SEARCH

SEARCH BY CITATION

Keywords:

  • breast neoplasms;
  • statins;
  • cancer;
  • 3-hydroxy-3-methylglutaryl conenzyme A inhibitors;
  • lipid-lowering drugs

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Statin use has increased dramatically in the U.S. in the past decade. Animal and mechanistic studies suggested that statins may have an inhibitory effect on cancer proliferation, including breast carcinoma. However, statins have been found to be carcinogenic in rodents and one clinical trial found an excess of breast carcinoma cases in the treatment group.

METHODS

The current study assessed whether the use of statins altered the risk of breast carcinoma in older women. The population-based, case–control study comprised female residents from three western Washington State counties. Cases included 975 women identified from the Cancer Surveillance System who were diagnosed with primary invasive breast carcinoma between 1997–1999, whose names appeared on a list of Social Security recipients provided by the Centers for Medicare and Medicaid Services. The cases were ages 65–79 years at the time of diagnosis. The comparison group was comprised of 1007 women without breast carcinoma who were randomly selected from the same list of Social Security recipients. Information pertaining to statin use, medical history, and health behaviors was ascertained through an in-person interview.

RESULTS

Compared with nonusers, women who were currently using statins or had ever used statins were not found to be at an increased risk for breast carcinoma (odds ratios [OR] = 0.9; 95% confidence interval [95% CI], 0.7–1.2). There was some indication that long-term statin use (> 5 years) was related to a slight decrease in breast carcinoma risk (OR = 0.7; 95% CI, 0.4–1.0).

CONCLUSIONS

The results of the current study provided some degree of reassurance to the increasing numbers of women using statins that such use is not associated with an increased risk of breast carcinoma. Although the data gave some support to a reduced risk of breast carcinoma among long-term users of statins, further research is needed to confirm this association. Cancer 2004. © 2004 American Cancer Society.

3-Hydroxy-3-methylglutaryl conenzyme A (HMG-CoA) inhibitors (statins) comprise a therapeutic class of agents that reduce plasma cholesterol levels by inhibiting hepatic HMG-CoA reductase, the rate-controlling enzyme in cholesterol synthesis.1 Statins were first introduced to the U.S. market in 1987. The use of statins has increased dramatically in the past decade and is likely to continue to increase. Four of the five statins on the American market were among the top 200 prescribed drugs for 2001 in the U.S.2

Uncertainties remain regarding the long-term safety of these agents, especially in relation to cancer incidence. A review of the findings concerning the rodent carcinogenicity of lipid-lowering drugs suggests that statins increase the frequency of cancer in rodents.3 One randomized clinical drug trial lasting 5 years reported 12 breast carcinoma cases among pravastatin users and only 1 case in the placebo group (P = 0.002),4 but this finding was not confirmed in other clinical trials of statin use.5–7 Evidence concerning the carcinogenicity of statins from clinical drug trials and observational studies remains inconclusive because of inconsistent results between studies, the limited range of statin exposure duration, and inadequate sample sizes.4–13

Contrary to concerns regarding the carcinogenicity of statins, a growing body of evidence suggests that statins may in fact have a chemopreventive potential against cancer. Laboratory studies demonstrate that statins induce apoptosis and reduce cell invasiveness in various cell lines,14–22 including breast carcinoma cells.23–26 Although not completely understood, many of the products of the mevalonate pathway are necessary for diverse cellular functions including the G1-S-phase transition of cell proliferation and the formation of cell membranes.27 Statins may inhibit cancer cell growth and lead to apoptotic cell death through their inhibition of the mevalonate pathway, although other mechanisms also have been suggested.27

To assess the association between statin use and invasive breast carcinoma, we analyzed data from a population-based, case–control study conducted among older women in western Washington State.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study Population

We conducted a population-based, case–control study of women ages 65–79 years living in the 3-county Seattle-Puget Sound metropolitan area. Cases were identified through the Cancer Surveillance System, a population-based tumor registry that serves 13 western Washington counties and participates in the Surveillance, Epidemiology, and End Results program of the National Cancer Institute. Eligible cases were women ages 65–79 years with a first diagnosis of primary invasive breast carcinoma made between April 1, 1997 and May 31, 1999, whose names appeared on a list of Social Security recipients prepared by the Centers for Medicare and Medicaid Services (CMS) and who resided in either King, Snohomish, or Pierce County, Washington at the time of diagnosis. The CMS Social Security list included all individuals age ≥ 65 years residing in the U.S. who are eligible for Medicare benefits. Approximately 97% of people age ≥ 65 years residing in the U.S. were enrolled in the Medicare program in 1991.28 Cases were excluded for blindness and inability to communicate. A total of 975 of the 1210 eligible breast carcinoma cases (80.6%) completed the study interview. Of the 235 cases not interviewed, 73% refused to be interviewed, 19% died before an interview could be conducted, 4% moved away from the area, and the physicians treating 4% of cases refused to allow contact with their patients.

