum separator tubes. Specimens were centrifuged at room temperature for 20 minutes at 1500 g, and plasma or serum was decanted and frozen at -80°C until assessment. Before assay, an additional centrifugation was performed at 10,000 g for 10 minutes at room temperature. The investigators were blinded to the nature of the collection formats. Analysis of variance was used to determine whether the collection format significantly affected measured TGF-ß₁ levels.

Pathologic Examination
Pathological examination of all prostatectomy specimens was performed by a single pathologist at our institution (TMW), who was blinded to clinical outcome. Pelvic lymph nodes were removed in a standard fashion during surgery and examined microscopically for the presence of metastatic prostate cancer. The radical prostatectomy specimens were processed by use of whole-mount technique, and pathologic parameters were evaluated as described previously.²⁶

Postoperative Follow-Up
Each patient typically was scheduled to undergo a digital rectal examination and analysis of serum PSA level every 3 months postoperatively for the 1st year, semiannually from the 2nd through the 5th year, and annually thereafter. A staging evaluation, including bone scan, prostascint scan, and/or PSA doubling time calculation was performed in 11 of the 15 patients who had PSA progression before the administration of salvage radiation or hormonal therapy. Biochemical progression was defined as a sustained PSA elevation greater than 0.2 ng/mL on two or more occasions. The date of progression was assigned as the date of the first value greater than 0.2 ng/mL. Two patients (1.7%) had lymph node-positive disease at the time of radical prostatectomy, and consequently surgery was aborted before prostate removal. These patients were categorized as treatment failures from the day after surgery. Two patients (1.7%) received adjuvant XRT before biochemical progression because of positive surgical margins. One of them subsequently experienced PSA relapse and was categorized with progression from the date of the first value greater than 0.2 ng/mL, and the second patient was censored on the date of the last follow-up examination. There were 17 treatment failures among the 120 men. PSA relapse was the sole indication of progression in 14 patients, and three patients had clinical as well as biochemical evidence of progression. Postprogression serum PSA doubling time was calculated for patients who had biochemical progression, and at least three PSA measurements were calculated after the date of progression with the formula²⁷:

equation

where DT is the serum PSA doubling time, T is the time interval between the initial and final PSA level, final PSA is the preradiation PSA level, and initial PSA is the PSA level noted at the time of the postoperative biochemical recurrence. The natural logarithm was used in all logarithmic transformations. Eight (53%) of the patients who experienced progression were treated with external-beam XRT limited to the prostatic fossa at The Methodist Hospital. Radiation was delivered with 15- to 20-MV photons, and the four-fields technique was used (anteroposterior/posteroanterior and opposing laterals) with customized field sizes. Total XRT dose ranged from 60 to 66 Gy delivered in daily fractions. A complete response to salvage XRT was defined as the achievement and maintenance of an undetectable serum PSA level. XRT was considered to have failed if the postradiation serum PSA levels did not decrease to and remain at an undetectable level.

Statistical Analysis
Differences in plasma TGF-ß₁ levels across collection formats were assessed by analysis of variance. Multiple comparisons were conducted by use of Fisher’s least significant difference when the overall test was significant at the 5% level. Differences in TGF-ß₁ levels among clinical and pathologic features were tested by use of the Mann-Whitney test. Spearman’s rank correlation coefficient was used to compare continuous variables. Logistic regression was used for multivariate analysis of binary outcome variables. The Kaplan-Meier method was used to calculate survival functions, and differences were assessed with the log-rank statistic. Multivariate survival analysis was performed with the Cox proportional hazards regression model. Preoperative PSA level had a skewed distribution and, therefore, was modeled with a log transformation. Clinical stage was evaluated as T1 versus T2. Biopsy and radical prostatectomy Gleason sum were evaluated as grade 2 to 6 versus grade 7 to 10. Statistical significance in this study was set as P < .05. All reported P values are two-sided. All analyses were performed with the SPSS statistical package version 10.0 for Windows (SPSS, Inc, Chicago, IL).

