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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3445-3450 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.7661 Aggressiveness of Familial Prostate Cancer
From the Glickman Urological Institute and Radiation Oncology Department, Cleveland Clinic Foundation, Cleveland, OH; and the Radiation Oncology Department, M.D. Anderson Cancer Center Orlando, Orlando, FL Address reprint requests to Patrick A. Kupelian, MD, Department of Radiation Oncology, M.D. Anderson Cancer Center Orlando, 1400 S Orange Avenue, Orlando, FL 32806; e-mail: patrick.kupelian{at}orhs.org
PURPOSE: To report on the aggressiveness of sporadic versus familial prostate cancer.
PATIENTS AND METHODS: The study sample consisted of 4,112 stage T1-3 prostate cancer patients. The outcome of interest was biochemical relapse-free survival (bRFS). The analysis was performed for two distinct time periods, 1986 to 1992 (year
RESULTS: A positive family history (FH positive) was reported in 16%. The 10-year bRFS rates for patients with negative family history (FH negative) versus FH positive were 59% and 63%, respectively (P = .90). However, in the year CONCLUSION: Family history was an independent predictor of biochemical failure only early in the PSA era, and men with an FH positive presented with more favorable disease later in the PSA era. This suggests that with stage migration and improved therapy, the impact of family history on prognosis has become minimal. However, underlying genetic factors affecting prostate cancer behavior in individuals with familial prostate cancer may still be important in determining individual prognosis.
Several studies including patient cohorts from early in the prostate-specific antigen (PSA) era have suggested that patients with familial prostate cancer, as defined by an affected first-degree relative, have a worse prognosis than sporadic disease.1-3 However, a number of subsequent reports in patients with localized disease treated with either radiotherapy or surgery failed to confirm these findings.4-10 There is evidence that the genetic makeup of prostate cancer might play a role in the clinical behavior of the disease.11-16 With the recognition that men with a positive family history are at a higher risk of developing prostate cancer, came the recommendation that they be screened at an earlier age; the potential for a clinical and pathologic stage migration that could favorably influence prognosis was also recognized. In this report, we re-examine our initial finding that a positive family history of prostate cancer in men with clinically localized disease portends a worse prognosis after treatment with radiation or surgery,1,2 and examine the effect of earlier screening and PSA-induced stage migration on family history as a prognostic variable.
The study sample consisted of a total of 4,112 stage T1-3 cancer patients treated consecutively at the Cleveland Clinic Foundation (Cleveland, OH) between 1986 and 2002 with either radical prostatectomy (RP) or radiation therapy (RT). All patients had available pretreatment PSA (iPSA) level and biopsy Gleason score (GS), no adjuvant radiotherapy after RP, no adjuvant or neoadjuvant androgen deprivation for more than 6 months, and a minimum follow-up of 2 years. The clinical T stage for all patients was determined using the 1992 American Joint Committee on Cancer clinical staging system.17 Staging by bone scan and computerized tomograms of the abdomen and pelvis were obtained according to individual physician preference. RP was the treatment in 1,971 patients (48%), and RT was the treatment in 2,141 patients (52%). Of the 2,141 patients who received RT, 573 (27%) were treated with a permanent seed implant, 550 (26%) were treated with conventional external-beam radiotherapy, and 1,018 (47%) were treated with conformal external-beam radiotherapy, either with a three-dimensional or intensity-modulated technique. Hormonal therapy for 6 months or less was used in 24% of cases. For all patients, family history was evaluated at the time of presentation as part of the initial patient evaluation. A positive family history was recorded when the index patient confirmed the diagnosis of prostate cancer in a first-degree relative, defined as a brother or father. The patient's demographic, clinical, pathologic, treatment, and follow-up information was recorded prospectively in a database approved by the institutional review board and compliant with Health Insurance Portability and Accountability Act. The main outcome of interest was biochemical relapse-free survival (bRFS). We defined biochemical relapse as an increase in PSA greater than 0.2 ng/mL after RP, and three consecutive increasing levels after RT.18 We obtained follow-up information, including PSA levels, from medical records, tumor registry data, or from contact with patients or outside physicians or hospitals. Follow-up information always included PSA levels, and a total of 35,831 follow-up PSA levels were available for and included in this analysis (average, nine per patient). The median follow-up was 65 months (range, 24 to 109 months). The numbers of patients observed up to 5, 10, and 15 years after treatment were 1,614, 228, and 11, respectively. Follow-up PSA levels were typically obtained every 6 to 12 months.
