|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2003.07.083 on August 11 2003 © 2003 American Society for Clinical Oncology
The Ingredients for Prostate Cancer Nomograms: The Addition of Biomarkers Sets the Table for Future RecipesGenitourinary Oncology, Dana Farber Cancer Center, Boston, MA PROSTATE CANCER treatment decisions are complicated by the biologic heterogeneity of the disease. At diagnosis patients and clinicians struggle with treatment options, which include surgery, radiation, hormone therapy, and even observation alone. For many patients with potentially curable prostate cancer, the benefits of treatment must be weighed against the risks of therapy and competing causes of mortality. Stratification of patients with early prostate cancer into prognostic groups has facilitated improved communication between clinicians and patients with regard to the expectation of cure. Unfortunately, despite currently available clinical parameters such as prostate-specific antigen (PSA), Gleason score, clinical stage, and percentage of core biopsies positive for prostate cancer, significant clinical variability remains. Prognostic markers have not answered two paramount clinical questions: how to distinguish indolent or potentially nonlethal cancers that do not require treatment from those that do require treatment, and how to predict response to systemic therapies. Among the strategies for risk stratification into prognostic groups is the use of nomograms. Similar to other risk stratification schemes, nomograms are based on clinical and pathologic data at presentation, which can be helpful in predicting patient outcomes, and thereby aid therapeutic decisions. The two main end points thus far used in prostate cancer nomograms are the probability of organ-confined disease at radical prostatectomy (Partin tables)1 and the probability of PSA failure after prostatectomy, external-beam radiation therapy, or prostate brachytherapy.2,3 Proof that risk-group stratification correlates with cause-specific or overall survival is lacking.4 Approximately 42 different risk stratification models have been published, some of which are available on the Web site www.nomograms.org.5 In this issue of the Journal of Clinical Oncology, Kattan et al6 report a nomogram which is the first to include serum biomarkers other than PSA, in addition to clinical stage, Gleason score, and percentage or number of positive core biopsies. Correlative science investigations in prostate cancer implemented during the last 10 years are beginning to advance our basic knowledge of prostate tumorigenesis and to also influence therapy. Kattan et al6 analyzed a cohort of 714 radical prostatectomy patients; they report that plasma levels of interleukin 6 soluble receptor (IL6SR) and transforming growth factor beta1 (TGF-ß1) improved the ability to predict biochemical (PSA) progression together with standard clinical parameters. This hypothesis was generated from earlier reports in which IL6SR and TGF-ß1 were independent predictors of progression in 120 radical prostatectomy patients.7,8 Three critical questions should be asked. First, is the inclusion of these serum markers biologically plausible? Second, are the results conclusive? Third, will this be clinically useful? Research has linked IL6SR and TGF-ß1with prostate cancer pathogenesis. At present, there are 50 protein members of the cytokine family, which regulate diverse bodily functions including coordination of the immune system, hematopoiesis, and nerve and bone homeostasis.9 Although membrane-bound IL-6 receptor is only present on hepatocytes, monocytes, neutrophils, and some lymphocytes, a soluble form of IL-6 receptor can exert a wide variety of biologic effects, including tumor growth. IL6SR is formed either by alternative splicing or by shedding of the membrane-bound receptor; when IL6SR is complexed with IL-6 ligand it induces signaling through gp130, which is expressed by all body cells.10 In the context of prostate cancer, IL-6 signals through the tyrosine kinase receptors ErbB2/neu and ErbB3 and the ras/MAP kinase pathway, inducing ligand-independent activation of the androgen receptor.10 In the Kattan cohort, the levels of IL6SR correlated with tumor Gleason score and tumor volume, but not clinical stage, such as extraprostatic or seminal vesicle extension. TGF-ß1 levels were associated with local extension. In addition, after radical prostatectomy IL6SR and IL-6 levels decreased significantly in patients who had a sustained remission as well as in patients who eventually experienced a biochemical failure. As the authors suggest, the preoperative levels of IL6SR correlate with the potential to metastasize postoperatively rather than with microscopic systemic disease. The opposite was true of TGF-ß1 levels, which correlated with the presence of microscopic systemic disease at the time of prostatectomy.6 Thus, these results seem biologically plausible. Are the results conclusive? This work improves the ability to predict the surrogate end point of biochemical failure. The addition of IL6SR and TGF-ß1 to this preoperative nomogram improved the bootstrap-corrected area under the receiver operating curve from 0.75 to 0.83. This change represents an 8% improvement