Of the 2,546 men diagnosed with prostate cancer during the follow-up, 989 (39%) were overweight (BMI 25–29.9 kg/m2
) and 87 (3.4%) were obese (BMI≥30 kg/m2
) at baseline (
). Overweight men had characteristics similar to men of normal weight. Greater proportions of obese men were past smokers, and were more likely to have extraprostatic, metastatic, or high Gleason grade (8
) cancer at diagnosis. BMI was unrelated to PSA concentration, with spearman correlation coefficients between BMI and baseline PSA concentrations of 0.06 (P=0.09, n=718) and −0.03 between BMI and PSA concentration at diagnosis (P=0.25, n=1869). As expected, baseline plasma C-peptide concentrations were weakly positively correlated with age (spearman partial correlation r=0.12, P
controlling for fasting status and assay batch) and BMI (r=0.25, P
controlling for fasting, batch, and age).
Characteristics among 2,546 prostate cancer cases (1982–2007), by baseline BMI
During the 24 years of follow-up, 281 (11.0%) men subsequently died of prostate cancer and 485 (19%) men died of other causes. Higher baseline BMI was significantly associated with higher risk of prostate cancer-specific mortality, independent of age at diagnosis and baseline smoking status (, ). Compared with men of normal weight, the HRs were 1.47 (1.16–1.88) for overweight men and 2.66 (1.62–4.39) for obese men (Ptrend < 0.0001). Controlling for the two trial components, aspirin and beta-carotene, did not change the results ().
Cox proportional hazard ratio (HR) a and 95% confidence interval (95% CI) of prostate cancer-specific mortality according to BMI
Figure 1 Survival curves show the probability of prostate cancer-specific survival after diagnosis according to baseline BMI measured in 1982 controlling for age at diagnosis, smoking status, and time between BMI measurement and cancer diagnosis (1A, 2,546 prostate (more ...)
Cox proportional hazard ratio (HR) a and 95% confidence interval (95% CI) of prostate cancer-specific mortality according to one unit increase in baseline BMI
We further included clinical stage and Gleason grade in the multivariate model to assess the independent association between baseline BMI and fatal prostate cancer. Controlling for these clinical predictors somewhat attenuated the magnitude of the association; the HRs were 1.26 (0.98–1.62) for overweight men and 1.95 (1.17–3.23) for obese men. However, the positive trend of increase in risk for each unit increase in BMI remained statistically significant (HR= 1.07, 1.02–1.12; Ptrend = 0.004, ). As expected, high Gleason score (7 or 8–10) and regional (clinical stageT3/T4/N0/M0) and metastatic disease (N1/M1) at diagnosis were strong predictors of lethal prostate cancer. The HRs were 2.25 (1.62–3.12) for Gleason grade 7 tumors (80 prostate cancer deaths) and 4.70 (3.37–6.56) for Gleason 8–10 tumors (93 prostate cancer deaths), compared with Gleason 2–6 (73 prostate cancer deaths). The HRs were 3.62 (2.61–5.02) for stage T3/T4/N0/M0 (78 prostate cancer deaths) and 10.62 (7.45–15.14) for stage N1/M1 disease (67 prostate cancer deaths) compared with localized (stage T1/T2/N0/M0) disease (105 prostate cancer deaths). Further controlling for PSA at diagnosis (<4, 4–9,≥10 ng/mL) in a subgroup of 1869 men (diagnosed in PSA era) strengthened the association for overweight (HR=1.80, 1.15–2.83) but attenuated the association for obesity (HR=1.61, 0.56–4.58). Controlling for baseline PSA (<4, 4–9,≥10 ng/mL, n=718 cases, most of whom were diagnosed during the pre-PSA era) in the multivariate model with clinical predictors did not materially change the results (HR=1.61, 1.11–2.34 for overweight and HR=2.83, 1.31–6.11 for obese).
Widespread PSA screening since early 1990s has significantly changed the clinical presentation of prostate cancer. Because information on screening was not uniformly available, we used the period of 1982–1990 and 1991–2007 as a surrogate of the pre-PSA and PSA screening era. Among the 415 men diagnosed with prostate cancer during 1982–1990 (pre-PSA era), 140 (33.7%) died of prostate cancer. Among the 2,131 men diagnosed with prostate cancer during 1991–2007 (PSA screening era), 141 (6.6%) died of the disease. Although the overall prostate cancer-specific mortality was dramatically different between the two periods (), the relative risk of prostate cancer-specific mortality in association with baseline BMI remained similar in age- and smoking-adjusted model (). Further controlling for clinical stage and Gleason grade significantly attenuated the association for prostate cancer diagnosed during 1982–1990. However, for prostate cancer diagnosed during the PSA screening era, excess body weight many years before diagnosis was a strong and significant predictor of poor survival.
