BREAST CA 2

Breast cancer:

why do people get it and can we prevent it?T. Kuan Yu, M.D., Ph.D.Houston Precision Cancer Center

What is Cancer? Our own cells that grows without controlGrow (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????

Basics of Cells

DNA RNA Protein

DNA 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?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 Statistics200,000 new cases in 200340,200 breast cancer deaths in 2003Most common female malignancySecond leading cause of female ca mortalitySEER data:Lifetime risk of developing breast ca13.1% in white American female9.6% in African-American female

Breast Cancer Risk FactorsAge Female sexInherited FactorsFamily historyBenign breast diseaseHormonesDietary FactorsEnvironmental factorsNon ModifiableModifiable

Largest Risk FactorsAgeDNA less stableAccumulation of previous changes

WomanHormone Breast tissue

( Courtesy of Dr. Arun Banu)

10 Relative with Breast Cancer( * RR = Relative Risk )

RR* of breast cancerPremenopausal3.2Postmenopausal1.5Premenopausal, b/l8.8Postmenopausal, b/l4.0

Personal history: 0.5-1%/yr

Family history: Lifetime risk: 20-30%MotherSisterBRCA 1& BRCA 2: Lifetime risk: 50-80%Family history of breast cancer

( Courtesy of Dr. Arun Banu)

Estrogen Exposure Can Drive Breast Cancer Development

Estrogen ExposureEarly menarche (< 12 yo)Late menopause (> 55 yo)Having no pregnancyChildbirth after 30 yo (RR: 4-5x)Exogenous estrogen useObesity (post-menopausal)

Combined Oral Contraceptive May Increase Risk of Breast Cancer53 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 Not Increase Risk of Breast Cancer4575 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 Replacement after Menopause

What Can We Do to Prevent Breast Cancer?Estrogen Exposure Risk: PregnancyEarly Childbirth Breast FeedLimit Exogenous Estrogen

Western Lifestyle/Food Increase Breast Cancer 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 Postmenopausal WomanObesity 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 Breast Cancer?Food Risk: Western diet/lifestyleWeight control (post-menopausal)Soy isoflavones may be protective for prememopausal breast cancer (RR 0.41)

Chemicals May Increase Breast Cancer riskMany chemicals led to cancer developments in lab animalNo 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 Hodgkins 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 Cancer risk

Prior RT to breastMantle RTRelative risk of breast ca depends on the age at which she received RT56% for women 19 yrs of age at RT7% for women b/ 20-29 yrs of age at RT1% for women 30 yrs of age at RTCancer develops 10-15 yrs laterUsually medial portion of the breast

What Can We Do to Prevent Breast Cancer?Chemical Risk: Not clearRadiation Risk: Avoid unnecessary exposure of RT such as diagnostic X-ray that are not needed

What Can We Do to Prevent Breast Cancer?Early Detection:Self Breast AwarenessAnnual Mammogram ( 40) Clinical breast exam about every 3 years for women in their 20s and 30s and every year for women 40

Screening MammographyHIP (Health Insurance plan of NY) Study61,000 women, age 0-64 yrsRandomization:Screening mammo vs. routine medical careResults:Mortality rate was reduced by 33% in screened women 50-59 yrs of ageSurvival difference was higher by 7 to 10 yrs after diagnosis in women who had screening mammography

The Gail ModelIncludes:Current ageNumber of 1st-degree female relatives with a history of breast cancerAge at first live birth, or nulliparityCalculates a womans 5-year and lifetime risk of developing breast cancer

Number of breast biopsiesHistory of atypical hyperplasiaAge at menarcheRace

For Woman with BRCA1/2 Mutations( Courtesy of Dr. Arun Banu)

NSABP-P1(BCPT): SchemaFisher et al. J Natl Cancer Inst 1998;90:1371-1388.

Invasive Breast Cancer Cases by ER StatusNegativePositiveUnknownNumber of Events050100150PlaceboER StatusAdapted from Fisher et al. J Natl Cancer Inst 1998;90:1371-1388.3138130411410Tamoxifen

Rate of Invasive Breast CancerAdapted from Fisher B, Constantion JP, Wickerham DL, et al. J Natl Cancer Inst. 1998;90:1371-1388.

Why Not Just Treat All High-Risk Women 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 eventRisk Ratio (all ages)Risk Ratio (ages 50)Endometrial cancer2.534.01Stroke1.591.75Pulmonary embolism3.013.19Deep vein thrombosis1.601.71

Breast Cancer PreventionRaloxifene (MORE Trial)*Post menopausal female with osteoporosisBreast cancer reduction by 62%Invasive breast cancer by 72%Invasive ER+ive breast cancerNo associated with uterine cancerSide Effects:Increased risk of thromboembolic event28% hot flashes with raloxifene vs. 21% in placebo40% reduction in cardiovascular events*Breast Cancer Res Treat 65:125-134, 2001

Prophylactic Mastectomy for High risk WomanRemoves most but not all breast tissueTotal (simple) mastectomy appears more effective than subcutaneous mastectomyShown to reduce risk of breast cancer by 90% in women with BRCA mutationsNew Engl J Med 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 Breast cancer

OophorectomyPrevents breast ca in BRCA 1 and 2RR reduction is 50% in premenopausal ptsRR 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

ConclusionsMany Non-Modifiable risk factors for breast cancerEarly dectectionMany Modifiable risk factors for breast cancerReduce estrogen exposureAdjust diet and weightPrevent exposure from unnecessary chemical and radiation

