Consistent with a previous nested-case-control study and with the recent observations on cholesterol-lowering statin drugs and prostate cancer, in the placebo arm of the PCPT we observed that men with low serum cholesterol had a lower risk of high-grade prostate cancer. We did not observe associations between low cholesterol and total, organ-confined, or low-grade prostate cancer. We also extended the previous observations by showing that the association was restricted to the highest grade cases, Gleason 8-10. No association was observed between serum cholesterol and prostate cancer in the men randomized to finasteride. The plausibility that cholesterol may influence prostate cancer cell survival has been reviewed recently (23
). Our findings add to the literature supporting a role for cholesterol in the etiology of prostate cancer with a worse prognosis.
There is a large literature indicating that low serum cholesterol is associated with a higher risk of all-cause cancer incidence and mortality, which may be due to reverse causation; that is, cancer influencing serum cholesterol. Despite this literature, the association between circulating cholesterol and prognostic characteristics of prostate cancer is largely unexplored, aside from the recently published nested case-control study on cholesterol and prostate cancer in the Health Professionals Follow-up Study (HPFS). In the HPFS, the OR of Gleason 7-10 disease (n=247) was 0.61 (95% CI 0.39-0.98) when comparing low (< 25th
percentile in controls) with high plasma cholesterol, and the association was modestly stronger in cases that were also organ-confined (OR=0.54, 95% CI 0.29-0.99); these associations were unchanged after excluding men who used cholesterol-lowering drugs (11
). Too few men in the HPFS were diagnosed with Gleason 8-10 prostate cancer to evaluate the cholesterol association in this subgroup. Low cholesterol was not associated with prostate cancer overall, organ-confined, or Gleason 2-6 cases in the HPFS. We noted the same patterns of association in PCPT. Earlier studies, most of which had a small number of prostate cancer cases, reported no association between circulating cholesterol and prostate cancer (14
) or that risk was lower among men with higher cholesterol (12
). The majority of the prostate cancer cases diagnosed in PCPT and HPFS were clinically organ-confined because of high PSA screening intensity in both cohorts, and additionally in the PCPT because of the low PSA eligibility criterion and the recommendation of a biopsy at the end of the trial. In contrast, some of the prior studies were conducted in the pre- or early PSA era during which time a greater proportion of cases were diagnosed later in their natural history. The discrepancy in the findings between the past studies and the HPFS and PCPT may be, in part, due to a lack of consideration of pathological characteristics of the tumor, including differentiation status. In addition, our findings may differ from past findings of a higher risk of prostate cancer incidence or death in men with low cholesterol because in HPFS and PCPT prostate cancer was diagnosed early in its natural history, and thus unlikely to have influenced circulating cholesterol concentrations.
We conducted the primary analysis among men randomized to the placebo arm of the trial. Unlike in the placebo arm, in the finasteride arm we did not find an association between serum cholesterol and high-grade prostate cancer. In other ongoing analyses, we have observed effect modification by finasteride as well. Several papers have been published describing differences in the detectability and the pathologic characteristics of the high-grade cases in the finasteride compared with placebo arm (26
). The finding of a lower risk of prostate cancer in men with low cholesterol in the placebo arm but no difference in risk in the finasteride arm could not be explained by the imperfect sensitivity of detecting high grade prostate cancer if in the placebo arm the sensitivity were the same in men with low and high cholesterol or higher in men with low than high cholesterol. The pattern that we observed could, in theory, be explained by the sensitivity being lower in men with low than high cholesterol, but this is not the expectation. Men with low cholesterol on average have a lower prostate volume (29
) and thus a greater proportion of the total prostate would be sampled by needle biopsy increasing the sensitivity of detection of high-grade cancers. Other possible explanations for the difference in the association for high-grade disease between the two arms of the trial might include that finasteride prevented the same subset of high-grade cases that low cholesterol would have prevented, or a difference in the accuracy of the detection of high-grade prostate cancer in those with low cholesterol in the placebo versus finasteride arms of the trial.
Important strengths of this study are its prospective design, large size, central pathology confirmation of diagnosis, stage, and grade, rich information on covariates and by its design, a reduced likelihood of detection bias. Studies in the PSA era are susceptible to detection bias: a) if the exposure of interest is associated with the likelihood of PSA screening and thus diagnostic work-up for prostate cancer, or b) if the exposure somehow influences the concentration of PSA in circulation. The likelihood of the first source of detection bias was limited in the PCPT because of the trial protocol that recommended annual PSA and DRE screening and biopsy at the end of the trial for men not diagnosed with prostate cancer during the trial, and because serum cholesterol was measured for all of the men at trial entry. Thus, the link between seeking medical care and being worked up for both elevated cholesterol and PSA was dissociated. The second source of detection bias was limited in the PCPT because elevated PSA was not the sole reason for biopsy; about 15% of the men without an elevated PSA or abnormal DRE were diagnosed with prostate cancer on the biopsy at the end of the trial. Further evidence that these biases are unlikely to be present is that the distribution of serum cholesterol was similar in men who did (211.1 ± 36.2; age-adjusted: 211.1, 95% CI 210.0-212.3) and did not (210.9 ± 37.6; 210.9, 95% CI 209.9-211.9) undergo biopsy at the end of the trial.
We cannot rule out that our results could be due to complex sources of selection bias related to the propensity to undergo the end of study biopsy per study protocol. Such a bias could occur if say, men with low cholesterol at baseline who had an occult high-grade prostate cancer present by the end of the trial were more likely to decline biopsy than men with low cholesterol at baseline who were free of prostate cancer at the end of the trial. To generate a bias in this scenario, the forces that would compel a man with low cholesterol to undergo the end of study biopsy dependent on whether he had a yet undetected high grade prostate cancer would have to be strong risk factors for both undergoing biopsy and for high-grade disease. What these factors might be is unknown.
We used serum cholesterol as a biomarker of the possible availability of cholesterol to the prostate, whether derived from the prostate, made by the liver, or made by other organs, including the prostate. It is unknown the extent to which serum cholesterol would reflect intraprostatic concentration or whether intraprostatic cholesterol is the relevant etiologic factor. It is also unknown whether other measures of cholesterol, such as lipoprotein fractions, would better capture the mechanisms underlying the association between serum total cholesterol and prostate cancer that we observed. Men in PCPT had a comparable mean serum cholesterol (~211 mg/dL) to similarly aged men in the US population during the same time interval (1988-1994: 216, 214, 205 in men 50-59, 60-74 and 75+ years old (30
)). However, whether the size of the difference in serum cholesterol concentration across quintiles is adequately large to affect cholesterol-dependent biological processes that influence risk of prostate cancer, especially high-grade disease, is not known. We were unable to evaluate whether the association that we observed was explained by a higher prevalence of statin use in men with low compared with high serum cholesterol. However, based on the findings from the HPFS (11
), this is unlikely to be explanatory.
Although the overall sample size was large, some subgroup analyses had a small number of cases. However, it should be noted that the small number of Gleason 8-10 cases in the low cholesterol group was not merely due to an insufficient sample size; the observed number of cases was 13, but 30 were expected based on the age- and race-adjusted proportion of Gleason 8-10 cases in men with high cholesterol. In addition, because of the intensive prostate cancer screening in the trial we could not address the association for advanced stage prostate cancer.
In summary, our prospective findings support that men with low cholesterol have a reduced risk of high-grade prostate cancer. The results of the present study along with those for cholesterol from the HPFS, as well as recent findings for statin drugs, suggest that in-depth study of cholesterol in the etiology of prostate cancer is warranted.