Kristi McIntyre M.D. Resident’s lecture Breast Cancer Kristi McIntyre M.D. Resident’s lecture

Breast cancer Risk factors Hereditary breast cancer Detection Staging Surgical intervention Prognostic factors Management of early stage breast cancer

Breast cancer risk factors Age/race Reproductive issues/Estrogen-related factors Breast histology Life style factors Family history/Genetic factors

Breast Cancer Risk Factors

Breast Cancer Incidence

Race/Ethnicity and Breast Cancer Risk Annual incidence Caucasian 137 African Americans 120 Hispanic 82 Asian 93 American Indian 59 SEER results: age adjusted only Jemal CA:Cancer J.Clin ;2003,53:5

Race/Ethnicity and Breast Cancer Risk “Adjusted Hazard Ratios” 0.4 0.6 0.8 1.0 1.2 African American .72 Hispanics American Indian Asian Only African Americans had lower breast cancer risk (p=o.oo6) than Caucasians Cheblowski JNCI ;March 2005

Race/Ethnicity and Breast Cancer Risk Combined Grade III and ER negative by race Cheblowski JNCI ;March 2005

Race/Ethnicity and Breast Cancer Risk Differences in breast cancer incidence rates between most ethnic groups can largely be explained by control of risk factors African American women are at significantly reduced risk African American women have a higher proportion of unfavorable features suggesting cause for higher mortality rates Cheblowski JNCI ;March 2005

Reproductive Factors and Breast Cancer Menarche < 16 Menopause >50 Menarche <16 OR 1.2 Menopause >50 OR 1.5 Null parity OR 2.0 Breastfeeding 4.3% decrease risk/yr First live birth<20 OR 0.5 First live birth >35 OR 1.5

WHI Trial of Estrogen plus Progestin E+P placebo p-value Invasive Breast cancers 199 150 0.003 SEER high stage 25% 16% 0.041 Abnormal Mammograms 716 395 0.0001 More breast cancers diagnosed at more advanced stage and increased abnormal mammograms More breast cancers diagnosed at more advanced stage and increased abnormal mammograms Chlebowski JAMA 2003;289. 3243

Breast histology and breast cancer risk Benign breast disease RR Fibrocystic disease 0 Atypical ductal hyperplasia 4.3 Atypical ductal hyperplasia and 11.0 family history

Risk Factors for Breast Cancer Family History Risk First Degree relative Premenopausal diagnosis 3.0 Bilateral disease 5.0 Premenopausal diagnosis and bilateral disease 9.0 Postmenopausal diagnosis 1.5 Second Degree relative Premenopausal diagnosis 1.2 Postmenopausal diagnosis 0

Hereditary

Family history and breast cancer risk Most hereditary breast cancers arise from mutations in BRCA1 and BRCA2 Autosomal dominant , tumor suppressor gene

BRCA mutations and lifetime cancer risk 50-85% breast cancer 50% Second breast cancers 15-45% ovarian cancer risk Other malignancies: prostrate pancreatic male breast cancer

Founder mutations and Breast cancer Ethnic background should be considered in risk assessment for breast cancer “ Founder” gene mutations discovered in individuals of Ashkenazi Jewish descent 50-90 % have gene susceptibility with positive family history Founder mutations have been found in populations of Iceland,Finland, France, Holland , Russia,and Sweden

Models for risk assessment Gail model Claus model http://bcra.nci.nih.gov/brc Age Age first live birth Age first menses FH-maternal only; no age # prior breast biopsies/ADH race Family history Age at diagnosis Both models inadequate : not useful for mutation carriers or individual risk www3.utsouthwestern.edu/cancergene/

Lifestyle factors and breast cancer risk Body mass index: postmenopausal women >30% excess BMI increased risk Dietary fat intake: increased risk NSAID use: decreases risk Physical activity: 1.25 to 2.5/hrs week brisk walking had 18 % decrease risk Smoking : increased risk Alcohol use: increased (dose dependent)

