Breast cancer: Breast cancer:

why do people get it and why do people get it and can we prevent it?can we prevent it?

T. Kuan Yu, M.D., Ph.D.

Houston Precision Cancer Center

What is Cancer? What is Cancer?

• Our own cells that grows without

control– Grow (faster or slower than normal cells)

– Die (slower than normal cells)

– Proteins and structures that are very similar to

normal cell

Why do we get cancer?Why do we get cancer?

???

Basics of CellsBasics of Cells

DNA DNA RNA RNA Protein Protein

DNA is Blueprint for CellsDNA is Blueprint for Cells

• DNA is blue print of cells.

• Its radius is 1 nm. If you stretch DNA into single strand, it would be 1600 km long.

• Only 1.5% of DNA are genes (~20,000) that encode proteins

Why do we get cancer?Why do we get cancer?

• Different events can “change” (i.e. mutate) the DNA and change the protein function

• With the “right” sets of mutations, the cells stop listening to the control of the body

Events that mutate DNA leads to cancer

Breast Cancer StatisticsBreast Cancer Statistics

• 200,000 new cases in 2003

• 40,200 breast cancer deaths in 2003

• Most common female malignancy

• Second leading cause of female ca mortality

• SEER data:– Lifetime risk of developing breast ca

• 13.1% in white American female

• 9.6% in African-American female

Breast Cancer Risk FactorsBreast Cancer Risk Factors

• Age

• Female sex

• Inherited Factors

• Family history

• Benign breast disease

• Hormones

• Dietary Factors

• Environmental factors

Non Modifiable

Modifiable

Largest Risk FactorsLargest Risk Factors

• Age– DNA less stable– Accumulation of previous changes

• Woman– Hormone – Breast tissue

( Courtesy of Dr. Arun Banu)

( Courtesy of Dr. Arun Banu)

1100 Relative with Breast Cancer Relative with Breast Cancer

RR* of breast cancer

Premenopausal 3.2

Postmenopausal 1.5

Premenopausal, b/l 8.8

Postmenopausal, b/l 4.0

( * RR = Relative Risk )

• Personal history: 0.5-1%/yr

• Family history: Lifetime risk: 20-30%

Mother

Sister

• BRCA 1& BRCA 2: Lifetime risk: 50-80%

Family history of breast cancerFamily history of breast cancer

( Courtesy of Dr. Arun Banu)

( Courtesy of Dr. Arun Banu)

( Courtesy of Dr. Arun Banu)

( Courtesy of Dr. Arun Banu)

( Courtesy of Dr. Arun Banu)

Estrogen Exposure Can Drive Estrogen Exposure Can Drive Breast Cancer DevelopmentBreast Cancer Development

Estrogen ExposureEstrogen Exposure

• Early menarche (< 12 yo)

• Late menopause (> 55 yo)

• Having no pregnancy

• Childbirth after 30 yo (RR: 4-5x)

• Exogenous estrogen use

• Obesity (post-menopausal)

Combined Oral Contraceptive May Combined Oral Contraceptive May Increase Risk of Breast CancerIncrease Risk of Breast Cancer

• 53 297 women with breast cancer and 100 239 women without breast cancer from 54 studies

• Combined oral contraceptives:

– current users RR 1.24 [1.15-1.33]

– 1-4 years after stopping RR 1.16 [1.08-1.23],

– 5-9 years after stopping RR 1.07 [1.02-1.13]

– 10+ years after stopping use RR 1.01 [NS](Lancet. (1996)22;347(9017):1713)

Combined Oral Contraceptive May Combined Oral Contraceptive May Not Increase Risk of Breast CancerNot Increase Risk of Breast Cancer

• 4575 women with breast cancer and 4682 controls

• Combined oral contraceptives:

– current users RR 1.0 [NS]

– Former users RR 0.9 [NS]

– No association with family history or use at young age

(Lancet. (1996)22;347(9017):1713)

Risk from Hormone Risk from Hormone Replacement after MenopauseReplacement after Menopause

What Can We Do to Prevent What Can We Do to Prevent Breast Cancer?Breast Cancer?

