Statins increase risk of breast cancer! Weren’t they supposed to cure Breast Cancer?


Jacob Schor, ND, FABNO
www.DenverNaturopathic.com
April 12, 2014


Biology is often confusing, medicine even more so. While we want to rely on the published science to base our decisions, sometimes the science isn’t conclusive. Case in point is the flipflopping research on the effect statin drugs have on breast cancer.

A new study by Jean McDougall and colleagues reports that statin drugs used to lower cholesterol may increase breast cancer risk in women.

These researchers used data from a population-based case-control study of breast cancer conducted in the Seattle-Puget Sound region to investigate the relationship between long-term statin use and breast cancer risk. Women diagnosed with invasive ductal carcinoma (IDC) or invasive lobular carcinoma (ILC) were compared with control women. All participants were interviewed in-person and data on hypercholesterolemia and all episodes of lipid-lowering medication use were collected through a structured questionnaire. The relationship between statin use and IDC and ILC risk was calculated

In all, there were 916 invasive ductal carcinoma (IDC) and 1,068 invasive lobular carcinoma (ILC) cases diagnosed in these women 55 to 74 years of age diagnosed between 2000 and 2008 were compared with 902 control women.

The women, who were currently using statins and who had been taking them for 10 years of longer, had a 83% higher risk of getting IDC and nearly double the risk of ILC compared with never users of statins. These associations were stronger limited to cases and controls with hyperlipidemia, with a doubled risk of ductal and a 2.4-fold risk of lobular breast cancer compared to never-users. [1] 

Oy, where do we start with this? 

About 25% of the women in the United States over age 45 are currently taking statin drugs to prevent stroke and heart disease. These drugs are effective at lowering high levels of blood lipids and by doing so lower risk of cardiovascular disease.
A number of papers published over the last two years have suggested that statins may also reduce risk of dying from cancer, in particular breast cancer. If so it would be good that so many women are already taking these drugs. This current paper by McDougall et al. contradicts the earlier papers and suggests that the opposite may be true. If so, having all these women taking statin drugs is not a good thing.

Knowing whether statins will inhibit cancer or increase cancer is important given the wide spread use of these drugs. Which is it?

This isn’t the first time our thinking on statins and cancer has taken a turn and reversed itself. 

When Alsheikh-Ali (2007) et al first reported a significant association between low levels of LDL cholesterol and cancer among patients taking statins, the initial worry was that the statins were causing cancer. This was a meta-analysis of 23 drug trials, yielding 309,506 person-years of follow-up, not a small study. Alsheikh-Ali reported that, “… the risk of cancer is significantly associated with lower achieved LDL-C levels …..” [2]

This wasn’t actually the case. A year later, in a second study, Alsheikh-Ali amended the initial conclusion, “There is no evidence that statin use causes cancer, although patients who reduce their LDL cholesterol level with statins appear to have a significantly increased risk of the disease…”

Alsheikh-Ali’s first paper used only data from patients taking statins. The second paper included data from both people taking statins and from people not taking them. Fifteen randomized, controlled trials provided data from 97,000 patients yielding 437,000 person-years of follow-up.

During these trials, 5,752 patients developed a new cancer. The incidence was 4%-27% per 1,000 person-years for those taking statins, and 6%-24% per 1,000 person-years for the people not taking statins, the same risk for both groups. The people who had low LDL cholesterol levels had an increased risk for cancer. This was true even for the patients taking placebo and not statins. The statins were not to blame. Low LDL cholesterol levels are just a warning that cancer is developing.

"We know that cancers can significantly lower cholesterol levels as much as 10 years before they surface clinically." [3] Cancer cells consume LDL cholesterol faster than normal cells. Statins were not the culprit. Statins were off the hook.