The CMS list of Social Security recipients were used to identify women from the general population of female residents of King, Snohomish, and Pierce counties who were the same ages (frequency matched) as the cases to serve as controls. Control reference dates were assigned to reflect the expected distribution of case diagnosis dates. Controls met the same exclusion criteria as cases. Of the 1365 eligible controls identified, 1007 (73.8%) were interviewed. Of the 358 controls who were not interviewed, 84% refused, 7% died after selection but before they could be interviewed, 6% moved away, and 4% could not be located. Cases and controls were asked to participate through letters and telephone calls. Subjects were paid $10 for their participation in the study.

Data Collection

The study protocol was approved by the institutional review board of the Fred Hutchinson Cancer Research Center (Seattle, WA). Informed consent was obtained from all study subjects. The in-person interview asked participants to provide information regarding demographic characteristics, reproductive history, lifestyle factors, medical history, and family history of breast carcinoma. In addition, a detailed inventory was collected concerning all lipid-lowering medications, cardiovascular medications, antidepressant medications, and hormone replacement therapy (HRT) used in the past 20 years. For each course of medication use, the brand name, strength, directions for use, indication(s) for use, start and stop dates, and total duration of use were recorded. Information concerning all current medication use was transcribed from the prescription labels on the medication containers provided by participants during the interview. A calendar of life events and a photograph book of lipid-lowering drugs, HRTs, and certain classes of antihypertensive drugs were used to improve the subject's recall of previous exposures. Weight and height were obtained from study subjects at the time of interview.

A validation study compared self-reported medication use to pharmacy records in a sample of our study population.29 The sensitivity estimates of self-reported statin use compared with pharmacy records among cases and controls were 83% (95% confidence interval [95% CI], 64–93) and 93% (95% CI, 69–99) for the 6-month period before the reference date, 75% (95% CI, 55–88) and 86% (95% CI, 60–96) for the 2-year period before the reference date, and 67% (95% CI, 42–85) and 75% (95% CI, 41–93) for the 8-year period before the reference date. Although the controls appeared to recall statin use better than cases, the sensitivity estimates were not found to be statistically different. All specificity estimates approximated or were equal to 100% and did not differ between cases and controls.

Missing Data

The majority of statin users had complete data regarding the start (96.9%) and stop (98.5%) year of use. July was imputed for missing start months (52% of statin use) and June was imputed for missing stop months (14% of statin use). January was imputed as the start month when subjects knew the duration of use within a given year, but not the exact start and stop month (15% of statin use). There was no difference noted between cases and controls with regard to the number of exact dates that were missing.

We were unable to determine whether 1 control was a statin user (defined as at ≥ 6 months of use) and the observation was dropped from all analyses. Subjects with unknown total duration of statin use were excluded from any duration of use analyses (one case and two controls). There were 25 women who reported at least one course of lipid-lowering therapy of an unknown brand or generic name. The proportion of women with unknown lipid-lowering drug names (1.7% cases and 0.8% controls) did not appear to differ between cases and controls. We used sensitivity analyses to explore how the current study findings would change if the courses of unknown drug therapy were assumed to be statins. These sensitivity analyses revealed trivial changes in the results.

Statistical Analysis

Statin users included women with ≥ 6 months' total duration of statin use before the reference date. Women who reported using statins for < 6 months were excluded from all analyses (cases = 14, controls = 23). Current use was defined as statin use at the reference date or within 12 months before the reference date. Nonusers of statins were the comparison group for all analyses. We were unable to use other lipid-lowering medication users (bile acid sequestrants, niacin, and fibric acid derivatives) as a second comparison group because of the small number of users (3.5% of all women).

Using unconditional logistic regression, we examined the association between statin use and breast carcinoma while simultaneously adjusting for the matching variables (age, reference date, and county) and confounding effects of other exposures.30 Adjusted odds ratio (OR) estimates and respective 95% CIs were computed for statin use (users vs. nonusers), duration of use, recency of use, and type of statin use. The following established and hypothesized breast carcinoma risk factors were evaluated as potential confounders: HRT use (never, < 1 year, 1–5 years, > 5 years); current HRT use (yes, no); maximum lifetime weight (quartiles based on control distribution); indices of body mass (BMI; National Institutes of Health classification); diagnosis of hypertension (yes, no); use of antihypertensives (yes, no); smoking status (never, current, past); income (quartiles based on control distribution), education (< 12 years, 12 years, > 12 years), average daily alcohol use during the 20 years prior to the reference date (none, < 8.2 g, ≥ 8.2 g); menopausal status (natural, induced, simple hysterectomy [hysterectomy without a bilateral oophorectomy]); age at menopause (10-year categories); number of mammograms in the past 10 years (none, 1–9, ≥ 10); family history of breast carcinoma (first-degree relative, no first-degree relative); parity; age at first still or live birth (never pregnant, 14–19 years, 20–24 years, 25–29 years, ≥ 30 years); and use of other cholesterol-lowering medications (yes, no). HRT use included any postmenopausal reported use of systemic estrogen (oral or patches) either alone or in combination with progestin. Antihypertensive medication use included any use of calcium channel blockers, beta-adrenergic blockers, angiotensin II receptor antagonists, angiotensin-converting enzyme inhibitors, diuretics, and other central and peripheral antiadrenergic agents.1 Only antihypertensive medication use appreciably (> 10%) altered the OR and consequently all adjusted models contained covariates for the use of antihypertensive medications, age (5-year categories), reference date, and county of residence. Tests for difference in risk across subgroups were conducted using the likelihood ratio test for multiplicative interaction. All the analyses were performed with the STATA statistical package, Version 7.0 (Stata, College Station, TX).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

