Abstract
Background/Aims
Statins are widely used and of high interest as potential chemopreventive agents for cancer. Preclinical studies suggest that lipophilic statins have anti-cancer properties targeting hormone receptor (HR)-negative breast cancer. Few epidemiologic studies have investigated the relationship between lipophilic statin use and risk of breast cancer, stratified by HR status. We conducted a large case-control study within the Kaiser Permanente of Northern California (KPNC) to determine whether chronic use of lipophilic statins is associated with decreased risk of HR-negative breast cancer, or other breast cancer subtypes.
Methods
We identified 22,488 breast cancer cases diagnosed during 1997-2007, and 224,860 controls matched to cases based upon birth year and duration of KPNC pharmacy coverage. Use of lipophilic statins was ascertained using KPNC's comprehensive electronic pharmacy records.
Results
We found no association between lipophilic statin use (≥2 years vs. never) and overall breast cancer risk (ORadj=1.02; 95%CI=0.97-1.08) in conditional logistic regression models adjusted for oral contraceptive and hormone therapy use. Women who used lipophilic statins did not have a decreased risk of HR-negative breast cancer (ORadj=0.98; 95%CI=0.84-1.14), nor altered risk of HR-positive disease (ORadj=1.03; 95%CI=0.97-1.10). Furthermore, lipophilic statin use was not associated with risk of any of the intrinsic subtypes, luminal A, luminal B, HER2+/ER- or triple negative.
Conclusions
Our results do not support an association of lipophilic statin use with the risk of breast cancer in general or with risks of HR-negative or other breast cancer subtypes specifically.
Impact
These findings do not confirm previous reports of a possible preventive association.
INTRODUCTION
Breast cancer is the most frequently diagnosed cancer and second leading cause of cancer death among US women (1). This heterogeneous disease is composed of distinct tumor subtypes with characteristic molecular profiles (2), patient prognoses (3, 4) and treatment options (5). Hormone receptor (HR) negative subtypes develop earlier, are more aggressive, and contribute disproportionately to breast cancer mortality (6-8). They also include the triple negative subtype, for which targeted treatment options are limited, because these tumors lack the therapeutic targets: estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2/ERBB2) (9). Statins, or HMG-CoA reductase inhibitors, can affect a wide range of molecular processes such as inflammation, cell migration, proliferation and apoptosis (10, 11), which are integral to the development of cancer, including breast cancer. Furthermore, they are widely prescribed for their cholesterol-lowering capabilities and are well tolerated. Therefore, even a small effect of statins on the risk of breast cancer, particularly the HR-negative subtypes, would have a significant public health impact in reducing breast cancer mortality.
Preclinical studies suggest that lipophilic statins may have anti-cancer effects specifically targeting HR-negative breast cancer. Lipophilic statins, such as atorvastatin, simvastatin and lovastatin (12) constitute the majority of statin medications prescribed today. This class of statins can freely diffuse across cell membranes, unlike hydrophilic statins, leading to greater bioavailability in peripheral tissues, such as breast. In vitro studies have shown that lipophilic statins cause significant growth inhibition in HR-negative breast cancer cell lines, but only limited effects in HR-positive cell lines (13-15). Interestingly, the human breast cancer cell line MD-231, which corresponds to the triple negative breast cancer phenotype, is particularly susceptible to lipophilic statins (14). In vivo studies in mouse models of breast cancer have shown that the chemopreventive effects of lipophilic statins on decreasing tumor multiplicity appear to depend on the mode of administration, proving modestly effective when injected intraperitoneally (16, 17), but ineffective when dosed orally (18).
Epidemiological studies have also suggested that use of lipophilic statins may reduce breast cancer risk, however several questions remain unanswered. A study including 4383 incident cases of invasive breast cancer within the Women's Health Initiative (WHI) cohort found that use of lipophilic statins specifically, but not statins generally, was associated with a modest reduction in overall breast cancer risk (19). Three subsequent meta-analyses found no differences in overall breast cancer risk associated with lipophilic statin use (20-22). Unfortunately, these previous studies did not stratify their findings for lipophilic statins by tumor hormone-receptor status, perhaps because of small numbers. Most recently, a case-only study of 2830 breast cancer patients diagnosed in 2003 within Kaiser Permanente of Northern California (KPNC) by Kumar et al. found that women with HR-negative breast tumors were less likely than those with HR-positive tumors to have used lipophilic statins (23). This finding has evoked debate on whether lipophilic statins, specifically, might reduce risk of HR-negative disease. However, as Byers (24) pointed out in an accompanying editorial, the absence of a control group limited this study's ability to distinguish between a reduction in risk of HR-negative breast cancers, an increase in risk of HR-positive tumors, or both.
We conducted a case-control study of 22,488 invasive breast cancer cases diagnosed during 1997-2007, and 224,860 matched controls, within the KPNC healthcare system to examine whether chronic use of lipophilic statins is associated with: (1) decreased risk of HR-negative breast cancer without affecting risk of HR-positive disease; (2) increased risk of HR-positive breast cancer without affecting risk of HR-negative disease; or (3) both decreased risk of HR-negative breast cancer and increased risk of HR-positive disease. Furthermore, we investigated whether lipophilic statins are associated with the risk of any of the intrinsic breast cancer subtypes, luminal A, luminal B, HER2+/ER- and triple negative, as defined by ER, PR and HER2 status. We also attempted to replicate the case-only study findings of Kumar et al. (23). KPNC is a non-profit, integrated healthcare delivery system with electronic records capturing in- and outpatient services, pharmacy information and central laboratory results for over 3 million members. To our knowledge, this study is the largest case-control study of lipophilic statin use and breast cancer risk to date, and the first to examine the risk of intrinsic breast cancer subtypes in relation to statin use.