Then two years ago, the tide turned and statins were suddenly good. The shift started with Nielsen’s November 2012 study that reported people in Denmark, who took statins, had a lower risk of dying from cancer than non-statin users. The researchers had assessed causes of mortality among all Danes diagnosed with cancer between 1995 and 2007, and followed through 2009. Of patients 40 years or older, 18,721 had used statins regularly before the cancer diagnosis and 277,204 had never used statins. Statin users had a 15% lower risk of dying from any cause and from cancer. Reduced cancer-deaths among statin users were seen for 13 cancer types.[4]

Then in April 2013, Teemu Murtola reported that statin use was associated with a 66% reduction in the risk of dying from breast cancer. Murtola had conducted a retrospective study looking at statin use and breast cancer mortality among the 31,114 women with breast cancer who were diagnosed in Finland between 1995-2003. During follow up 6,011 of the women died, 3,169 due to breast cancer. The death rate among statin users was 7.5% while among non-statin users it was 21%.

Women with localized disease who took statins were 67% less likely to die than nonusers (hazard ratio, 0.33). Among those with metastatic disease, statins use was associated with a 48% decreased risk of death (HR, 0.52). Finland’s national health database allowed calculation of hazard ratios risk by the type of statin taken: including simvastatin (HR, 0.47), atorvastatin (HR, 0.27), fluvastatin (HR, 0.35) and pravastatin (HR, 0.50). Median follow-up was about 3 years, but ranged from less than 1 year to 9 years.[5] 

These are the kind of numbers that get our attention. Suddenly statins, in particular atorvastatin, might be a powerful therapy in breast cancer treatment.

In the months since these two positive studies were published a number of others have also shown benefit.

Brewer et al (2013) reported that hydrophilic statins improved progression free survival in patients with inflammatory breast cancer (IBC). They analyzed data from 723 IBC patients treated at MD Anderson from 1995 -2011. Statins were classified by Ahern’s system ranking them from hydrophilic to lipophilic (H-statins vs. L-statins). H-statins use was associated with significantly improved progression free survival compared with no statin (HR=0.49). [6]

Other in vitro and animal experiment reported positive effects such as increasing breast cancer apoptosis [7] , preventing carcinogenesis [8] , tumor growth inhibition [9] , and inhibiting growth of triple negative breast cancer cells [10] .

Unfortunately not all trials report clear benefit.

A clinical trial that gave lovastatin (40 mg twice a day for 6 months) to women at high risk of breast cancer (Vinayak 2103) found no significant change in breast duct cytology or other biomarkers of breast cancer risk. [11] 

A study that (Chan 2014) compared 565 breast cancer cases with 2260 controls found no significant differences in breast cancer risk between women who took statins and those who did not.[12]

A large German (Nickels 2013) was also inconclusive. Data from 3189 patients with invasive breast cancer stage I-IV and 3024 patients with breast cancer stage I-III were analyzed for recurrence risk. During a median 5.3 years follow-up, 404 of 3189 stage I-IV patients died, and 286 deaths were attributed to breast cancer. While statistically non significant, use of lipid-lowering drugs was associated with an increase in non-breast cancer mortality (HR) 1.49, 95% CI 0.88-2.52) and increased overall mortality (HR 1.21, 95% CI 0.87-1.69). Limiting data to only stage I-III breast cancer patients, lipid-lowering drug use was non-significantly associated with a reduced risk of recurrence (HR 0.83, 95% CI 0.54-1.24) and of reduced breast cancer-specific mortality (HR 0.89, 95% CI 0.52-1.49).[13] 

Non-significant results, even if trending in a good direction are still non-significant and probably should be ignored. 

A particularly large meta-analysis (Undela 2012) on statin use and the risk breast cancer risk found no significant effect. “A total of 24 (13 cohort and 11 case-control) studies involving more than 2.4 million participants, including 76,759 breast cancer cases contributed to this analysis… Statin use and long-term statin use did not significantly affect breast cancer risk (RR = 0.99, 95 % CI = 0.94, 1.04 and RR = 1.03, 95 % CI = 0.96, 1.11, respectively).” [14] 

Another meta-analysis (Emberson 2012) analyzed data drawn from 22 randomized, controlled trials with 66,582 patients receiving statins and 66,604 receiving placebo. Five years of statin therapy had no effect on the risk of cancer-related death (RR 1.00; 95% CI 0.93, 1.08). [15]

