Statins and Microcalcifications

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					    Statins and
Microcalcifications of
     the Breast
  Katie Gores & Beth Rau

  Breast cancer is the most common
   cancer in women in the United States
  Estimated lifetime risk of breast cancer
   for a woman is 1 in 8
  In addition to further defining causes and
   risk factors, newer research is focusing
   on strategies for prevention

  Statins are a good research target
   because they are:
      Safe (short and long term)
      Low side effect profile
      Cost-effective
      Health Promoting
  But how effective are they?
Previous Studies

  Hydrophobic statin use has been associated
   with an 18% reduction in breast cancer
  Although there are a number of theories as
   to how statins may inhibit carcinogenesis,
   the exact mechanism is unknown
  Radiographic mammary microcalcifications
   occur in 30 to 50% of breast cancers
    One of the most important markers of both
     benign and malignant lesions of the breast
 Statins have increasingly well defined
  pleiotropic effects
 Previous laboratory studies have shown
  that Atorvastatin protects against vessel
  calcification in vascular disease
 It has also been shown to inhibit renal
  crystal retention and stone formation
Research Question

  Does hydrophobic statin use decrease
   the risk of microcalcifications of the

  A retrospective case control study
   conducted using electronic medical
   records at Medcenter One hospital.
   Charts were identified using ICD-9 codes
    Cases were women with new
     microcalcifications by mammography or
     pathology report
    Controls were women with a negative
     screening mammogram

  Hydrophobic Statin use was defined as
   period of treatment lasting at least 1
   month some time prior to diagnosis of
   microcalcifications or screening
  Hydrophobic Statins include Atorvastatin,
   Simvastatin, Fluvastatin, and Lovastatin
 Inclusion criteria
   For cases: histologically or
    radiographically confirmed
    microcalcifications of the breast
    diagnosed between Jan 2007 and Dec
   For controls: women who had a negative
    mammogram between the same time
    period and at the same hospital as cases

 Exclusion criteria:
   Prior or current diagnosis of any cancer
    other than low-grade squamous or
    basal cell skin carcinoma
   Non-female sex
   Non-caucasian race
Variables Collected
  Statin use (one month     Number of Live Births
   or longer)                Oral Contraceptive
  History of Breast          Use
   Cancer in first degree    Hormone Replacement
   relative                   Therapy Use
  Height                    Presence/Absence of
  Weight                     Microcalcifications
  Age at Menarche           Serum Calcium
  Menopausal Status         Serum Magnesium
  Age at Menopause          Race
                             Alcohol Use
Study Population

  Cases:
    215 women without history of breast or other
     malignancy who had microcalcifications on
     mammogram or pathology report
  Controls:
    209 women without history of cancer who
     had a negative screening mammogram in
     the same time period
Table 1: Distribution of 215 cases of breast microcalcifications and 208 controls according to
                           demographic and clinical characteristics.
Family History
                   CASES   CONTROLS
  MOTHER             21       15
  SISTER             21       9
 DAUGHTER             3       2
   DAUGHTER           1       0
                     2        3
    SISTER &
   DAUGHTER          1        0
    YES              3        0
    NO              157      177
  MISSING            6        2
Age at Diagnosis
                                   P-value = 0.01

              140                121                120
              100                                            88

              60                                                  Controls


                         20-54                       55-90
Statin Use
                  P-value = 0.79

 40               35             36
 25                                                         Combo
 20                                                         Hydrophilic
 15                                                         Hydrophobic
              5              7
 10                                           Hydrophobic
  5       4            6                Hydrophilic
  0                                   Combo
Statin Use
 Adjusting for age, women on statins were
  35% less likely to develop
  microcalcifications than those who were
  not on statins
   OR=0.65 95% CI = (0.39, 1.07)
 Adjusting for age women on hydrophobic
  statins were 32% less likely to develop
   OR= 0.68 95% CI= (0.40, 1.18)
     Consistent with overall protective effect

  When looking at hydrophobic statins
   specifically the 95% CI is much wider
   (0.40, 1.18) and includes 1
    Will require much larger sample size to
     detect significant difference

  Statistical Significance was defined as p-value
   < 0.05
  Statistically significant variables included:
      Age (p=0.01)
      BMI (p=0.01)
      Oral Contraceptive Use (p=0.04)
      Post-Menopausal Status (p=0.004)
      History of Hormone Therapy (p=0.02)
  Central finding is that compared to women with
   normal mammograms, women who used
   statins (of any kind or hydrophobic) were less
   likely to develop microcalcifications of the
    Difference was not statistically significant
  Odds ratio suggests protective effect
    95% CI includes 1 which means difference could be
     due to chance alone
  This is concurrent with the findings from
   Cauley study Statin Use and Breast
Limitations of the Study

  Small sample size
     For an alpha=0.05, a power of 80%, and a
      difference to detect of 4%, a total sample size of
      3466 would be needed to confirm/reject the
  Difficulty in defining microcalcifications of
   significance concretely
        Variation among radiologists
  Retrospective Study
     Electronic records only to 2003
Future Research

  Much larger retrospective study: 3466
    Limiting the study to women over the age of 40
     would maximize the chances of statin exposure
    Would allow for comparison of groups with more
     equal risk factors for cancer
  Prospective study
  Does decreased risk of microcalcifications =
   decreased risk of breast cancer?
Possible Implications

  If statins do decrease the risk of
   microcalcifications AND breast cancer
    Statins could be prescribed as a
     preventative measure for breast cancer
    This knowledge could be used to develop
     other drugs more specifically targeting
  Much more research is needed in this
    Cancer facts and figures (2009) American Cancer Society
    JA, McTiernan A, Rodabough RJ, LaCroix A, Bauer DC, Margolis KL, Paskett ED,
     Vitolins MZ, Furberg CD, Chlebowski RT; “Statin use and breast cancer:
     prospective results from the Women’s Health Initiative.” Cauley Women's Health
     Initiative Research Group. J Natl Cancer Inst. 2006 May 17;98(10):700-7
    Morgan MP, Cooke MM, McCarthy GM. Microcalcifications associated with breast
     cancer: an epiphenomenon or biologically significant feature of selected tumors?
     J Mammary Gland Biol Neoplasia. 2005 Apr;10(2):181-7.
    Liu C, Wan J, Yang Q, Qi B, Peng W, Chen X. Effects of atorvastatin on warfarin-
     induced aortic medial calcification and systolic blood pressure in rats. J
     Huazhong Univ Sci Technolog Med Sci. 2008 Oct;28(5):535-8.
    Son BK, Kozaki K, Iijima K, et al. Statins protect human aortic smooth muscle cells
     from inorganic phosphate-induced calcification by restoring Gas6-Axl survival
     pathway. Circ Res. 2006 Apr 28;98(8):1024-31.
    Kizu A, Shioi A, Jono S, Koyama H, Okuno Y, Nishizawa Y. Statins inhibit in vitro
     calcification of human vascular smooth muscle cells induced by inflammatory
     mediators. J Cell Biochem. 2004 Nov 15;93(5):1011-9.
    Tsujihata M, Momohara C, Yoshioka I, et al. Atorvastatin Inhibits Renal Crystal
     Retention in a Rat Stone Forming Model. J Urol. 2008 Nov;180(5):2212-7.

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