	RESULTS

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Impact of Collection Formats on TGF-ß₁ Levels
The effect of the collection format on TGF-ß₁ levels was studied initially. Mean TGF-ß₁ levels, measured in Vacutainer CPT citrate plasma, Vacutainer K₃ EDTA plasma, and Vacutainer Brand SST serum (Becton Dickinson Vacutainer Systems) from synchronously drawn blood specimens of 10 consecutive, healthy screening patients were 4.21 ± 1.16 ng/mL, 8.34 ± 2.94 ng/mL, and 23.89 ± 5.35 ng/mL, respectively (Table 1). TGF-ß₁ levels measured in serum were three times higher than those measured in EDTA plasma and six times higher than those measured in citrate plasma. Although analysis of variance demonstrated TGF-ß₁ intercollection format differences to be statistically significant (P < .001), TGF-ß₁ levels measured in specimens collected by all three sample formats were found to be highly correlated with each other (P < .001). However, levels of TGF-ß₁ measured in specimens from the two plasma formats were the most highly correlated (correlation coefficient, 0.987). We used plasma from Vacutainer CPT sodium citrate tubes for TGF-ß₁ measurements.

View larger version (18K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimates of PSA progression-free probability for the 120 patients with clinically localized prostate cancer who were treated with radical prostatectomy, stratified into groups above or below the median TGF-ß1 level of 4.9 ng/mL.

TGF-ß1 in Healthy and Metastatic Patients
Mean TGF-ß₁ levels in the 44 healthy screening patients, the 19 patients with prostate cancer metastatic to regional lymph nodes, and the 10 patients with metastatic prostate cancer were 4.5 ± 1.2 ng/mL, 14.24 ± 2.6 ng/mL, and 15.51 ± 2.4 ng/mL, respectively (Table 3). Plasma TGF-ß₁ levels in patients with lymph node metastases and bone metastases were higher than those in the cohort of 120 prostatectomy patients and in healthy subjects (P < .001). However, plasma TGF-ß₁ levels in the prostatectomy patients were not higher than those in healthy subjects (P = .053). Similarly, plasma TGF-ß₁ levels in patients with bone metastases were not different from those in patients with lymph node metastases (P = .108).

TGF-ß1 and Prostate Cancer Stage and Progression
Figure 2 shows box plots of the TGF-ß₁ levels in 109 of our 120 consecutive prostatectomy patients who were followed for at least 48 months. These are stratified by progression status at 48 months in 44 healthy men without cancer, 19 men with prostate cancer metastatic to regional lymph nodes, and 10 men with prostate cancer metastatic to bone. TGF-ß₁ levels were not different between healthy men, patients with organ-confined disease who did not have disease progression, and patients with extracapsular disease who did not have disease progression (P > .229). However, TGF-ß₁ levels in these three groups were lower than in patients with biochemical progression who had organ confined disease, extracapsular disease, or seminal vesicle invasion, lower than in patients with lymph node metastases, and lower than in patients with bone metastases (P < .005). The group of patients with lymph node metastases or bone metastases had similar TGF-ß₁ levels (P = .271), which were higher than those in any of the other groups (P < .001).

View larger version (20K): [in this window] [in a new window]   Fig 2. Box plot of the TGF-ß1 levels in radical prostatectomy patients, stratified by progression status at 48 months in healthy men and patients with prostate cancer metastatic to lymph nodes or to bone. Abbreviations: OC, organ confined; ECE, extracapsular extension; SVI, seminal vesicle involvement; LN mets, lymph node metastases; Bone mets, bone metastases.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

In radical prostatectomy patients, the plasma TGF-ß₁ level was independently associated with pathologic stage. An association between elevated TGF-ß₁ levels and locally advanced prostate cancer has been reported previously.²⁰ In a small pilot study, Ivanovic et al²⁰ found that patients with advanced pathologic stage demonstrated an increase in TGF-ß₁ levels twice that of patients with confined disease and four times that of healthy controls. After radical prostatectomy, however, the majority of patients with organ-confined extracapsular disease and even seminal vesicle invasion, whose local tumor is completely removed as evidenced by a negative surgical margin, experience long-term freedom from biochemical progression.^28-31 On the other hand, in most, if not all, patients with lymph node involvement, local therapy eventually fails, and they develop distant metastases regardless of success in the eradication of local disease.^32-34 Nomograms that incorporate biomarkers, which can predict disease progression rather than simply pathologic features in patients who undergo radical prostatectomy for prostate cancer, would be the most useful in the management of patients with prostate cancer.³⁵

