Breast Cancer A Family Medicine Perspective

Breast CancerA Family Medicine Perspective By Robert R. Zaid, DO PrimeCare of Novi

Overview • Epidemiology • Etiology • Risk Factors • Screening • Presentation • Workup • Staging • Treatment

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Incidence: Invasive breast cancer 1 1.4 million new cases in 2008 Incidence rates for 2002 varied internationally 3.9 cases per 100,000 in Mozambique 101.1 cases per 100,000 in the United States Past 25 years Breast cancer incidence rates have risen globally Highest rates occurring in the westernized countries Change in reproductive patterns Increased screening Dietary changes Decreased activity Mortality Mortality has been decreasing Especially in industrialized countries. Breast CancerEpidemiology 1 American Cancer Society

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Projection (2009) United States Estimated 192,370 new cases in women 1,910 cases in men Incidence rates 70’s to 90’s had increasing incidence 1999-2005 Decreased by 2.2% per year Why? Reduced use of hormone replacement therapy (HRT) Women’s Health Initiative in 2002 Breast CancerEpidemiology Swart, R; Downey, L, www.emedicine.com, Breast Cancer

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Lifetime Risk of Breast Cancer All Women 12.7% Non-Hispanic Whites 13.3% African American Women 9.98% More likely to be diagnosed with larger, advanced stage tumors (>5 cm) Breast CancerEpidemiology Swart, R; Downey, L, www.emedicine.com, Breast Cancer

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Death rates Steadily decreased since 1990 Estimated 40,610 breast cancer deaths for 2009 Women < 50 years Largest decrease in mortality 3.3% per year Thought to represent Earlier detection Improved treatment modalities Breast CancerEpidemiology Swart, R; Downey, L, www.emedicine.com, Breast Cancer

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Mechanism- Current understanding of breast tumorigenesis Molecular alterations at the cellular level Outgrowth and spread of breast epithelial cells Immortal features Uncontrolled growth Genomic profiling Demonstrated the presence of discrete breast tumor subtypes Luminal A Luminal B Basal HER2+ The exact number of disease subtypes and molecular alterations from which these subtypes derive remains to be fully elucidated Generally align closely with the presence or absence of hormone receptor and mammary epithelial cell type (luminal or basal). Breast CancerEtiology Swart, R; Downey, L, www.emedicine.com, Breast Cancer

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Breast CancerEtiology

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Risk factors found by studies Many of these factors form the basis for breast cancer risk assessment tools. Common denominator Level and duration of exposure to endogenous estrogen Increase lifetime exposure to estrogen Premenopausal women Early menarche Nulliparity Late menopause Postmenopausal women Obesity and hormone replacement therapy Breast CancerRisk Factors

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Family History of breast cancer 1st degree relative Risk 5 times greater in women with 2 or more first-degree relatives A family history of ovarian cancer in a first-degree relative Especially if the disease occurred at an early age (< 50 years old) Associated with a doubling of risk of breast cancer Breast CancerRisk Factors

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Exogenous hormones Oral contraceptives (OCs) Hormone replacement therapy (HRT) 1.25 increased risk among current users of oral contraceptives Risk appears to decrease As age and time from oral contraceptive discontinuation increases Breast cancer risk returns to that of the average population after approximately 10 years following cessation of oral contraceptives Breast CancerRisk Factors

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment HRT Consistent epidemiologic data support an increased risk of breast cancer incidence and mortality (2003) with the use of postmenopausal HRT Directly associated with length of exposure Lobular (relative risk [RR]=2.25, 95% confidence interval [CI]= 2.00-2.52) Mixed ductal–lobular (RR=2.13, 95% CI= 1.68-2.70) Tubular cancers (RR=2.66, 95% CI= 2.16-3.28). Breast CancerRisk Factors

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Combo estrogen plus progestin Increased risk as compared to estrogen only Not statistical significance (p=0.06) Women’s Health Initiative (WHI) Indicate that the adverse outcomes associated with long-term use outweigh the potential disease prevention benefits particularly for women older than 65 years Protective factors Late menarche Anovulation Early menopause (spontaneous or induced) Lowering endogenous estrogen levels Shortening the duration of estrogenic exposure. Breast CancerRisk Factors

Breast CancerRisk Factors • Epidemiology • Etiology • Risk Factors • Screening • Presentation • Workup • Staging • Treatment

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Multivariate Methods for estimating breast cancer 2 types Estimate absolute risk of developing cancer Estimate likelihood that an individual is a carrier of a gene mutation BRCA1 BRCA2 Breast CancerRisk Assessment Tools