Risk Reduction Strategies Average Risk Moderate Risk Early childbirth Exercise Maintain normal weight Avoid smoking/alcohol Avoid prolonged HRT Chemoprevention

Most breast cancers are non palpable masses discovered only on screening mammograms Malignant breast densities have irregular borders, are stellate and distort surrounding architecture

Breast Cancer Detection United States Preventive Services Task Force Mammogram every 1-2 years for female age 40-49(average risk) Age > 50 annual mammography and clinical exam Age > 70 debatable Mammography detects only 85% of biopsy proven breast cancer hence not a substitute for tissue sampling of palpable mass

Breast Cancer Screening There is almost universal agreement that randomized controlled trials of screening have demonstrated death rate from breast cancer can be reduced by periodic screening with mammography

MRI Breast Implant evaluation Axillary adenopathy ?occult primary Breast cancer patients (extent of disease, response to neoadjuvant therapy) Screening evaluation for high risk patient Further evaluation of mammographic abnormality

Staging of breast cancer Estimate extent of disease Determine prognosis Guide therapy

Staging of breast cancer Stage 0 (DCIS) Stage I node negative Stage II node positive Stage III advanced node Stage IV distant metastasis 2003 AJCC staging change Distinction between micrometastasis and isolated tumor cells Identifiers for sentinel nodes #number of positive LN

Management of Early stage breast cancer 1950 Halsted “radical mastectomy” “breast cancer spreads in an orderly fashion” 12% 10 year survival 20-30% node negative breast cancer patients will develop metastatic disease Micrometastatic disease paradigm

Management of Early stage breast cancer Radical Mastectomy Whole breast radiation Axillary dissection Lumpectomy Partial breast radiation Sentinel node biopsy MORE LESS

Surgical intervention for Breast Cancer NSABP B-04 Total Mastectomy + Axillary dissection Lumpectomy + Breast radiation Lumpectomy alone No difference in Overall Survival or Disease Free Survival (20 year follow-up) Fisher et al.NEJM2002;347:1456-61

Surgical Intervention of Breast Cancer NSABP B-04 Cumulative incidence of ipsilateral breast cancer Standard of care: lumpectomy+ Xrt 39% 14%

Surgical intervention for Breast Cancer NSABP B-04 Fisher,et al.NEJM(2002):347;1454-61

Surgical Staging of Axilla Axillary dissection= removal of level I and Level II lymph nodes Morbidity : wound infection motion restriction arm stiffness pain lymphedema

Sentinel node mapping

Chemotherapy for early stage breast cancer

Prognostic factors in Breast cancer Recognized Factors Potential factors Proliferative index Tumor grade Vascular invasion Her- 2 Gene microarray Nodal status Tumor size Histologic type ER/PR

Prognostic factors in Breast cancer The most significant prognostic indicator for patients with early stage breast cancer is the presence or absence of axillary lymph node involvement.

Prognostic factors in Breast cancer Recognized Factors Potential factors Proliferative index Tumor grade Vascular invasion Her- 2 Gene microarray Nodal status Tumor size Histologic type ER/PR

Prognostic factors in breast cancer Multigene assay: Paik et al.NEJM 2004;351:2817-26

Gene Microarray

Multigene assay to predict recurrence in node negative breast cancer

HER- 2/neu Her-2/neu oncogene encodes for transmembrane receptor belonging to EGFR family Amplified in 25-30% breast cancer Overexpression associated with tumor aggressiveness and increased rates of recurrence

Her-2/neu Basis for molecular targeted therapy with Herceptin

NCI clinical alert –April 25,2005 NSABP B-31 Operable breast cancer Her 2 +, node + Randomization 52% decrease in disease recurrence AC x4cycles Taxol x4 cycles + Herceptin AC x4cycles Taxol x4 cycles

Thank you !