MATERIALS AND METHODS
Study Population
We conducted a case-control study within the member population of the KPNC healthcare delivery system. Statin use was ascertained via the KPNC Pharmacy Information System (PIMS), which records prescription medications dispensed at all KPNC pharmacies since August 1994. We restricted our analysis to cases and controls with follow-back periods of ≥ 2 years from the diagnosis/index date to the beginning of their prescription drug coverage (“coverage”). Cases were identified through KPNC Cancer Registry (KPNCCR) records. Cases consisted of all women diagnosed with invasive breast cancer with known hormone receptor status between January 1, 1997 and December 31, 2007. Controls were matched to cases based upon exact year of birth and duration of coverage, at a ratio of 10:1, if available (mean 9.9, range 6 -10 controls per case).
This study was approved by the Institutional Review Board (IRB) of the Kaiser Foundation Research Institute.
Statin Use
Nearly 98% of all dispensed statins by KPNC pharmacies are composed of the lipophilic statins, lovastatin, simvastatin and atorvastatin (25). Therefore, we restricted our analysis to these three agents and will henceforth refer to them simply as “statins”. Using the KPNC automated pharmacy database, we ascertained statin brands and refill dates for all study participants. We restricted our analysis to statin use that preceded the breast cancer diagnosis/index date. Women had to receive at least two prescriptions to be considered statin users because, without a refill, statin use may have been discontinued promptly due to side effects or other reasons. Women with zero or one statin prescription were considered “never” users.
In our primary analysis, statin use was defined as at least two years of use to reduce the possibility of detection bias, i.e. the detection of a tumor as a consequence of a physician visit at which statins were prescribed. Therefore, cases and controls were restricted to those with at least 2 years of enrollment and pharmacy benefits prior to diagnosis/index date. To explore a possible duration effect, statin use was also categorized as “never”, as defined above, “< 1 year”, “1 to < 2 years”, “2 to < 3 years”, “3 to <5 years” and “≥ 5 years” of use. Duration of statin use before the diagnosis/index date was calculated by adding up the days supply of all prescriptions, accounting for dispensing before the previous prescription was to be used up, and not differentiating between receipt of a single statin and sequential combination of any of the three statins studied.
We also obtained prescription information on oral contraceptive (OC) use and menopausal hormone therapy (HT) use from the KPNC pharmacy database. A minimum of two filled prescriptions of OC or HT was required to be classified as a user. We considered women to be OC users if they had documented OC use within 10-years, and HT users if they used HT within 5-years prior to diagnosis, in accordance with the estimated time periods when breast cancer risk is elevated (26, 27). HT included both estrogens and progestins because a previous study of lipophilic statin use and overall breast cancer risk in the KPNC health care system showed no appreciable confounding by HT when adjusting separately for estrogens, progestins and other female hormone preparations (25).
Tumor Characteristics
Information on tumor characteristics was obtained from the KPNCCR. Histological grade is scored based on Scarff Bloom Richardson criteria as: I (low grade), II (moderate grade), or III (high grade). Tumor stage is recorded as: LOC (localized malignancy), REG (regional malignancy), or DIS (distant metastases) in accordance with the Surveillance, Epidemiology, and End Results (SEER) reporting guidelines (28).
Immunohistochemistry (IHC) testing was conducted by the KPNC IHC Laboratory: a high volume reference laboratory with over 11,000 patients yearly, of which approximately one third are breast cancer cases. Breast cancer cases are routinely tested for ER, PR and HER2. IHC stains are manually interpreted by 4 full-time immunopathologists. The laboratory has been designated as a center of excellence for HercepTest interpretation by the DAKO Corporation, licensed by the Clinical Laboratory Improvement Amendments (CLIA), and certified by the College of American Pathologists (CAP). Fluorescence in-situ hybridization (FISH) assays were conducted by the KPNC Genetics Laboratory.
ER and PR testing results have been routinely documented in the electronic pathology records of the KPNCCR since 1996. Tumors with > 5% nuclear staining were considered positive for ER and PR expression. Tumor expression of HER2 was assessed by IHC, and if 2+ or specifically requested by a clinician, by FISH. Tumors with IHC staining of 0, 1+, or 2+ and negative FISH results were considered HER2-negative, while tumors with either IHC staining of 3+ or positive FISH results (ratio > 2.0) were considered HER2-positive, in accordance with the guidelines of the American Society of Clinical Oncology (ASCO) and CAP (29). While HER2 testing has been routinely performed on invasive breast cancers since 2000, we restricted our analyses requiring HER2 data to the years 2002-2007, when the HER2 results were considerably more complete in the KPNCCR than in prior years.
HR-positive tumors were ER-positive, PR-positive, or both. HR-negative tumors were ER-negative/PR-negative or ER-negative/PR-unknown. We defined the intrinsic breast cancer subtypes (2, 3) luminal A, luminal B, HER2+/ER- and triple negative based on tumor ER, PR and HER2 expression, similarly to what was done by Carey et al. (7). Intrinsic subtypes classified by IHC-based tumor markers have been shown to be equally predictive of patient prognosis as their gene expression-based counterparts (7). Subtype luminal A was defined as ER-positive and/or PR-positive and HER2-negative; luminal B as ER-positive and/or PR-positive and HER2-positive; HER2+/ER- as ER-negative and PR-negative and HER2-positive; and triple negative tumors as ER-negative and PR-negative and HER2-negative. The triple negative tumor category contains the basal-like and the normal breast-like subtypes. IHC testing is not routinely done for the other two markers (CK 5/6 and HER1) used by Carey et al. to identify the basal-like group.