The median time between baseline BMI and prostate cancer diagnosis was 13 to 14 years (), we therefore controlled for time between BMI measurements to prostate cancer diagnosis in all the analyses. In addition, BMI obtained in the 8th year of follow-up (in 1990) was highly correlated with baseline BMI in 1982 (correlation coefficient = 0.8), suggesting strong tracking over time. The prospective association between prediagnostic BMI and prostate cancer-specific mortality in the PSA screening era (1991–2007) was quite similar using BMI obtained in 1982 or in 1990 (), with or without controlling for clinical stage and Gleason grade, further demonstrating the robust relationship.
To evaluate potential confounding factors, we conducted a series of subgroup sensitivity analyses with baseline BMI as a continuous variable, which gives more statistical power (), and controlling for age and smoking status. Compared with the overall risk of prostate cancer-specific mortality with a one unit increase in BMI (HR = 1.09, 95% CI: 1.05–1.14), the association remained virtually unchanged after each of the following exclusions: men who died of any cause during the first five years of follow-up, current smokers, men with history of diabetes, or non-Caucasians. This suggests that these factors cannot explain the strong positive association between baseline BMI and prostate cancer mortality. In addition, excluding men with stage T1 or stage N1/M1 prostate cancer at diagnosis did not materially change the results suggesting that early cancer detection by PSA (stage T1) or delayed diagnosis (metastasis) had little impact on the association.
We have baseline blood available in a subgroup of 827 men; 634 of these blood samples were collected less than 8 hours since last meal (nonfasting). We therefore measured plasma C-peptide as a surrogate for insulin secretion, and assessed the link between C-peptide concentration and prostate cancer-specific mortality, adjusting for time between last meal and blood draw. Baseline characteristics and clinical features in this subgroup of men were similar to those in the overall study population (data shown in Supplemental Webtable 1
). Among the 117 prostate cancer deaths, a significantly higher proportion (44, 21%) had baseline C-peptide concentrations in the highest quartile compared to those in the lowest quartile (21, 10%). After controlling for age, fasting status, and time interval from baseline to prostate cancer diagnosis, men with baseline C-peptide concentration in the highest quartile had an HR of 2.38 (1.31–4.30) for prostate cancer mortality compared with the lowest quartile, Ptrend
(, ). The increased risk was mainly among men in the highest quartile suggesting a threshold effect (). Including BMI in the model slightly attenuated the association for C-peptide (inter-quartile HR = 2.01, 95% CI: 1.11–3.66; Ptrend
) but BMI remained a strong predictor (HR = 1.61, 95% CI: 1.10–2.35, for overweight, HR = 2.37, 95% CI: 1.04–5.37, for obesity; Ptrend
). The HR for the highest quartile of C-peptide remained statistically significant (HR = 1.93; 95% CI: 1.03–3.63; Ptrend
) after controlling for clinical stage and Gleason grade. However, including both BMI and clinical predictors in the same model attenuated the associations for both BMI (HR=1.76, 95%CI: 1.19–2.61, for overweight and HR=1.87, 95%CI: 0.80–4.37, for obesity) and C-peptide (inter-quartile HR = 1.72, 95% CI: 0.92–3.24, Ptrend
). This finding suggests that part of the impact of BMI on prostate cancer prognosis is mediated through insulin ().
Cox proportional hazard ratio (HR) and 95% confidence interval (95% CI) of prostate cancer-specific mortality according baseline plasma C-peptide concentration
When assessing the joint association between BMI and C-peptide, we found that the increased risk of prostate cancer mortality associated with higher concentrations of C-peptide was statistically significant among men with BMI≥25 kg/m2 (Ptrend=0.007) but not among men with BMI<25 kg/m2 (Ptrend=0.38) (). Overweight men with C-peptide in the highest quartile were over four times (the multivariate-adjusted HR=4.22, 95% CI: 2.10–8.48, Pinteraction=0.017) more likely to die of prostate cancer compared to men of normal weight and with C-peptide in the lowest quartile. Further controlling for clinical stage and Gleason grade did not change the result (the multivariate-adjusted HR=4.12, 95% CI: 1.97–8.61, Pinteraction=0.001).
Cox proportional hazard ratio (HR) and 95% confidence interval (95% CI) of prostate cancer-specific mortality according baseline BMI and plasma C-peptide concentrations