To study the effect of family history on treatment outcome, Kaplan-Meier survival curves were calculated and the log-rank test statistic was used to test for statistically significant differences between curves. Proportional hazards multivariate time-to-failure analysis was then used to adjust for the potential confounders of clinical stage (cT1-2A v cT2B-C), biopsy GS (continuous), iPSA (continuous), age (continuous), treatment modality (RP v RT), use of androgen deprivation therapy (yes v no), and year of therapy (continuous). The multivariate analysis was performed separately for patients treated in two distinct time periods, 1986 to 1992 (year
Sixteen percent of all patients reported a positive family history of prostate cancer. Table 1 lists the frequency distribution of demographic, clinical, and treatment factors of patients with a positive versus negative family history. There was no association between the presence of a family history of prostate cancer and any of these characteristics except age, for which those with a positive family history presented at a younger age (median, 64 v 66 years; P = .017). Table 2 shows the frequency of risk groups as defined by biopsy GS, clinical T stage, and PSA at diagnosis among patients with positive versus negative family history in the two different time periods (1986 to 1992 v 1993 to 2002). Risk groups were defined as either low risk (stage T1C-2A, PSA  10, and GS 6), intermediate risk (stage T2B, or PSA > 10 and 20, or GS 7), or high risk (stage T2Cm or PSA > 20, or GS  8).22 Patients with a positive family history diagnosed in the year 1992 period had 48% high-risk disease, versus only 23% in the year 1993 period (P < .001).
Figure 1 shows the bRFS curves for all patients with respect to a family history of prostate cancer. The bRFS 10-year rate was 60%. The 10-year bRFS rates for patients with a negative family history versus a positive history were 59% and 63%, respectively (P = .90). However, in patients treated in the year 1992 period, the 10-year bRFS rates for patients with a negative family history versus a positive history were 45% and 34%, respectively (P = .015). In patients treated in the year 1993 period, the 10-year bRFS rates for patients with a negative family history versus a positive history were 61% and 67%, respectively (P = .54). In the multivariate analysis (Table 3) family history was not an independent predictor of biochemical relapse (P = .42). However, for patients treated in the year 1992 period, family history was an independent predictor of biochemical relapse (hazard ratio, 1.43; P = .038), in addition to iPSA (P < .001) and GS (P < .001). In the subset of patients treated in the year 1993 period, the multivariate analysis failed to reveal family history of prostate cancer as an independent predictor of biochemical relapse (P = .89). The overall clinical relapse-free survival rate at 10 years was 90%. As shown in Figure 2 A, for patients with a family history of prostate cancer, the clinical relapse-free survival rate at 10 years was 88% v 90% for patients with a negative family history (P = .21). However, for patients treated in the year 1992 period, the 10-year clinical relapse-free survival rates for patients with a negative family history versus a positive history were 78% and 62%, respectively (P = .019; Fig 2B). In patients treated in the year 1993 period, the 10-year clinical relapse-free survival rates for patients with either negative or positive family history were identical at 93% (P = .75; Fig 2C). On multivariate analysis, clinical T stage, iPSA, GS, and family history of prostate cancer were still independent predictors of clinical disease-free survival for patients treated in the year 1992 period (hazard ratio,1.61; P = .044).