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment BRCA screens BRCAPRO Identifies 50% of mutation negative families Fails to screen 10% of mutation carriers Myriad I, II Manchester Ontario Family History U.S. Preventive Services Task Force (USPSTF) Does not specifically endorse any of these genetic risk assessment models because of insufficient data to evaluate their applicability to asymptomatic, cancer-free women. USPSTF does support the use of a greater than 10% risk probability for recommending further evaluation with an experienced genetic counselor for decisions regarding genetic testing. Breast CancerRisk Assessment Tools

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Risk Prediction Models Gail Model (1989) Made from data from Breast Cancer Detection and Demonstration study Probability of developing breast cancer over a defined age interval Intended to improve screening guidelines Gail Model 2 Includes history of first-degree affected family members Used extensively in clinical practice Most accurate for non-Hispanic White women who receive annual mammograms Tends to overestimate risk in younger women who do not receive annual mammograms Reduced accuracy in populations with demographics (age, race, screening habits) that differ from the population on which it was built http://www.cancer.gov/bcrisktool/ Breast CancerRisk Assessment Tools

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Care Address concerns regarding applicability of the Gail Model to African American women Data from a large case control study of African American CARE Model demonstrated high concordance between the numbers of breast cancer predicted and the number of breast cancers observed among African American women when validated in the WHI cohort. Breast CancerRisk Assessment Tools

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Heredity 5-10% of women have an identifiable familial predisposition 20-30% of women with breast cancer have a relative with history BRCA1 and BRCA2 mutations Responsible for 3-8% of all cases of breast cancer 15-20% of familial cases Gene mutation on Chromosome 17 and 18 Account for majority of inherited disease Believed to be tumor suppressor genes Rare mutations are seen in the PTEN, TP53, MLH1, MLH2, and STK11 genes. Breast CancerGenetic Factors

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Mutation rates may vary by ethnic and racial groups. BRCA1 mutations Highest rates occur among Ashkenazi Jewish women (8.3%) Hispanic women (3.5%) Non-Hispanic white women (2.2%) African American women (1.3%) Asian American women (0.5%) Women with BRCA1 or BRCA2 gene Estimated 50-80% lifetime risk of developing breast cancer. Breast CancerGenetic Factors

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Early detection Primary defense available to patients Preventing the development of life-threatening breast cancer Breast tumors that are smaller or nonpalpable Treatable and have a more favorable prognosis Survival benefit of early detection Early detection is widely endorsed Women younger than 40 years Monthly breast self-examination practices Clinical breast exams every 3 years are recommended, beginning at age 20 years. Breast CancerBreast Cancer Screening

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Mammography Annual screening mammography beginning at age 40 years Widely recommended approach in the United States U.S. Preventive Services Task Force (USPSTF) Nov 2009 Updated breast cancer screening guidelines Recommend against routine mammography before age 50 years 40 to 49 years of age USPSTF suggests that the decision to start regular screening mammography be individualized and should include the patient's values regarding specific benefits and harms American College of Obstetricians and Gynecologists (ACOG) Continues to recommend adherence to current ACOG guidelines Screening mammography every 1-2 years for women aged 40-49 Screening mammography every year for women age 50 or older ACOG notes, however, that because of the USPSTF downgrading, some insurers may no longer cover some of these studies. Breast CancerBreast Cancer Screening

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Breast self-examination Inexpensive and noninvasive procedure Evidence supporting effectiveness Controversial and largely inferred Not been found to reduce mortality Improvements in treatment for early, localized disease Breast self-examination and clinical breast exam, continues to be recommended Clinical trials support combining clinical breast exam with mammography Breast CancerBreast Self Examination

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Recommendations USPSTF Inadequate evidence to make a recommendation for teaching or performing BSE 2009 USPSTF guidelines recommend against teaching women how to perform BSE Resulted in additional imaging procedures and biopsies ACOG Continues to recommend counseling BSE has potential to detect palpable breast cancer Breast CancerBreast Self Examination

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Mammography Demonstrated to be an effective tool Prevention of advanced breast cancer in women at average risk Best available population-based method to detect breast cancer at an early stage Often reveals a lesion before it is palpable by clinical breast examination On average 1-2 years before noted by breast self-examination 20-30% of women still do not undergo screening as indicated Physician recommendation Access to health insurance Digital Mammograpy Allows the image to be recorded and stored Computer-aided diagnosis (CAD) systems Using an image modified to improve evaluation of specific areas in question. Breast CancerMammography

