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Loss of p16 Expression Is of Prognostic Significance in Locally Advanced Prostate Cancer: An Analysis From the Radiation Therapy Oncology Group Protocol 86–10

A. Chakravarti, K. Heydon, C.L. Wu, E. Hammond, A. Pollack, M. Roach, H. Wolkov, P. Okunieff, J. Cox, J. Fontanesi, R. Abrams, M. Pilepich, W. Shipley

From the Radiation Therapy Oncology Group (RTOG) Genitourinary Translational Research Program, representing: Massachusetts General Hospital/Harvard Medical School Department of Radiation Oncology; RTOG Headquarters, Massachusetts General Hospital/Harvard Medical School, Department of Pathology, Boston, MA; Latter-Day Saints Hospital Department of Pathology, Salt Lake City, UT; and the departments of radiation oncology of: Fox Chase Cancer Center, Philadelphia, PA; University of California, San Francisco, San Francisco, CA; Sutter Cancer Center, Sacramento, CA; University of Rochester, Rochester, NY; M.D. Anderson Cancer Center, Houston, TX; Harper Hospital, Detroit, MI; Johns Hopkins Hospital, Baltimore, MD; and St. Joseph Mercy Hospital, Ann Arbor, MI.

Address reprint requests to Arnab Chakravarti, MD; Massachusetts General Hospital, Deparment of Radiation Oncology, 100 Blossom Street, Founders House, Room 536, Boston, MA 02114; email: achakravarti{at}partners.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: The retinoblastoma (RB) cell cycle regulatory pathway is known to be deregulated in virtually all known human tumors. The protein product of the RB gene, pRB, and its upstream regulator, p16, are among the most commonly affected members of this pathway. We investigated the prognostic significance of both pRB and p16 expression in locally advanced prostate cancers, from patients treated on the Radiation Therapy Oncology Group (RTOG) protocol 86–10.

Materials and Methods: Sixty-seven cases from RTOG 86–10 had immunohistochemically stained slides, judged interpretable for both p16 and pRB, available for analysis. Median follow-up was 8.9 years (range, 6.0 to 11.8 years) for surviving patients. Staining for each marker was then correlated with overall survival, local progression, distant metastasis, and disease-specific survival.

Results: Loss of p16 expression, as defined by expression was significantly associated with reduced overall survival (P = .039), disease-specific survival (P = .006), and higher risk of local progression (P = .0007) and distant metastasis (P = .026) in the univariate analysis. In the multivariate analysis, loss of p16 was significantly associated with reduced disease-specific survival (P = .0078) and increased risk of local failure (P = .0035) and distant metastasis (P = .026). A borderline association with reduced overall survival (P = .07) was also evident. Loss of pRB was associated with improved disease-specific survival on univariate (P = .028) and multivariate analysis (P = .043), but carried no other significant outcome associations.

Conclusion: Loss of p16 is significantly associated with adverse clinical outcome in cases of locally advanced prostate cancer.

	INTRODUCTION

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THE RETINOBLASTOMA protein (pRB) tumor suppressor pathway has been found to be deregulated in virtually all human tumor types.^1,2 The known functions of this pathway are to regulate the G1/S cell cycle checkpoint to prevent uncontrolled cellular proliferation. It has been more recently found that the pRB pathway plays an important role in apoptosis and transcriptional regulation.³ Deregulation of the pRB pathway may occur at the level of pRB itself or at the level of upstream regulators of pRB, which include the cyclin-dependent kinases (CDK) and CDK inhibitors such as p16. In the present model, CDKs can lead to phosphorylation of pRB, which, in turn, leads to its dissociation from E2F family members. Free E2F can stimulate cell proliferation, which is a hallmark of most known human tumors. CDK inhibitors such as p16 can inhibit phosphorylation of pRB, thereby preserving the integrity of the G1/S checkpoint and also suppressing the transcriptional program involved in cellular proliferation.

As loss of pRB and p16 function by gene deletion, mutation, or loss of heterozygosity are quite common in human tumors and have important functional implications, we investigated whether loss of expression of these proteins, as determined immunohistochemically, was associated with adverse clinical outcome in cases of locally advanced prostate cancer. Patients in this study were treated on the Radiation Therapy and Oncology Group (RTOG) protocol 86–10, a phase III trial that randomly assigned patients with locally advanced prostate cancers (T2-T4) without evidence of distant metastasis to receive goserelin (3.6 mg) every 4 weeks and flutamide (250 mg) three times a day for 2 months before radiation therapy and during radiation therapy or radiation therapy alone.⁴ The study opened on April 15, 1987 and closed on June 1, 1991 with a total of 471 patients; 456 of the patients were analyzed. Results from the trial demonstrated a significant reduction in local progression and a prolongation of progression-free survival for the patients receiving neoadjuvant hormonal therapy.