There was a higher proportion of white women, current smokers, and past smokers among cases than controls. Hypertension, use of antihypertensive medications, HRT use, and first-degree family history of breast carcinoma were more prevalent in cases than controls. Cases also had a somewhat higher maximum lifetime weight, older age at menopause, and more frequent mammograms in the past 10 years compared with controls. Other patient characteristics were comparable for the two groups (Table 1). Hypertension, use of antihypertensive medications, hyperlipidemia, and use of other lipid-lowering medications were more prevalent among statin users than nonusers (Table 2). Statin users had higher BMI values and were more likely to report natural menopause than nonusers.

Table 1. Characteristics of Study Participants by Case–Control Status, 1982 Women Ages 65–79 Years
CharacteristicsControls (n = 1007) (%)Cases (n = 975) (%)
  • a

    Includes calcium channel blockers, beta-blockers, angiotensin II receptor antagonists, angiotensin-converting enzyme inhibitors, other antiadrenergic agents, and diuretics.

  • b

    Includes systemic estrogen (oral or patches) either alone or in combination with progestin.

  • c

    Includes bile acid sequestrants, niacin, and fibric acid derivatives.

Demographics  
 Reference age (yrs)  
  65–69 330 (32.8)300 (30.8)
  70–74 381 (37.8)381 (39.1)
  75–79 296 (29.4)294 (30.2)
 Race  
  White 925 (91.9)929 (95.3)
  Black  37 (3.7) 16 (1.6)
  Asian/Pacific Islander  29 (2.9) 19 (2.0)
  Other/unknown  16 (1.6) 11 (1.1)
 Annual income  
  < $15,000 191 (21.7)177 (21.3)
  $15,000–$25,000 214 (24.3)198 (23.9)
  $25,000–$50,000 296 (33.6)296 (35.7)
  > $50,000 180 (20.4)159 (19.2)
  Missing126145
 Education  
  Less than high school 153 (15.2)126 (12.9)
  High school graduate 395 (39.3)376 (38.6)
  Some college 286 (28.4)312 (32.0)
  College graduate 172 (17.1)161 (16.5)
  Missing10
 Marital status  
  Married/Living as married 536 (53.2)517 (53.0)
  Widowed 315 (31.3)301 (30.9)
  Divorced/separated 121 (12.0)125 (12.8)
  Single  35 (3.5) 32 (3.3)
Lifestyle  
 Smoking status  
  Current 116 (11.5)129 (13.2)
  Past 369 (36.6)395 (40.6)
  Never 522 (51.9)450 (46.2)
  Missing01
 Average no. of g of alcohol per day  
  None 518 (51.6)461 (47.5)
  < 8.2 248 (24.7)249 (25.7)
  ≥ 8.2 238 (23.7)260 (26.8)
  Missing35
 Body mass index (kg/m2) at reference date  
  < 18.5  19 (2.0) 16 (1.7)
  18.5–24.9 389 (40.4)339 (36.1)
  25–29.9 318 (33.0)335 (35.7)
  ≥ 30 237 (24.6)249 (26.5)
  Missing4436
 Maximum weight (kg)  
  ≤ 63.5 287 (28.6)231 (23.8)
  63.6–72.6 264 (26.4)258 (26.6)
  72.7–83.5 235 (23.4)255 (26.3)
  83.6+ 216 (21.6)227 (23.4)
  Missing54
Reproductive history  
 Age at menopause (yrs)  
  23–39  64 (9.9) 38 (6.6)
  40–44  99 (15.3) 77 (13.4)
  45–49 172 (26.6)165 (28.7)
  50–54 222 (34.3)217 (37.8)
  55–68  90 (13.9) 77 (13.4)
  Missing360401
 Type of menopause  
  Natural 607 (61.6)583 (61.4)
  Induced 148 (15.0)129 (13.6)
  Simple hysterectomy 231 (23.4)237 (25.0)
  Missing2126
Medical history  
 First-degree family history of breast carcinoma  
  No 771 (82.9)703 (77.2)
  Yes 159 (17.1)208 (22.8)
  Missing7764
 Hypercholesterolemia  
  No 652 (65.3)638 (65.9)
  Yes 347 (34.7)330 (34.1)
  Missing87
 Hypertension  
  No 538 (53.4)477 (48.9)
  Yes 469 (46.6)498 (51.1)
 Mammograms in past 10 yrs  
  None 129 (12.9) 99 (10.3)
  1–9 596 (59.8)514 (53.8)
  ≥ 10 272 (27.3)343 (35.9)
  Missing1019
Medication use  
 Antihypertensivesa  
  No 510 (50.8)443 (45.9)
  Yes 494 (49.2)523 (54.1)
  Unknown39
 Hormone replacement therapy (yrs)b  
  Nonusers 339 (33.8)284 (29.3)
  < 1 118 (11.8) 94 (9.7)
  1–5 116 (11.6) 95 (9.8)
  > 5 431 (42.9)497 (51.2)
  Unknown35
 Nonstatin lipid-lowering drugsc  
  No 966 (96.2)942 (96.8)
  Yes  38 (3.8) 31 (3.2)
  Unknown32
Table 2. Characteristics of Study Participants by Statin Use
CharacteristicsNonusers (n = 1713)Statin users (n = 231)d
  • a

