Low Cholesterol May Be Marker of Undiagnosed Cancer

Roxanne Nelson

November 05, 2009

November 5, 2009 — For decades, researchers have observed an apparent association between low serum cholesterol levels and higher overall cancer incidence and mortality. However, 2 new papers published online November 3 in Cancer Epidemiology, Biomarkers & Prevention appear to have put that concern to rest and shed new insight into the role that cholesterol plays in cancer.

Some experts have attributed the association between low cholesterol levels and increased cancer risk/mortality to reverse causation — undiagnosed cancer causing a reduction in cholesterol levels. The first of the new studies adds evidence to the hypothesis that lower levels of serum cholesterol might be a marker of existing malignancy, not a causal factor. That study results also found that high-density-lipoprotein (HDL) cholesterol was modestly but significantly associated with an overall decreased cancer risk.

The results from this analysis should help dispel any lingering doubts that low cholesterol can cause cancer.

"The results from this analysis should help dispel any lingering doubts that low cholesterol can cause cancer," said Eric Jacobs, PhD, strategic director of pharmacoepidemiology at the American Cancer Society, during a press briefing that was held to discuss the results of these 2 papers.

"It also raises an interesting question about whether levels of HDL cholesterol might lower the risk for some cancers," added Dr. Jacobs, who coauthored an accompanying editorial. "This is a new and exciting question but we need to do a great deal more research before we have any clear answers."

The second study found that men with low circulating cholesterol levels have a reduced risk for high-grade prostate cancer. The authors observed that men with low levels of total cholesterol (<200 mg/dL) had a lower risk for prostate cancer with a Gleason score of 8 to 10 than men with high cholesterol (odds ratio [OR], 0.41; 95% confidence interval [CI], 0.22 - 0.77). Overall, participants with serum cholesterol levels below 200 mg/dL had a 59% reduction in their risk for high-grade disease.

The second study raises a different question: Does having low total cholesterol reduce the risk for very high-grade prostate cancer? "There is increasing evidence that this may be true, but evidence from human studies is still limited," said Dr. Jacobs. "Again, more research is needed before we have clear answers to this question."

Dr. Jacobs notes that the results from the 2 studies provide 1 answer and raise 2 new issues. Results from the first study clearly show that low total cholesterol is unlikely to increase the risk for cancer and, at the same time, raise a concern about the potential role of high HDL cholesterol in reducing risk for cancer.

Results from the second study raise concern about the association between low total cholesterol and a reduced risk for high-grade disease. "Analyses to replicate the association between low total cholesterol and reduced risk of high-grade prostate cancer are well justified," according to the editorial, which is coauthored by Susan M. Gapstur, PhD, MPH, also from the American Cancer Society. "Analyses of associations of cholesterol levels and use of cholesterol-lowering drugs with prostate cancer progression among men with localized low-grade prostate cancer could also clarify the role of cholesterol in prostate carcinogenesis."

ATBC Study

In the first study, researchers from the National Cancer Institute (NCI) and the National Institute for Health and Welfare in Helsinki, Finland, examined the relation between serum total and HDL cholesterol and the risk for overall and site-specific cancers among participants enrolled in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. The cohort consisted of 29,093 male smokers residing in Finland. The trial period concluded on April 30, 1993, but follow-up continued until diagnosis, death, or March 31, 2003.

Fasting serum total and HDL cholesterol were assayed at baseline, and a total of 7545 incident cancers were identified during follow-up, which was as long as 18 years.

"Several studies have attempted to exclude reverse causality by looking at time trends, but most [were not] large enough or had insufficient length of follow-up to provide more definitive information on this point," said study author Demetrius Albanes, MD, a senior investigator at NCI, during the briefing. "At the same time, very few studies mentioned HDL cholesterol and any relationship between HDL cholesterol and overall cancer risk."

"With this background in mind, we set out to enhance our scientific understanding of the cholesterol/cancer relationship," he added.

