IntroductionBreast cancer is a malignant proliferation of epithelialcells lining the ducts or lobules of the breast. In theyear 2010, about 180,000 cases of invasive breastcancer and 40,000 deaths will occur in the UnitedStates. In addition, about 2000 men will be diagnosedwith breast cancer. Epithelial malignancies of thebreast are the most common cause of cancer in women(excluding skin cancer), accounting for about one-thirdof all cancer in women. As a result of improvedtreatment and earlier detection, mortality rate frombreast cancer has begun to decrease very
Risk Factors - Unchangeable Being a woman Age Genetic factors - mutations in BRCA1 orBRCA2; 50-60% of women inheriting a BRCA1mutation from either parent will have breastcancer by age 70 Family history of breast cancer (not related toBRCA mutations) Personal history of hyperplastic breast disease
Risk Factors - Unchangeable/contd. Personal history of breast cancer Race: incidence is higher in Caucasian comparedwith African-American, Hispanic or Asian womenRadiation treatment: chest irradiation as achild/young woman can significantly increase risk ofdeveloping breast cancerMenstrual history: early menarche (<12 yr) or latemenopause (>50yr) has some association withincreased risk. Also nulliparous, or first childbirth at>30 yrs.
Risk Factors Associated with Lifestyle Oral contraceptives - remains controversial Hormone replacement therapy - >5 years of therapy with combined estrogen and progesterone may increase risk Not breast feeding Diet and obesity; physical activity Smoking - still being investigated Alcohol - 2-5 drinks/day can increase risk x 1.5 over non-drinkers.
Breast awareness and self-examBeginning in their 20s, women should be toldabout the benefits and limitations of breastself-exam (BSE). Women should be aware of howtheir breasts normally look and feeland report any new breast changes to a healthprofessional as soon as they are found.Finding a breast change does not necessarilymean there is a cancer.
Mammography Standard positions are used in all over the world. It can be easily documented and repeated Cost-effective and non-invasive That is only method showing microcalcifications safely
At What Age Mammography Screening Should Start?All women starting at 40 years old should be screened with mammography
What Intervals Mammographic Screening Should be Done? EVERY YEAR
What is the Role of Breast Examination in Screening? Mammography is not sufficient alone for screening Some breast tumors not detected by mammograpy can be diagnosed with PE 5-7% of breast cancers are only detected with breast exam
Digital Mammography Provide equivalent detection level compared with conventional mammography Offers a lower average dose of radiation Easier access to images and computer- assisted diagnosis Superior in pre and postmenopausal women with dense breast and women under the age of 50
Breast US It is more subjective than mammography Could not detect microcalcifications Sonographic contrast is week betweentumor and adipous tissue Documentation is problematic Not useful for screening
Breast MRI Expensive Higher sensitivity with lower spesificity Not safe for detection of microcalcification Useful for additional screening method for high risk women having mammography
MRI for Evaluation of the Breast Highly sensitive but high false positive rate Useful for screening BRCA patients May be useful in staging known breast cancer May become an important screening modality
MRI Screening for High Risk WomenEvidence-based indications: With BRCA mutated women 1. degree relatives of BRCA mutated women Whole life risk of breast cancer about 20-25% according to family historyBased on concensus indications: Women who received radiation to chest at the ages of 10- 30 Li-Fraumeni syndrome patients and their first degree relatives Saslow D, CA Cancer J Clin 2007;57:75–89
Other Imaging Modalities Tc99m sestamibi scan (Miraluma) Tomosynthesis (variation of mammogram)
Breast Cancer Risk Factors Greatly increased risk RR>4.0 Inherited genetic mutations for breast cancer ≥ 2 first degree relatives with breast cancer diagnosed at early age Personal history of breast cancer Age >65 (increasing risk with increasing age to 80)
Screening for High Risk Women Mammographic screening should be start at 30 years of age (rarely before this age) Screening interval can be shorter (e.g. 6 mos) MRI can be added US can be added
Screening Guidelines for the Early Detection of Breast Cancer, American Cancer Society Yearly mammograms are recommended starting at age 40. A clinical breast exam should be part of a periodic health examination, about every 3 years for women in their 20s and 30s. Asymptomatic women aged 40 and older should continue to undergo a clinical breast exam, preferably annually*. Beginning in their early 20s, women should be told about the benefits and limitations of breast-self examination. Women should know how their breasts normally feel and report any breast changes promptly to their health care providers. Beginning at age 40 years, annual CBE should be performed prior to mammography
TreatmentBreast-conserving treatments, consisting of the removal ofthe primary tumor by some form of lumpectomy with orwithout irradiating the breast, result in a survival that is asgood as (or slightly superior to) that after extensive surgicalprocedures, such as mastectomy or modified radicalmastectomy, with or without further irradiation.Postlumpectomy breast irradiation greatly reduces the riskof recurrence in the breast. While breast conservation isassociated with a possibility of recurrence in the breast, 10-year survival is at least as good as that after moreextensive surgery. Postoperative radiation to regionalnodes following mastectomy is also associated with animprovement in survival.