Statistical Analyses
We compared the distribution of individual characteristics among various patient groups using chi-square tests for discrete variables and t-tests for continuous variables. In matched case-control analyses, odds ratios (ORs) for specific breast cancer subtypes associated with statin use were estimated using conditional logistic regression models and adjusted for OC and HT use. Adjustment for OC and HT use resulted in a ~2% change in the OR; these weak potential confounders were retained in all analyses to be conservative. We used unconditional logistic regression models (dichotomous outcomes) and polytomous logistic regression (multinomial outcomes) to estimate the ORs for the association of statin use and various tumor characteristics in case-only analyses. These unconditional regression models were adjusted for the matching variables age at diagnosis (“age”) modeled as age + age2 and duration of prescription coverage (“coverage”) categorized into quartiles, in addition to OC use, HT use and Race/Ethnicity (“race”) modeled as a categorical variable (Non-Hispanic white, Hispanic white, African American, Asian/Pacific Islander, Other). In polytomous logistic regression models, we calculated odds ratios comparing each category to a common reference group and examined global changes in the distribution of categorical tumor characteristics between statin users and non-users by the Maximum Likelihood ANOVA/Chi square test. All analyses were performed using SAS, version 9.1 (SAS Institute Inc., Cary, North Carolina).
Sensitivity Analysis
To evaluate the sensitivity of our results to the effects of unmeasured confounders we performed external adjustments (30, 31) for established risk factors for breast cancer that were also associated with statin use in KPNC's 2002 Member Health Survey (MHS). We restricted the survey population to 6985 women > 40 years of age who had a minimum of 2 years of prescription coverage in order to resemble the characteristics of our study cohort. In this random sample of KPNC members, statin use (≥2 years vs. never) was significantly associated with BMI (OR=1.67, ≥30 vs. <30) and alcohol consumption (OR=0.52, ≥7 vs. <7 drinks/week), and African American race (OR=1.50, African American vs. non-Hispanic whites) but not with any other racial/ethnic group or menopausal status (OR=1.01, post- vs. pre-menopausal) after adjusting for age, coverage, OC and HT use. The prevalence of statin use (≥ 2 years), obesity (BMI ≥30), alcohol consumption (≥ 7 drinks/week), and African Americans was 0.091, 0.238, 0.151, and 0.060, respectively, in the MHS population. We used the following literature-based estimates of the relative risks of HR-negative and HR-positive breast cancer, respectively: 1.06 and 1.82 in association with BMI ≥30 vs. <30 (32); and 1.10 and 1.22 in association with ≥7 vs. <7 alcoholic drinks per week (33).
We carried out external adjustment using the method of Schneeweiss (30) for BMI and alcohol consumption, and the method of Suissa (31) for African-American race in order to utilize the available race information in cases only. Briefly, in the Schneeweiss (30) external adjustment procedure the prevalence of the dichotomized confounders and the multivariate-adjusted ORs for their relationship with statin use were estimated from the MHS data. Estimates of the relative risks for HR-specific breast cancer associated with the potential confounders were obtained by using the most extreme estimate reported in the most recent meta-analyses (32, 33) found by conducting a PubMed literature search. Finally, the net bias of all confounders was estimated by the weighted average of the percent bias attributed to each confounder, where the weights correspond to the prevalence of each confounder. The Suissa (31) external adjustment procedure is similar except that it does not rely upon literature-based estimates of the confounder-disease relationship, utilizing the confounder information available among cases and inferred for controls using data from an external population instead.
RESULTS
Study Population
Our case-control study population consisted of 224,860 controls and 22,488 invasive breast cancer cases. Cases and controls were well matched with respect to age at time of diagnosis/index date and duration of follow-up in the KPNC pharmacy database (Table 1). As expected, we observed higher frequencies of oral contraceptives (OC) and menopausal hormone therapy (HT) in cases compared to controls. The prevalence and duration of statin use was similar between cases and controls (Table 1).
Table 1.
Characteristics of breast cancer cases diagnosed during 1997-2007 at KPNC and matched controls, by disease and hormone receptor status.