Possibly the largest prospective study on this topic (Desai 2013) reported “no relationship between statins and breast cancer risk.” Using Women's Health Initiative (WHI) yielded data from 154,587 postmenopausal women, with 7,430 confirmed breast cancer cases. Of these women, 11,584 (7.5%) used statins at baseline. “The annualized rate of breast cancer was 0.42% among statin users and 0.42% among nonusers.”[16] 

If the effect was as large as Nielsen and Murtola had reported, why wasn’t it showing up in these other studies? 

When considered as a group these studies unfortunately “…have not identified a strong relationship between statin use and reduced breast cancer incidence. These studies have several limitations and were not designed to detect modest effects in high-risk populations. Additional focused epidemiological and translational studies in high-risk populations are needed to justify and guide definitive large prospective trials.” [17] 

Bonovas writing in March 2014 sums it up: “As of today, the accumulated epidemiological evidence does not support the hypothesis that statin use affects the risk of developing breast cancer when taken at low doses for managing hypercholesterolemia. However, current evidence cannot exclude an increased risk of breast cancer with statin use in subsets of individuals, for example, the elderly. [18] 


How could Nielsen’s data have been so far off? One explanation suggested is that in Nielsen’s study women taking statins were more likely to have cardiovascular disease (70% vs. 21%) and diabetes (18% vs. 3%) than non-statin users. This could have led to disproportionately higher use of aspirin and or metformin in the statin users. Both medications are associated with reduced cancer-related mortality. Nielsen did relook at the data with possible aspirin use in mind, and eliminated all participants with cardiovascular disease (the only indication in Denmark for routine aspirin use) and this second analysis yielded the same results.[19] 

Perhaps statins do better only in observational studies but fail in randomized controlled trials. Healthy-user bias in observational studies may explain this difference. Doctors may unconsciously but selectively under-prescribe statins to obese patients or smokers because of their unhealthy lifestyles.[20] Healthier patients might be the ones who end up taking statins. 

We also have to ask another question. If statin use is associated with such a significant increased risk of breast cancer as seen in the McDougall study, why wasn’t it apparent in these other studies?

These results are so inconsistent that we must question whether we are blind to some confounder? We may be grouping too many different, genetically diverse, types of cancer together under the blanket term breast cancer. Some of these cancers may be more sensitive to statins than others. For example, some tumors express HMG-CoA reductase (HMGCR), and these tumors may be the ones that respond to statins.

Swedish data (Bjarnadottir 2013) suggest that testing HMGCR can predict if cancers will respond to statin treatment. Tissue samples from 50 women diagnosed with invasive breast cancer and given high dose atorvastatin (80 mg/day) for two weeks before cancer surgery were compared between pre and post statin therapy. Ki-67 expression between paired samples decreased non-significantly by only 7.6% after statin treatment (P=0.39) but in tumors expressing HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, Ki-67 dropped a significant 24% (P=0.02). Statins have the most effect on HMGCR positive tumors. [21] 

There may be other ways to predict which tumors will respond to statins.

A 2014 paper reports on a study in which 19 different breast cancer cell lines with a statin drug (fluvastatin) and this yielded a range of responses; cell death was triggered only in a subset of sensitive cell lines and this response was associated with an estrogen receptor alpha (ERα)-negative, basal-like tumor subtype. Using these data, researchers claim they are developing a gene signature test that will predict statin sensitivity (Goard 2014). [22] 

We may also be grouping too many different drugs together under the term statin.
the Ahern system for classifying statins as H-statins or L-statins based on whether they are hydrophilic or lipophilic may help. The more lipophilic the statin, the greater impact it has on non-hepatic tissues. The more hydrophilic the statin is, the greater the impact on the liver. Thus H-statins are thought to reduce adverse drug effects. [23] Simvastatin is among the most lipophilic of the statins while Pravastatin is one of the least.