    Includes calcium channel blockers, beta-blockers, angiotensin II receptor antagonists, angiotensin-converting enzyme inhibitors, other antiadrenergic agents, and diuretics.

  • b

    Includes systemic estrogen (oral or patches) either alone or in combination with progestin.

  • c

    Includes bile acid sequestrants, niacin, and fibric acid derivatives.

  • d

    Includes statin use of ≥ 6 months.

Demographics  
 Reference age (yrs)  
  65–69 542 (31.6) 75 (32.5)
  70–74 660 (38.5) 91 (39.4)
  75–79 511 (29.8) 65 (28.1)
 Race  
  White1607 (93.8)216 (93.5)
  Black  44 (2.6)  5 (2.2)
  Asian/Pacific Islander  41 (2.4)  6 (2.6)
  Other/unknown  21 (1.2)  4 (1.7)
 Annual income  
  < $15,000 325 (22.1) 38 (18.5)
  $15,000–$25,000 345 (23.4) 57 (27.8)
  $25,000–$50,000 509 (34.6) 72 (35.1)
  > $50,000 294 (20.0) 38 (18.5)
  Missing24026
 Education  
  Less than high school 240 (14.0) 33 (14.3)
  High school graduate 659 (38.5) 96 (41.6)
  Some college 517 (30.2) 68 (29.4)
  College graduate 296 (17.3) 34 (14.7)
  Missing10
 Marital status  
  Married/living as married 906 (52.9)125 (54.1)
  Widowed 528 (30.8) 79 (34.2)
  Divorced/separated 219 (12.8) 21 (9.1)
  Single  60 (3.5)  6 (2.6)
Lifestyle  
 Smoking status  
  Current 210 (12.3) 27 (11.7)
  Past 646 (37.7)104 (45.0)
  Never 856 (50.0)100 (43.3)
  Missing10
 Average no. of g of alcohol per day  
  None 843 (49.4)116 (50.9)
  < 8.2 428 (25.1) 59 (25.9)
  ≥ 8.2 437 (25.6) 53 (23.2)
  Missing53
 Body mass index (kg/m2) at reference date  
  < 18.5 635 (38.7) 75 (33.2)
  18.5–24.9  35 (2.1)  0
  25–29.9 567 (34.6) 77 (34.1)
  ≥ 30 403 (24.6) 74 (32.7)
  Missing735
 Maximum weight (kg)  
  ≤ 63.5 465 (27.3) 43 (18.7)
  63.6–72.6 446 (26.2) 64 (27.8)
  72.7–83.5 415 (24.3) 66 (28.7)
  83.6+ 379 (22.2) 57 (24.8)
  Missing81
Reproductive history  
 Age at menopause (yrs)  
  23–39  91 (8.6) 10 (7.3)
  40–44 156 (14.7) 17 (12.3)
  45–49 287 (27.0) 42 (30.4)
  50–54 385 (36.2) 46 (33.3)
  55–68 143 (13.5) 23 (16.7)
  Missing65193
 Type of menopause  
  Natural 978 (59.9)151 (70.6)
  Induced 253 (15.5) 17 (7.9)
  Simple hysterectomy 402 (24.6) 46 (21.5)
  Missing  
Medical history  
 First-degree family history of breast carcinoma  
  No1282 (80.3)164 (78.1)
  Yes 314 (19.7) 46 (21.9)
  Missing11721
 Hypercholesterolemia  
  No1287 (75.7)  3 (1.3)
  Yes 413 (24.3)227 (98.7)
  Missing131
 Hypertension  
  No 925 (54.0) 72 (31.2)
  Yes 788 (46.0)159 (68.8)
 Mammograms in past 10 yrs  
  None 203 (12.1) 18 (7.8)
  1–9 967 (57.4)120 (52.0)
  ≥ 10 514 (30.5) 93 (40.3)
  Missing290
Medication use  
 Antihypertensivesa  
  No 889 (52.2) 50 (21.7)
  Yes 813 (47.8)180 (78.3)
  Unknown111
 Hormone replacement therapy (yrs)b  
  Nonusers 547 (32.1) 64 (27.7)
  < 1 177 (10.4) 32 (13.9)
  1–5 177 (10.4) 29 (12.6)
  > 5 804 (47.2)106 (45.9)
  Unknown80
 Nonstatin lipid-lowering drugsc  
  No1678 (98.1)196 (86.0)
  Yes  33 (1.9) 32 (14.0)
  Unknown23