| Characteristic | All Controls N=224,860 | All Cases N=22,488 | HR-negative Cases N=3,996 | HR-positive Cases N=18,492 |
|---|---|---|---|---|
| Age at diagnosis/index date (years): mean ± s.d. | 61.11 ± 13.32 | 61.11 ± 13.32 | 57.68 ± 13.46 | 61.85 ± 13.17 |
| Years of prescription drug coverage: mean ± s.d. | 7.28 ± 3.19 | 7.28 ± 3.19 | 7.20 ± 3.15 | 7.30 ± 3.19 |
| *Oral contraceptive use: n, (%) | 19,080 (8.5) | 2,220 (9.9) | 468 (11.7) | 1,752 (9.5) |
| †Menopausal hormone therapy use: n, (%) | 89,664 (39.9) | 9,593 (42.7) | 1,553 (38.9) | 8,040 (43.5) |
| Lipophilic statin use: n, (%) | ||||
| Never use | 169,816 (75.5) | 17,079 (76.0) | 3,160 (79.1) | 13,919 (75.3) |
| “Ever” use | 55,044 (24.5) | 5,409 (24.0) | 836 (20.9) | 4,573 (24.7) |
| “≥ 2 years” use | 18,614 (8.3) | 1,888 (8.4) | 260 (6.5) | 1,628 (8.8) |
| Years of lipophilic statin use: mean ± s.d. | ||||
| Among “Ever” users | 0.53 ± 1.38 | 0.54 ± 1.41 | 0.44 ± 1.22 | 0.56 ± 1.45 |
| Among “≥ 2 years” users | 4.47 ± 2.20 | 4.55 ± 2.28 | 4.34 ± 2.27 | 4.58 ± 2.28 |
| ‡Race/ethnicity: n, (%) | ||||
| Non-Hispanic white | n/a | 16,256 (72.3) | 2,485 (62.2) | 13,771 (74.5) |
| Hispanic white | n/a | 1,574 (7.0) | 360 (9.0) | 1,214 (6.6) |
| African American | n/a | 1,803 (8.0) | 590 (14.8) | 1,213 (6.6) |
| Asian/Pacific Islander | n/a | 2,410 (10.7) | 463 (11.6) | 1,947 (10.5) |
| Other | n/a | 455 (2.0) | 98 (2.5) | 347 (1.9) |
Oral contraceptive “ever” use within 10 years prior to diagnosis/index date
Hormone therapy “ever” use within 5 years prior to diagnosis/index date
Race/ethnicity information was captured by the KPNC Cancer Registry and was available for cases only
Of the 22,488 invasive breast cancer cases in our study population, 82.2% were diagnosed with HR-positive and 17.8% with HR-negative tumors. Women diagnosed with HR-negative breast cancer were more likely to have used OCs within 10-years prior to diagnosis (p<0.0001) and less likely to have used HT within 5-years prior to diagnosis (p<0.0001) compared to HR-positive cases. HR-negative cases were less likely than HR-positive cases to have used statins (20.9% vs. 24.7%; p<0.0001) and tended to have used statins for shorter durations (0.44 vs. 0.56 years on average; p<0.0001), in part because of their younger age at diagnosis. HR-positive cases were more likely to be Non-Hispanic white and less likely to be Hispanic or African American than were HR-negative cases. The distribution of Asians and women within the ‘Other’ category was similar between HR-negative and HR-positive cases.
Risk of breast cancer in relation to statin use
In case-control analyses, we found no statistically significant association between statin use (≥ 2 years vs. never) and overall breast cancer risk (OR=1.02; 95% CI=0.97-1.08; p=0.42). Women who used statins for ≥ 2 years did not have a decreased risk of HR-negative breast cancer (OR=0.98; 95% CI=0.84 -1.14; p=0.74), or an increased risk of HR-positive breast cancer (OR=1.03; 95% CI=0.97-1.10; p=0.31) (Table 2). These null findings did not vary significantly among women aged 55 years or older versus younger than 55. Longer duration of statin use was also not consistently associated with decreasing risk of HR-negative breast cancer (ptrend=0.86) or increasing risk of HR-positive breast cancer (ptrend =0.58).
Table 2.
Risk of HR negative or positive breast cancer associated with statin use
| Statin Use | HR-negative Cases N=3,996 n (col%) | *Matched Controls N=39,960 n (col%) | †OR (95% CI) | HR-positive Cases N=18,492 n (col%) | ‡Matched Controls N=184,900 n (col%) | §OR (95% CI) |
|---|---|---|---|---|---|---|
| Never | 3,160 (79.1) | 31,694 (79.3) | Reference | 13,919 (75.3) | 138,122 (74.7) | Reference |
| ≥ 2 years | 260 (6.5) | 2,612 (6.5) | 0.98 (0.84-1.13) | 1,628 (8.8) | 16,002 (8.7) | 1.03 (0.97-1.10) |
| Never | 3,160 (79.1) | 31,694 (79.3) | Reference | 13,919 (75.3) | 138,122 (74.7) | Reference |
| < 1 yr | 440 (11.0) | 4,477 (11.2) | 1.02 (0.91-1.16) | 2,299 (12.4) | 24,107 (13.0) | 1.00 (0.95-1.05) |
| ≥ 1 – 2 yrs | 136 (3.4) | 1,177 (2.9) | 1.17 (0.97-1.41) | 646 (3.5) | 6,669 (3.6) | 0.97 (0.89-1.05) |
| ≥ 2 – 3 yrs | 93 (2.3) | 831 (2.1) | 1.13 (0.91-1.42) | 475 (2.6) | 4,827 (2.6) | 0.98 (0.89-1.08) |
| ≥ 3 – 5 yrs | 96 (2.4) | 1,040 (2.6) | 0.93 (0.75-1.16) | 604 (3.3) | 6,099 (3.3) | 0.99 (0.90-1.08) |
| ≥ 5 yr | 71 (1.8) | 741 (1.9) | 0.97 (0.75-1.25) | 549 (3.0) | 5,076 (2.7) | 1.08 (0.98-1.19) |
Controls matched to HR-negative cases bases on age at diagnosis/index date and years of prescription drug coverage
Odds ratios based on conditional logistic regression among HR-negative cases and their matched controls, adjusted for OC and HT use
Controls matched to HR-positive cases bases on age at diagnosis/index date and years of prescription drug coverage
Odds ratios based on conditional logistic regression among HR-positive cases and their matched controls, adjusted for OC and HT use
Subtype-specific case-control analyses showed little evidence that statin use was associated with the risk of developing a particular intrinsic breast cancer subtype (Table 3). Statin use of ≥ 2 years was associated with a slight, non-statistically significant increase in risk of luminal A type breast cancer, (OR=1.09; 95% CI=1.00 -1.18; p=0.057). We found no evidence that statin use altered the risk of the luminal B, HER2+/ER- or triple negative breast cancer subtypes. Therefore, it is unlikely that statins affect the risk of the four intrinsic breast cancer subtypes differentially.
