CoChat
Sign Up
Cited by 62Cancer, Lipids, and MetabolismBreast Cancer Treatment StudiesMetabolism, Diabetes, and Cancer

Association of statin use with clinical outcomes in patients with triple‐negative breast cancer

Open access
Nowakowska, Malgorzata K., Lei, Xiudong, Thompson, Mikayla T., Shaitelman, Simona F., Wehner, Mackenzie R., Woodward, Wendy A., Giordano, Sharon H., Nead, Kevin T.·2021·Cancer
DOI 10.1002/cncr.33797PMC PMC11912801
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: Previous studies have examined the association of statin therapy and breast cancer outcomes with mixed results. The objective of this study was to investigate the clinical effects of incident statin use among individuals with triple‐negative breast cancer (TNBC). Methods: Data from the Surveillance, Epidemiology, and End Results‐Medicare and Texas Cancer Registry‐Medicare databases were used, and women aged ≥66 years who had stage I, II, and III breast cancer were identified. Multivariable Cox proportional hazards regression models were used to examine the association of new statin use in the 12 months after a breast cancer diagnosis with overall survival (OS) and breast cancer‐specific survival (BCSS). Results: When examining incident statin use, defined as the initiation of statin therapy in the 12 months after breast cancer diagnosis, a significant association was observed between statin use and improved BCSS (standardized hazard ratio, 0.42; 95% confidence interval [CI], 0.20‐0.88; P = .022) and OS (hazard ratio, 0.70; 95% CI, 0.50‐0.99; P = .046) among patients with TNBC (n = 1534). No association was observed with BCSS (standardized hazard ratio, 0.99; 95% CI, 0.71‐1.39; P = .97) or OS (hazard ratio, 1.04; 95% CI, 0.92‐1.17; P = .55) among those without TNBC (n = 15,979). The results were consistent when examining statin exposure as a time‐varying variable. Conclusions: Among women with I, II, and III TNBC, initiation of statin therapy in the 12 months after breast cancer diagnosis was associated with an OS and BCSS benefit. Statins may have a role in select patients with breast cancer, and further investigation is warranted.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/cncr.33797

