Strategies for Breast Cancer Prevention John Park Hannah Connolly Jeff Tice Mary S. Beattie.
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Transcript of Strategies for Breast Cancer Prevention John Park Hannah Connolly Jeff Tice Mary S. Beattie.
Strategies for Breast Cancer Strategies for Breast Cancer PreventionPrevention
John Park
Hannah Connolly
Jeff Tice
Mary S. Beattie
Is breast cancer preventable?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 & 2005Change in the US Death Rates* by Cause, 1950 & 2005
* Age-adjusted to 2000 US standard population
HeartDiseases
CerebrovascularDiseases
Influenza &Pneumonia
Cancer
1950
2005
Rate Per 100,000
20.3
180.7
48.1
586.8
193.9
46.6
183.8211.1
0
100
200
300
400
500
600
Why 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 inThe 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
Gail et al. J Natl Cancer Inst 81:1879; 1989.
Based on Caucasian women undergoing regular screening (BCDDP)
Gail Model on NCI website
• 5 year and lifetime estimates by race
Validated for populations; but modest Validated for populations; but modest discriminatory value for the individualdiscriminatory value for the individual.
Rockhill et al. J Natl Cancer Inst 93:358, 2001.
http://www.cancer.gov/bcrisktool/
Risk factors not included in Gail modelRisk factors not included in Gail model
• Age of diagnosis for family members
• 2nd degree relatives
• Alcohol intake
• Diabetes
• Physical activity
• Use of HRT
• Lactation history
• Height
• Weight
• IGF-1, IGF-BP3
• Hormone level (E2, T, SHBG)
• Bone mineral density
• Mammographic density
• NAF/Lavage
• SNPs
No association with breast cancerNo 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:Alcohol and breast cancer risk:Meta-analysisMeta-analysis
00 1010 2020 3030 4040 5050 6060Total Alcohol Intake g/dTotal Alcohol Intake g/d
Mu
ltiv
aria
te R
elat
ive
Ris
kM
ult
ivar
iate
Rel
ativ
e R
isk 2.52.5
2.02.0
1.51.5
1.01.0
00
Smith-Warner, 1998
Exercise and risk of breast cancerExercise and risk of breast cancer
• Overall 25-30% decreased risk
• Greatest in thinner women
• Lifetime exercise matters
• Modest amounts: 1-3 hours brisk walking/week 0
0.2
0.4
0.6
0.8
1
1.2
0 Š5 5 to10
>40
MET-h/wek
RR
WHI Observational Cohort(n=74,171; 1780 cancers)
McTiernan, JAMA, 2003.
Effect modification by HT useEffect 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 BC2nd 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 Reducing the risk of breast cancerrisk 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 RiskContinuum of Risk
Surgical preventionSurgical prevention
0%0% 100%100%
LifestyleLifestyleLifestyleLifestyle
ChemopreventionChemopreventionChemopreventionChemoprevention
Increased SurveillanceIncreased SurveillanceIncreased SurveillanceIncreased Surveillance
Risk-reducing SurgeriesRisk-reducing SurgeriesRisk-reducing SurgeriesRisk-reducing Surgeries
Women’s Health Initiative: Breast Women’s Health Initiative: Breast Cancer with HRT and ERTCancer with HRT and ERT
ERT ERT
JAMA 2002JAMA 2002 JAMA 2004JAMA 2004
PlaceboPlaceboHRTHRT
PlaceboPlacebo
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, 1998Fisher, JNCI, 1998
Tamoxifen reduced risk at all ages
Age (years)Age (years)
PlaceboPlaceboTamoxifenTamoxifen
Fisher, et al. JNCI 1998;90:1371Fisher, et al. JNCI 1998;90:1371
Rat
e p
er 1
,000
Rat
e p
er 1
,000
00
22
44
66
88
≤≤4949 50 - 5950 - 59 ≥ ≥ 6060
Tamoxifen in very high risk women
1313
10.110.1
9.99.9
6.86.8
5.75.7
1.41.4
5.15.1
3.43.4
00 55 1010 1515
LCISLCIS
AtypicalAtypicalhyperplasiahyperplasia
≥≥2 relatives2 relatives
All womenAll women
Rate per 1,000Rate per 1,000Fisher JNCI 1998; 90:1371Fisher JNCI 1998; 90:1371
PlaceboPlaceboTamoxifenTamoxifen
SERMs reduced the risk of ER+ SERMs reduced the risk of ER+ but not ER- cancerbut not ER- cancer
130
3141
36
0
20
40
60
80
100
120
140
Positive Negative
Estrogen receptor status
PlaceboTamoxifen
76
76% reduction
Adverse Events From Prevention Trials Adverse Events From Prevention Trials of Tamoxifen & Raloxifeneof 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 outcomesSTAR Trial: Key outcomesper 1000 woman-yearsper 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 & prev.
osteoporosis & breast ca prev.
Population pre and post post-menopause
Adverse and Side Effects
DVT, hot flashes, cateracts, uterine ca
DVT, hot flashes, flu-like syndrome, edema
Duration rec 5 yrs or less Studied x 8 yrs
Raloxifene vs. TamoxifenRaloxifene 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?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 : JenniferCase : 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 The Gail Model Can Underestimate Hereditary Risk of Breast CancerHereditary Risk of Breast Cancer
This woman’s breast cancer risk This woman’s breast cancer risk greatly underestimated by Gail modelgreatly underestimated by Gail model
Breast, 44Breast, 44
Breast, 38Breast, 38 Breast, 29Breast, 29Ovary, 42Ovary, 42
Jennifer, 37
ASCO
How Much Breast Cancer Is How Much Breast Cancer Is Hereditary?Hereditary?
SporadicSporadic
Family clustersFamily clusters
HereditaryHereditary
Breast CancerBreast Cancer
5%–10%5%–10%
15%15%20% 20%
Features that indicate increased Features that indicate increased likelihood of BRCA mutationslikelihood 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 BRCA1/2 Mutations Increase the Risk of Early-Onset Breast CancerEarly-Onset Breast Cancer
Population RiskPopulation Risk
Hereditary RiskHereditary Risk
By age 50By age 50
2%2%
33%-50%33%-50%
By age 70By age 70
7%7%
56%-87%56%-87%
By age 40By age 40
10%-20%10%-20%0.5%0.5%
• Penetrance = Degree to which individuals possessing a genetic trait express that trait
• Prevalence = Number of carriers in a population at a specific time
• Research ongoing
Moving Targets:Penetrance, Prevalence
0
10
20
30
40
50
60
70
20 30 40 50 60 70
BRCA1
BRCA2
sporadic
Breast Cancer Penetrance byBRCA1 or BRCA2 and Age
Prevalence depends on population98-99.8% of US population is -
Breast Cancer Penetrance byBRCA1 or BRCA2 and Age
Prevalence depends on population98-99.8% of US population is -
Screening and Chemoprevention in Screening and Chemoprevention in BRCA CarriersBRCA 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 carriersSurgical 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 pointsSummary 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 UCSFPrograms 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 BRCA testing can modify 5-year risk beyond family historybeyond 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*FH = mother, sister, or daughter with breast cancer any age