Transcript Risk Assessment and Primary Prevention of Breast Cancer

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
193.9
180.7
200
183.8
100
46.6
48.1
20.3
0
Heart
Diseases
Cerebrovascular
Diseases
Influenza &
Pneumonia
* Age-adjusted to 2000 US standard population
Cancer
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
for family members
• Height
• 2nd degree
relatives
• IGF-1, IGF-BP3
• Weight
• Alcohol intake
• Hormone level (E2, T,
SHBG)
• Diabetes
• Bone mineral density
• Physical activity
• Mammographic
density
• Use of HRT
• Lactation history
• NAF/Lavage
• 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
Multivariate Relative Risk
Alcohol and breast cancer risk:
Meta-analysis
2.5
2.0
1.5
1.0
Smith-Warner, 1998
0
0
10 20 30 40 50
Total Alcohol Intake g/d
60
Exercise
Exercise and risk of breast cancer
• Overall 25-30%
decreased risk
WHI Observational Cohort
(n=74,171; 1780 cancers)
• Greatest in
thinner women
1.2
• Lifetime exercise
matters
0.8
• Modest amounts:
1-3 hours brisk
walking/week
RR
1
0.6
0.4
0.2
0
0
McTiernan, JAMA, 2003.
Š5 5 to >40
10
MET-h/wek
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
• WHI:
RR (95% CI)
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
Rate per 1,000
Tamoxifen reduced risk at all ages
Placebo
Tamoxifen
8
6
4
2
0
≤49
Fisher, et al. JNCI 1998;90:1371
50 - 59
Age (years)
≥ 60
Tamoxifen in very high risk women
Placebo
Tamoxifen
6.8
All women
3.4
9.9
≥2 relatives
5.1
Atypical
hyperplasia
10.1
1.4
13
LCIS
5.7
0
5
10
Rate per 1,000
Fisher JNCI 1998; 90:1371
15
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
Side Effects
Duration rec
DVT, hot
flashes,
cateracts,
uterine ca
5 yrs or less
DVT, hot flashes,
flu-like syndrome,
edema
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%
Hereditary Risk 10%-20%
2%
33%-50%
7%
56%-87%
Moving Targets:
Penetrance, Prevalence
• Penetrance = Degree
to which individuals
possessing a
genetic trait express
that trait
70
60
50
40
BRCA1
BRCA2
sporadic
30
20
• Prevalence =
Number of carriers
in a population at a
Breast Cancer Penetrance by
specific time
10
0
20
30
40
50
60
70
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