	MATERIALS AND METHODS

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Study Population
For this analysis, a subset of patients entered in RTOG 86–10 who had sufficient pathologic material available was studied. Diagnostic material (from needle biopsies or transurethral resections) was reviewed centrally for 461 (98%) of the 471 patients, and the tumors were graded according to the Gleason criteria.⁵ Tissue blocks were requested from participating institutions (>100) at the time of central pathology review for all cases that were reviewed. Pretreatment serum prostatic-specific antigen (PSA) determinations were available for less than 15% (10/67) of the patients considered in this study and hence PSA was not used as an outcome parameter in this study.

Tissue Array
For this study, paraffin blocks of formalin fixed tumor tissue were used to create a tumor tissue array. The paraffin blocks were used to prepare a Hematoxylin and Eosin stained slide. This slide was reviewed by one of the investigators (E.H.) to select regions of invasive tumor without inflammation or necrosis. Regions with such tumor areas were outlined with a cytology marking pen. The tissue array was created using published method and stylus of 0.6 mm. Punches were arrayed in rows with locations designated by ink impregnated lung tissue at upper left and lower right corners. After creation, array was stained with Hematoxylin and Eosin to confirm that the punches contained tumor. Subsequent sections for use in immunohistochemistry were cut at 4 microns onto Superfrost "Plus" slides (Allegiance Healthcare Corp, McGaw Park, IL). Control tissues for each reaction are also cut onto the array slide, so that positive control and tissue array are simultaneously stained.

Immunohistochemical Technique
For immunohistochemistry, the tissue array was routinely deparaffinized. Antigen retrieval was accomplished using citrate buffer pretreatment at pH 6.0 with heating and cooling in a pressure cooker for 50 minutes. After antigen retrieval, samples were placed on an autostainer (DakoCytomation, Glostrup, Denmark) and incubated with antibody directed against p16 (Santa Cruz Biotechnology Inc, Santa Cruz, CA; 1:100 dilution for 10 minutes) or pRB (DakoCytomation; 1:100 dilution for 20 minutes), LSAB 2 kit (DakoCytomation) and diaminobenzidine as an enzyme substrate. The negative control was a similarly processed tissue array processed with omission of the p16 or pRB antibody incubation, respectively. The positive control for p16 was a positively staining case of fibromatosis. The positive control for pRB was a positively staining section of hyperplastic prostate tissue. After staining, the slides were counterstained with Hematoxylin and coverslipped and evaluated.

Definition of End Points
The four end points used in the analysis of p16 and pRB were overall survival, disease-specific survival, local progression, and distant metastasis. Overall survival and distant metastasis were defined as in the initial treatment report (Pilepich et al⁴). For disease-specific survival, failure was defined as death due to prostate cancer, protocol treatment toxicity, or unknown cause of death with active disease. Local progression was defined as an increase in tumor size of more than 50% for cases where complete tumor regression did not occur, or recurrence of a palpable nodule when there was complete regression or a positive biopsy of the prostate after 2 or more years of follow-up. Distant metastasis was defined as clinical or radiologic evidence of disease outside the pelvis. Overall and disease-specific survival time was measured from the date of randomization to the date of death or last follow-up date if the patient did not fail. Time to local progression and distant metastasis were measured from the date of randomization to the date of failure, death (competing event), or the last date of assessment for specific disease progress, if the patient did not fail (censored).

Statistical Analysis
The analysis was performed using the 456 eligible and assessable patients with follow-up. Of those patients, 67 had both p16 and pRB determinations available. As of June 30, 2000, the median follow-up of the living patients in the study cohort (N = 67) is 8.9 years (range, 6 to 11.8 years). The first failure events reported were as follows: 13 local failures only, 23 distant failures, five both local and distant, and 10 deaths unrelated to prostate cancer. Of the 13 patients with first local failures, seven developed a subsequent distant failure. Of the 23 patients with first distant failures, four developed a subsequent distant failure. There were 46 deaths at the time of analysis, and 24 were attributable to prostate cancer. The distributions of patient characteristics and treatment assignments were compared by the Pearson ² test with the Yates correction factor.

