The median age at prostate cancer diagnosis was 68.9 ± 7.3 years (range 47.7-84.3 years). Of the 90.5% of cases for whom stage and grade were known, 82.1% were organ confined at diagnosis (T1b-T2b) and the Gleason sum distribution was 2-5: 22.3%, 6: 38.8%, 7: 29.0%, and 8+: 10.0%. The mean time between blood draw for cholesterol analysis and prostate cancer diagnosis was 3.1 ± 1.8 years. Compared with controls, cases were more likely to have a family history of prostate cancer (p = 0.02), consumed slightly more saturated fat (p = 0.11), and consumed fish slightly less frequently (p = 0.05), but otherwise were similar on lifestyle and other dietary factors (). High-grade cases were slightly older (p = 0.08), were more likely to be white (p = 0.11), were taller (p = 0.05), were more likely to use a vitamin E supplement (p = 0.03), and had a higher intake of energy than low-grade cases (p = 0.07) ().
Characteristics1 of 698 prostate cancer cases and 698 matched controls nested in the health professionals follow-up study
Among the controls and adjusting for age, compared with men who had higher cholesterol, men who had low cholesterol were leaner (25.5 vs. 26.1 kg/m2, p = 0.03), drank less alcohol (8.6 vs. 12.6 g/day, p = 0.005), were less likely to have smoked in the past 10 years (12.3 vs. 19.1%, p = 0.06), were less likely to have ever had high cholesterol (27.5 vs. 55.1%, p < 0.0001) or triglycerides (18.0 vs. 35.8%, p < 0.0001) although they were similar (all p > 0.4) on intake of energy (2038 vs. 2035 kcal/day), cholesterol (249.0 vs. 251.1 mg/day), total fat (65.5 vs. 66.3 g/day), saturated fat (21.2 vs. 21.7 g/day), and polyunsaturated fat (11.9 vs. 11.8 g/day).
Mean pre-diagnostic plasma cholesterol concentration did not differ between the prostate cancer cases and the controls (). Cases were less likely to have a history of elevated cholesterol (42.8% versus 48.7%; p = 0.03) and were less likely to have ever used cholesterol-lowering medications than controls (9.2% versus 12.3%; p = 0.07) (). There was no association by quartile of plasma cholesterol with total prostate cancer, clinically organ-confined disease, or low-grade disease either before or after multivariable adjustment (). However, risk of high-grade prostate cancer was greater in each of the top three quartiles of total plasma cholesterol than in the bottom quartile (). For advanced disease, men in the top quartile of plasma cholesterol did not have an increased risk when compared to the bottom quartile, although there was a suggestion that men in the middle two quartiles were at increased risk.
Mean plasma cholesterol concentration, dietary cholesterol intake, and history of elevated cholesterol in prostate cancer cases and matched controls nested in the health professionals follow-up study
Odds ratio of prostate cancer by plasma cholesterol concentration, 698 matched pairs nested in the health professionals follow-up study
Because we hypothesized that low plasma cholesterol would be associated with lower risk of prostate cancer, and given the patterns across the quartiles we observed, we evaluated the association between low plasma cholesterol, defined as below the 25th percentile (versus at or above; cutpoints: 1996 192.8 mg/dL, 1998 185.7 mg/dL, and 2000 140.1 mg/dL), and prostate cancer (). Inverse associations for low plasma cholesterol were observed with high-grade disease (OR = 0.61, 95% CI: 0.39-0.98) and possibly with advanced disease (OR = 0.42, 95% CI: 0.13-1.36), but not with prostate cancer overall, organ-confined disease, or low-grade disease. The associations for low cholesterol persisted after excluding men who were diagnosed with prostate cancer within two years of blood draw (data not shown).
To determine whether the inverse association of low cholesterol with high-grade and advanced disease was merely due the use of statins or other cholesterol-lowering drugs by the men who had low cholesterol, we reran the analysis excluding men who had ever used any cholesterol-lowering medications (). The associations with high-grade (OR = 0.69, 95% CI: 0.44-1.08) and advanced disease (OR = 0.60, 95% CI: 0.23-1.61) remained inverse, albeit not statistically significant, among never users and null for the other endpoints. Among men who had ever used cholesterol-lowering drugs, the association for low cholesterol and total prostate cancer was similar to that among never users (data not shown).
This inverse association for low cholesterol was present in men with prostate cancer that was both high grade and organ-confined, even after excluding men who used cholesterol-lowering drugs; there was no association for men who had both low-grade and organ-confined disease ().
FIGURE 1 Association of low plasma cholesterol with high and low-grade prostate cancer restricted to men with organ-confined disease. Low plasma cholesterol was defined as below the 25th percentile of the distribution of plasma cholesterol concentration among (more ...)
Restricting the analysis to cases only, no association was observed for low plasma cholesterol when comparing advanced- with organ-confined disease (OR = 1.01, 95% CI: 0.52-1.99; excluding cholesterol-lowering drug users: OR = 1.08, 95% CI: 0.53-2.13). When comparing high- with low-grade disease, a modest inverse association for low plasma cholesterol (OR = 0.75, 95% CI: 0.50-1.12; excluding cholesterol-lowering drug users: OR = 0.86, 95% CI: 0.57-1.30) was suggested, which was enhanced when restricting the high-grade and low-grade cases to those with organ-confined disease (OR = 0.50, 95% CI: 0.30-0.84; excluding cholesterol-lowering drug users: OR = 0.58, 95% CI: 0.35-0.99).
The null association of low plasma cholesterol with total prostate cancer and the inverse association with high-grade prostate cancer did not differ by age at diagnosis (p interaction = 0.46, 0.91, respectively), family history of prostate cancer (p interaction = 0.44, 0.25), or body mass index (p interaction = 0.80, 0.26).