One hundred twelve cases (11.6%) and 119 controls (12.1%) used statins for ≥ 6 months. The median duration of statin use was 44 months (range, 6–361 months) for cases and 51 months (range, 6–256 months) for controls. The majority of these women were current users at the reference date (92% and 94%, respectively). Subjects tended to receive the same type of statin with only 27% changing the type of statin.

Compared with women who reported never using statins, ever users of statins (defined as ≥ 6 months of use) did not differ with regard to their risk of breast carcinoma (OR = 0.9; 95% CI, 0.7–1.2) (Table 3). There was some indication that among current users, long-term statin use (> 5 years) was related to a slight decrease in the risk of breast carcinoma (OR = 0.7; 95% CI, 0.4–1.0). We found no difference in breast carcinoma risk among the five different types of statins. The association between statin use and breast carcinoma was similar in subgroups defined by ever use of HRT, current HRT use, weight, BMI, and antihypertensive medication use.

Table 3. OR Estimates and 95% CIs for any Statin Use and Type of Statin Use: Results of Logistic Regression Models
ExposureNo. of cases (%)No. of controls (%)Adjusted model
ORc95% CI
  • OR: odds ratio; 95% CI: 95% confidence interval.

  • a

    Statin users of < 6 months' duration (14 cases, 23 controls) were excluded from all analyses. One subject was excluded for unknown use.

  • b

    Current use defined as the use of statins within the past 12 months. One case and two controls were excluded from duration analysis because of unknown duration of use.

  • c

    Odds ratio adjusted for age at reference date (5-year categories), reference year, county of residence, and use of antihypertensive medication (yes, no).

Nonuser849 (88.4)864 (87.9)1.0 
Ever statin usea112 (11.6)119 (12.1)0.90.7–1.2
Current user (yrs)b103 (10.7)112 (11.4)0.90.7–1.2
 ≤ 567 (7.1)61 (6.3)1.10.7–1.5
 > 535 (3.7)49 (5.0)0.70.4–1.0
Type of statin    
 Atorvastatin29 (3.3)34 (3.8)0.80.5–1.4
 Fluvastatin21 (2.4)18 (2.0)1.10.6–2.1
 Lovastatin36 (4.1)33 (3.7)1.00.6–1.7
 Pravastatin26 (3.0)25 (2.8)1.00.5–1.7
 Simvastatin34 (3.8)37 (4.1)0.90.6–1.4

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

There are several weaknesses that should be considered when interpreting the results of the current study. The main limitation of the current study, which included information collected retrospectively, is the possibility that self-reported histories of medication use and/or confounders were inaccurate. However, we believe that statin use is likely well remembered, because statins are typically taken daily, used for long durations, and have only been available on the American market since 1987. Greater than 90% of statin users (cases and controls) were current users and the majority of these women were able to produce their prescription bottles at interview. Results of our validation study indicate that statin use is recalled relatively well among older women.29

Although we do not know the exact adherence rate among the statin users, we did ask subjects to provide information concerning the number of pills prescribed per day/week/month and the average number of pills actually taken per day/week/month. We found that 99% of the statin users reported taking the same number of pills on average per day as that prescribed by their physician. In addition, < 1% of these women reported stopping the medication for > 6 months and only 1 subject reported taking statins on an as-needed basis. However, at least 2 cohort studies have found that adherence to statin therapy declines > 25% in the first 6 months after the original prescription, with a further declines in adherence the longer the cohort was followed.31, 32

Another limitation of the current study is the difference in response rates between cases and controls (80.6% vs. 73.8%). This could have biased our results if women who used statins participated differently in the study. It has been suggested that statin users may differ from nonusers with regard to socioeconomic status.33 However, we adjusted for income and education in assessment of potential confounding and they did not appear to alter the study findings. We were unable to adjust for serum cholesterol level in our analyses, but we do not believe that this would have appreciably confounded the current study results because several large cohort studies have failed to find any association between cholesterol level and breast carcinoma risk.34–37

The strengths of this case–control study include the following: use of a population-based design to select cases and controls; histologically confirmed breast carcinoma cases; the use of a calendar of life events and photograph books of selected medications, including statins, to improve recall; the high response rate of both cases and controls; and the ascertainment of information on an extensive range of potential confounders.

