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Study of Tamoxifen and RaloxifeneSTAR

Larry Wickerham, MD

NSABP STAR Project Officer

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0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7

# EventsPlacebo 93Tamoxifen 60

50

40

30

20

10

0

# EventsPlacebo 250Tamoxifen 145

50

40

30

20

10

0

Cu

mu

lati

ve R

ate/

1000

Invasive Breast Cancer

NoninvasiveBreast Cancer

Time to Breast Cancer (Years)

P < 0.0001

P= 0.008

NSABP P1 Study

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STRATIFICATION• Age• Gail Model Risk• Race• History of LCIS• Hysterectomy

Tamoxifen20 mg/dayx 5 years

Study DesignSTAR

Raloxifene60 mg/dayx 5 years

Risk-Eligible Postmenopausal Women

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Inclusion and Exclusion CriteriaSTAR

Inclusion

– At least 35 years of age

– Postmenopausal

– Risk eligible

Lobular carcinoma in situ or

5-year Gail risk of breast cancer >1.66%

Exclusion

History of:

– Invasive breast cancer

– Ductal carcinoma in situ

– DVT, PE

– CVA, TIA

– Uncontrolled diabetes, hypertension or atrial fibrillation

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Primary AimsSTAR

• The primary aim of the study was to determine which of the following three statements is true:

– Compared to tamoxifen, raloxifene significantly reduces the incidence rate of IBC

– Compared to raloxifene, tamoxifen significantly reduces the incidence rate of IBC

– The statistical superiority of one of the treatments cannot be demonstrated and the choice of therapy should be based on benefit/risk considerations

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Primary ObjectiveSTAR

Evaluate the effect of raloxifene versus tamoxifen in reducing the incidence of invasive breast cancer in postmenopausal women who are at increased risk.

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Secondary Objectives STAR

•Non-invasive breast cancer

•Endometrial cancer

•Ischemic heart disease

•Fractures of the hip, spine or wrist

•Toxicity and side effects

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Screening, Accrual and Follow-upSTAR

Screened 184,460

Eligible 96,368

Randomized 19,747

Woman-years of follow-up 79,173

Average follow-up (years) 4.06

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Baseline CharacteristicsSTAR

Age (mean) 58.5

Caucasian 93%

Hysterectomy 51%

First degree relative(s)with breast cancer 71%

History of

Lobular carcinoma in situ 9%

Atypical hyperplasia 23%

5-year predicted Gail risk ofinvasive breast cancer (mean) 4.03%

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Effects on Invasive Breast Cancer STAR

Time Since Randomization (months)

0 6 12 18 24 30 36 42 48 54 60 66 72Cu

mu

lati

ve in

cid

ence

per

100

0 w

om

en

0

5

10

15

20

25

30Tamoxifen (n=168)Raloxifene (n=173)

RR (95% CI) = 1.02 (0.82, 1.27)

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Invasive Breast Cancer STAR

0

2

4

6

8

10

12

Gail Model Expectedif Untreated

Tamoxifen Raloxifene

Inci

denc

e pe

r 10

00 w

oman

-yrs

168 173

325

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Invasive Breast Cancer by 5-year Predicted RiskSTAR

0

2

4

6

8

10

12

≤3% 3.01 - 5% ≥5.01%

Predicted 5-year Risk

Inci

denc

e pe

r 10

00 w

oman

-yrs

Tamoxifen

Raloxifene

33

63

72

4449

80

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Invasive Breast Cancer Tumor CharacteristicsSTAR

Tamoxifenn=168

Raloxifenen=173

Estrogen Receptor Status

+ 72% 69%

- 28% 31%

Tumor Size

<1 29% 39%

1.1-3 61% 54%

>3.1 10% 8%

Nodal Status

- 74% 80%

+ 26% 20%

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0

3

6

9

12

Inci

den

ce p

er 1

000

wo

man

-yrs Tamoxifen

Raloxifene

LCISN=1783

Atypical Hyperplasia N=4429

34 35

4741

Invasive Breast Cancer in Women with aHistory of LCIS or Atypical Hyperplasia

STAR

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Non-Invasive Breast Cancer STAR

Time Since Randomization (months)

0 6 12 18 24 30 36 42 48 54 60 66 72Cu

mu

lati

ve

in

cid

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ce

pe

r 1

00

0 w

om

en

0

5

10

15

20

25

30

Tamoxifen (n=60)Raloxifene (n=83)

RR (95% CI) = 1.38 (0.98-1.95)

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Non-Invasive Breast CancerSTAR

Tamoxifen(n)

Raloxifene(n)

RR (95%CI)

DCIS 32 47 1.46 (0.91-2.37)

LCIS 23 29 1.26 (0.70-2.27)

Mixed 5 7 1.39 (0.38-5.57)

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Uterine Cancer STAR

Time Since Randomization (months)

0 6 12 18 24 30 36 42 48 54 60 66 72Cu

mu

lati

ve in

cid

ence

per

100

0 w

om

en

0

5

10

15

20

25

30Tamoxifen (n=37)Raloxifene (n=23)

RR (95% CI) = 0.61 (0.34, 1.05)

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Tamoxifen(n)

Raloxifene(n)

RR (95% CI)

Hysterectomyduring study

246 92 0.37 (0.28, 0.47)

Hyperplasia 100 17 0.17 (0.09, 0.28)

with atypia 15 2 0.13 (0.01, 0.56)

w/o atypia 85 15 0.17 (0.09, 0.30)

Uterine Hyperplasia and HysterectomySTAR

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Ischemic Heart Disease STAR

Tamoxifen(n)

Raloxifene(n)

RR (95% CI)

Myocardial infarction

53 39 0.73 (0.47-1.13)

Severe angina 55 71 1.28 (0.89-1.86)

Acute ischemic syndrome

17 28 1.64 (0.87-3.19)

Total 125 138 1.10 (0.86-1.41)

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Osteoporotic Fractures STAR

Tamoxifen(n)

Raloxifene(n)

RR (95% CI)

Hip 28 26 0.92 (0.52-1.63)

Spine 58 58 0.99 (0.68-1.46)

Wrist 27 27 0.99 (0.56-1.76)

Total* 111 108 0.97 (0.73-1.27)

*Columns not additive because one patient may have had fractures at multiple sites.

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MortalitySTAR

Tamoxifen(n)

Raloxifene(n)

Cancer 52 52

Breast cancer 5 2

Circulatory/vascular 25 21

Other 32 31

Any cause 109 104RR (95% CI)

0.95 (0.72-1.25)

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Venous Thromboembolic EventsSTAR

Time Since Randomization (months)

0 6 12 18 24 30 36 42 48 54 60 66 72Cu

mu

lati

ve

in

cid

en

ce

pe

r 1

00

0 w

om

en

0

5

10

15

20

25

30Tamoxifen (n=150)Raloxifene (n=105)

RR (95% CI) = 0.69 (0.53, 0.90)

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Cataracts and Cataract Surgery During Follow-upSTAR

0

2

4

6

8

10

12

14

Cataracts Cataract Surgery

Incid

en

ce p

er

1000 w

om

an

-yrs Tamoxifen

Raloxifene435

295

343

240

RR = 0.78(95% CI = 0.68–0.91)

RR = 0.81(95% CI = 0.68–0.96)

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Summary STAR

Compared with tamoxifen, raloxifene was:

• similar in decreasing the risk of invasive breast cancer

• not as effective at decreasing the risk of non-invasive breast cancer

• associated with fewer:

– adverse events related to uterus

– VTEs

– cataracts and cataract surgery