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Breast Cancer
Heather A. Dalton, MD
Amy M. Davis, MD
image BASICS
DESCRIPTION
  • Malignant neoplasm of cells native to the breast— epithelial, glandular, or stroma
  • Types: DCIS, infiltrating ductal carcinoma, infiltrating lobular carcinoma, Paget disease, phyllodes tumor, inflammatory breast cancer, angiosarcoma
  • Molecular subtypes: luminal A (HR+/HER2-), triple negative (HR-/HER2-), luminal B (HR+/HER2+), HER2-enriched (HR-/HER2+)
EPIDEMIOLOGY
Incidence
  • Estimated new female breast cancer (BC) cases for in situ 60,290; invasive 231,840 in 2015
  • Estimated new male BC cases 2,350
  • Estimated deaths in 2015 for females 40,290; males 440
  • Second most common newly diagnosed cancer, leading cause of cancer death for U.S. women
Prevalence
Estimated 3.1 million of 162 million U.S. women (1.9%) as of January 1, 2014 (1)
ETIOLOGY AND PATHOPHYSIOLOGY
  • Genes such as BRCA1 and BRCA2 function as tumor suppressor genes and mutation leads to cell cycle progression and limitations in DNA repair (2)
  • Mutations in estrogen/progesterone induce cyclin D1 and c-myc expression, leading to cell cycle progression
  • Additional tumors (33%) may cross-talk with estrogen receptors and epidermal growth factors receptors (EGFR), leading to similar abnormal cellular replication
Genetics
  • Criteria for additional risk evaluation/gene testing in affected individual (2)[A]
    • BC at age ≤50 years
    • BC at any age and ≥ 1 family member with BC ≤50 years of age or ovarian/fallopian tube/primary peritoneal CA any age or ≥2 family members with BC or pancreatic CA any age or population at increased risk (e.g., Ashkenazi Jew with BC or ovarian CA at any age)
    • Triple-negative BC (ER-, PR-, HER2-)
    • Two BC primaries in single patient
    • Ovarian/fallopian tube/primary peritoneal CA
    • 1 + family member with BC and CA of thyroid, adrenal cortex, endometrium, pancreas, CNS, diffuse gastric, aggressive prostate (Gleason >7), leukemia, lymphoma, sarcoma, dermatologic manifestations, and/or macrocephaly, GI hamartomas
    • Male BC
    • Known BC susceptibility gene mutation in family
  • Criteria for additional risk evaluation/gene testing in unaffected BC individual
    • First- or second-degree relative with BC ≤45 years of age
    • ≥2 breast primaries in one individual or ≥1 ovarian/fallopian tube/primary peritoneal CA from same side of family or ≥2 w/ breast primaries on same side of family
    • 1 + family member with BC and CA of thyroid, adrenal cortex, endometrium, pancreas, CNS, diffuse gastric, aggressive prostate (Gleason >7), leukemia, lymphoma, sarcoma, dermatologic manifestations, and/or macrocephaly, GI hamartomas
    • Ashkenazi Jewish with breast/ovary cancer at any age
    • Male BC
    • Known BC susceptibility gene mutation in family
  • BRCA1 and BRCA2 account for 5-10% of female and 5-20% male cancers; 15-20% familial BCs
    • Mutations higher in Ashkenazi Jewish descent (2%)
    • Mutation in BRCA raises risk to 45-65% from 7% at age 70
  • Other genes: ATM, BARD1, BRIP, CDH1, PTEN, STK11, CHEK2, p53, ERBB2, DIRAS3, NBN, RAD50, RAD51
  • Cowden syndrome (PTEN): autosomal dominant, BC, hamartomas of skin, intestine, oral mucosa (trichilemmoma), microencephaly, endometrial CA, nonmedullary thyroid CA, benign thyroid lesions
  • Li-Fraumeni syndrome (TP53): autosomal dominant, BC and CA in CNS, leukemia, sarcoma, osteosarcoma, adrenal cortex
  • Ataxia-telangiectasia (ATM): autosomal recessive, ataxia, telangiectasia, lymphoma, leukemia, CA of breast, stomach, ovary
  • Peutz-Jeghers (STK11): autosomal dominance; hamartomatous polyps of GI tract, mucocutaneous melanin in lips, buccal mucosa, fingers, toes; CA in GI, lung, breast, uterus, ovary
RISK FACTORS
  • Risk Assessment Tool: http://www.cancer.gov/bcrisktool/
  • >4.0 increase in relative risk: age >65, atypical hyperplasia, BRCA mutation, DCIS, LCIS, personal history <40, 2 or more first-degree relatives at early age
  • 2.1 to 4.0 RR: post-menopausal, radiation history, dense breasts (>50%), single first-degree relative
  • 1.1 to 2.0 RR: EtOH, Ashkenazi Jewish, DES exposure, early menarche, high socioeconomic status, first pregnancy >30, fibroadenoma, never breast fed, no full term pregnancies, obesity, personal history >40, personal history of endometrial, ovarian, colon cancer, HRT long term, recent OCP use
  • 20-25% lifetime risk: BRCA mutation, first-degree relative with BRCA mutation, history of radiation age 10 to 30 years, Li-Fraumeni or Cowden syndrome or first-degree relative with the same
  • 15-20% lifetime risk: personal history of BC, DCIS, LCIS, atypical ductal hyperplasia, atypical lobular hyperplasia, dense or unevenly dense breasts
GENERAL PREVENTION
  • Maintain healthy weight—lean, avoid weight gain, limit high calorie foods, drinks
  • Be physically active—150 minutes of moderate-intensity or 75 minutes vigorous activity weekly
  • Eat healthy diet—limit processed/red meat, 2 1/2 cups of vegetables and fruits daily, limit refined-grain
  • Limit EtOH to no more than 1 drink daily for women, 2 for men
  • Clinical breast exam (CBE):
    • ACS: Does not recommend in average-risk
    • USPFTF: Insufficient evidence to assess clinical benefits and harms (3)[A]
  • Mammography:
    • ACS: women 45 to 54 annually, >55 until <10 year life expectancy biennial; 40 to 44 optional
    • USPSTF: women biennial at age 50 to 74 (3)[B]
image DIAGNOSIS
PHYSICAL EXAM
  • Visualize breasts with patient sitting for skin dimpling, peau d'orange, asymmetry
  • Palpation of breast and regional lymph node exam: supraclavicular, infraclavicular, axillary
DIFFERENTIAL DIAGNOSIS
  • Benign breast disease: fibrocystic disease, fibroadenoma, intraductal papilloma (bloody nipple discharge), duct ectasia, cyst, sclerosing adenosis, fat necrosis (s/p breast trauma)
  • Infection: abscess, cellulitis, mastitis
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Mammography BI-RADS: Breast Imaging-Reporting and Data System is a quality assurance (QA) method published by the American Radiology Society.
