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The statins are a class of cholesterol-lowering drugs first marketed in 1987 (lovastatin [Mevacor, Merck, West Point, PA]). They are commonly used among persons age 50 and older; atorvastatin (Lipitor, Pfizer, New York, NY) is among the ten most commonly prescribed drugs in the United States. 1 A growing body of laboratory data suggests that the statins may have chemopreventive potential against cancer at various sites, including colon, 2 lung, 3 breast, 4–6 and prostate. 7–9 Specifically, lovastatin and simvastatin (Zocor [Merck]) suppress the growth of cancer cells in vitro by causing the cells to pause in the G1 phase of the mitotic cycle 4 and by increasing cell death (apoptosis). 10,11 The statins inhibit the synthesis of cholesterol by inhibiting a key enzyme in the cholesterol pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The growth-suppressing properties of the statins may be due to the inhibition of HMG-CoA reductase, but other mechanisms have also been suggested. 12
The only data on cancer incidence in persons who used statins come from five randomized, controlled trials, 13–17 each of which traced participants for an average of 5 years. In a trial of pravastatin, there was a deficit of colon cancer in the treatment group (12 in the treatment group and 21 in the placebo group). In the same trial, there was an excess of breast cancer in the treatment group (12 in the treatment group and 1 in the placebo group). 14 In a trial of lovastatin, there was a significant deficit of melanoma in the treatment group (14 in the treatment group and 27 in the placebo group). 16 Otherwise, cancer incidence in the treatment and placebo groups did not differ significantly in any trial.
We have collected data on statin use among patients enrolled in the hospital-based Case-Control Surveillance Study of Drugs and Serious Illness. The cancer sites for which data were sufficient for informative analysis of statin use were breast and prostate. We report here the relation of statin use to the risk of these cancers.
Methods
Data Collection
Since 1976, we have collected health information from patients with cancer and other diagnoses admitted to hospitals in Massachusetts, New York, Baltimore, and Philadelphia in the Case-Control Surveillance Study. 18 Nurse-interviewers have administered standard questionnaires to obtain information on demographic factors, reproductive and medical history, and lifetime history of medication use. Use of statins has been elicited by asking about drugs used for “blood fat/cholesterol” and for “heart conditions.” The present analyses are based on patients age 50–79 interviewed from 1987 (the first year a statin was marketed) through March 2001. The study was approved by the Institutional Review Boards of all participating institutions. Of the patients approached for an interview, 95% participated. All participants signed informed consent documents.
Cases
The breast cancer cases comprised 1,132 women with a first occurrence of primary breast cancer diagnosed within the previous year, confirmed by pathology report, and with no concurrent or previous cancer. The prostate cancer cases comprised 1,009 men with a first occurrence of primary prostate cancer diagnosed within the previous year, confirmed by pathology report, and with no concurrent or previous cancer. Ninety-four per cent of both breast and prostate cancer cases were diagnosed within the 6 months before hospital admission.
Controls
Patients admitted with diagnoses that were judged to be unrelated to statin use served as controls: trauma (excluding wrist and hip fractures) and orthopedic conditions (589 women and 694 men), as well as other conditions (eg, acute infection, cholecystitis, or kidney stones) (742 women and 693 men). No cancer diagnoses were included, because an emerging literature suggests that statins inhibit the proliferation of many cancer cell types in vitro. Wrist and hip fractures were excluded because a number of studies have reported a reduced risk of osteoporosis among users. 19–21 The prevalence of statin use that began at least 1 year before admission was 4.3% among women admitted for trauma or orthopedic conditions and 4.1% among women admitted for other conditions, standardized for 5-year age group, year of interview, and study center. Among male controls, the prevalence of statin use was 4.9% among trauma/orthopedic conditions and 5.4% among other conditions.
Analysis
We considered all reported use of lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, or atorvastatin. Use that did not begin at least a year before admission would not have predated the onset of the cancer or its symptoms and was therefore categorized separately (recent use). All reported use was daily use, and more than 90% was for a duration of at least 6 months. Statin use of unknown duration was reported by one breast cancer case, one prostate cancer case, two female controls, and one male control, all of whom were excluded from the analysis.
We used unconditional logistic regression models to estimate the odds ratio (OR) 22 and 95% confidence interval (CI) for use of statins that began at least 1 year before admission, compared with never use. Among both male and female controls, statin use was positively associated with age, year of interview, and number of doctor visits 2 years before hospitalization. Use was also associated with study center (highest in Baltimore and lowest in New York), religion (highest among Jewish patients), race (higher among whites), and alcohol use (highest among never drinkers). Among women, use was positively associated with use of hormones, including conjugated estrogens, female hormones (eg, progesterone or estradiol), and oral contraceptives. Among men, use was positively associated with education and body mass index. Odds ratios for breast cancer were adjusted for all of these variables. Odds ratios for prostate cancer were adjusted for all variables except hormone use.