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 52

  1. [1]Manthravadi S, Shrestha A, Madhusudhana S. Impact of statin use on cancer recurrence and mortality in breast cancer: A systematic review and meta-analysis. Int J Cancer. 2016; 139(6): 1281– 1288. 27176735
  2. [2]Beckwitt CH, Brufsky A, Oltvai ZN, Wells A. Statin drugs to reduce breast cancer recurrence and mortality. Breast Cancer Res. 2018; 20(1): 144. 30458856 PMC6247616
  3. [3]Ehmsen S, Pedersen MH, Wang G, Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome. Cell Rep. 2019; 27(13): 3927– 3938.e3926. 31242424
  4. [4]Spampanato C, De Maria S, Sarnataro M, Simvastatin inhibits cancer cell growth by inducing apoptosis correlated to activation of Bax and down-regulation of BCL-2 gene expression. Int J Oncol. 2012; 40(4): 935– 941. 22134829 PMC3584570
  5. [5]Beckwitt CH, Clark AM, Ma B, Whaley D, Oltvai ZN, Wells A. Statins attenuate outgrowth of breast cancer metastases. Br J Cancer. 2018; 119(9): 1094– 1105. 30401978 PMC6220112
  6. [6]Rao S, Lowe M, Herliczek TW, Keyomarsi K. Lovastatin mediated G1 arrest in normal and tumor breast cells is through inhibition of CDK2 activity and redistribution of p21 and p27, independent of p53. Oncogene. 1998; 17(18): 2393– 2402. 9811471
  7. [7]Ghosh-Choudhury N, Mandal CC, Ghosh Choudhury G. Simvastatin induces derepression of PTEN expression via NFkappaB to inhibit breast cancer cell growth. Cell Signal. 2010; 22(5): 749– 758. 20060890 PMC2826504
  8. [8]Mandal CC, Ghosh-Choudhury N, Yoneda T, Choudhury GG. Simvastatin prevents skeletal metastasis of breast cancer by an antagonistic interplay between p53 and CD44. J Biol Chem. 2011; 286(13): 11314– 11327. 21199873 PMC3064188
  9. [9]Borgquist S, Giobbie-Hurder A, Ahern TP, Cholesterol, Cholesterol-Lowering Medication Use, and Breast Cancer Outcome in the BIG 1–98 Study. J Clin Oncol. 2017; 35(11): 1179– 1188. 28380313
  10. [10]Van Wyhe RD, Rahal OM, Woodward WA. Effect of statins on breast cancer recurrence and mortality: a review. Breast Cancer (Dove Med Press). 2017; 9: 559– 565. 29238220 PMC5716320
  11. [11]Garwood ER, Kumar AS, Baehner FL, Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer. Breast Cancer Res Treat. 2010; 119(1): 137– 144. 19728082 PMC4087110
  12. [12]Bjarnadottir O, Romero Q, Bendahl PO, Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial. Breast Cancer Res Treat. 2013; 138(2): 499– 508. 23471651
  13. [13]Jung HH, Lee SH, Kim JY, Ahn JS, Park YH, Im YH. Statins affect ETS1-overexpressing triple-negative breast cancer cells by restoring DUSP4 deficiency. Sci Rep. 2016; 6: 33035. 27604655 PMC5015082
  14. [14]Liu H, Song Y, Qiu H, Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis. Cell Death Differ. 2020; 27(3): 966– 983. 31296961 PMC7206060
  15. [15]Lacerda L, Reddy JP, Liu D, Simvastatin radiosensitizes differentiated and stem-like breast cancer cell lines and is associated with improved local control in inflammatory breast cancer patients treated with postmastectomy radiation. Stem Cells Transl Med. 2014; 3(7): 849– 856. 24833589 PMC4073823
  16. [16]Castellanos-Esparza YC, Wu S, Huang L, Synergistic promoting effects of pentoxifylline and simvastatin on the apoptosis of triple-negative MDA-MB-231 breast cancer cells. Int J Oncol. 2018; 52(4): 1246– 1254. 29436616
  17. [17]Lin Z, Zhang Z, Jiang X, Mevastatin blockade of autolysosome maturation stimulates LBH589-induced cell death in triple-negative breast cancer cells. Oncotarget. 2017; 8(11): 17833– 17848. 28147319 PMC5392290
  18. [18]Ahern TP, Pedersen L, Tarp M, Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst. 2011; 103(19): 1461– 1468. 21813413 PMC3186780
  19. [19]Murtola TJ, Visvanathan K, Artama M, Vainio H, Pukkala E. Statin use and breast cancer survival: a nationwide cohort study from Finland. PLoS One. 2014; 9(10): e110231. 25329299 PMC4203770
  20. [20]Borgquist S, Broberg P, Tojjar J, Olsson H. Statin use and breast cancer survival - a Swedish nationwide study. BMC Cancer. 2019; 19(1): 54. 30634941 PMC6330431
  21. [21]Cardwell CR, Hicks BM, Hughes C, Murray LJ. Statin use after diagnosis of breast cancer and survival: a population-based cohort study. Epidemiology. 2015; 26(1): 68– 78. 25304447
  22. [22]Mc Menamin Ú, Murray LJ, Hughes CM, Cardwell CR. Statin use and breast cancer survival: a nationwide cohort study in Scotland. BMC Cancer. 2016; 16: 600. 27491389 PMC4973520
  23. [23]Kwan ML, Habel LA, Flick ED, Quesenberry CP, Caan B. Post-diagnosis statin use and breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors. Breast Cancer Res Treat. 2008; 109(3): 573– 579. 17674197 PMC3507509
  24. [24]Nickels S, Vrieling A, Seibold P, Mortality and recurrence risk in relation to the use of lipid-lowering drugs in a prospective breast cancer patient cohort. PLoS One. 2013; 8(9): e75088. 24086446 PMC3783471
  25. [25]Warren JL, Klabunde CN, Schrag D, Bach PB, Riley GF. Overview of the SEER-Medicare data: content, research applications, and generalizability to the United States elderly population. Med Care. 2002; 40(8 Suppl): IV-3–18. 12187163