In the population-based, case–control study of older women, we found no evidence of an increased risk of breast carcinoma among statin users. This is especially important because of safety concerns that have been raised regarding statin use and cancer.3, 4, 38–40 On the contrary, the results of the current study suggest a reduction in the risk of breast carcinoma in relation to statin use of > 5 years. Current users of statins for > 5 years duration had a 30% reduced risk of breast carcinoma compared with nonusers.

The few studies to date that have reported on the relation between statins and breast carcinoma have found little evidence of an association. Blais et al.8 conducted a large nested case–control study to explore the association between statins and cancer incidence in men and women age ≥ 65 years. The investigators reported that ever-use of statins was associated with a reduced risk of overall cancer incidence (relative risk [RR] = 0.72; 95% CI, 0.57–0.92), and possibly a reduced risk of female breast carcinoma incidence (RR = 0.67; 95% CI, 0.33–1.38). A population-based cohort study conducted by Olsen et al.9 comprising women of a wide age span, found no evidence of an association between statin use and overall cancer risk (standardized incidence ratio [SIR] = 0.8; 95% CI, 0.5–1.3) or breast carcinoma risk (SIR = 1.5; 95% CI, 0.3–4.3). Both studies were limited by a small number of breast carcinoma cases. Coogan et al.10 reported an increase in breast carcinoma risk among statin users (OR = 1.5; 95% CI, 1.0–2.3) in a hospital-based, case–control study among women ages 50–79 years. The increase in risk was confined largely to the cases with carcinoma in situ (OR = 1.8; 95% CI, 0.9–3.6) and did not appear to be present in the invasive disease cases (OR = 1.2; 95% CI, 0.7–2.0). A population-based, case–control study recently was conducted among 1233 women (224 cases and 1009 controls) women ages 50–79 years using the General Practice Research Database.11 Compared with women with no diagnosis of hyperlipidemia or lipid-lowering drug use, there was no apparent association between statin use and breast carcinoma risk (OR = 1.0; 95% CI, 0.6–1.6). There was no validation of breast carcinoma cases or a distinction between carcinoma in situ and invasive breast carcinoma. Unlike the current study, there was limited information available regarding potential cofounders and duration of statin use. The wide 95% CI values reported in the studies by Kaye et al.11 and Coogan et al.10 are primarily due to the small number of cases exposed to statins. Beck et al.12 reported an RR of 0.81 (95% CI, 0.53–1.24) among statin users age ≤ 55 years and an RR of 1.15 (95% CI, 0.97–1.37) among statin users age > 55 years. Subanalyses of women age > 55 years revealed increases in breast carcinoma risk among short-term statin users (< 6 months) and among statin users with long-term HRT. Most recently, a cohort study of lipid-lowering medications and breast carcinoma risk among older women found a reduced risk of breast carcinoma among statin users (RR = 0.28; 95% CI, 0.09–0.86) and users of other lipid-lowering drugs (RR = 0.37; 95% CI, 0.14–0.99).13

The current study results are supportive of the growing body of laboratory data that suggests regular statin use may protect against certain cancers, including invasive breast carcinoma.27 At least one statin, lovastatin, has been found to reduce mouse mammary tumor formation and metastatic diffusion of established mammary carcinoma.25 Small clinical trials have evaluated the dosing and scheduling of statins as adjuncts to chemotherapeutic agents.20, 41–44 The trials have found dosing to be significant, and dose-related toxicity to be minimal, but there has been only slight tumor response. One trial of longer duration (54 days) found a more favorable response among patients with leukemia.20 Additional clinical trials of low-dose statin regimens over longer time periods currently are underway.

Further complicating the conclusions regarding the relation between statin use and cancer is conflicting information regarding whether statins promote or inhibit angiogenesis.45–48 Angiogenesis is characterized by the formation of new capillaries from preexisting vessels. It has long been established that tumor growth and metastasis require new blood vessel growth.49, 50 It has been suggested that statins, specifically simvastatin, activate protein kinase Akt in the endothelium, leading to increased nitric oxide release.45, 48 This, in turn, increases angiogenesis both in vitro and in vivo.45, 48 Alternatively, at least two studies have shown that statins inhibit tumor-induced angiogenesis by reducing metabolites of the mevalonate pathway that are pivotal in angiogenesis.46, 47