Estrogen Exposure Risk:

•Pregnancy

•Early Childbirth

•Breast Feed

•Limit Exogenous Estrogen

Western Lifestyle/Food Increase Breast Western Lifestyle/Food Increase Breast Cancer Risk in Asian-AmericanCancer Risk in Asian-American

• >1500 Asian-American immigrants (1983)

• born in the West 60% higher risk than born in the East.

• Among those born in the West: women with three or four grandparents born in the West 50% higher risk than those with all grandparents born in the East.

• Among those born in the East: lived in the West for > 10 years 80% higher than more recent migrants.

• Risk was unrelated to age at migration for women migrating at ages less than 36 years.

(JNCI (1993) 85 (22): 1819)

Obesity Increases Breast Cancer Risk in Obesity Increases Breast Cancer Risk in Postmenopausal WomanPostmenopausal Woman

• Obesity leads to 11,000 to 18,000 deaths per year from breast cancer in U.S. for women over age 50

• Obesity increase the risk of breast cancer by 1.5 fold among postmenopausal women who do not use menopausal hormones

• Due to increased levels of estrogen in obese post-menopausal women, whose ovary is not functioning

What Can We Do to Prevent What Can We Do to Prevent Breast Cancer?Breast Cancer?

Food Risk:

•Western diet/lifestyle

•Weight control (post-menopausal)

•Soy isoflavones may be protective for prememopausal breast cancer (RR 0.41)

Chemicals May Increase Breast Chemicals May Increase Breast Cancer riskCancer risk

• Many chemicals led to cancer developments in lab animal

• No association seen with DDT, DDE, polychlorinated biphenyls and High power line in population studies

• Woman of the atomic bombings in Japan during World War II;

• Women with Hodgkin’s disease treated with radiation therapy

• Girls treated with RT for non-malignant conditions

• Young women with large numbers of diagnostic x-ray to monitor treatment for TB or severe scoliosis.

Radiation Increases Breast Radiation Increases Breast Cancer riskCancer risk

Prior RT to breastPrior RT to breast

• Mantle RT– Relative risk of breast ca depends on the age at

which she received RT• 56% for women 19 yrs of age at RT

• 7% for women b/ 20-29 yrs of age at RT

• 1% for women 30 yrs of age at RT

– Cancer develops 10-15 yrs later– Usually medial portion of the breast

What Can We Do to Prevent What Can We Do to Prevent Breast Cancer?Breast Cancer?

Chemical Risk:

•Not clear

Radiation Risk:

•Avoid unnecessary exposure of RT such as diagnostic X-ray that are not needed

What Can We Do to Prevent What Can We Do to Prevent Breast Cancer?Breast Cancer?

Early Detection:

•Self Breast Awareness•Annual Mammogram (≥ 40) •Clinical breast exam about every 3 years for women in their 20s and 30s and every year for women ≥ 40

Screening MammographyScreening Mammography

• HIP (Health Insurance plan of NY) Study– 61,000 women, age 0-64 yrs– Randomization:

• Screening mammo vs. routine medical care

– Results:• Mortality rate was reduced by 33% in screened women

50-59 yrs of age

• Survival difference was higher by 7 to 10 yrs after diagnosis in women who had screening mammography

The Gail ModelThe Gail Model

Includes:Includes:• Current ageCurrent age

• Number of 1Number of 1stst-degree -degree female relatives with a female relatives with a history of breast cancerhistory of breast cancer

• Age at first live birth, Age at first live birth, or nulliparityor nulliparity

Calculates a woman’s 5-year and lifetime risk of Calculates a woman’s 5-year and lifetime risk of developing breast cancer developing breast cancer

•Number of breast biopsiesNumber of breast biopsies

•History of atypical History of atypical hyperplasiahyperplasia

•Age at menarcheAge at menarche

•Race Race

For Woman with BRCA1/2 MutationsFor Woman with BRCA1/2 Mutations

( Courtesy of Dr. Arun Banu)

NSABP-P1(BCPT): SchemaNSABP-P1(BCPT): Schema

Fisher et al. Fisher et al. J Natl Cancer InstJ Natl Cancer Inst 1998;90:1371-1388. 1998;90:1371-1388.