Results
Breast Cancer
Among breast cancer cases and female controls, the odds ratio for statin use that began at least 1 year before hospital admission compared with never use was 1.5 (95% CI = 1.0–2.3) (Table 1). The increased risk was most apparent among cases with carcinoma in situ (CIS) (OR = 1.8; 95% CI = 0.9–3.6); the odds ratio for those with invasive breast cancer was 1.2 (95% CI = 0.7–2.0). The odds ratios for women whose statin use occurred exclusively in the year before admission (recent use) were not elevated for any of the breast cancer groups. The odds ratios were greater for longer-duration use (≥3 years): 2.1 (95% CI = 1.1–4.0) overall, 3.4 (95% CI = 1.5–8.0) for cases with CIS, and 1.5 (95% CI = 0.7–3.1) for cases with invasive breast cancer.
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Table 1: Use of Statins Among Breast Cancer Cases and Controls
Odds ratios for the individual statins (lovastatin, simvastatin, and pravastatin) were slightly elevated for breast cancer overall. Among CIS cases, the odds ratios were elevated for lovastatin and simvastatin (2.1 [95% CI = 1.0–4.4] and 2.7 [95% CI = 1.0–7.5], respectively), but not among cases of invasive cancer.
Women with invasive cancer differed from women with CIS on several variables related to use of medical care (Table 2). The age distributions of the women with CIS or invasive breast cancer were similar. Cases with CIS made more doctor visits in the 2 years before diagnosis, were more educated, and were more likely to have had their disease discovered by mammogram. Women with invasive cancers were more likely to have performed breast self-examination.
Table 2: Characteristics of Cases with Carcinoma In Situ (CIS) and Invasive Cancer
Among invasive cases with metastases the adjusted odds ratio for statin use was 1.1 (95% CI = 0.6–2.3) (11 case users), and among those without metastases the odds ratio was 1.3 (95% CI = 0.7–2.2) (22 case users). Among invasive cases whose cancer was discovered by symptoms the odds ratio was 0.9 (95% CI = 0.3–2.3) (5 case users); among those whose cancer was discovered by mammography or self-examination the odds ratio was 1.4 (95% CI = 0.8–2.3) (26 case users).
Prostate Cancer
The odds ratios for prostate cancer with use of statins that began at least 1 year before admission were not substantially elevated among all cases as a group, or in any strata of stage at diagnosis (Table 3). For all stages, the odds ratio for any duration of use was 1.2 (95% CI = 0.8–1.7), and it was 1.0 (95% CI = 0.6–1.6) among subjects who had used statins for at least 3 years. The odds ratio associated with use of any duration was higher for cases who were diagnosed at the earliest stage (A) (OR = 1.4) than for later stages (C and D) (OR = 0.9). The odds ratio for recent use only was 1.1 (95% CI = 0.5–2.1). Odds ratios were not higher for longer than for shorter durations of use. The odds ratio for patients with Stage B cancer who had used statins for less than 3 years was 2.1 (95% CI = 1.1–3.9); among those who had used statins for at least 3 years, the odds ratio was 0.7 (95% CI = 0.4–1.4). Odds ratios for the use of lovastatin, simvastatin, and pravastatin were all close to the null value.
Table 3: Use of Statins Among Prostate Cancer Cases and Controls
Discussion
The present study does not provide evidence of a protective effect of statins against breast or prostate cancer. There was a 50% increase in the odds ratio for breast cancer among women who had taken statins beginning more than 1 year before hospital admission. The increase was largely accounted for by an odds ratio of 1.8 among cases with CIS; the odds ratio among women with invasive cancer was 1.2. Similarly, when cases were confined to those with CIS, there were increases in the odds ratios among women who had used statins for at least 3 years, among women who used lovastatin, and among women who used simvastatin. Among cases with invasive cancers, the odds ratios were not increased except for women who had used statins for at least 3 years. Odds ratios for prostate cancer did not differ substantially from the null value among all users, by duration, or for any specific drug.
Detection bias is a possible explanation for the increased odds ratios observed for CIS as compared with invasive breast cancer. Several studies have reported that women whose breast cancer is diagnosed at an early stage are of higher socioeconomic status than those diagnosed at a later stage. 23,24 Thus, women diagnosed with early-stage compared with late-stage cancer may have more access to preventive medical services, including mammography and cholesterol monitoring. In our data, women whose cancer was in situ at diagnosis were more educated, made more doctor visits 2 years before hospital admission, and were more likely to have discovered their disease via mammogram than women with invasive breast cancer. They may also have been more likely to have had their cholesterol levels checked and treated than were women diagnosed at a later stage. Odds ratios among subgroups of the invasive cases also support an interpretation of detection bias, although numbers were small: those who did not have metastases at diagnosis had a slightly higher odds ratio than those with metastases, and those whose cancer was discovered by screening had a higher odds ratio that those whose cancer was discovered by symptoms.
Detection bias may also have influenced the results for prostate cancer; the odds ratio for statin use that began more than 1 year before admission was higher for Stage A cases than for those diagnosed at later stages, but the pattern was not as striking as that seen for breast cancer. Chance is the most likely explanation for the elevated odds ratio of 2.1 among short-term statin users who were Stage B at diagnosis, given the number of comparisons made and the reduced odds ratio with longer-term use.