Adjuvant RegimensAdjuvant therapy is the use of systemic therapies inpatients whose known disease has received local therapybut who are at risk of relapse. Selection of appropriateadjuvant chemotherapy or hormone therapy is highlycontroversial in some situations. Meta-analyses havehelped to define broad limits for therapy but do not help inchoosing optimal regimens or in choosing a regimen forcertain subgroups of patients. In general, premenopausalwomen for whom any form of adjuvant systemic therapy isindicated should receive multidrug chemotherapy.Antihormone therapy improves survival in premenopausalpatients with positive estrogen receptors and should beadded following completion of chemotherapy.
Why Do We Need Prevention? “Prevention is better than healing because it saves the labor of being sick” Thomas Adams 17th Century Physcian Limited efficacy of chemotherapies High morbidity and mortality of surgical and chemotherapeutic treatments Improved methods to predict cancer risk
Cancer Prevention Research Nutritional Science Cellular and Molecular Infectious Biology Disease Surgery Public Health Epidemiology Policy Behavioral Imaging/ Medicine Screening Pharmacology
Life Style Changes Observational studies suggest that ; Regular exercise Reducing body weight Decreasing or stopping alcohol intake may reduce the risk of breast cancer Increased dietary folate appears to reduce the increased risk of breast cancer due to alcohol intake Women`s Health Initiative found that a low fat diet was associated 9% risk reduction (but NS) Most very large prospective studies have found no association between intakes of fruits and vegetables and risk of breast cancer
Breast Cancer Development as a Long-term Process Breast cancer turn into invasive form in a long-term period Normal Intraductal Intraductal Intraductal Invazive duct Hyperplasia Hyperplasia Carcinoma Ductal with aytpia In situ Cancer X 2 risk X 4 risk X 10 risk
Breast Cancer: Risk-Treatment OptionsWomen at high risk: Follow-up may be the option Chemoprevention Prophylactic mastectomy Prophylactic oopherectomy
Chemoprevention Primary: Prevention of cancer at healthy women Secondary: Prevention of cancer at women with premalignant lesion Tertiary: Prevention of second cancer at women have a previous cancer
Tamoxifen in Breast Cancer Decrease risk of invasive breast cancer risk 43-49 % Primary prevention: Use for prevention with high risk women Secondary prevention: DCIS Tertiary prevention: Decreasing the incidence of contralaterally breast cancer
Tamoxifen Prevention Studies Breast Cancer/ Breast Invazive 1000 women-year cancer Women-annual f/uStudy Number risk Cancer Placebo Tam.Italian 5408 Low-Intermed 20,731 41 2.3 2.1IBIS-I 7144 Not 29,718 70 6.8 4.6 reportedNSABP-P1 13,388 High 52,401 264 6.8 3.4 (modified Gail model) Fisher et al. J Natl Cancer Inst 1998;90:1371-1388; Veronesi et al. Lancet 1998;352:93-97; Powles et al. Lancet 1998;352:98-101.
NSABP-P1 High risk women (5-years risk 1.66%) Randomisation n = 13,388Tamoxifen Placebo 5 Year 5 Year n = 6681 n = 6707 Fisher et al. J Natl Cancer Inst 1998; 90:1371-1388.