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Recommendations: USPSTF Estimates benefit of mammography in women 50-74 years to be a 30% reduction risk of death 40-49 years, the risk of death is decreased by 17% Non-white women and those of lower socioeconomic status remain less likely to obtain mammography services and more likely to present with life-threatening, advanced-stage disease Breast CancerMammography

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Ultrasound Widely available and useful adjunct to mammography MRI Combination of T-1, T-2, and 3-D contrast-enhanced MRI techniques has been found to be highly sensitive Approximating 99% Limitations 10-fold higher cost than mammography Poor specificity (26%) Significantly more false-positive reads Significant additional diagnostic costs and procedures. Breast CancerMammography

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Below are the criteria for using breast MRI screening per the American Cancer Society (ACS).6 Annual breast MRI Evidence based BRCA mutation First-degree relative of BRCA carrier, but untested Lifetime risk approximately 20-25% or greater as defined by BRCAPRO or other risk models Lifetime risk of breast cancer Radiation to chest when aged 10-30 years Li-Fraumeni syndrome and first-degree relatives Cowden and Bannayan-Riley-Ruvalcaba syndromes and first-degree relatives Breast CancerMammography

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Insufficient evidence to recommend for or against MRI screening Lifetime risk 15-20%, as defined by BRCAPRO or other risk models Lobular carcinoma in situ or atypical lobular hyperplasia (ALH) Atypical ductal hyperplasia (ADH) Heterogeneously or extremely dense breast on mammography Women with a personal history of breast cancer, including ductal carcinoma in situ American Cancer Society does not recommend the use of breast MRI in women who have less than 15% lifetime risk Breast CancerMammography

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Mammogram- Often irst detected as an abnormality on a mammogram Mammographic features Asymmetry Microcalcifications A mass Architectural distortion Larger tumors May present as a painless mass Pain 5% of patients with a malignant mass present with breast pain Other symptoms Immobility Skin changes (ie, thickening, swelling, redness) Nipple abnormalities (ie, ulceration, retraction, spontaneous bloody discharge) Breast CancerPresentation

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Core biopsy Percutaneous vacuum-assisted Image guided breast biopsy Recommended diagnostic approach Performed with Ultrasound Stereotactic, or MRI guidance Core biopsies spare the need for operative intervention Provides pathological results quicker than surgical excisions Excisional biopsy As the initial operative approach Shown to increase the rate of positive margins Breast CancerWorkup

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Palpation directed core biopsy If a breast mass may be palpable but not correlate with imaging Complications of a diagnostic core or excisional biopsy Hematoma Infection Scarring Re-operation Sampling error resulting in inaccurate diagnosis. Breast CancerWorkup

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Ductal Carcinoma in situ (DCIS) Lobular Carcinoma in situ (LCIS) Medullary Carcinoma Mucinous Carcinoma Tubular Carcinoma Papillary Carcinoma Metaplastic Carcinoma Mammary Paget’s Disease Breast CancerHistological Findings

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Ductal Carcinoma in situ (DCIS) Identified in ducts (non-invasive) Identified on mammography Suspicious calcifications, Distribution Linear Clustered Segmental Focal Mixed DCIS is divided into comedo (ie, cribriform, micropapillary, solid) and noncomedo subtypes, which provides additional prognostic information regarding likelihood of progression or local recurrence Breast CancerHistological Findings

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Ductal Carcinoma in situ (DCIS) Standard treatment of DCIS is surgical resection with or without radiation Adjuvant radiation and hormonal therapies Reserved for Younger women Patients undergoing lumpectomy Comedo subtype Mastectomy 30% of women with DCIS in the United States Conservative Surgery 30% with conservative surgery alone Conservative surgery with whole breast radiation 40% with conservative surgery followed by whole-breast radiation therapy Breast CancerHistological Findings

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Ductal Carcinoma in situ (DCIS) Axillary or sentinel lymph node dissection is not routinely recommended for patients with DCIS Metastatic disease Disease to the axillary node in 10% of patients Whole-breast radiotherapy Delivered 5-6 weeks following Tamoxifen Adjuvant therapy for breast conserving surgery Only hormonal therapy currently approved Aromatase inhibitor (anastrozole) Currently in clinical trials Breast CancerHistological Findings

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Lobular Carcinoma in situ (LCIS) Found in the lobules (or glands) Non-palpable mass Diffuse distribution throughout the breast Incidence Doubled over last 25 years 2.8% per 100,000 women Peak incidence is in women aged 40-50 years No consistent features on breast imaging Often an incidental finding 10-20% of women with LCIS develop invasive breast cancer Within 15 years from diagnosis. LCIS is considered a biomarker of increased breast cancer risk Treatment options Chemoprevention with a SERM Bilateral mastectomy Close observation. Breast CancerHistological Findings