Using this classification system, Harvard researchers (Ahern 2011) reported that after analyzing data on all the women in Denmark diagnosed with invasive breast cancer between 1996 and 2003 (18,769) that cancer rates varied by the type of statin women took. Women who used simvastatin, a lipophilic statin, had approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up compared with women who were not prescribed a statin. Women who took hydrophilic statins had about the same risk of breast cancer recurrence as women not taking statins. Thus the type of statin could matter, as it is only the lipophilic ones, the L-statins that act. [24] This may in explain the high frequency of breast cancer for women taking pravastatin in the Cholesterol and Recurrent Events CARE cohort as this drug is an H-statin. Women in this trial (Sacks 1996), who received pravastatin, were 12 times as likely to have breast cancer as controls receiving placebos. [25] 

Perhaps if all of these studies paid more attention to the particular statin drugs the women were taking, the results might make more sense. 

There is also the issue of 27-hydoxycholesterol discussed in a recent issue of the Natural Medicine Journal. [link] Several recent studies link cholesterol metabolism to breast cancer. A specific cholesterol metabolites can promote [26, 27] breast cancer.

This cholesterol metabolite, 27-hydroxycholesterol (27HC), is of interest because in several animal models, it interacts with the estrogen receptor and increases breast cancer growth and metastasis. Greater amounts of the enzyme that breaks down 27HC is associated with improved patient survival. Increased amounts of the enzyme that converts cholesterol to 27HC are found in more aggressive breast tumors. There is more 27 HC in breast tumors than in healthy breast tissue of the same patients and far more 27HC in patients with cancer than in patients without. Some statin drugs may interfere with breast cancer because they prevent conversion of cholesterol to 27HC. [28] Others may not. At this point we do not know.


A March 2014 editorial sums up the current situation: “As of today, the accumulated epidemiological evidence does not support the hypothesis that statin use affects the risk of developing breast cancer when taken at low doses for managing hypercholesterolemia. However, current evidence cannot exclude an increased risk of breast cancer with statin use in subsets of individuals, for example, the elderly. On the other hand, some studies show that statins might be useful to prevent recurrence and improve survival in patients already suffering from certain breast cancer types. They could also be combined with certain anticancer drugs and potentiate their effects, ameliorate their side effects or prevent the development of resistance. Further research is warranted to clarify these issues.” [29] 

While the results reported by both Nielsen and Murtola were exciting when published, McDougall et al should have a sobering influence. In our rush to help people, we have to be careful not to hurt them.

Risk of doing a patient harm always trumps unproven benefit.


References:

1. McDougall JA, Malone KE, Daling JR, Cushing-Haugen KL, Porter PL, Li CI. Long-term statin use and risk of ductal and lobular breast cancer among women 55 to 74 years of age. Cancer Epidemiol Biomarkers Prev. 2013 Sep;22(9):1529-37. doi: 10.1158/1055-9965.EPI-13-0414. Epub 2013 Jul 5.

2. Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol. 2007 Jul 31;50(5):409-18. 

3. J Steinberg D. Statin treatment does not cause cancer. Am Coll Cardiol. 2008 Sep 30;52(14):1148-9.

4. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012 Nov 8;367(19):1792-802. 

5. Murtola TJ, Visvanathan K, Artama M, Vainio H, Pukkala E. Statins and Breast Cancer mortality. Annual Meeting April 7, 2013. American Association for Cancer Research

6. Brewer TM, Masuda H, Liu DD, Shen Y, Liu P, Iwamoto T, Kai K, Barnett CM, Woodward WA, Statin use in primary inflammatory breast cancer: a cohort study. Reuben JM, Yang P, Hortobagyi GN, Ueno NT.Br J Cancer. 2013 Jul 23;109(2):318-24. doi: 10.1038/bjc.2013.342. Epub 2013 Jul 2.PMID:23820253

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8. Kubatka P, Zihlavniková K, Kajo K, Péc M, Stollárová N, Bojková B, Kassayová M, Orendás P. Antineoplastic effects of simvastatin in experimental breast cancer. Klin Onkol. 2011;24(1):41-5.

