Strategies for Breast Cancer

Prevention
John Park
Hannah Connolly
Jeff Tice
Mary S. Beattie
Breast Cancer Prevention!
Is breast cancer preventable?

• 5-fold variation in rates around

the world (West >> Asia)
• Migrants assume rate of new
country in 1 or 2 generations
• 4-fold increase in incidence in
Iceland over 80 years*

*Tryggvadottir JNCI 2006

Change in the US Death Rates* by Cause, 1950 & 2005

Rate Per 100,000

600 586.8

1950
500
2005
400

300

211.1
180.7 193.9 183.8
200

100
46.6 48.1
20.3
0
Heart Cerebrovascular Influenza & Cancer
Diseases Diseases Pneumonia

* Age-adjusted to 2000 US standard population

Risk Assessment
 Why risk assessment?

• Tamoxifen and raloxifene FDA

approved for prevention in high
risk women: a 5-year risk >1.66%
• “American Cancer Society
advises MRI for high risk
women.” - March 28, 2007
Defined as 20-25% lifetime risk.
 Factors Considered in
The Gail Risk Model
• Current age
• Race / Ethnicity
• Age at menarche
• Age at first live birth
• Number of 1° relatives with BC
• Number of breast biopsies
• Presence of ADH
Based on Caucasian women undergoing
regular screening (BCDDP)

Gail et al. J Natl Cancer Inst 81:1879; 1989.

 Gail Model on NCI website

http://www.cancer.gov/bcrisktool/

• 5 year and lifetime estimates by race

Validated for populations; but modest

discriminatory value for the individual.

Rockhill et al. J Natl Cancer Inst 93:358, 2001.

Risk factors not included in Gail model

• Age of diagnosis • Height

for family members • Weight
• 2nd degree • IGF-1, IGF-BP3
relatives • Hormone level (E2, T,
• Alcohol intake SHBG)
• Diabetes • Bone mineral density
• Physical activity • Mammographic
density
• Use of HRT
• NAF/Lavage
• Lactation history • SNPs
Prevention: Lifestyle
DIET
No association with breast cancer

• Dietary fat intake

– Hunter 1996
– Pooled prospective studies
– 4980 cases in 337,819 women
• Fruits & vegetables
– Smith-Warner, JAMA, 2001
– Pooled prospective studies
– 7377 cases in 351,825 women
• Carotenoids; Vitamins A, C, E
• Selenium
 Alcohol and breast cancer risk:
Meta-analysis
2.5
Multivariate Relative Risk

2.0
1.5

1.0

Smith-Warner, 1998

0
0 10 20 30 40 50 60
Total Alcohol Intake g/d
Exercise
Exercise and risk of breast cancer

• Overall 25-30% WHI Observational Cohort

decreased risk (n=74,171; 1780 cancers)
1.2
• Greatest in
thinner women 1

0.8
• Lifetime exercise

RR
matters 0.6

• Modest amounts: 0.4

1-3 hours brisk 0.2

walking/week 0
0 Š5 5 to >40
10
MET-h/wek
McTiernan, JAMA, 2003.
Obesity
 Effect modification by HT use

Quintile BMI No HT HT
1 1.00 1.00
2 1.52 0.89
3 1.40 0.86
4 1.70 0.92
5 2.52 0.96

WHI Observational Cohort, n=85 917; 1030 cancers.

P interaction < 0.001
Libby, CCC, 2002
 2nd Look: Low fat diet RCTs for BC

RR (95% CI)
• WHI: 0.91 (0.86-1.01)
– Primary prevention
– 25% of total calories

• WINS: 0.76 (0.60-0.98)

– Secondary prevention
– 20% of total calories
• WHEL: 0.96 (0.80-1.14)
Prentice JAMA 2006; Chlebowski JNCI 2006; Pierce JAMA 2007.
 Reducing the
risk of breast cancer
1. Early childbirth, breast feed
2. Exercise 3-7 hours / week
3. Maintain normal body weight
4. Minimize alcohol
5. Avoid long term HT, especially
progestins
6. Low fat diet?

Estimated 30-80% reduction in risk

 Continuum of Risk

0% 100%

Lifestyle

Increased Surveillance
Surgical prevention
Chemoprevention

Risk-reducing Surgeries
 Hormones and
Chemoprevention
Women’s Health Initiative: Breast
Cancer with HRT and ERT

HRT
Placebo

Placebo
ERT

JAMA 2002 JAMA 2004

 Ravden NEJM 07

Ravdin P et al. N Engl J Med 2007;356:1670-1674

 Breast Cancer Prevention Trial
(BCPT)

• 13,388 women age > 35

– Estimated 5 year risk ≥ 1.66%
• 20 mg tamoxifen vs. placebo
• Stopped after average of 4 yrs;
median follow-up: 55 months

Fisher, JNCI, 1998

 Tamoxifen reduced risk at all ages

Placebo
8 Tamoxifen
Rate per 1,000

0
≤49 50 - 59 ≥ 60
Age (years)

Fisher, et al. JNCI 1998;90:1371

 Tamoxifen in very high risk women

Placebo
All women 6.8 Tamoxifen
3.4

≥2 relatives 9.9
5.1
Atypical 10.1
hyperplasia 1.4

LCIS 13
5.7

0 5 10 15
Rate per 1,000
Fisher JNCI 1998; 90:1371
SERMs Reduce the Risk of Breast Cancer
SERMs reduced the risk of ER+
but not ER- cancer
Adverse Events From Prevention Trials
of Tamoxifen & Raloxifene

• DVT/PE: 1.9 (1.4-2.6)

• Endometrial cancer 2.4 (1.5-4.0)
•  risk fatal stroke
•  risk cataracts
•  risk hot flashes
** Majority of adverse events in women ≥ 50
years

Fisher JNCI,1998; Cuzick Lancet, 2003; Barrett-Conner, NEJM, 2006.