Using an independent data set of 50 patients, univariate analyses were performed on both p16 and pRB to determine the best cut-point, simultaneously evaluating all four end points. Univariate comparisons using the log-rank test were performed to evaluate various cutpoints for both p16 and pRB in this independent data set. For p16, we examined the median (39), 25% quartile (25), and 75% quartile (61). We also considered a cut point of 20 based on previously published results.⁶ The univariate analysis showed that p16 (> 25 v 25) was significantly associated with all four end points and was adopted as the cut point for further analysis. The cut point of 20 was only significant for the end point of local progression for p16. Further, there was biologic rationale for selection of the cutpoint of 25% for p16, as it was determined that ~25% of these 50 cases in the independent data set demonstrated p16 gene deletion or promoter hypermethylation, which represent common underlying mechanisms of p16 protein loss. For pRB, we chose a similar approach to cut point analysis. The 25% quartile (1), the median (5), and the 75% quartile (15) were evaluated. pRB failed to show any significant association between outcome and any of the cut points tested. However, it was determined in the independent data set that 20% of cases demonstrated either RB gene deletion, loss of heterozygosity, or mutation. Further, the cutpoint of 20% for pRB has been previously reported.^7,8 Given the genomic data of RB inactivation as well as previously reported data, it was decided to adopt 20% as a cut point for pRB analysis.

Once the best cut-point was determined (using an unadjusted P value), univariate analyses of all four end points were performed. Univariate comparisons of time related end points were made using the log-rank test (Mantel). Overall survival was estimated by the Kaplan-Meier method⁹ and the log-rank statistic was used to test for differences.¹⁰ Because disease-specific (prostate cancer) survival, local progression, and distant metastasis are a cause-specific failure and patients could die without failing, we also performed the cumulative incidence function¹¹ and used the Gray’s test to test for differences.¹²

Usual multivariate Cox proportional hazard models were generated to evaluate overall survival for both p16 and pRB.¹³ The other end points were evaluated using a proportional hazard model for the subdistribution of a competing risk.¹⁴ The models were used to determine if p16 had prognostic value after adjusting for initial treatment, Gleason score, tumor stage, and age. All factors were considered as dichotomous variables and coded as follows: protocol treatment (0, radiotherapy [RT] alone v 1, RT + hormones); grouped Gleason score (0, score 2 to 6 v 1, score 7 to 10); stage (0, T2 v 1, T3); p16 (0, > 25 v 1, 25); pRB (0, > 20 v 1, 20); and, in the overall survival model, age (0, < = 75 v 1, > 75). The parameter from the fitted model is used to estimate the relative risk associated with each prognostic variable and corresponding 95% confidence interval. A ratio of 1 would indicate no difference between the two subgroups. The bigger the difference from 1, the greater is the difference in the failure rates between the two subgroups. The treatment effect was modeled in such a way that a value less than 1 favored the addition of hormones. All the statistical comparisons were made with two-tailed tests.

	RESULTS

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Pathologic Correlates of p16 and pRB Immunostaining
Tissue blocks were obtained from 261 (55%) of the 471 patients entered in RTOG 86–10. It was found that sufficient tumor material for interpretation of p16 and pRB staining was available for 67 patients. Pretreatment characteristics of the 456 assessable patients with or without p16/pRB determinations are shown in Table 1. Patients with determined p16/pRB data had tumors with a higher Gleason score (P = .08) and a higher clinical stage (P = .03). In addition, patients with determined p16/pRB data had a higher percentage of patients enrolled on the RT-alone treatment arm (RT alone, 56%, v RT + hormone therapy [HT], 44%). The differences with the four end points between the two groups are shown in Table 2. The patients with the determinations had a tendency towards poorer outcomes with the exception of local progression.

View this table: [in this window] [in a new window]   Table 3. Distribution of Patients With p16/pRB Data by p16 ( 25 v > 25) (N = 67)

View larger version (17K): [in this window] [in a new window]   Fig 1. Association of Gleason score by (A) p16 and (B) pRB immunostaining. No significant association is revealed between p16 (P = .35) and pRB (P = .45), respectively, with Gleason score.

View larger version (144K): [in this window] [in a new window]   Fig 2. Representative stained slides for p16 and pRB. (A) p16 negative immunostaining; (B) p16 positive immunostaining; (C) pRB negative immunostaining; (D) pRB positive immunostaining.