  26. [26]Grundy SM, Stone NJ, Bailey AL, 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019; 139(25): e1082– e1143. 30586774 PMC7403606
  27. [27]Klabunde CN, Potosky AL, Legler JM, Warren JL. Development of a comorbidity index using physician claims data. J Clin Epidemiol. 2000; 53(12): 1258– 1267. 11146273
  28. [28]Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk. In. Vol 94. Journal of the American Statistical Association 1997: 496– 509.
  29. [29]Harborg S, Heide-Jørgensen U, Ahern TP, Ewertz M, Cronin-Fenton D, Borgquist S. Statin use and breast cancer recurrence in postmenopausal women treated with adjuvant aromatase inhibitors: a Danish population-based cohort study. Breast Cancer Res Treat. 2020; 183(1): 153– 160. 32572715 PMC7376511
  30. [30]Lv H, Shi D, Fei M, Association Between Statin Use and Prognosis of Breast Cancer: A Meta-Analysis of Cohort Studies. Front Oncol. 2020; 10: 556243. 33178584 PMC7596255
  31. [31]Yao H, He G, Yan S, Triple-negative breast cancer: is there a treatment on the horizon? Oncotarget. 2017; 8(1): 1913– 1924. 27765921 PMC5352107
  32. [32]Shaitelman SF, Stauder MC, Allen P, Impact of Statin Use on Outcomes in Triple Negative Breast Cancer. J Cancer. 2017; 8(11): 2026– 2032. 28819403 PMC5559964
  33. [33]Engebraaten O, Vollan HKM, Børresen-Dale AL. Triple-negative breast cancer and the need for new therapeutic targets. Am J Pathol. 2013; 183(4): 1064– 1074. 23920327
  34. [34]Freed-Pastor WA, Mizuno H, Zhao X, Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell. 2012; 148(1–2): 244– 258. 22265415 PMC3511889
  35. [35]Boudreau DM, Yu O, Johnson J. Statin use and cancer risk: a comprehensive review. Expert Opin Drug Saf. 2010; 9(4): 603– 621. 20377474 PMC2910322
  36. [36]Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008; 18(1): 54– 61. 18387799 PMC2476215
  37. [37]Borgquist S, Bjarnadottir O, Kimbung S, Ahern TP. Statins: a role in breast cancer therapy? J Intern Med. 2018; 284(4): 346– 357. 29923256 PMC6175478
  38. [38]Chabottaux V, Noel A. Breast cancer progression: insights into multifaceted matrix metalloproteinases. Clin Exp Metastasis. 2007; 24(8): 647– 656. 17968664
  39. [39]Mannello F, Tonti GA. Statins and breast cancer: may matrix metalloproteinase be the missing link. Cancer Invest. 2009; 27(4): 466– 470. 19219650
  40. [41]Wolfe AR, Debeb BG, Lacerda L, Simvastatin prevents triple-negative breast cancer metastasis in pre-clinical models through regulation of FOXO3a. Breast Cancer Res Treat. 2015; 154(3): 495– 508. 26590814 PMC5901982
  41. [42]Park YH, Jung HH, Ahn JS, Im YH. Statin induces inhibition of triple negative breast cancer (TNBC) cells via PI3K pathway. Biochem Biophys Res Commun. 2013; 439(2): 275– 279. 23973711
  42. [43]Green JL, La J, Yum KW, Paracrine Wnt signaling both promotes and inhibits human breast tumor growth. Proc Natl Acad Sci U S A. 2013; 110(17): 6991– 6996. 23559372 PMC3637696
  43. [44]Sulaiman A, McGarry S, Li L, Dual inhibition of Wnt and Yes-associated protein signaling retards the growth of triple-negative breast cancer in both mesenchymal and epithelial states. Mol Oncol. 2018; 12(4): 423– 440. 29316250 PMC5891054
  44. [45]Sadeghi-Aliabadi H, Minaiyan M, Dabestan A. Cytotoxic evaluation of doxorubicin in combination with simvastatin against human cancer cells. Res Pharm Sci. 2010; 5(2): 127– 133. 22049271 PMC3203264
  45. [46]Gopalan A, Yu W, Sanders BG, Kline K. Eliminating drug resistant breast cancer stem-like cells with combination of simvastatin and gamma-tocotrienol. Cancer Lett. 2013; 328(2): 285– 296. 23063651
  46. [47]Kou X, Jiang X, Liu H, Simvastatin functions as a heat shock protein 90 inhibitor against triple-negative breast cancer. Cancer Sci. 2018; 109(10): 3272– 3284. 30039622 PMC6172049
  47. [48]Emilsson L, García-Albéniz X, Logan RW, Caniglia EC, Kalager M, Hernán MA. Examining Bias in Studies of Statin Treatment and Survival in Patients With Cancer. JAMA Oncol. 2018; 4(1): 63– 70. 28822996 PMC5790310
  48. [49]Levesque LE, Hanley JA, Kezouh A, Suissa S. Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes. BMJ. 2010; 340: b5087. 20228141
  49. [50]Danaei G, Tavakkoli M, Hernán MA. Bias in observational studies of prevalent users: lessons for comparative effectiveness research from a meta-analysis of statins. Am J Epidemiol. 2012; 175(4): 250– 262. 22223710 PMC3271813
  50. [51]Khatib R, McKee M, Shannon H, Availability and affordability of cardiovascular disease medicines and their effect on use in high-income, middle-income, and low-income countries: an analysis of the PURE study data. Lancet. 2016; 387(10013): 61– 69. 26498706
  51. [52]Mnatzaganian G, Ryan P, Norman PE, Hiller JE. Accuracy of hospital morbidity data and the performance of comorbidity scores as predictors of mortality. J Clin Epidemiol. 2012; 65(1): 107– 115. 21803545
  52. [53]Ferket BS, van Kempen BJ, Heeringa J, Personalized prediction of lifetime benefits with statin therapy for asymptomatic individuals: a modeling study. PLoS Med. 2012; 9(12): e1001361. 23300388 PMC3531501