Table 3.
Risk of intrinsic breast cancer subtypes associated with statin use
| Study Population | Statin use ≥ 2 years | Statin use “Never” | OR* (95% CI) |
|---|---|---|---|
| Luminal A | |||
| Controls | 8,990 (17.5) | 42,355 (82.5) | Reference |
| Cases | 948 (18.2) | 4,265 (81.8) | 1.09 (1.00 - 1.18) |
| Luminal B | |||
| Controls | 1,841 (14.4) | 10,910 (85.6) | Reference |
| Cases | 178 (13.8) | 1,110 (86.2) | 0.99 (0.82 -1.19) |
| HER2+/ER- | |||
| Controls | 676 (12.9) | 4,574 (87.1) | Reference |
| Cases | 71 (13.0) | 474 (87.0) | 1.05 (0.78-1.42) |
| Triple negative | |||
| Controls | 1118 (12.3) | 7,984 (87.7) | Reference |
| Cases | 111 (12.1) | 810 (87.9) | 0.93 (0.74 - 1.18) |
Odds ratios based on conditional logistic regression among cases classified by intrinsic subtype and respective matched controls, adjusted for OC and HT use
Tumor characteristics in relation to statin use
In analyses restricted to breast cancer cases, we examined whether HR status was associated with statin use, to replicate the findings of one previous smaller study (23). While statin use was slightly less likely among HR-negative breast cancer cases than among HR-positive cases (OR=0.91; 95%CI=0.78-1.05; p=0.18), this difference was not statistically significant. To further understand the difference between our study findings based upon 11 years of data and a previous study, which only included data from 2003 (23), we repeated our case-only (Figure 1A) and case-control (Figure 1B) analyses, stratified by year. We observed considerable fluctuations in the estimated OR on a year-by-year basis. The year 2003 appeared to be an outlier because it was the only year during the 11-year study period with a statistically significantly lower proportion of HR-negative cases in statin users (Figure 1A). This result was likely due to an unusually low risk of HR-negative breast cancer in statin users, particular to the year 2003, because the risk of HR-positive disease in statin users appeared to be stable across the 11-year study period (Figure 1B).
Figure 1. Trends in annual estimates of the association between statin use and breast cancer, by HR status.
Figure 1A shows annual estimates of the odds ratios (triangles) with 95% confidence intervals for the association of statin use (≥ 2 years vs. never) with hormone receptor status (HR- vs. HR+) in case-only analyses during the years 1997-2007. Figure 1B shows annual estimates of the odds ratios with 95% confidence intervals for the association of statin use (≥ 2 years vs. never) with risk of HR-negative (diamonds, solid lines) and HR-positive (squares, dashed lines) breast cancer in case-control analyses during the years 1997-2007. Summary estimates for the entire observation period are presented in each figure.
Among cases only, we also examined whether other tumor characteristics were associated with statin use (Table 4). After adjusting for race in addition to age, coverage, OC and HT use, cases who were statin users were slightly less likely than non-users to have tumors that were negative for ER expression (OR=0.88; 95%CI=0.76-1.02; p=0.086), PR expression (OR=0.89; 95%CI=0.80-0.99; p=0.036) and aberrant HER2 overexpression/amplification (OR=0.90; 95%CI=0.77-1.06, p=0.22). Only the result for PR expression reached borderline statistical significance and may be explained by chance in light of the multiple comparisons that were performed. There were no statistically significant differences in the global distributions of the intrinsic breast cancer subtypes between cases that were statin users vs. nonusers (χ23df = 5.16; p=0.16). Finally, statin use did not correlate with downshifts in either stage of diagnosis (χ22df =0.53; p=0.77) or histological tumor grade (χ22df =2.22; p=0.33).
Table 4.
Tumor characteristics associated with statin use
| Tumor Characteristic | Statin use ≥ 2 years | Statin use “Never” | OR* (95% CI) |
|---|---|---|---|
| ER Status | |||
| ER + | 1,623 (10.6) | 13,730 (89.4) | Reference |
| ER – | 265 (7.33) | 3,349 (92.7) | 0.88 (0.76-1.02) |
| PR Status | |||
| PR + | 1,307 (10.5) | 11,181 (89.5) | Reference |
| PR – | 571 (8.9) | 5,840 (91.1) | 0.89‡ (0.80-0.99) |
| HER2 Status† | |||
| HER2 – | 1,059 (17.3) | 5,075 (82.7) | Reference |
| HER2 + | 250 (13.6) | 1,585 (86.4) | 0.90 (0.77 - 1.06) |
| Intrinsic Subtype† | |||
| Luminal A | 948 (18.2) | 4,265 (81.8) | Reference |
| Luminal B | 178 (13.8) | 1,110 (86.2) | 0.94 (0.85-1.04) |
| HER2+/ER- | 71 (13.0) | 474 (87.0) | 0.93 (0.79-1.07) |
| Triple negative | 111 (12.1) | 810 (87.9) | 0.90 (0.78-1.01) |
| Tumor Stage | |||
| Localized | 1,325 (10.7) | 11,011 (89.3) | Reference |
| Regional | 493 (8.3) | 5,422 (91.7) | 0.99 (0.93 - 1.05) |
| Metastasis | 60 (10.3) | 520 (89.7) | 1.05 (0.90 - 1.20) |
| Tumor Grade | |||
| Grade I | 460 (11.6) | 3,492 (88.4) | Reference |
| Grade II | 783 (10.7) | 6,544 (89.3) | 1.02 (0.96-1.09) |
| Grade III | 397 (7.8) | 4,714 (92.2) | 0.97 (0.90-1.05) |
Adjusted for age, prescription drug coverage, OC use, HT use and race
HER2 status was only evaluated in tumors 2002-2007
p<0.05
Sensitivity analysis
External adjustment for obesity, alcohol consumption, and race showed that the magnitude of confounding due to these factors was small in our study. External adjustment for obesity and alcohol consumption using the Schneeweiss method (30) minimally changed the OR for the association of statin use with the risk of breast cancer from 0.98 to 0.97 for HR-negative cancer, and from 1.03 to 0.99 for HR-positive breast cancer. Similarly, external adjustment for race using the method of Suissa (31) minimally changed the crude OR from 1.00 to 0.98 for HR-negative cancer, while having no effect on the crude OR of 1.01 for HR-positive breast cancer. Furthermore, adjustment for race using the available data in case-only analyses barely changed the OR for the association of statin use with HR-negative vs. HR-positive tumors from 0.91 to 0.92. These results indicated that the main results of our study were not sensitive to the effects of obesity, alcohol, or race, and that other weaker unmeasured potential confounders were unlikely to influence our interpretation.