Clearly, the effects of statins on cancer are not completely understood. Further research, both experimental and nonexperimental, will be useful in disentangling the potentially complex relation. The findings of the current study were obtained in a relatively older age group of patients and further studies in younger populations may be needed. Given the high and growing prevalence of statin use, it also is important to continue monitoring their long-term safety profiles. In the current study, only 13% of statin users had taken statins for ≥ 10 years, which limited our ability to explore a more detailed duration-response relation. Studying the long-term effects of statins on cancer and other endpoints is becoming more feasible as both the prevalence of use and the time available on the market increases. The increasing trend of statin use is likely to continue because of an aging population, aggressive direct-to-consumer advertising campaigns, expanded indications for the primary prevention of coronary heart disease, and widely publicized U.S. guidelines to expand the detection and treatment of coronary disease risk factors.51 The current study results both provide reassurance concerning the safety of statin use among older women and support the emerging evidence that statins may have a chemopreventive action on breast carcinoma risk.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    SewesterCS, DombekCE, OlinBR, KastrupEK, HebelSK, editors. Drug facts and comparisons, 2001 ed. St. Louis, MOi: Facts and Comparisons, 2001.
  • 2
    Sandox N. RxList. 1995. The internet drug index [database on-line]. Available from URL: www.rxlist.com [Accessed 16 July 2002].
  • 3
    Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA. 1996; 275: 5560.
  • 4
    Lewis SJ, Sacks FM, Mitchell JS, et al. Effect of pravastatin on cardiovascular events in women after myocardial infarction: the cholesterol and recurrent events (CARE) trial. J Am Coll Cardiol. 1998; 32: 140146.
  • 5
    Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA. 1998; 279: 16151622.
  • 6
    The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998; 339: 13491357.
  • 7
    Miettinen TA, Pyorala K, Olsson AG, et al. Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S). Circulation. 1997; 96: 42114218.
  • 8
    Blais L, Desgagne A, LeLorier J. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study. Arch Intern Med. 2000; 160: 23632368.
  • 9
    Olsen JH, Johansen C, Sorensen HT, et al. Lipid-lowering medication and risk of cancer. J Clin Epidemiol. 1999; 52: 167169.
  • 10
    Coogan PF, Rosenberg L, Palmer JR, Strom BL, Zauber AG, Shapiro S. Statin use and the risk of breast and prostate cancer. Epidemiology. 2002; 13: 262267.
  • 11
    Kaye JA, Meier CR, Walker AM, Jick H. Statin use, hyperlipidaemia, and the risk of breast cancer. Br J Cancer. 2002; 86: 14361439.
  • 12
    Beck P, Wysowski DK, Downey W, Butler-Jones D. Statin use and the risk of breast cancer. J Clin Epidemiol. 2003; 56: 280285.
  • 13
    Cauley JA, Zmuda JM, Lui LY, et al. Lipid-lowering drug use and breast cancer in older women: a prospective study. J Womens Health. 2003; 12: 749756.
  • 14
    Jones KD, Couldwell WT, Hinton DR, et al. Lovastatin induces growth inhibition and apoptosis in human malignant glioma cells. Biochem Biophys Res Commun. 1994; 205: 16811687.
  • 15
    Reedquist KA, Pope TK, Roess DA, et al. Lovastatin inhibits proliferation and differentiation and causes apoptosis in lipopolysaccharide-stimulated murine B cells. Biochem Biophys Res Commun. 1995; 211: 665670.
  • 16
    Wong WW, Tan MM, Xia Z, Dimitroulakos J, Minden MD, Penn LZ. Cerivastatin triggers tumor-specific apoptosis with higher efficacy than lovastatin. Clin Cancer Res. 2001; 7: 20672075.
  • 17
    Newman A, Clutterbuck RD, Powles RL, Catovsky D, Millar JL. A comparison of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors simvastatin, lovastatin and pravastatin on leukemic and normal bone marrow progenitors. Leuk Lymphoma. 1997; 24: 533537.
  • 18
    Dimitroulakos J, Yeger H. HMG-CoA reductase mediates the biological effects of retinoic acid on human neuroblastoma cells: lovastatin specifically targets P-glycoprotein-expression cells. Nat Med. 1996; 2: 326333.
  • 19
    Clutterbuck RD, Millar BC, Powles RL, et al. Inhibitory effect of simvastatin on the proliferation of human myeloid leukaemia cells in severe combined immunodeficient (SCID) mice. Br J Haematol. 1998; 102: 522527.
  • 20
    Minden MD, Dimitroulakos J, Nohynek D, Penn LZ. Lovastatin induced control of blast cell growth in an elderly patient with acute myeloblastic leukemia. Leuk Lymphoma. 2001; 40: 659662.
  • 21
