Strategies for Breast Cancer Strategies for Breast Cancer PreventionPrevention

John Park

Hannah Connolly

Jeff Tice

Mary S. Beattie

Breast Cancer Prevention!Breast Cancer Prevention!

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

Risk Assessment

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

Prevention: Lifestyle

DIETDIET

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

ExerciseExercise

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.

ObesityObesity

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

Hormones and Chemoprevention

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

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

Ravden NEJM 07Ravden NEJM 07

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 Reduce the Risk of Breast CancerSERMs Reduce the Risk of Breast Cancer

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