Eligible Women at High RiskEligible Women at High Risk(5-yr risk (5-yr risk 1.66% or age over 60) 1.66% or age over 60)

RandomizationRandomizationn = 13,388n = 13,388

TamoxifenTamoxifen5 Years5 Yearsn = 6681n = 6681

PlaceboPlacebo5 Years5 Yearsn = 6707n = 6707

Invasive Breast Cancer Cases by ER Status

NegativeNegative PositivePositive UnknownUnknown

Num

ber

of E

vent

sN

umbe

r of

Eve

nts

00

5500

110000

115500

PPllaacceebboo

ER StatusER Status

Adapted from Fisher et al. Adapted from Fisher et al. J Natl Cancer InstJ Natl Cancer Inst 1998;90:1371-1388. 1998;90:1371-1388.

31313838

130130

4141

14141010

TamoxifenTamoxifen

Rate of Invasive Breast CancerRate of Invasive Breast Cancer

PlaceboPlacebo

TamoxifenTamoxifen

00 11 22 33 5544

PlaceboPlacebo 175 175 43.4 43.4TamoxifenTamoxifen 89 89 22.0 22.0

EventsEvents Rate per 1000Rate per 1000

Rat

e/10

00R

ate/

1000 PP < 0.00001 < 0.00001

00

1100

2200

3300

4400

YearsYears

49% reduction

Adapted from Fisher B, Constantion JP, Wickerham DL, et al. Adapted from Fisher B, Constantion JP, Wickerham DL, et al. J Natl Cancer Inst.J Natl Cancer Inst. 1998;90:1371-1388. 1998;90:1371-1388.

Why Not Just Treat All High-Risk Why Not Just Treat All High-Risk Women Women With Tamoxifen?With Tamoxifen?

• Less than 5% of high-risk women elect to take tamoxifen when offered.

• Tamoxifen has some serious side effects (particularly for women ≥ age 50).

Type of eventType of event Risk RatioRisk Ratio(all ages)(all ages)

Risk Ratio Risk Ratio (ages (ages ≥≥ 50) 50)

Endometrial Endometrial cancercancer

2.532.53 4.014.01

StrokeStroke 1.591.59 1.751.75

Pulmonary Pulmonary embolismembolism

3.013.01 3.193.19

Deep vein Deep vein thrombosisthrombosis

1.601.60 1.711.71

Breast Cancer PreventionBreast Cancer Prevention

• Raloxifene (MORE Trial)*– Post menopausal female with osteoporosis– Breast cancer reduction by 62%– Invasive breast cancer by 72%– Invasive ER+ive breast cancer– No associated with uterine cancer– Side Effects:

• Increased risk of thromboembolic event• 28% hot flashes with raloxifene vs. 21% in placebo• 40% reduction in cardiovascular events

*Breast Cancer Res Treat 65:125-134, 2001

Prophylactic Mastectomy for High risk WomanProphylactic Mastectomy for High risk Woman

• Removes most but not all breast tissue

• Total (simple) mastectomy appears more effective than subcutaneous mastectomy

• Shown to reduce risk of breast cancer by 90% in women with BRCA mutations

New Engl J MedNew Engl J Med 2001;345:159-64 2001;345:159-64Hartmann LC, Sellars TA, Schaid DJ, et al. J Natl Cancer Inst. 2001;93:1633-37.

Oophorectomy for Woman with High Risk for Oophorectomy for Woman with High Risk for Breast cancerBreast cancer

• Oophorectomy– Prevents breast ca in BRCA 1 and 2– RR reduction is 50% in premenopausal pts– RR reductions may be higher if done before the

age of 40 yrs and that the duration of protection is approx. 15yrs

JCO 23(8):1656-1663; 2005

ConclusionsConclusions

• Many Non-Modifiable risk factors for breast cancer– Early dectection

• Many Modifiable risk factors for breast cancer– Reduce estrogen exposure– Adjust diet and weight– Prevent exposure from unnecessary chemical and

radiation

Thank YouThank You

Acknowledgement for materials in slides:

Dr. Arun Banu

Dr. Hemangini Shah