Thank YouAcknowledgement for materials in slides:Dr. Arun BanuDr. Hemangini Shah

*Slide 5: Hereditary Breast and Ovarian CancerAll cancer is genetic, because it results from mutations in genes that normally control cell division. Most such mutations are acquired during a person's lifetime, but in a minority of people mutations in critical genes are inherited.Approximately 7% of breast cancer and 10% of ovarian cancer results from such genetic mutations passed down from either the father or mother1. The majority (approximately 84%) of hereditary breast cancer results from inherited mutations in two genes called BRCA1 and BRCA22. Although sometimes referred to as the breast cancer genes, BRCA1 and BRCA2 are also associated with the majority of hereditary cancers of the ovary.Although the risk of breast or ovarian cancer may sometimes be increased in other hereditary cancer syndromes, there do not appear to be other genes (such as a so-called "BRCA3") that are responsible for a significant proportion of hereditary breast and ovarian cancer. Recent studies have in fact indicated that if there are additional genes, they are of minor importance, compared with BRCA1 and BRCA2, in families with breast and ovarian cancer3."It is estimated that millions of people, worldwide, carry mutations in BRCA1 or BRCA2.References:1. Claus EB, Schildkraut JM, Thompson WD, Risch NJ: The genetic attributable risk of breast and ovarian cancer. Cancer 1996;77:2318-24.2. Ford D, Easton DF, Stratton M, et al: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. American Journal of Human Genetics 1998;62:676-89.3. Gayther SA, Russell P, Harrington P et al: The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: No evidence for other ovarian cancer-susceptibility genes. American Journal of Human Genetics 1999;65:1021-9.Core slide for a health care professional presentationCore slide for a community presentation

*The Gail model estimates the absolute risk, or probability, that a woman of a given age with certain risk factors will develop breast cancer over a specified time interval. The risk factors currently included in the Gail model are: Current age Number of first-degree female relatives with a history of breast cancer Age at first live birth, or nulliparity Number of breast biopsies History of atypical hyperplasia Age at menarche Race

*The BCPT enrolled a total of 13,388 healthy women 35 years of age who were at increased risk of breast cancer.1 Women were randomized to receive 20 mg/day of NOLVADEX (tamoxifen citrate) (n=6681) for 5 years or placebo (n=6707). The data monitoring committee recommended the trail be halted earlier than anticipated because the benefit of tamoxifen became obvious..*The most striking finding related to the cancers that occurred in the BCPT relates to estrogen receptor (ER) status. There was no difference in the number of ER-negative cancers that occurred between the two groups, and no indication that NOLVADEX (tamoxifen citrate) therapy resulted in any increase in ER-negative breast cancers. However, NOLVADEX therapy resulted in a dramatic reduction in ER-positive breast cancers. The annual rate of ER-positive breast cancers was 69% less in women in the NOLVADEX group (1.58 cases per 1000 women) compared with women in the placebo group (5.02 cases per 1000 women).1 This finding is consistent with the known greater efficacy of NOLVADEX in receptor-positive breast cancer.

*The Breast Cancer Prevention Study cannot predict beyond five years because women in the placebo arm of the study were allowed to crossover to tamoxifen therapy after the results of the study were announced. However, another NSABP clinical trialB-14suggests that taking tamoxifen for five years may be sufficient for permanently reducing the risk of breast cancer. B-14 examined tamoxifens value in preventing a second new cancer in the contralateral breast in women previously diagnosed with an ER-positive breast cancer and negative axillary lymph nodes. The study found no additional preventive benefits in taking tamoxifen beyond five years.SOURCE: Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001;93:684-690.

It also should be noted that although the P-1 study determined tamoxifen reduced the risk of estrogen receptor-positive tumors, it also found that the drug made no difference in the occurrence of estrogen receptor-negative tumors. Approximately 20% of breast cancer cases are estrogen receptor-negative. *Despite the demonstrated preventive benefit that tamoxifen offers women at high risk for breast cancer, less than 5% of high-risk women elect to take the drug when offered. Most cite worries about tamoxifens side effects and inconvenience as their reasons for not choosing drug therapy. As we have seen, those side effects include an increased risk of endometrial cancer, stroke, pulmonary emboli, and deep vein thrombosis, particularly for women aged 50 or older. Counseling a patient to better understand her personal risk of breast cancer includes a careful exploration of the risk/benefit of tamoxifen therapy.

*Slide 22: Prophylactic MastectomyPreviously, prophylactic mastectomy was shown to reduce the risk of breast cancer in high risk women by more than 90%1, and recent studies have demonstrated that prophylactic mastectomy specifically reduces the risk of breast cancer in women with mutations in BRCA1 or BRCA22. In fact, no breast cancer following prophylactic mastectomy was observed among any of the study participants with such mutations.Because of the efficacy of surveillance in detecting most early-stage breast cancer, and the high cure rate of breast cancers detected at an early stage, prophylactic mastectomy is chosen by only a minority of women with cancer-predisposing mutations3. Prophylactic mastectomy may nonetheless be considered by women whose mammographic assessment is compromised by extensive fibrocystic change, or by women who have relatives or friends whose breast cancer was advanced or fatal despite rigorous surveillance.References:1. Hartmann LC, Schaid DJ, Woods JE, et al: Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. New England Journal of Medicine 1999, 340:77-84.2. Meijers-Heijboer H, van Geel B, van Putten WLJ, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. New England Journal of Medicine 2001;345:159-164.3. Lerman C, Narod S, Schulman K, et al: BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes. Journal of the American Medical Association 1996;275:1885-1892.Core slide for a health care professional presentation

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BREAST CA 2