It is not likely that information bias contributed to the increased odds ratios for CIS breast cancer cases, because hypotheses linking statin use to either reduced or increased breast cancer risk were not commonly known during any period of the study. In addition, statin use is likely to be well remembered, as these drugs are taken daily and have been available only in recent years. Bias in control selection is likely to be minimal, because the control groups excluded diagnoses linked with statin use (cancers, and fractures associated with osteoporosis) and because rates of statin use were similar among subcategories of controls. Furthermore, any information and selection biases would influence results for both CIS and invasive cancer.
Statin use was correlated with a number of risk factors for both breast and prostate cancer, particularly factors that are indicators of access to health care (eg, number of doctor visits 2 years before hospitalization, or education). These were controlled in the analyses. However, residual confounding, or confounding by unknown factors, may have contributed to the observed increases in odds ratios.
Although there are some reports of increased incidence of gastrointestinal and liver cancers among rodents fed statins, 25 a growing body of laboratory data suggests that regular statin use might protect against both breast and prostate cancer. Four reports have described the growth-inhibiting effects of lovastatin on murine 7 and human 8,9,26 prostate cancer cells in vitro. Six studies have reported that lovastatin 4,5,12,27,28 and simvastatin 29 have the same effect in human breast cancer cells. The mechanism by which the HMG-CoA reductase inhibitors arrest the growth of normal and tumor cells has not been established. However, this class of drugs inhibits the synthesis of cholesterol and other proteins that play various roles in cell proliferation. 4 In addition, one study has identified another mechanism by which lovastatin induces cell cycle arrest that is independent of HMG-CoA reductase. 12 This mechanism involves the inhibition of proteasome activity, a pathway that plays a key role in cell cycle progression. Inhibition of this pathway results in the accumulation of the cyclin-dependent kinase inhibitors p21 and p27, which have tumor suppressor abilities. The inhibitory effect of statins on breast and prostate cancer cells has thus far been tested only in vitro; they may behave differently in vivo. Specifically, statins are selectively localized to the liver, and less than 5% of a given dose reaches the systemic circulation. Thus, statins may not reduce the risk of cancer at sites distant from the liver given their low systemic availability. 30
Although statins may have potential in cancer prevention, an excess of breast cancers occurred in one trial of pravastatin treatment as compared with the placebo group (12 in the former compared with 1 in the latter). 14 In the treatment group, three cancers were recurrences, one was CIS, and one occurred in a woman who had taken pravastatin for 6 weeks; the 1 case in the placebo group was a recurrence. On the basis of population incidence data, the study investigators concluded that the difference in breast cancer incidence between the treatment and placebo groups was due to a deficit of cases in the placebo group rather than an excess in the treatment group. 31 In the other trial of pravastatin that included women (the LIPID trial), 9 invasive and 1 in situ breast cancer cases occurred in the treatment group compared with 10 invasive cases in the placebo group. 17 In our data, there was a slight increase in risk among users of pravastatin.
Statins are commonly used, and their use is increasing. 32 The National Cholesterol Education Program recently issued new guidelines for the management of high cholesterol, 33 which are expected to increase greatly the number of people prescribed cholesterol-lowering medication. Merck Research Laboratories recently petitioned the Food and Drug Administration to reclassify lovastatin as an over-the-counter drug, although the petition was denied. Given the high and growing prevalence of statin use, 32 as well as the association of statins with various cancers in vitro and in vivo, it is important to monitor the effects of statin use on cancer incidence. Long-term follow-up of the participants in randomized trials of statins will be helpful. However, the ability of such studies to detect small or moderate differences in cancer incidence or mortality between the treatment and placebo groups, particularly among women, will be limited by the relatively small numbers of participants; approximately 3,900 women were randomized in four trials and 27,000 men in five trials. A report of follow-up in the Scandinavian Simvastatin Survival Study (4S) has been published; 2 years after the end of treatment, there was a small decrease in cancer mortality in the statin compared with the placebo group. 34 As statins are so commonly used, additional case-control studies will be feasible (and more powerful) for the study of specific cancers. The potential for confounding by healthcare utilization must be considered in such studies.
Acknowledgments
We thank the many physicians who allowed their patients to be interviewed; the nurse-interviewers who collected the data; Marguerite Angeloni, who coordinated data collection; and Leonard Gaetano, who was responsible for data management.
The following hospitals participated in this study: in New York, Brookhaven Memorial Hospital, Lenox Hill Hospital, Memorial Sloan-Kettering Cancer Center, and New York Hospital; in Philadelphia, American Oncologic Hospital, Crozier Chester Medical Center, Hahnemann University Hospital, Hospital of the Medical College of Pennsylvania, Hospital of the University of Pennsylvania, Lankenau Hospital, Montgomery Hospital, Pennsylvania Hospital, Presbyterian Hospital, and Thomas Jefferson University Hospital; in Massachusetts, Sancta Maria, Beth Israel, Newton Wellesley, Mount Auburn, Massachusetts General, Brigham and Women’s, University, and New England Medical Center; and in Maryland, Johns Hopkins Hospital, University of Maryland Medical Center, Sinai Hospital, Greater Baltimore Medical Center, and Mercy Medical Center.
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