DISCUSSION
We report the results of the largest case-control study of statin use and breast cancer risk to date, to our knowledge, with 22,488 cases, which allowed us to investigate associations with risk of specific breast cancer subtypes. The use of lipophilic statins was not associated with risk of breast cancer overall. Statin use was not associated with a reduced risk of HR-negative breast cancer or an increased risk of HR-positive disease. We also found no statistically significant association with risk of luminal A, luminal B, HER2+/ER- or triple negative subtypes. Furthermore, our study showed no evidence that statin use affects the tumor expression of ER, PR or HER2, or the histological grade or stage at diagnosis. Collectively, our results indicate that use of lipophilic statins neither increases nor decreases the overall risk of breast cancer and argue against tumor subtype specific risk modulations.
Our finding that the overall risk of breast cancer is not associated with statin use contributes to existing evidence that statin medications are neutral with regard to breast cancer risk, a reassuring notion considering the widespread use of statins. Our relative risk estimate of OR=1.02 is consistent with that of a recent meta-analysis, which reported an overall relative risk of 1.01 (95% CI 0.79-1.30) based on seven randomized controlled trials (RCTs) (21). Such close agreement is important, because it suggests minimal effects of unmeasured confounders, which can be problematic in observational studies but are accounted for by randomization in RCTs. Furthermore our results agree with a large prospective cohort study in the KPNC membership, focusing on lipophilic statins specifically, that reported a relative risk of 1.02 (95% CI 0.86-1.21) for any breast cancer with at least 5 years of use (25). We could not confirm the WHI findings of an overall reduction in breast cancer risk associated with lipophilic statin use (HR = 0.82; 95% CI = 0.70 to 0.97) (19).
In our study, lipophilic statin use was not associated with either a reduction in risk of HR-negative or an increase in HR-positive breast cancer. These observations are consistent with the null findings of two earlier studies looking at HR-specific breast cancer risk (34, 35). However, these studies included both hydrophilic and lipophilic statins and did not stratify by lipophilicity. Furthermore, lipophilic statin use was not significantly associated with the risk of developing any of the four intrinsic breast cancer subtypes. To our knowledge, this is the first study to examine the risk of intrinsic breast cancer subtypes in relation to statin use.
The results of our 1997-2007 case-only analysis did not support the finding of a previous case-only study by Kumar et al. conducted among KPNC breast cancer patients diagnosed in 2003 (23). While our study found that HR-negative breast cancer patients were slightly less likely than HR-positive patients to have used statins (OR=0.91; 95%CI=0.78-1.05), this difference was not statistically significant. Interestingly, the year 2003 represented an outlier in the context of our 11 year study period. It was the only year for which HR-negative cases were statistically significantly less likely than HR-positive cases to have used lipophilic statin. To our knowledge there were no changes in reporting practices at KPNC, statin use, or breast cancer incidence that might explain the exceptional pattern in the year 2003. Therefore, while we were able to duplicate Kumar et al.'s (23) findings, based on 34 HR-negative and 269 HR-positive cases who had used statins for ≥1 year, these observations for the year 2003 likely reflect random variation and small numbers, rather than a true association between lipophilic statin use and breast cancer risk. Additionally, we found no evidence of significant alteration in ER, PR, or HER2 expression with statin use, that would be suggestive of a phenotypic switch to a more favorable breast cancer subtype, as postulated based on Kumar et al.'s findings (23, 24).
Our study design has several important strengths. First, the large size of our study allowed us to examine subtype-specific risks and provided high power to detect even modest associations between lipophilic statin use and HR-specific breast cancer risk. The size of our study further enabled us to stratify our analysis by calendar year, uncovering considerable variation, especially during the year 2003 upon which previous findings have been based (23). Second, KPNC electronic pharmacy records enabled accurate ascertainment of the timing and duration of lipophilic statin use. Electronic pharmacy records are highly accurate compared to interview or questionnaire-based methods, which rely on patient recall. Third, because nearly 98% of statins prescribed at KPNC are lipophilic, and all incident invasive breast cancer cases who met the eligibility criteria were included in our study, we minimized the potential for bias due to either sampling of cases or exclusion of hydrophilic statin users. Finally, the KPNC membership of over 3 million residents resembles the underlying general population in the greater Bay area (36) and more closely represents the racial/ethnic composition of the US population than patients in randomized controlled trials (37), adding to the external validity of our results.