    Padayatty SJ, Marcelli M, Shao TC, Cunningham GR. Lovastatin-induced apoptosis in prostate stromal cells. J Clin Endocrinol Metab. 1997; 82: 14341439.
  • 22
    Xia Z, Tan MM, Wong WW, Dimitroulakos J, Minden MD, Penn LZ. Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells. Leukemia. 2001; 15: 13981407.
  • 23
    Denoyelle C, Vasse M, Korner M, et al. Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in-vitro study. Carcinogenesis. 2001; 22: 11391148.
  • 24
    Dimitroulakos J, Ye LY, Benzzaquen M, et al. Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications. Clin Cancer Res. 2001; 7: 158167.
  • 25
    Alonso DF, Farina HG, Skilton G, Gabri MR, De Lorenzo MS, Gomez DE. Reduction of mouse mammary tumor formation and metastasis by lovastatin, an inhibitor of the mevalonate pathway of cholesterol synthesis. Breast Cancer Res Treat. 1998; 50: 8393.
  • 26
    Inano H, Suzuki K, Onoda M, Wakabayashi K. Anti-carcinogenic activity of simvastatin during the promotion phase of radiation-induced mammary tumorigenesis of rats. Carcinogenesis. 1997; 18: 17231727.
  • 27
    Wong WW-L, Dimitroulakos J, Minden MD, Penn LZ. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia. 2002; 16: 508519.
  • 28
    Apodaca R, Judkins D, Lo A, Skellan K. Sampling from HCFA lists. Alexandria, VA: American Statistical Association, Proceedings from the Survey Research Methods Section, 1992: 250255.
  • 29
    Boudreau DM, Daling JR, Malone KE, Gardner JS, Blough DK, Heckbert SR. A validation study of patient interview data and pharmacy records for antihypertensive, statin, and antidepressant medication use among older women. Am J Epidemiol. 2004; 159: 308317.
  • 30
    Schlesselman JJ. Case-control studies. Design, conduct, analysis. Oxford, UK: Oxford University Press, 1982.
  • 31
    Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA. 2002; 288: 462467.
  • 32
    Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J. Long-term persistence in use of statin therapy in elderly patients. JAMA. 2002; 288: 455461.
  • 33
    Mamdani MM, Tu K, Austin PC, Alter DA. Influence of socioeconomic status on drug selection for the elderly in Canada. Ann Pharmacother. 2002; 36: 804808.
  • 34
    Tornberg SA, Holm LE, Carstensen JM. Breast cancer risk in relation to serum cholesterol, serum beta-lipoprotein, height, weight, and blood pressure. Acta Oncol. 1988; 27: 3137.
  • 35
    Williams RR, Sorlie PD, Feinleib M, McNamara PM, Kannel WB, Dawber TR. Cancer incidence by levels of cholesterol. JAMA. 1981; 245: 247252.
  • 36
    Gaard M, Tretli S, Urdal P. Risk of breast cancer in relation to blood lipids: a prospective study of 31,209 Norwegian women. Cancer Causes Control. 1994; 5: 501509.
  • 37
    Knekt P, Reunanen A, Aromaa A, Heliovaara M, Hakulinen T, Hakama M. Serum cholesterol and risk of cancer in a cohort of 39,000 men and women. J Clin Epidemiol. 1988; 41: 519530.
  • 38
    Bjerre LM, LeLorier J. Do statins cause cancer? A meta-analysis of large randomized clinical trials. Am J Med. 2001; 110: 716723.
  • 39
    Dalen JE, Dalton W. Does lowering cholesterol cause cancer? JAMA. 1996; 275: 6769.
  • 40
    Davey Smith G, Pekkanen J. Should there be a moratorium on the use of cholesterol lowering drugs? BMJ. 1992; 304: 431434.
  • 41
    Kawata S, Yamasaki E, Nagase T, et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer. 2001; 84: 886891.
  • 42
    Thibault A, Samid D, Tompkins AC, et al. Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res. 1996; 2: 483491.
  • 43
    Larner J, Jane J, Laws E, Packer R, Myers C, Shaffrey M. A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme. Am J Clin Oncol. 1998; 21: 579583.
  • 44
    Kim WS, Kim MM, Choi HJ, et al. Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma. Invest New Drugs. 2001; 19: 8183.
  • 45
    Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000; 6: 10041010.
  • 46
    Vincent L, Chen W, Hong L, et al. Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect. FEBS Lett. 2001; 495: 159166.
  • 47
    Feleszko W, Balkowiec EZ, Sieberth E, et al. Lovastatin and tumor necrosis factor-alpha exhibit potentiated antitumor effects against Ha-ras-transformed murine tumor via inhibition of tumor-induced angiogenesis. Int J Cancer. 1999; 81: 560567.
  • 48
    Simons M. Molecular multitasking: statins lead to more arteries, less plaque. Nat Med. 2000; 6: 965966.
  • 49
    Saaristo A, Karpanen T, Alitalo K. Mechanisms of angiogenesis and their use in the inhibition of tumor growth and metastasis. Oncogene. 2000; 19: 61226129.
  • 50
    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996; 86: 353364.
  • 51
    Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001; 285: 24862497.