in the chance of the prediction that when two patients are randomly selected (one with progression and one with longer follow-up), the patient who progressed first had the worse prognosis. As the authors note, one limitation of their nomogram is that it is based on—and therefore only applies to— patients who have all ready decided to have a radical prostatectomy, which excludes all others with newly diagnosed, organ-confined disease. In addition, the nomogram only predicts outcome to 5 years, which is a short time period in the biology of prostate cancer. Importantly, the biochemical failure end point by itself is not a hard clinical end point such as metastasis or cancer-specific survival. To date only a posttreatment parameter at relapse, namely the PSA doubling time, seems to predict the likelihood of prostate cancer–specific death after biochemical failure.11 Although the addition of IL6SR and TGF-ß1 by themselves will likely not change practice patterns, such risk stratification may be useful for the design and interpretation of clinical trials, particularly in the neoadjuvant or adjuvant setting. These results of Katten will need to be validated before we can determine their accuracy. Will this nomogram be clinically useful? Clinicians have adopted and patients readily understand stratification into low-, intermediate-, and high-risk groups. The Kattan nomogram, although it is more quantitative than risk-group stratification, can be somewhat cumbersome to calculate as more variables are added, and may be perceived as less user friendly. Given the real but marginal improvement in predictive accuracy of this nomogram, the results do not justify the increased cost and patient inconvenience to measure these markers in all newly diagnosed prostate cancer patients at this time. At diagnosis, prostate tumors are biologically heterogeneous and the challenge is to develop predictive profiles of genomic or proteomic changes that may be more likely to correlate with clinical behavior than are single gene alterations.12,13 Information from profiling studies is starting to emerge but validation and integration into clinical practice remains a challenge. A recently published RNA expression profile predicted patient outcomes after prostatectomy,12 and proteomic profiling predicted the presence prostate cancer correctly in 36 of 38 patients and benign prostate conditions in 177 of 228 patients (78%).13 It is anticipated that the accuracy and clinical applicability of multivariable profiling will improve as more tumor samples from a variety of clinical stages are analyzed, and statistical methods evolve and become standardized. The next frontier will then be to translate the knowledge gained from basic cancer biology and clinical correlation into novel targeted therapeutics. We applaud Kattan et al for their ongoing efforts in risk stratification in prostate cancer. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Performed contract work within the past 2 years: Mary-Ellen Taplin, Abbott Laboratories. Received more than $2,000 a year from a company for either of the past 2 years: Mary-Ellen Taplin, Astra-Zeneca, Aventis. REFERENCES 1. Partin AW, Yoo J, Carter HB, et al: The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 150:110–114, 1993[Medline]
2. Kattan MW, Eastham JA, Stapleton AM, et al: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 90:766–771, 1998
3. D’Amico AV, Whittington R, Malkowicz SB, et al: Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer. J Clin Oncol 17:168–172, 1999 4. D’Amico AV, Moul J, Carroll PR, et al: Vital statistics following surgery or radiation for patients with clinically localized prostate cancer managed during the PSA era. Proc Am Soc Clin Oncol 22:381, 2003 (abstr 1528) 5. Ross P, Scardino P, Kattan MW: A catalog of prostate cancer nomograms. J Urol 165:1562–1568, 2001[CrossRef][Medline]
6. Kattan MW, Shariat SF, Andrews B, et al: The addition of interleukin-6 soluble receptor and transforming growth factor beta1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer. J Clin Oncol 21:3573–3579, 2003 7. Shariat SF, Andrews B, Kattan MW, et al: Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis. Urology 58:1008–1015, 2001[CrossRef][Medline]
8. Shariat SF, Shalev M, Menesses-Diaz A, et al: Preoperative plasma levels of transforming growth factor beta1 (TGF-beta1) strongly predict progression in patients undergoing radical prostatectomy. J Clin Oncol 19:2856–2964, 2001 9. Jones SA, Rose-John S: The role of soluble receptors in cytokine biology: The agonistic properties of the sIL-6R/IL-6 complex. Biochim Biophys Acta 1592:251–263, 2002[Medline] 10. Kallen KJ: The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases. Biochim Biophys Acta 1592:323–343, 2002[Medline]
11. D’Amico AV: Predicting prostate-specific antigen recurrence established: Now, who will survive? J Clin Oncol 20:3188–3190, 2002 12. Singh D, Febbo PG, Ross K, et al: Gene expression correlates of clinical prostate cancer behavior. Cancer Cell 1:203–209, 2002[CrossRef][Medline]
13. Petricoin ER, Ornstein DK, Paweletz CP: Serum proteomic patterns for detection of prostate cancer. J Natl Cancer Inst 94:1576–1578, 2002
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