Cited by

Sorted by citations

Authors
Nowakowska, M. K., Lei, X., Thompson, M. T., Shaitelman, S. F., Wehner, M. R., Woodward, W. A., Giordano, S. H., & Nead, K. T.
Affiliations
  • Baylor College of Medicine (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • School of Public Health and Health Professions University at Buffalo Buffalo New York
Corresponding author
Nead, Kevin T.
ORCID
Venue
Cancer
Publisher
Wiley
Published
2021-08-03
Volume
127
Issue
22
Pages
4142-4150
ISSN
  • 0008-543X (ISSN-L)
  • 1097-0142
DOI
10.1002/cncr.33797
PMC
PMC11912801
OpenAlex
W3191447714
Cited by
62
References
1
Citations by year
2026: 6 · 2025: 15 · 2024: 19 · 2023: 9 · 2022: 12 · 2021: 1
FWCI
4.08
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (CCSG P30 CA016672)
  • Susan G. Komen (Komen SAC150061)
  • Cancer Prevention and Research Institute of Texas (CPRIT FP9178, CPRIT RP160674, CPRIT RR190077)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
statins, triple-negative breast cancer, overall survival, breast cancer-specific survival, older women
MeSH terms
Aged, Breast Neoplasms, Female, Medicare, Humans, United States, Proportional Hazards Models, Databases, Factual, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Triple Negative Breast Neoplasms

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review