NSABP-P1 Cumulative Events Invasive Meme Kanseri Invaziv breast cancer Noninvasive breast cancer Noninvaziv Meme Kanseri Events Rate per 1000 40 Events Rate per 1000 40 Placebo 175 43.4 Placebo 69 15.9 Tamoxifen 89 22.0 Tamoxifen 35 7.7 Placebo 30 30 Rate/1000Rate/1000 P < 0.00001 20 20 Placebo 10 10 Tamoxifen Tamoxifen 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Analysis included women who had LCIS at baseline. Fisher et al. J Natl Cancer Inst 1998; 90:1371-1388
NSABP-P1 : Invasive Breast Cancer According to the Risk Level Placebo 60 Tamoxifen 55 42 43 Events number 40 35 29 27 20 20 13 0 2.00 2.01-3.00 3.01-5.00 5.01 5 years estimated breast cancer risk Fisher et al. J Natl Cancer Inst 1998; 90:1371-1388
NSABP-P1 Adverse Effects of TMX Endometrial cancer (RR 2.5)Thromboembolic events Deep vein thrombosis Pulmonary embolus Cerebral vascular accident
STAR: Tamoxifen vs Raloxifen for Breast Cancer Prevention 5 years NSABP P-2 study Tamoxifen 20 mg/day-5 years (n = 9726) High risk postmenopausal women Stratified according to the age, race, Gail model risk, LCIS history (N = 19,747) Raloxifen 60 mg/day-5 age (n = 9745) Median follow-up: 47.3 months Wickerham DL, et al. ASCO 2006. Abstract LBA5
STAR: Tamoxifen vs Raloxifen for Breast Cancer Prevention Raloxifene is as effective as tamoxifen in reducing invasive breast cancer incidence Less effective in the prevention of the non- invasive breast cancer Tamoxifen Raloxifene Risk RatioAnnual rate per 1000 (n = 9726) (n = 9745) (% 95 CI)Invazive breast cancer 4.30 4.41 1.02 (0.82-1.28)Noninvazive breast cancer 1.51 2.11 1.40 (0.98-2.00)• DCIS 0.79 1.16 1.46 (0.90-2.41)• LCIS 0.56 0.76 1.37 (0.76-2.54)• Mix 0.16 0.18 1.16 (0.33-4.18) Wickerham DL, et al. ASCO 2006. Abstract LBA5.
STAR: Tamoxifen vs Raloxifen for Breast Cancer Prevention Women received raloxifen: Endometrial cancer: RR = 0.62 (% 95 CI: 0.35- 1.08) Thromboembolic events: RR = 0.70 (% 95 CI: 0.54-0.91) Cataract: RR = 0.79 (% 95 CI: 0.68-0.92) Stroke, ishemic heart disease and bone fractures rates were similar in both groups Wickerham DL, et al. ASCO 2006. Abstract LBA5
Chemoprevention-Ongoing Studies New Chemopreventive Agents Less toxic Effective for ER (-) breast cancer Short-term prevention studies
ATAC Trial: Study Design Postmenopausal breast cancer 84 % HR+; 61 %Node- Surgery Radiotherapy Chemotherapy (20%) Randomisation1:1:1 -5 yearsAnastrozole 1 mg/day Tamoxifen 20 mg/day Anastrozole 1 mg/day + Placebo + Placebo + Tamoxifen 20 mg/day* (n=3125) (n=3116) (n=3125) ATAC = Arimidex, Tamoxifen, Alone or in Combination; HR = hormon receptor. *Stopped at 33 months due to toxicity and efficay results similar to tamoxifen
ATAC Study: Contralaterally Breast Cancer Incidence in HR-Positive Patients Hazard ratio (95% CI) P value HR+ 0.47 (0.29-0.75) .001 ITT 0.58 (0.38-0.88) .01 60 53 50 DCIS 5 DCIS Case numbers Invazive 40 30 26 48 5 DCIS Invasive* 20 21 10 Invasive* 0 Anastrozol Tamoxifen (n=2618) (n=2598)
SERMs in Breast Cancer Prevention: Proven EfficacyTrial OutcomeNSABP B-14 Contralateral cancersNSABP P1 invasive/preinvasive breast cancerRoyal Marsden No in riskItalian Study Risk in HRT users onlyMORE Study Invasive cancersIBIS 1 invasive/preinvasive breast cancerSTAR invasive/preinvasive breast cancerIBIS 2 Ongoing
Who can Receive SERM? LCIS DCIS Atypical ductal lobular hyperplasia BRCA-1? or BRCA-2 mutation 5-year breast cancer risk is > 1.66% according to the Gail model
Ongoing Breast Cancer Risk Reduction Studies with Aromatase Inhibitors Study Group Agents IBIS-II UK Anastrozole vs. placebo MAP-3 NCIC Exemestan vs. placeboStellar (P-4) NSABP Letrozole vs. raloxifen
Ongoing Phase II TrialsPeriareolar fine needle aspiration model: Anastrozole Targretin Statins Curcumin Cyclooxygenase-2 inhibitors