Risk Benefit and Conclusions

1
Risk Benefit and Conclusions

• George Sledge, MDIndiana University School of
  Medicine

2
Do We Need a New Chemoprevention Agent?

• Breast cancer continues to represent a major
  cause of morbidity and mortality
• Few women actually receive tamoxifen as
  chemoprevention for breast cancer
• Real toxicities (VTE, uterine cancer) limit its
  use
• Perception that it is a cancer drug with poor
  risk/benefit ratio

3
Raloxifene Demonstrates Efficacyin
Postmenopausal WomenAcross a Spectrum of Breast
Cancer Risk
56
RR 1.02
71
44
4
Confirmation of Raloxifenes Effectiveness
Relative to Tamoxifen in STAR
STAR Primary Analysis RR (95 CI) 1.02 (0.82,
1.27)
STAR Non-inferiority Analysis Proportion
retention of tamoxifens effect (95 CI) 97
(65, 128)
Tamoxifens effect based on women 50 years or
older in P-1
5
Raloxifene as an Alternative to Tamoxifen Benefit

• Similar efficacy with regard to prevention of
  invasive breast cancer
• Less effect on noninvasive cancers

6
Non-Invasive Breast Cancerin Placebo-Controlled
Studies MORE, CORE, RUTH
SEER
11/5044
5/5057
2/1274
5/2716
5/2576
3/2557
(N5133)
(N3990)
(N10,101)
SEER annual US incidence rate per 1,000 in white
women 50 (2000 data)
7
Efficacy and Important Safety Outcomes STAR
FAVORS RALOXIFENE
FAVORS TAMOXIFEN
P0.057

P0.055



P lt 0.05 vs. tamoxifen
Difference in Number of Events (95 CI) per 1000
Women/Yr
8
Differences in Outcomes forRaloxifene versus
TamoxifenSTAR
Difference in of events per 1000treated per 5
years (RALOXIFENE VS. TAMOXIFEN)
Outcome
Non-invasive breast cancer 3 more DCIS only 2
more Hysterectomy 40 fewer Hyperplasia 20
fewer Uterine cancer 4 fewer Venous
thromboembolism 6 fewer Deep vein
thrombosis 3 fewer Pulmonary embolism 3
fewer Cataracts 10 fewer Cataract surgery 9
fewer
P lt 0.05
9
Invasive Breast Cancer Risk Reduction Compares
Favorablywith Other Prevention Therapies
Therapy Event NNT
Atorvastatin1 MI/CHD death 294
Antihypertensives2 Strokes 370
Coronary event 417
Aspirin3 MI 753
Tamoxifen4 Invasive BrCa 303
Raloxifene (MORE) Invasive BrCa 323
Raloxifene (CORE) Invasive BrCa 335
Raloxifene (RUTH) Invasive BrCa 862
NNT number of patients needed to treat for 1
year to prevent 1 outcome
1Sever PS et al., Lancet. 2003 Apr
5361(9364)1149-58 2MRC Working Party Br Med J
1992304405-412 3Berger JS et al. JAMA
2006295306-313 4Fisher B et al., J Natl Cancer
Inst. 1998 Sep 1690(18)1371-88.
10
Postmenopausal women at high risk for breast
cancer should now have a choice
11
Raloxifene and Postmenopausal Women with
Osteoporosis

• Well established, FDA approved agent for
  prevention and treatment of osteoporosis
• Reduced risk of invasive breast cancer observed
  in MORE has been confirmed in RUTH and STAR
• Clinically important benefit for these women

12
Invasive Breast Cancer and Vertebral Fracture
MORE and P-1
12
10
8
Invasive Breast Cancer (No. per 1000/yr)
6
4
2
0
0
2
4
6
8
10
12
Clinical Vertebral Fracture (No. per 1000/yr)
13
Invasive Breast Cancer and Vertebral Fracture
MORE and P-1
12
10
8
Invasive Breast Cancer (No. per 1000/yr)
6
4
2
0
0
2
4
6
8
10
12
Clinical Vertebral Fracture (No. per 1000/yr)
14
Invasive Breast Cancer and Vertebral Fracture
MORE and P-1
12
10
P-1 (age50)
8
Invasive Breast Cancer (No. per 1000/yr)
Placebo
MORE
6
3.6 fewer
Placebo
4
Tamoxifen
3.1 fewer
5.2 fewer
0.5 fewer
2
Raloxifene
0
0
2
4
6
8
10
12
Clinical Vertebral Fracture (No. per 1000/yr)
15
Postmenopausal women considering raloxifene for
treatment of osteoporosis should be informed
about the potential additional benefit on their
risk of invasive breast cancer
Slide Modified
Memo
16
Conclusion

• Since 1998 an estimated 22 million postmenopausal
  women worldwide have received raloxifene to
  prevent or treat osteoporosis.
• Clinical trials involving more than 37,000
  postmenopausal women now provide information on
  the benefits and risks of the use of raloxifene
  to reduce the risk of invasive breast cancer.
• The benefit-risk is favorable in postmenopausal
  women at high risk for breast cancer and in
  postmenopausal women taking raloxifene for
  osteoporosis.