Jack Cuzick, Ph.D.Wolfson Institute of Preventive Medicine

St Bartholomew’s Medical School London, United Kingdom

Implementation Issues

for Chemoprevention

of Breast Cancer

thousandsthousands

World-wide Burden of Cancer in Women

GLOBOCAN 2002GLOBOCAN 2002

Incidence

Mortality

Breast Cancer Prevention Trials using Tamoxifen

Trial (Entry Dates)

Population Number Randomised

Agents (vs Placebo)

and daily dose

Intended Duration of Treatment

Royal Marsden (1986-1996)

High Risk Family History

2471 Tamoxifen 20mg 5-8y

NSABP-P1 (1992-1997)

High risk women >1.6% 5y risk

13 388 Tamoxifen 20mg 5y

Italian (1992-1997)

Normal Risk Hysterectomy

5408 Tamoxifen 20mg 5y

IBIS-I (1992-2001)

>2-fold relative risk 7139 Tamoxifen 20mg 5y

Adjuvant Overview (1976-1995)

Women with ER+ operable breast

cancer in 11 trials

~15000 Tamoxifen 20-40mg with or without

chemotherapy in both arms.

3 years or more

(average ~5 yrs)

Tamoxifen Overview : ER Positive Invasive Breast Cancer

All Tam Prev

IBIS

Italian

P1

Marsden

.1 .3 .52 1 1.5 Odds Ratio

Outcome in 1000 women at high risk of breast cancer followed for 5 years

No TreatmentTamoxifen for 5 years

Breast Cancer

VTE

Endometrial Cancer

30 19

6 12

2 5

Prevention Trials using Raloxifene

Trial (Entry Dates)

Population Number Randomised

Agents (vs Placebo)

and daily dose

Intended Duration of Treatment

MORE

(1994-1999)

Normal Risk

Post-menopausal women with

osteoporosis

7705

Raloxifene 60 or

120mg (3 arm)

4y

CORE

(2000-2004)

Normal Risk

Post-menopausal women with

osteoporosis

4011

Raloxifene 60mg

Additional 4y

RUTH

(1998-2000)

STAR (2001 -2005)

Post menopausal women ? 55y with CHD or risk factor

High risk post-menopausal women

>1.6% 5y risk

10101

19 747

Raloxifene 60mg

Raloxifene 60mg vs Tamoxifen

(20mg)

5y

5y

ALL INVASIVE BREAST CANCERS, 0-10ySERM vs. placebo

Fixed-effect model: -38.3% [-44.2%;-29.6%], p<0.001Fixed-effect model: -38.3% [-44.2%;-29.6%], p<0.001Random-effect model: -39.3% [-51.1%;-24.7%], p<0.001Random-effect model: -39.3% [-51.1%;-24.7%], p<0.001

Test for heterogeneity: Q(8df) = 23.79, p=0.002Test for heterogeneity: Q(8df) = 23.79, p=0.002

Hazard ratio.1 .2 .5 1 2 5 10

Combined

PEARL 50 mg

PEARL 25 mg

STAR

RUTH

MORE/CORE

Marsden

IBIS1

NSABP P1

Italian

Tamoxifen vs. placebo

Raloxifene vs. placebo

Lasofoxifene vs. placebo

Contralateral Tumours in Aromatase Inhibitor Trials

Odds Ratio (log scale)

.3 .5 1 1.5 Combined

B-33

MA-17

IES

ITA/ARNO/ABCSG

BIG 1-98

ATAC

New (Contralateral) Breast Primaries - AI adjuvant trials

47%

50%

ATAC

EBCTCG

? 75%

0

10

20

30

40

50

60

70

80

90

100

Anastrozole Tamoxifen Placebo

MAP3 - Cumulative Incidence of Invasive Breast

Cancer

Goss et al NEJM, 2011

IBIS II- PREVENTION STRATUM

n = 4,000 High Risk

• High Risk Post-menopausal women, aged 40-70.• Placebo controlled 2-arm trial for high risk• 5 Year Treatment

RANDOMISATION

PLACEBOANASTROZOLE

1mg

Implementation Issues

• No agents licensed for prevention in Europe

• Tamoxifen and Raloxifene approved in the US

• Only manufacturer can apply for license

• All drugs off patent protection