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Dr. Nate Link on the STAR-2 trial October 24, 2006

Posted by rajkmd in Primary Care, Women's Health.
1 comment so far
This comment is in relation to the following trial:
The STAR P-2 trial is the most recent of several studies assessing the impact of SERMS on breast cancer. In the NSABP P-1 trial (NCI 1998;90:1371), tamoxifen prevented about 4 cases of breast cancer per 1000 high risk women treated per year (a 50% relative risk reduction!) but caused modest increases in thromboembolism, stroke, and endometrial cancer. In the MORE trial (JAMA 1999;282:637) raloxifene prevented 4 breast cancers and 6 vertebral fractures per 1000 women per year but also caused increases in thromboembolism and stroke. The STAR P-2 trial was the first to compare these two drugs head to head.Based on all three trials we would expect either raloxifene or tamoxifen to reduce the incidence of invasive breast cancer by 50%, but all the prevented cancers will be estrogen receptor positive, the tumors that are the easiest to treat and cure anyway. The studies were not large enough or long enough to determine whether breast cancer mortality will be affected by the SERMS. The scorecard: for every 1000 women at high risk for breast cancer who take raloxifene for one year, one can expect treatment to prevent 4 cases of invasive breast cancer and 6 cases of vertebral fracture, and to cause 1 stroke and 2 cases of thromboembolism. Mortality is unlikely to be affected in the short-term. Tamoxifen appears to be somewhat more likely to cause thromboembolism and uterine cancer – probably about 1 case per 1000 of each – and less likely to prevent fractures. Overall, raloxifene appears to have an edge in benefits versus risks.
Despite the favorable publicity surrounding these results, the nuances of the data and modest increases in serious outcomes such as stroke and thromboembolism preclude a simple recommendation for use of SERMS. The higher the baseline risk of breast cancer, the more favorable will be the benefit/risk ratio, but patient preference clearly needs to be a part of this decision.

Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes: The Star-2 Trial (JAMA, June 21, 2006) September 30, 2006

Posted by rajkmd in Women's Health.
3 comments

The Big Picture

  • According to CDC, in women, breast cancer is the most commonly diagnosed cancer after skin cancer and the second leading cause of death after lung cancer.
  • In 2002, 182,000 women were diagnosed and 41,000 women died from breast cancer.
  • American women of European ancestry are more likely to be diagnosed from the disease, while African American women have the highest rates of death from breast cancer.
  • Annually, it is estimated more than $7 billion ( in 2000 dollars) is spent on the diagnosis and treatment of breast cancer  
  • Raloxifene was first discovered and patented by Ely Lilly and sold under the trade name Evista.  It was approved in 1997 for the prevention of osteoporosis
    • According to the prnewswire, Evista has annual sales of around $635 million
    • Ely Lilly plead guilty in 2005 for illegally promoting Evista in prevention of invasive breast cancer and is currently paying fines as part of its settlement with the government.
    • There was patent dispute between Barr Labrotories and Ely Lilly in 2001
  •  Tamoxifen
    • Went off patent in 2002
    • More than half a million women annually take the drug
    • According to IMS Health, while on patent, it had more $1 billion in sales, but after the drug went off patent and other classes of drugs have been found to be more effective sales have slumped  to $53 million in 2004
  • To read article about this study in the nytimes click here

 Background

  • Tamoxifen is a selective estrogen receptor modulator (SERM)
    • It has been used to treat both early and advanced breast cancer for more than 3 decades
  • Raloxifene is a second generation SERM
    • Studies have shown that it decreases the development of breast cancer  and reduces the risk of invasive breast cancer
    • It is also used in the treatment of osteoporosis
  • The STAR-2 trial was funded by National Surgical Adjuvant Breast and Bowel Project (NSABP), which is an arm of the CDC
    • The study was completely publicly funded
    • Some of the authors, though, did have relationship with the drug manufacturers 