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13. Nickels S, Vrieling A, Seibold P, Heinz J, Obi N, Flesch-Janys D, Chang-Claude J Mortality and recurrence risk in relation to the use of lipid-lowering drugs in a prospective breast cancer patient cohort. PLoS One. 2013 Sep 25;8(9):e75088. doi: 10.1371/journal.pone.0075088. eCollection 2013.PMID: 24086446

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15. Emberson JR, Kearney PM, Blackwell L, et al. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One 2012;7:e29849-e29849

16. Desai P, Chlebowski R, Cauley JA, Manson JE, Wu C, Martin LW, Jay A, Bock C, Cote M, Petrucelli N, Rosenberg CA, Peters U, Agalliu I, Budrys N, Abdul-Hussein M, Lane D, Luo J, Park HL, Thomas F, Wactawski-Wende J, Simon MS. Prospective analysis of association between statin use and breast cancer risk in the women's health initiative. Cancer Epidemiol Biomarkers Prev. 2013 Oct;22(10):1868-76. doi: 10.1158/1055-9965.EPI-13-0562. Epub 2013 Aug 23

17. Santa-Maria CA, Statins and Breast Cancer: Future Directions in Chemoprevention. Stearns V. Curr Breast Cancer Rep. 2013 Sep 1;5(3):161-169.PMID: 23997864

18. Bonovas S1, Lytras T, Sitaras NM. .Statin use and breast cancer: do we need more evidence and what should this be? Expert Opin Drug Saf. 2014 Mar;13(3):271-5. doi: 10.1517/14740338.2014.888806. Epub 2014 Feb 11

19. Singh S, Singh PP. Statin a day keeps cancer at bay. World J Clin Oncol. 2013 May 10;4(2):43-6. doi: 10.5306/wjco.v4.i2.43.

20. Brookhart MA, Patrick AR, Dormuth C, Avorn J, Shrank W, Cadarette SM, Solomon DH. Adherence to lipid-lowering therapy and the use of preventive health services: an investigation of the healthy user effect. Am J Epidemiol. 2007 Aug 1;166(3):348-54. Epub 2007 May 15.

21. Bjarnadottir O, Romero Q, Bendahl PO, Jirström K, Rydén L, Loman N, Uhlén M, Johannesson H, Rose C, Grabau D, Borgquist S. Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial. Breast Cancer Res Treat. 2013 Apr;138(2):499-508. doi: 10.1007/s10549-013-2473-6. Epub 2013 Mar 8.

22. Identifying molecular features that distinguish fluvastatin-sensitive breast tumor cells. Goard CA, Chan-Seng-Yue M, Mullen PJ, Quiroga AD, Wasylishen AR, Clendening JW, Sendorek DH, Haider S, Lehner R, Boutros PC, Penn LZ. Breast Cancer Res Treat. 2014 Jan;143(2):301-12. doi: 10.1007/s10549-013-2800-y. Epub 2013 Dec 17.

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25. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC,Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996 Oct 3;335(14):1001-9.

26. Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, Carver NJ, Pillai RV, Sullivan PM, Sondhi V, Umetani M, Geradts J, McDonnell DP 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology.
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27. Wu Q, Ishikawa T, Sirianni R, Tang H, McDonald JG, Yuhanna IS, Thompson B, Girard L, Mineo C, Brekken RA, Umetani M, Euhus DM, Xie Y, Shaul PW. 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep. 2013 Nov 14;5(3):637-45. doi: 10.1016/j.celrep.2013.10.006. Epub 2013 Nov 7.

28. Silvente-Poirot S, Poirot M. Cholesterol and cancer, in the balance.
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29. Bonovas S, Lytras T, Sitaras NM. Statin use and breast cancer: do we need more evidence and what should this be? Expert Opin Drug Saf. 2014 Mar;13(3):271-5. doi: 10.1517/14740338.2014.888806. Epub 2014 Feb 11.


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