View larger version (16K): [in this window] [in a new window]   Fig 3. Adverse outcome in prostate cancer patients with tumors demonstrating p16 loss. These survival curves demonstrate loss of p16 expression is significantly associated with (A) overall survival by p16 (P = .039); (B) disease-specific survival by p16 (P = .006); (C) local progression by p16 (P = .0007); and (D) distant metastasis by p16 (P = .026).

	DISCUSSION

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According to the current paradigm of the pRB-E2F pathway, it would be predicted that loss of p16 and pRB would result in similar effects. In this light, the observed differences in predictive value between loss of expression of p16 and pRB in cases of locally advanced prostate cancer are intriguing. These observations suggest that p16 and pRB functions may not be entirely redundant in prostate cancer cells, and, indeed, there is increasing evidence supporting this possibility.^15,16

It must also be considered that the CDKN2A locus that houses coding sequences for not only p16, but also for p14^ARF. p14^ARF has been found to prevent mdm2-mediated degredation of p53.¹⁷ Since p16 loss has been associated with homozygous deletion of the CDKN2A locus, if this were to be the underlying mechanism for the observed loss of p16 in locally advanced prostate cancer, two critical pathways would be concomittantly disrupted: the pRB and p53 pathways (via loss of p14^ARF). Simultaneous inactivation of both of these critical regulatory pathways may explain the worse outcome observed with p16, as opposed to pRB loss.

Second, these findings are of potential clinical significance as loss of p16 was significantly associated with adverse outcome. There is increasing data that loss of p16 may be of prognostic value in a variety of different tumor types.^16,18–22 Intriguingly, a recent study reported that p16 overexpression, in contrast to p16 loss, was associated with adverse prognosis in prostate cancer. In contrast to our study, Jarrad et al⁶ examined the prognostic value of p16 expression in prostate cancer patients treated by radical prostatectomy, not by radiotherapy. Further, the Jarrad study included predominantly patients with early-stage disease (~76% with cT1 tumors), whereas in our study, patients had predominantly locally advanced disease (~81% with cT3 disease). Hence, these conflicting results could be secondary to differences in treatment and patient population.

In our study, it is notable that p16 loss remained significantly associated with increased risk of local progression and distant metastasis in the multivariate analysis, even when other important pretreatment characteristics such as Gleason grade and clinical T-stage were taken into account. The increased risk of local failure in p16-negative tumors suggests that these tumors may be more treatment-resistant (radiation ± hormone therapy) than their p16-positive counterparts. Again, it is unclear whether this is directly attributable to p16 loss or whether concomitant loss of p14^ARF is the actual underlying cause.

The strong association between p16 loss by immunostaining and the subsequent development of distant metastasis is also intriguing and raises interesting clinical possibilities. It has been recently found that over 50% of patients with pathologically organ-confined disease had evidence of microscopic spread of disease to the bone marrow.²³ Given that a substantial percentage of patients who are staged M0 at initial diagnosis will have progression with distant metastasis at 15 years,^24–28 it is important to identify these high-risk patients since systemic therapy has potential value in eradicating micrometastatic disease. Although Gleason grade in its extremes does predict for distant metastasis, the vast majority of patients present with moderately differentiated tumors, which may represent a niche where a potential predictive marker like p16 may be most useful. If p16 immunostaining does, indeed, have predictive value over that of Gleason grade alone, as this study suggests, then it may have potential to be an independent prognostic marker of significance.

Future studies are currently planned by the RTOG to validate this data on a larger patient population. Ideally, its predictive value must be tested not only in the context of current pretreatment parameters (eg, Gleason grade, PSA, T-stage), but also in the context of other molecular markers of potential significance.^16,29,30 Understanding the precise mechanisms by which loss of p16 leads to enhanced rates of local progression and distant metastasis may also ultimately lead to the development of more effective molecular-based therapies that can enhance the effects of conventional agents in the management of patients with locally advanced prostate cancers.

	NOTES

 
This study was supported by RTOG U10 CA21661, CCOP U10 CA37422, and Stat U10 CA32115 grants from the National Cancer Institute (NCI). The contents of this manuscript are the sole responsibility of the authors and do not necessarily represent the official views of the NCI.

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Submitted December 26, 2002; accepted June 18, 2003.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chakravarti, A. Articles by Shipley, W. Search for Related Content PubMed PubMed Citation Articles by Chakravarti, A. Articles by Shipley, W.