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Medullary Carcinoma Relatively uncommon (5%) Invasive Occurs in younger women Presentation Bulky palpable mass with axillary lymphadenopathy Diagnosis Sheets of anaplastic tumor cells with scant stroma Moderate or marked stromal lymphoid infiltrate Histologic circumscription or a pushing border Other findings DCIS may be observed in the surrounding normal tissues ER, PR, and HER2/neu are typically negative, and TP53 is commonly mutated. Roughly 30% of patients have lymph node metastasis. Prognosis Good Breast CancerHistological Findings

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Mucinous Carcinoma Rare histologic type Fewer than 5% of invasive breast cancer Produces Mucin Usually presents during the seventh decade Excellent prognosis (>80% 10-year survival). Breast CancerHistological Findings

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Tubular Carcinoma Uncommon histologic type 1-2% of all breast cancers Single layer of epithelial cells Low incidence of lymph node involvement Very high overall survival rate Breast CancerHistological Findings

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Papillary Carcinoma 1-2% of all carcinomas Usually seen in women older than 60 Types Cystic (non-invasive) Good prognosis Micropapillary ductal carcinoma (invasive) Poor prognosis Lymph node metastasis Breast CancerHistological Findings

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Metaplastic Carcinoma 1% of breast cancers Combination of adenocarcinoma plus mesenchymal and epithelial components Wide variety of histological patterns Spindle-cell carcinoma Carcinosarcoma Squamous cell carcinoma of ductal origin Adenosquamous carcinoma Carcinoma with pseudosarcomatous metaplasia Matrix-producing carcinoma Metaplastic breast cancer tumors Larger More rapidly growing Commonly node negative Typically ER, PR, and HER-2 negative Average age of onset in the sixth decade Higher incidence in African Americans. Breast CancerHistological Findings

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Metaplastic Carcinoma Demonstrated a worse prognosis for metaplastic breast cancer as compared to infiltrating ductal carcinoma 3-year overall survival rate of 48-71% 3-year disease-free survival rate of 15-60% Prognosis / predictors of poor overall survival Large tumor size Advanced stage Nodal status does not appear to impact survival in metaplastic breast cancer Breast CancerHistological Findings

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Mammary Paget’s Disease 1-4% of all breast cancers Peak incidence is seen in the sixth decade of life (mean age 57 y) Adenocarcinoma Localized within the epidermis of the nipple-areola complex Paget cells Large Pale epithelial cells Presentation Lesions Unilateral developing insidiously Scaly Fissured Oozing Erythematous nipple-areola complex Retraction or ulceration of the nipple is often noted Itching, tingling, burning, or pain. Mammary Paget disease is associated with an underlying breast cancer in 75% of cases. Overall 5-year and 10-year survival rates are 59% and 44%, respectively. Breast CancerHistological Findings

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Predictors / prognostic factors of BC Axillary lymph node status Tumor size Lymphatic/vascular invasion Patient age Histologic grade Histologic subtypes (eg, tubular, colloid [mucinous], papillary) Response to neoadjuvant therapy Estrogen receptor/progesterone receptor status Her2/neu gene amplification and/or overexpression Breast cancer predictive factors include the following: Estrogen receptor/progesterone receptor status Her2/neu gene amplification and/or overexpression Lymph node status Breast CancerPrognosis

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment T- tumor size N- Lymph node status M- Metastasis Separated into stages 0- IV Survival Rates 5 year Stages 0 99-100% I 95-100% II 86% III 57% IV 20% Breast CancerStaging

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment National Cancer Center Network (NCCN) guideline Stage I or II Recommends a history and physical examination Laboratory studies (CBC with differential, liver and renal function tests, and calcium levels) Stage III Chest x-ray or CT scan of the chest CT scan of the abdomen and pelvis Bone scan for evaluation of distant metastasis Tumor markers (CEA and CA15.3 or CA27.29) may also be obtained in these patients Breast CancerStaging

Epidemiology Etiology Risk Factors Screening Presentation Workup Staging Treatment Lumpectomy Mastectomy Breast Reconstruction Management of Contralateral breast Sentinel Node Dissection Axillary Lymph node dissection Breast Conserving radiation therapy Adjuvant Chemotherapy Adjuvant Hormonal Therapy Behavioral therapy--- Very Important Breast CancerTreatment

Breast Cancer A Family Medicine Perspective