We found a strong association between circulating TGF-ß₁ levels and disease progression after radical prostatectomy. To process the radical prostatectomy specimens, we used a whole-mount step-section technique that has been demonstrated to be the most accurate method to detect positive surgical margins and determine pathologic stage.³⁶ In this more recent series, the positive margin rate was 13.3%, compared with the 16% to 46% positive margin rates reported in older series for patients with clinically localized prostate cancer.^37,38 Positive surgical margins may suggest the presence of residual local tumor in the surgical bed, a finding that has been demonstrated to be a strong predictor of local recurrence.³⁹ Furthermore, complete and durable response to salvage XRT may be the best indication of isolated, locally recurrent disease. We reported previously that postrecurrence PSA doubling time predicts the presence of biopsy-proven local recurrence and the response to salvage XRT.⁴⁰ The lower rate of positive surgical margins (13.3%) and the high rate of presumed distant failures (67%), based on a PSA doubling time of less than 10 months,⁴¹ the failure to respond to salvage local radiation therapy or a positive metastatic work-up, suggested that the association between preoperative TGF-ß₁ levels and disease progression in these patients was more likely due to an association with the presence of occult metastatic disease at the time of surgery rather than with incomplete resection of potentially curable disease. For example, TGF-ß₁ was not associated with surgical margin status, and in a postoperative multivariate model, both TGF-ß₁ and surgical margin status were independently associated with disease progression. The finding that patients with presumed distant disease whose treatment failed had significantly higher TGF-ß₁ levels than patients with presumed local failure supports our hypothesis that TGF-ß₁ is associated with occult metastases present at the time of surgery. To further explore this hypothesis, we analyzed TGF-ß₁ levels in 109 of our 120 consecutive prostatectomy patients who had at least 48 months of follow-up, stratified the data by progression status at 48 months, and found that preoperative TGF-ß₁ levels were significantly elevated in patients with biochemical progression irrespective of the pathologic stage. After further confirmation of these results, TGF-ß₁ could be included in preoperative nomograms for prediction of progression.⁷

To further evaluate the association between TGF-ß₁ and metastases, we assessed TGF-ß₁ levels in 10 patients with bone scan-proven metastatic disease, in 19 men with prostate cancer metastatic to regional lymph nodes, and in 44 healthy men without cancer. Our findings, which are consistent with those of all studies,^20-22 except one²³ earlier report, demonstrated dramatically elevated levels of TGF-ß₁ in patients with distant prostate cancer metastases. The only study that did not detect an association between TGF-ß₁ levels and metastases relied on serum samples, which are less reliable for measurement of TGF-ß₁ levels.²³ To date, only one other group has investigated levels of TGF-ß₁ in patients with regional nodal metastases. Kakehi et al,²² whose findings were similar to ours, reported that TGF-ß₁ levels in patients with prostate cancer metastatic to regional lymph nodes were significantly elevated. In contrast to all previous studies, however, our study demonstrated that there was no overlap between TGF-ß₁ levels in patients with regional or distant metastatic disease and those in controls or patients with either localized or advanced prostate cancer.^20-22 In concordance with previous studies, we observed no statistically significant difference in plasma TGF-ß₁ levels between patients with pathologically localized prostate cancer and healthy men without cancer, which suggests a limited value of TGF-ß₁ as a diagnostic tool for the early detection of localized prostate cancer.^22-24

We found that TGF-ß₁ levels were three to six times higher when measured in serum than when measured in plasma. Because TGF-ß₁ is present in platelet granules and is released on platelet activation, the higher levels of TGF-ß₁ in serum probably are at least partly attributable to release from damaged platelets, which makes the quantification of nonplatelet-derived TGF-ß₁ less accurate. To ensure complete platelet removal, we performed an additional centrifugation as recommended by Adler et al.²¹ Although, as expected, TGF-ß₁ values in serum were less strongly correlated with those in the plasma formats (correlation coefficients, 0.79 and 0.80), the plasma formats were strongly correlated with each other (correlation coefficient, 0.99). TGF-ß₁ levels measured in the citrate plasma were lower than those measured in the EDTA plasma, because the top plasma layer was diluted primarily by the 1.0 mL of 0.1 mol/L sodium citrate anticoagulant contained within each Vacutainer CPT tube.