Methods

  • The trial was double blinded
  • There was no placebo group
  • Patient Characterisitcs
    • At least a 5 year predicited predicited breast cancer risk of 1.66% based on the Gail Model (for a breast cancer risk assessment tool based on the Gail Model, click here)
    • At least 35 yo
    • Post menopausal
    • No taking tamoxifen, raloxifene, hormone therapy, oral contraceptives, or androgens in the previous three months to enrollment
    • Not taking warfarin or cholestyramine
    • No h/o of stroke, pulm embolism, DVT,
    • No h/o of malignancy diagnosed less than 5 years before randomization except basal or squamous cell cancer of the skin or carcinoma in situ of the cervix
    • No uncontrolled atrial fibrillation, hypertension, diabetes, or psychiatric condition
    • Post menopausal women 35 yo or older with a history of lobular in situ (LCIS) could be enrolled as long as they had been treated with local excision alone
  • Study flow 
    • A total of 184,460 were screened
    • 93,368 had a 5 yr risk greater or equal to 1.66%
    • 19,747 were actually randomized
    • 9,872 recieved tamoxifen and 9,875 recieved raloxifene
    • Of these, 9,726 in the tamoxifen arm and 9,745 in the raloxifene arm were included in the primary analysis
    • Eligible women were assigned to recieve ramoxifen or raloxifene for a max of 5 yrs
  • Patient Characterisitics
    • Mean age – 58.5
    • More than 93% were women of European decent, 2.5% were African American, 2% were Hispanic, and the remainder were other ethnic groups
    • 9 percent had a history of LCIS
    • 22 percent had a history of breast biopsy results before randomization that showed either atypical ductal or lobular hyperplasia 
  • Mean follow-up was 3.9 years
  • There was a nonadherence rate of 9.2 percent
  • Primary endpt was invasive breast cancer
  • Secondary enpt
    • endomertrial cancer
    • in situ breast cancer
    • CV disease
    • Pulm embolism
    • DVT
    • TIA
    • Cataracts
    • Death
    • Quality of life
  • Randomization occured by stratifiying pts by age, race/ethnicity, history of LCIS, and 5 yr breast cancer risk
  • Pt’s were followed every 6 months for 5 years

Results

  • There was no difference between the effect of tamoxifen or raloxifene on the incidence of invasive breast cancer
    • Moreover, there was also no difference within in the groups even after taking into account age, history of LCIS, history of atypical hypreplasia, 5 year predicted breast cancer risk, or family history
    • There was also no difference between the types of breast cancer or the size of the cancers that developed.
  • There was a difference, albiet not statistically significant (p<.052), in the development of noninvasive breast cancers between the tamoxifen and raloxifene groups
    • There were 57 incident cases of noninvasive breast cancers in the tamoxifen group and 80 in the raloxifene group
  • There was a trend for decrease in uterine cancer in the raloxifene group that was not sig statistic (p= .07)
    • But there was a statistifically significant difference in the incidence of uterine hyperplasia, as pts treated with raloxifene were 84% less likely to develop hyperplsia than the tamixifen group
    • Also pt’s on raloxifene underwent a fewer hysterectomies compared to the tamoxifen group
  • No statistically significant difference in other invasive malignancies.
  • Raloxifene group had fewer DVT and pulmonary embolism, which was statisticall significant (RR 0.70 95% CI 0.54-0.91)
  • No difference in the number of fractures between both groups
  • Decreased cataracts in the raloxifene group.
  • Mortalility was similar in both groups

Conclusion

  • Raloxifene does not provide additional protection against the risk of invasive breast cancer when compared to tamoxifen in patients with an elevated GAIL score and LCIS
  • Raloxifene does, however, have decreased incidence of thromboembolic disease and uterine hyperplasia when compared to tamoxifen.
    • Of note, more than half the patients in this study were s/p hysterectomy

THE BOTTOM LINE:  In 1,000 high risk (as defined by the study design) women, without treatment 40 women would develop invasive breast cancer over next five years.  If all 1,000 were treated, then this number drops to 20 regardless if you use raloxifene to tamoxifen.  This means you would treat 980 women who would not benefit from the treatment to prevent 20 cases of invasive breast cancer.  Also, all treated women would be at increased risk of developing a pulmonary embolism or DVT, but the patients treated with raloxifene will develop fewer thromboemblic complications when compared to tamoxifen.