The main limitation of our study was that information on potential confounding factors such as obesity, alcohol consumption, race/ethnicity or socioeconomic status was not available in the electronic records for all cases and controls. However, our sensitivity analysis showed minimal changes in the HR-specific relative risk estimates after externally adjusting for obesity, race/ethnicity and alcohol consumption, suggesting that these unmeasured confounders did not have a major impact on our results. This is consistent with the observations of other population-based studies of statins and breast cancer, which ascertained many potential confounders, but reported little difference between age-adjusted and fully-adjusted risk estimates (34, 35). A second limitation of our study is that ductal carcinomas in situ (DCIS), which today make up nearly 25% of newly diagnosed breast lesions, were not evaluated. We decided to focus our analysis on invasive breast cancer cases only because routine testing of DCIS tumors for ER and PR was not performed until 2000 in KPNC and HER2 testing is rarely done on DCIS tumors. In contrast to our study, Kumar et al. included 11.2% cases diagnosed at in situ stage (23); however, we obtained similar results for the year 2003, indicating that the exclusion of DCIS was unlikely to affect our conclusions.
In conclusion, our results do not support an association between lipophilic statin use and breast cancer risk in general or the risk of ER, PR and HER2-defined subtypes specifically. Any effect, if it exists at all, is likely to be much smaller than previous studies have suggested. These findings are reassuring with respect to the safety of chronic statin use, and should be considered in the interpretation of several ongoing breast cancer chemoprevention trials of lipophilic statins (38) as well as in the planning of future interventional studies using statin medications.
ACKNOWLEDGEMENTS
This work was supported by grant #R01 CA 098838 from the National Cancer Institute. SW was supported by the Cancer Prevention Fellowship Program, Office of the Director, National Cancer Institute.
REFERENCES
- 1.Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer Statistics, 2009. CA Cancer J Clin. 2009 doi: 10.3322/caac.20006. [DOI] [PubMed] [Google Scholar]
- 2.Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52. doi: 10.1038/35021093. [DOI] [PubMed] [Google Scholar]
- 3.Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869–74. doi: 10.1073/pnas.191367098. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003;100:8418–23. doi: 10.1073/pnas.0932692100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Turner NC, Jones AL. Management of breast cancer--Part II. BMJ. 2008;337:a540. doi: 10.1136/bmj.a540. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Aaltomaa S, Lipponen P, Eskelinen M, et al. Hormone receptors as prognostic factors in female breast cancer. Ann Med. 1991;23:643–8. doi: 10.3109/07853899109148097. [DOI] [PubMed] [Google Scholar]
- 7.Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295:2492–502. doi: 10.1001/jama.295.21.2492. [DOI] [PubMed] [Google Scholar]
- 8.Anderson WF, Chu KC, Chatterjee N, Brawley O, Brinton LA. Tumor variants by hormone receptor expression in white patients with node-negative breast cancer from the surveillance, epidemiology, and end results database. J Clin Oncol. 2001;19:18–27. doi: 10.1200/JCO.2001.19.1.18. [DOI] [PubMed] [Google Scholar]
- 9.Anders C, Carey LA. Understanding and treating triple-negative breast cancer. Oncology (Williston Park) 2008;22:1233–9. discussion 9-40, 43. [PMC free article] [PubMed] [Google Scholar]
- 10.Bellosta S, Ferri N, Bernini F, Paoletti R, Corsini A. Non-lipid-related effects of statins. Ann Med. 2000;32:164–76. doi: 10.3109/07853890008998823. [DOI] [PubMed] [Google Scholar]
- 11.Demierre MF, Higgins PD, Gruber SB, Hawk E, Lippman SM. Statins and cancer prevention. Nat Rev Cancer. 2005;5:930–42. doi: 10.1038/nrc1751. [DOI] [PubMed] [Google Scholar]
- 12.Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19:117–25. doi: 10.1111/j.1472-8206.2004.00299.x. [DOI] [PubMed] [Google Scholar]
- 13.Mueck AO, Seeger H, Wallwiener D. Effect of statins combined with estradiol on the proliferation of human receptor-positive and receptor-negative breast cancer cells. Menopause. 2003;10:332–6. doi: 10.1097/01.GME.0000055485.06076.00. [DOI] [PubMed] [Google Scholar]
- 14.Campbell MJ, Esserman LJ, Zhou Y, et al. Breast cancer growth prevention by statins. Cancer Res. 2006;66:8707–14. doi: 10.1158/0008-5472.CAN-05-4061. [DOI] [PubMed] [Google Scholar]
- 15.Koyuturk M, Ersoz M, Altiok N. Simvastatin induces apoptosis in human breast cancer cells: p53 and estrogen receptor independent pathway requiring signalling through JNK. Cancer Lett. 2007;250:220–8. doi: 10.1016/j.canlet.2006.10.009. [DOI] [PubMed] [Google Scholar]