Our study was limited partly by the low rate of disease progression (14%) in the patient cohort after a median follow-up of 53.8 months, which yielded an estimated 5-year progression-free probability of 85%. The low progression rate in our population may be caused by the lower cancer stage and volume observed in more recent surgical series, which has accompanied the increasing awareness of prostate cancer in the general population and the wide availability of PSA-based screening.⁴² In other reported series, approximately 44% to 47% of men who underwent radical prostatectomy had pathologically nonorgan-confined disease,^43,44 and in our cohort, only 34.2% of cancers were not organ confined. The pathologic stage of prostate cancer is known to be a strong predictor of progression after radical prostatectomy.³⁹ Nevertheless, 92.5% of our patients had a preoperative PSA level above 4 ng/mL; 32.5% had extraprostatic extension in their pathologic prostatectomy specimen, and 50% had a final pathologic Gleason sum of 7 or above, which is representative of patients who currently undergo radical prostatectomy for clinically localized prostate cancer. In addition to a slightly more favorable profile in pathologic parameters in our study cohort, the lower progression rate may be attributable to differences in surgical technique, a factor that has been demonstrated to strongly influence outcome after radical prostatectomy.^37,39,45,46 The positive margin rate in our present series was only 13.3%, which may have decreased the rate of progression attributable to local failure.

Preoperative PSA was not associated with disease progression in our study. The restricted low range of preoperative PSA (25th and 75th percentile, 5.4 and 11.3 ng/mL, respectively) may have limited the predictive value of preoperative PSA reported in previous studies of radical prostatectomy patients who had a wider range of preoperative PSA levels.^32,33 Noguchi et al⁴⁷ recently reported that a PSA level less than 9 ng/mL reflects benign prostatic hyperplasia rather than prostate cancer and does not independently predict progression after radical prostatectomy.⁴⁸ With the continued widespread use of PSA-based screening, current patients who undergo radical prostatectomy have lower levels of PSA, which further supports the need for novel markers that better predict disease outcome in these patients.

Viewed in the context of similar observations made for other cancers, these data support a relationship between elevated circulating TGF-ß levels and metastatic cancer, particularly bone metastases.⁴⁹ Studies have demonstrated that dissemination of prostatic cells occurs early in the disease process.^50,51 After radical prostatectomy, however, the percentage of patients with detectable disseminated cells decreases dramatically,⁵² which suggests that these cells probably have variable biologic potential. Although a substantial proportion of disseminated cells are nontumorigenic, eliminated by host factors, or biologically incapable of engraffement, adaptation, and growth, a subgroup of these cells eventually grow and develop into overt metastases. Therefore, the biologic and prognostic implications of micrometastases need to be defined more accurately. Elevated TGF-ß seems to be associated with biologically active and clinically significant disease.

Classic tumor markers are synthesized directly by malignant cells and are related to tumor volume and biologic potential. In patients with prostate cancer, circulating levels of PSA are derived directly from tumor cells. Circulating levels of TGF-ß seem to be associated with a more complex relationship between metastatic cancer and the host response to disease. Although local TGF-ß has features of classic tumor markers such as the overexpression in cancer and association with tumor burden, invasiveness, and clinical outcome,¹⁴ circulating levels may also be related to either tumor or host factors associated with disease progression and metastases.⁵³ We found that the predictive value of circulating TGF-ß levels remains significant even when controlled for other tumor-specific markers of biologically aggressive disease such as Gleason grade, tumor invasiveness, and PSA. TGF-ß levels also seem to be associated with the presence of clinically undetected, low-volume metastases. It remains unclear whether elevated circulating TGF-ß levels are produced by host factors such as distant organ response to invasion or are the result of tumor-induced metabolic changes. A better understanding of the biologic mechanism for elevation of circulating TGF-ß in patients with metastatic cancer possibly would allow improved clinical management of these patients and provide new targets for therapy in patients with metastatic disease.

Plasma TGF-ß₁ levels are markedly elevated in men with prostate cancer metastatic to regional lymph nodes and bone. In men without clinical or pathologic evidence of metastases, the preoperative plasma TGF-ß₁ level is a strong predictor of biochemical progression after surgery, presumably because of an association with occult metastatic disease present at the time of radical prostatectomy. Larger prospective studies are required to confirm these results and to construct a potentially better preoperative nomogram for the prediction of prostate cancer progression after radical prostatectomy or XRT.

	ACKNOWLEDGMENTS

 
Supported in part by grant no. SPORE CA58203 from the National Cancer Institute Specialized Program of Research Excellence and grants from the Frost Foundation, Inc, Santa Fe, NM, and the Max Kade Foundation, Inc, Vienna, Austria.

	REFERENCES

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Submitted September 6, 2000; accepted February 22, 2001.

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