Familial prostate cancer has been defined as the occurrence of the cancer in a patient with an affected first-degree relative. Approximately 10% to 20% of patients with localized prostate cancer are reported to present with a positive family history of prostate cancer. Although it has been clearly described as a finding most common in younger versus older men, there is still significant controversy about the importance of the presence of a positive family history of prostate cancer with respect to presentation and prognosis. At the genetic level, there has been some evidence of differences between sporadic and familial prostate cancer. Paris et al15 described an allelic imbalance at 16q23 that was correlated with a positive family history of prostate cancer. Neville et al13 described an allelic imbalance in a region at 7q32-33, an area correlated with more aggressive prostate cancer, which is associated with a positive family history of prostate cancer. Haeusler et al11 reported the association of a specific haplotype of the CAV1 gene, located at 7q31-33, linked to aggressive cancers in some families. The initial clinical observations of familial prostate cancer having an impact on prognosis came from two separate sources, both reported in 1997. One was from a prospective epidemiologic study reported by Rodriguez et al3 in a cohort of 481,011 men enrolled in 1982. During 9 years of follow-up, 1,922 deaths from prostate cancer had been observed, and a family history of prostate cancer predicted death from prostate cancer with a relative risk of 1.60. The strength of this study is that the end point was mortality from prostate cancer (and not biochemical failure—PSA rise) and the patient population was not limited to those with localized disease. Conversely, this cohort was recruited and diagnosed in the pre-PSA era. The other source was a retrospective analysis of patients from the Cleveland Clinic, a subset of the patients analyzed in the current report.1,2 Patients with localized disease and familial prostate cancer were found to have a worse outcome compared with patients with sporadic disease, independently from other well-known prognosticators such as T stage, GS, and pretreatment PSA levels. The group of patients analyzed in those series was diagnosed and treated early in the PSA era. However, several subsequent reports from different institutions failed to confirm these findings.4-10 In all of these later reports, familial prostate cancer did not exhibit any different behavior compared with sporadic prostate cancer. In an attempt to reconcile these observations, a larger cohort of patients spanning a long time period (1986 to 2002) was studied for differences in outcomes between familial and sporadic prostate cancers. It is important to note several issues that can affect observations on outcomes after treatment of localized disease in the context of a positive family history. First is the end point itself. In patients with localized prostate cancer, treatment with either surgery or radiotherapy results in relatively fewer failures than observed in the pre-PSA era and in the early versus later PSA era. Biochemical failures are the most common failure event, and as seen in Figures 2B versus 2C, the relative numbers of events have gradually dropped. With patients diagnosed and treated today, approximately 20% of all patients with localized disease are expected to experience failure after therapy long-term, versus approximately 50% in patients diagnosed and treated in the late 1980s. The lower failure rate in more recently treated patients could mask a small but significant effect of family history on outcome and make differences more difficult to detect. Second, the realization that a family history of prostate cancer increases the risk of developing prostate cancer has led to the recommendation of more aggressive screening for prostate cancer in men with a positive family history. Men with positive family history may therefore seek screening at a younger age, resulting in diagnosis at a more favorable stage. This could potentially result in relatively more favorable presentations of the disease in men with a family history of prostate cancer, thereby potentially offsetting the possible more aggressive nature of familial prostate cancers. The change in the presentation of localized prostate cancer patients in the context of a family history of prostate cancer can be seen in the report from Marotte et al.20 They reported on a series of 559 men with localized prostate cancer treated with radical prostatectomy, comparing presentation parameters in the period from 1989 to 1992 versus 1993 to 2000. From 1989 to 1992, there was no statistical difference between patients with a family history and those without a family history with respect to age, preoperative PSA, PSA density, clinical or pathologic stage, GS, or total tumor volume. However, after 1992, patients with a positive family of prostate cancer tended to be younger than the patients with a negative family history, and to have a lower PSA at the time of diagnosis. The authors comment that these differences are predominantly driven by more aggressive screening in patients with a family history of prostate cancer rather than any true genetic differences. In a follow-up study on the same study population, the authors also noted that patients with a positive family history had lower preoperative PSA levels, lower grades at the final pathologic evaluation of the prostatectomy specimens, and actually had a lower rate of biochemical/clinical recurrence compared with patients