Cancer Marker Rather Than Cause

Dr. Albanes and colleagues found that, in a multivariate model, higher serum total cholesterol was associated with a lower overall cancer incidence. Patients in the highest quintile for serum total cholesterol concentration had lower overall risk for cancer than those in the lowest quintile (>276.7 vs <203.9 mg/dL; relative risk [RR], 0.85; 95% confidence interval [CI], 0.79 - 0.91; P < .001).

"Cancers of the lung, kidney, and liver contributed substantially to this finding," Dr. Albanes said. "However, this relationship disappeared when we excluded cases diagnosed within the first half of the follow-up period or within 9 years of when their baseline blood sample was collected."

"This finding supports the idea that the low serum cholesterol levels that we detected as a possible risk factor may actually have been the result of undiagnosed cancers," he added. "In addition, we observed a greater decline in total serum cholesterol from baseline to 3 years, specifically among the cases that were diagnosed in the early half of the observation, as opposed to the latter portion."

The researchers also observed that higher HDL cholesterol levels were associated with a decreased risk for cancer (>55.3 vs <36.2 mg/dL; RR for the highest vs the lowest quintile, 0.89; 95% CI, 0.83 - 0.97; P = .01). This inverse association of HDL cholesterol was evident for cancers of the lung, prostate, liver, and hematopoietic system.

This is the first study to show a significant relationship between higher HDL and lower risk for all cancer combined.

This is the "first study to show a significant relationship between higher HDL and lower risk for all cancer combined, with an 11% lower risk for the highest category of HDL," Dr. Albanes said.

In contrast to the findings for total cholesterol, the exclusion of cases in the early years of follow-up made the HDL association stronger rather than weaker, he emphasized. "Thus, the 11% lower risk we had earlier became a 14% to 15% lower risk in the highest HDL cholesterol category."

Prostate Prevention Trial

In the second study, Elizabeth Platz, ScD, MPH, codirector of the Cancer Prevention and Control Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, and colleagues evaluated the association between low serum cholesterol and prostate cancer risk. The cohort in this prospective study consisted of 5586 men, 55 years and older, who were participants in the Prostate Prevention Trial and who had been randomized to the placebo group of that study between 1993 and 1996.

Unlike previous studies, the authors note, the number of high-grade cases in the placebo group of this trial was sufficiently large to allow the estimation of the association between cholesterol levels and disease with a Gleason score of 8 to 10.

In a previous study, explained Dr. Platz, they had observed that men who were using statin drugs had a lower risk for advanced prostate cancer and, with longer-term follow-up, had a lower risk for high-grade disease, but there was no association between statin use and overall prostate cancer risk.

Association With Gleason Score of 8 to 10

A total of 1251 cases of prostate cancer were identified: 993 cases with a Gleason score of 2 to 6, 199 cases with a Gleason score of 7, and 59 cases with a Gleason score of 8 to 10. Although an association was observed between low cholesterol levels and a Gleason score of 8 to 10, none was observed for overall prostate cancer risk (OR, 0.97; 95% CI, 0.85 - 1.11). In addition, no association was observed for disease with a Gleason score of 2 to 6 (OR, 1.03; 95% CI, 0.89 - 1.18) or with a Gleason score of 7 (OR, 0.93; 95% CI, 0.69-1.24).

"Our results confirm the prior work that we did and are compatible with the findings we had for statins and prostate cancer," said Dr. Platz.

The next move might be to look not just at total cholesterol but also the relation with high HDL and low low-density-lipoprotein cholesterol, she said. Another step might be to "evaluate whether cholesterol lowering, rather than low cholesterol as the usual state, would explain this relationship," she added.

Both studies were funded by the National Institutes of Health. The authors and editorialists have disclosed no relevant financial relationships.

Cancer Epidemiol Biomarkers Prev. 2009;18:2805-2806, 2807-2813, 2814-2821.

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