- 16.Shibata MA, Kavanaugh C, Shibata E, et al. Comparative effects of lovastatin on mammary and prostate oncogenesis in transgenic mouse models. Carcinogenesis. 2003;24:453–9. doi: 10.1093/carcin/24.3.453. [DOI] [PubMed] [Google Scholar]
- 17.Shibata MA, Ito Y, Morimoto J, Otsuki Y. Lovastatin inhibits tumor growth and lung metastasis in mouse mammary carcinoma model: a p53-independent mitochondrial-mediated apoptotic mechanism. Carcinogenesis. 2004;25:1887–98. doi: 10.1093/carcin/bgh201. [DOI] [PubMed] [Google Scholar]
- 18.Lubet RA, Boring D, Steele VE, Ruppert JM, Juliana MM, Grubbs CJ. Lack of efficacy of the statins atorvastatin and lovastatin in rodent mammary carcinogenesis. Cancer Prev Res (Phila Pa) 2009;2:161–7. doi: 10.1158/1940-6207.CAPR-08-0134. [DOI] [PubMed] [Google Scholar]
- 19.Cauley JA, McTiernan A, Rodabough RJ, et al. Statin use and breast cancer: prospective results from the Women's Health Initiative. J Natl Cancer Inst. 2006;98:700–7. doi: 10.1093/jnci/djj188. [DOI] [PubMed] [Google Scholar]
- 20.Kuoppala J, Lamminpaa A, Pukkala E. Statins and cancer: A systematic review and meta-analysis. Eur J Cancer. 2008;44:2122–32. doi: 10.1016/j.ejca.2008.06.025. [DOI] [PubMed] [Google Scholar]
- 21.Browning DR, Martin RM. Statins and risk of cancer: a systematic review and metaanalysis. Int J Cancer. 2007;120:833–43. doi: 10.1002/ijc.22366. [DOI] [PubMed] [Google Scholar]
- 22.Dale KM, Coleman CI, Henyan NN, Kluger J, White CM. Statins and cancer risk: a meta-analysis. JAMA. 2006;295:74–80. doi: 10.1001/jama.295.1.74. [DOI] [PubMed] [Google Scholar]
- 23.Kumar AS, Benz CC, Shim V, Minami CA, Moore DH, Esserman LJ. Estrogen receptor-negative breast cancer is less likely to arise among lipophilic statin users. Cancer Epidemiol Biomarkers Prev. 2008;17:1028–33. doi: 10.1158/1055-9965.EPI-07-0726. [DOI] [PubMed] [Google Scholar]
- 24.Byers T. Statins, breast cancer, and an invisible switch? Cancer Epidemiol Biomarkers Prev. 2008;17:1026–7. doi: 10.1158/1055-9965.EPI-08-0290. [DOI] [PubMed] [Google Scholar]
- 25.Friedman GD, Flick ED, Udaltsova N, Chan J, Quesenberry CP, Jr., Habel LA. Screening statins for possible carcinogenic risk: up to 9 years of follow-up of 361,859 recipients. Pharmacoepidemiol Drug Saf. 2008;17:27–36. doi: 10.1002/pds.1507. [DOI] [PubMed] [Google Scholar]
- 26.Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1996;347:1713–27. doi: 10.1016/s0140-6736(96)90806-5. [DOI] [PubMed] [Google Scholar]
- 27.Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997;350:1047–59. [PubMed] [Google Scholar]
- 28.Young JL, Roffers SD, Ries LAG, Fritz AG, Hurlbut AA, editors. SEER Summary Staging Manual - 2000: Codes and Coding Instructions. National Cancer Institute; Bethesda, MD: 2001. [Google Scholar]
- 29.Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118–45. doi: 10.1200/JCO.2006.09.2775. [DOI] [PubMed] [Google Scholar]
- 30.Schneeweiss S. Sensitivity analysis and external adjustment for unmeasured confounders in epidemiologic database studies of therapeutics. Pharmacoepidemiol Drug Saf. 2006;15:291–303. doi: 10.1002/pds.1200. [DOI] [PubMed] [Google Scholar]
- 31.Suissa S, Edwardes MD. Adjusted odds ratios for case-control studies with missing confounder data in controls. Epidemiology. 1997;8:275–80. doi: 10.1097/00001648-199705000-00008. [DOI] [PubMed] [Google Scholar]
- 32.Suzuki R, Orsini N, Saji S, Key TJ, Wolk A. Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis. Int J Cancer. 2009;124:698–712. doi: 10.1002/ijc.23943. [DOI] [PubMed] [Google Scholar]
- 33.Suzuki R, Orsini N, Mignone L, Saji S, Wolk A. Alcohol intake and risk of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis of epidemiological studies. Int J Cancer. 2008;122:1832–41. doi: 10.1002/ijc.23184. [DOI] [PubMed] [Google Scholar]
- 34.Boudreau DM, Yu O, Miglioretti DL, Buist DS, Heckbert SR, Daling JR. Statin use and breast cancer risk in a large population-based setting. Cancer Epidemiol Biomarkers Prev. 2007;16:416–21. doi: 10.1158/1055-9965.EPI-06-0737. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Eliassen AH, Colditz GA, Rosner B, Willett WC, Hankinson SE. Serum lipids, lipid-lowering drugs, and the risk of breast cancer. Arch Intern Med. 2005;165:2264–71. doi: 10.1001/archinte.165.19.2264. [DOI] [PubMed] [Google Scholar]
- 36.Krieger N. Overcoming the absence of socioeconomic data in medical records: validation and application of a census-based methodology. Am J Public Health. 1992;82:703–10. doi: 10.2105/ajph.82.5.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Rothwell PM. External validity of randomised controlled trials: “to whom do the results of this trial apply?”. Lancet. 2005;365:82–93. doi: 10.1016/S0140-6736(04)17670-8. [DOI] [PubMed] [Google Scholar]
- 38.Vinayak S, Kurian AW. Statins may reduce breast cancer risk, particularly hormone receptor-negative disease. Current Breast Cancer Reports. 2009;1:9. doi: 10.1007/s12609-009-0021-5. [DOI] [PMC free article] [PubMed] [Google Scholar]