with a negative family history.21 The authors concluded that the better outcomes observed in patients with a positive family history could be related to the earlier age at diagnosis and more favorable features at presentation. This suggests that early diagnosis and the known pretreatment prognostic factors such as pretreatment PSA and GS are prominent predictors of biochemical/clinical recurrence, and potentially can obscure any aggressive features of familial prostate cancers. The current study with longer follow-up confirms our initial observation of the more aggressive behavior of familial prostate cancer in men diagnosed early in the PSA era. However, it also demonstrates that in a more modern series of prostate cancer patients, familial prostate cancer does not appear to behave more aggressively than sporadic disease. In the final analysis, the importance of any difference in the clinical behavior of familial prostate cancer seems small in patients diagnosed and treated in more recent years. The more important aspect of this issue is the potential difference in the genetic makeup of prostate cancer in men with sporadic versus familial prostate cancer. If identified, such genetic factors could lead to significant advances in our understanding of not only the development of prostate cancers, but also their clinical behavior.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Kupelian PA, Klein EA, Witte JS, et al: Familial prostate cancer: A different disease? J Urol 158:2197-2201, 1997[CrossRef][Medline] 2. Kupelian PA, Kupelian VA, Witte JS, et al: Family history of prostate cancer in patients with localized prostate cancer: An independent predictor of treatment outcome. J Clin Oncol 15:1478-1480, 1997[Abstract] 3. Rodriguez C, Calle EE, Miracle-McMahill HL, et al: Family history and risk of fatal prostate cancer. Epidemiology 8:653-657, 1997[CrossRef][Medline] 4. Azzouzi AR, Valeri A, Cormier L, et al: Familial prostate cancer cases before and after radical prostatectomy do not show any aggressiveness compared with sporadic cases. Urology 61:1193-1197, 2003[CrossRef][Medline] 5. Bauer JJ, Srivastava S, Connelly RR, et al: Significance of familial history of prostate cancer to traditional prognostic variables, genetic biomarkers, and recurrence after radical prostatectomy. Urology 51:970-976, 1998[CrossRef][Medline] 6. Gronberg H, Damber L, Tavelin B, et al: No difference in survival between sporadic, familial and hereditary prostate cancer. Br J Urol 82:564-567, 1998[Medline] 7. Hanlon AL, Hanks GE: Patterns of inheritance and outcome in patients treated with external beam radiation for prostate cancer. Urology 52:735-738, 1998[CrossRef][Medline] 8. Hanus MC, Zagars GK, Pollack A: Familial prostate cancer: Outcome following radiation therapy with or without adjuvant androgen ablation. Int J Radiat Oncol Biol Phys 43:379-383, 1999[CrossRef][Medline] 9. Sacco E, Prayer-Galetti T, Pinto F, et al: Familial and hereditary prostate cancer by definition in an Italian surgical series: Clinical features and outcome. Eur Urol 47:761-768, 2005[CrossRef][Medline] 10. Valeri A, Azzouzi R, Drelon E, et al: Early-onset hereditary prostate cancer is not associated with specific clinical and biological features. Prostate 45:66-71, 2000[CrossRef][Medline] 11. Haeusler J, Hoegel J, Bachmann N, et al: Association of a CAV-1 haplotype to familial aggressive prostate cancer. Prostate 65:171-177, 2005[CrossRef][Medline] 12. Neville PJ, Conti DV, Krumroy LM, et al: Prostate cancer aggressiveness locus on chromosome segment 19q12-q13.1 identified by linkage and allelic imbalance studies. Genes Chromosomes Cancer 36:332-339, 2003[CrossRef][Medline] 13. Neville PJ, Conti DV, Paris PL, et al: Prostate cancer aggressiveness locus on chromosome 7q32-q33 identified by linkage and allelic imbalance studies. Neoplasia 4:424-431, 2002[CrossRef][Medline] 14. Ohtake N, Hatori M, Yamanaka H, et al: Familial prostate cancer in Japan. Int J Urol 5:138-145, 1998[Medline] 15. Paris PL, Witte JS, Kupelian PA, et al: Identification and fine mapping of a region showing a high frequency of allelic imbalance on chromosome 16q23.2 that corresponds to a prostate cancer susceptibility locus. Cancer Res 60:3645-3649, 2000 16. Sigurdsson S, Thorlacius S, Tomasson J, et al: BRCA2 mutation in Icelandic prostate cancer patients. J Mol Med 75:758-761, 1997[CrossRef][Medline] 17. Han M, Walsh PC, Partin AW, et al: Ability of the 1992 and 1997 American Joint Committee on Cancer staging systems for prostate cancer to predict progression-free survival after radical prostatectomy for stage T2 disease. J Urol 164:89-92, 2000[CrossRef][Medline] 18. Consensus statement: Guidelines for PSA following radiation therapy: American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 37:1035-1041, 1997[CrossRef][Medline] 19. Klein EA, Kupelian PA, Witte JS: Does a family history of prostate cancer result in more aggressive disease? Prostate Cancer Prostatic Dis 1:297-300, 1998[CrossRef][Medline] 20. Marotte JB, Ferrari MK, McNeal JE, et al: Time trends in pathologic features of radical prostatectomy: Impact of family history. Urol Oncol 22:169-173, 2004[Medline] 21. Lee KL, Marotte JB, Ferrari MK, et al: Positive family history of prostate cancer not associated with worse outcomes after radical prostatectomy. Urology 65:311-315, 2005[CrossRef][Medline] 22. D'Amico AV: How to compare results after surgery or radiation for localized prostate carcinoma. Cancer 95:2041-2043, 2002[CrossRef][Medline] Submitted January 17, 2006; accepted May 5, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
