Of 172 men with localized prostate cancer, 40% had high grade tumors and 19% had tumor volume greater than 25% (). During 28 years of follow-up, 40 men died of cancer (N=39) or were alive with bone metastases (N=1); 49 were long-term survivors who lived >10 years after their diagnosis without development of metastases; and 83 died of causes other than prostate cancer. Mean follow-up to development of metastatic disease was 7.6 years (range 0.1–27.1), and from metastasis to death was 2.0 years.
Characteristics of Örebro Watchful Waiting Cohort, 1977–2005
Men classified as having a lethal disease tended to have tumors with higher Gleason grade, higher nuclear grade, and greater tumor extent than men with the indolent phenotype (). Men with lethal phenotype were also more likely to have fusion positive tumors. Men classified as indeterminate had clinical characteristics between lethal and indolent phenotypes, reflecting in this group a mixture of men with indolent and those who would have developed lethal disease if they lived long enough.
Expression of Jagged1 and MTA1 were most strongly correlated with expression of other markers, showing correlation coefficients of 0.3 to 0.4 for positive correlations and −0.3 to −0.4 for inverse correlations; no one marker was correlated with all others. We evaluated each specific marker to predict prostate cancer death, adjusted for clinical parameters. The strongest molecular predictors (HR, 95% CI) of prostate cancer death were MTA1 (3.4, 1.2–9.2), p63 (1.8, 0.8–4.2), jagged1 (1.8, 0.7–4.5) and ABP280 (1.6, 0.7–3.6). Interestingly, these markers were among the strongest discriminators of metastatic vs. localized disease in the publication by Bismar et al (15
Using the molecular markers, the age-adjusted hazard ratio of prostate cancer death increased with increasing risk group classification, with a 16-fold increased risk of cancer death comparing the highest versus lowest risk groups (). The multigene signature remained a significant predictor of lethal prostate cancer even controlling for clinical parameters: the hazard ratio of developing lethal disease was 12.3 (95% CI 1.5–100.7) comparing extreme risk groups, and there was increased risk for all risk categories compared to the lowest (p for trend = 0.0015). Moreover, the molecular signature was a significant predictor of lethal disease among men with low grade (Gleason score 4–6) tumors (HR = 16.9, p=0.007).
The multigene model as a predictor of lethal prostate cancer: alone and in combination with clinical data, Örebro Watchful Waiting Cohort 1977–2005
Gleason grade, tumor volume and nuclear grade were each independent predictors of prostate cancer prognosis. Men classified as highest risk based on the clinical markers were 13 times (95% CI 4.3–40.5) more likely to die of prostate cancer compared to the lowest risk group (). Interestingly, among men characterized as low or intermediate risk based on clinical parameters, the multigene signature could further stratify who would have good or bad prognosis (p for trend 0.028).
While both the molecular and clinical signatures independently predicted lethal phenotype, the best discrimination came from a score combining the multigene and clinical information. No man classified as lowest risk in the combined score developed metastasis or died of his disease (). As a result, we combined the two lowest risk strata as the referent category to calculate hazard ratios. With this comparison, the hazard ratio of developing lethal prostate cancer was 11-fold higher (95% CI 4.0–32.8).
shows cumulative incidence of lethal prostate cancer at 5, 10, 15 and 20 years of follow-up based on risk according to the combined multigene and clinical parameters. Even at 5-years, higher risk groups identified those who developed lethal disease (cumulative incidence difference 28.7%, 95% CI 17.4–40.0%). With continued follow-up, the difference in cumulative incidence of lethal cancer between the lowest and highest risk group increased. Although the greatest discrimination in prediction was in contrasting the highest and lowest risk groups, the intermediate risk groups also were predictive of outcome.
Cumulative incidence of lethal prostate cancer during follow-up, based on the combined multigene and clinical risk score
ROC curves are presented in . At 15 years follow-up, the predictive ability of the molecular signature alone (AUC 0.68) was similar to that of the clinical markers alone (AUC 0.71). The model that combined the molecular and clinical parameters provided the greatest discrimination (AUC 0.78), with a 10% improvement over the clinical markers alone (p=0.04). The highest risk score based on clinical parameters was a better classifier (higher sensitivity) than the molecular signature of those who would develop lethal disease. However, 10% of the lowest risk men based on clinical markers died of cancer or developed metastasis during follow-up, compared to 3% classified as low risk by the molecular signature and 0% classified by the molecular-clinical model, suggesting the molecular data could improve classification of those who would have a good prognosis.
Receiver operator curves of the multigene and clinical models to predict development of lethal prostate cancer
Information was previously collected on the presence or absence of the TMPRSS2:ERG fusion on a subset of 107 men in the cohort.(20
). Information onTMPRSS2:ERG fusion status improved prognostication of the multigene model. At 15-years follow-up, the AUC for the multigene signature + fusion data was 0.79, and for the combined molecular/clinical + fusion data was 0.83.