 STAR Trial: Key outcomes
per 1000 woman-years
• 19,747 women randomized, 5 year f/u
• Postmenopausal, average risk 4.0%
Outcome Tam 20 mg Ralox 60 mg
Invasive BC 4.3 4.4
Uterine Ca 2.0 1.2
*DVT/PE 3.7 2.6
Osteop. Fx 2.7 2.5
CVD event 4.4 4.6
*Cataracts 12.3 9.7
* P < 0.05 Vogel, JAMA, 2006
 Comparison of 2 SERMs

Tamoxifen Raloxifene
FDA Approval breast ca rx osteoporosis &
& prev. breast ca prev.
Population pre and post post-menopause
Adverse and DVT, hot DVT, hot flashes,
Side Effects flashes, flu-like syndrome,
cateracts, edema
uterine ca
Duration rec 5 yrs or less Studied x 8 yrs
 Raloxifene vs. Tamoxifen

• Pro raloxifene
– Equivalent reduction in IBC
– Less thromboembolism, uterine
cancer, and cataracts
– Primary care comfort with therapy
• Con raloxifene
– Post-menopausal women only
– Generic tamoxifen less $$$
Aromatase inhibitors: the future?

• Block conversion of T to E
• ATAC: Treatment trial n=9366, 8 years
– Anastrazole vs. Tamoxifen
– 40% reduction in contralateral cancer
– Less endometrial cancer, VTE, stroke
– More fractures and musculoskeletal pain
• Letrozole after tamoxifen
– 37% reduction in contralateral cancer

ATAC, Lancet Onc, 2008;

Goss, JNCI, 2005. Ingle Annal Onc 2008.
 Case : Jennifer

• 34 year old woman

• My mother’s fine and I don’t have
a sister.
• But my dad had 4 sisters, 2 of
whom developed breast cancer
and my paternal grandmother
also had breast cancer
• 5-year Gail risk = .31%
The Gail Model Can Underestimate
Hereditary Risk of Breast Cancer

Breast, 44

Breast, 38 Breast, 29
Ovary, 42

Jennifer, 37

This woman’s breast cancer risk

greatly underestimated by Gail model
 How Much Breast Cancer Is
Hereditary?

15%20%

5%–10%

Breast Cancer
Sporadic
Family clusters
Hereditary
ASCO
 Features that indicate increased
likelihood of BRCA mutations
• Multiple cases of early onset breast cancer
• Ovarian cancer
• Breast and ovarian cancer in the same
woman
• Bilateral breast cancer
• Ashkenazi Jewish heritage
• Male breast cancer
BRCA1/2 Mutations Increase the Risk of
Early-Onset Breast Cancer
By age 40 By age 50 By age 70

Population Risk 0.5% 2% 7%

Hereditary Risk 10%-20% 33%-50% 56%-87%
 Moving Targets:
Penetrance, Prevalence
70

• Penetrance = Degree 60

to which individuals 50

possessing a 40 BRCA1

genetic trait express 30

BRCA2
sporadic

that trait 20

• Prevalence = 10

Number of carriers 0
20 30 40 50 60 70
in a population at a
Breast Cancer Penetrance by
specific time
BRCA1 or BRCA2 and Age
• Research ongoing Prevalence depends on population
98-99.8% of US population is -
Screening and Chemoprevention in
BRCA Carriers

• Breast cancer
–CBE q 6 months, MRI/mammo at 25 y/o
–Tamoxifen may be more effective for
BRCA2 than BRCA1 (80% of BRCA2 is ER+
and 80% of BRCA1 is ER-)
• Ovarian cancer
–Efficacy of CA125 and U/S unclear-- When
to start? How frequently? Whether to?
–OCP’s for 3-5 years: 50% ↓ ovarian cancer
 Surgical options for BRCA carriers

• Risk-reducing salpingo-oophrectomy
(RRSO)
–↓ ovarian and tubal cancers by 95%
– Fine sectioning detects “occult tumors”
in about 10% of tubes/ovaries
–If pre-menopausal, 50% ↓ in breast cancer
• Risk-reducing mastectomy (RRM)
–↓ breast cancer by 95%
–Many reconstruction options
 Summary points

• Lifestyle
– Exercise, weight loss or maintenance
– Minimize alcohol
– Avoid/stop HT
– Low fat diet?
• Consider tamoxifen or raloxifene for high
risk women
• Assess familial risk
– Consider prophylactic surgery for
BRCA carriers
“Grateful patients are few
in preventive medicine …
where success is marked
by a non-event”

Geoffrey Rose
UK epidemiologist
 Programs at UCSF

• Cancer Risk Program

– Genetic counseling and testing
– 415-885-7779
– 877-RISK4CA (toll-free)
• Breast Care Center: High Risk
Program
– 415-353-7070
BRCA testing can modify 5-year risk
beyond family history

Age No FH Any FH* BRCA+

30 0.11% 0.23% 3.5%
35 0.28% 0.58% 5.7%
40 0.58% 1.10% 7.9%
45 0.97% 1.61% 8.4%
50 1.3% 1.9% 7.3%
55 1.5% 2.3% 5.7%

*FH = mother, sister, or daughter with breast cancer any age