  • BI-RADS interpretation: 0: incomplete (need additional imaging); 1: negative; 2: benign; 3: probably benign; 4: suspicious; 5: highly suggestive of malignancy; 6: known biopsy—proven malignancy
  • All newly diagnosed BC: history and physical, CBC, LFTs, ALP, pathology review, ER/PR and HER2 status determination, genetic counseling if high risk, fertility counseling if indicated
  • Palpable mass ≥30 years: Obtain mammogram.
    • If BI-RADS 1 to 3, then get ultrasound ± biopsy.
    • If BI-RADS 4 to 6, then get core needle biopsy ± surgical excision.
  • Palpable mass <30 years: Obtain ultrasound ± mammogram ± biopsy; if low clinical suspicion, observe for 1 to 2 menstrual cycles for resolution.
  • Spontaneous, reproducible nipple discharge: Obtain mammogram, ± ultrasound.
    • If BI-RADS 1 to 3, then get ductogram or MRI.
    • If BI-RADS 4 to 5, then surgical excision
  • Asymmetric thickening/nodularity ≥30 years: Obtain mammogram + ultrasound ± biopsy.
  • Asymmetric thickening/nodularity <30 years: Obtain ultrasound ± mammogram ± biopsy.
  • Skin changes, peau d'orange: Obtain mammogram ± ultrasound ± biopsy.
Follow-Up Tests & Special Considerations
  • Early disease (clinical stage I and IIB)
  • Consider additional studies only if signs and symptoms warrant.
  • Advanced disease (stage IIIA or higher)
  • Chest diagnostic CT, abdominal ± pelvis CT, FDG positron emission tomography (PET)/CT scan, bone scan or sodium fluoride PET/CT if FDG-PET/CT indeterminate
  • Most common metastasis: lungs, liver, bone, brain
  • Bone scan: localized pain, elevated alkaline phosphate
  • Abdominal ± pelvis CT: abdominal symptoms, elevated alkaline phosphate, abnormal LFTs
  • Chest imaging: pulmonary symptoms
  • MRI: CNS/spinal cord symptoms
P.139

Diagnostic Procedures/Other
  • Primary tumor: FNA, ultrasound-guided core needle biopsy, stereotactic-guided core needle biopsy ± wire localization, sentinel lymph node, surgical excision, sentinel lymph node biopsy; post biopsy may get inflammatory changes/hematoma.
  • Genomic assay on formalin-fixed tissue for select + ER, -HER2, node negative tumor to assess chemotherapy responsiveness
Test Interpretation
  • Ductal/lobular/other: tumor size, inflammatory component, invasive/noninvasive, margins, nodal involvement
  • Nodal micrometastases: increased risk of disease recurrence
  • ER, PR, HER2 assay
image TREATMENT
MEDICATION
  • Secondary prevention
    • ASA use at least once per week may be associated with as much as a 50% reduction in death from BC (see “Additional Reading”)
    • Chemoprevention/hormone therapy for patients ages ≥35 years
    • Risk reduction for ER-positive tumors
  • Hormone therapy for ER-positive tumors
    • Tamoxifen: premenopausal at diagnosis: 5-year treatment and consider for additional 5 years; avoid during lactation, pregnancy, or with history of deep venous thrombosis/pulmonary embolism; routine CYP2D6 testing not recommended; use strong CYP2D6-inhibiting medications with caution in conjunction
    • Aromatase inhibitors: postmenopausal women, 5-year treatment following tamoxifen for 4.5 to 6 years, or tamoxifen for up to 10 years
    • Ovarian ablation or suppression with luteinizing hormone-releasing hormone agonists: premenopausal women
    • Anti-HER2/neu antibody (e.g., trastuzumab) in select HER2/neu-positive patients
    • Monitor cardiac toxicity via ECG, especially with anthracycline.
  • Neoadjuvant chemotherapy: Premenopausal women should be counseled on potential effect of chemotherapy on fertility, refer to fertility expert.
    • Locally advanced, inoperable advanced BC (stage III)
    • Early operable BC for breast conservation surgery
    • Triple negative BC
  • Cytotoxic therapy: anthracyclines, taxanes, alkylating agents, antimetabolites
    • Higher risk patients with nonmetastatic operable tumors
    • Patients with high risk of recurrence after local treatment (serial/parallel [s/p] surgery ± radiation)
    • Online tool to estimate recurrence risk and benefits of adjuvant chemotherapy (http://www.adjuvantonline.com/online.jsp)
  • Dose-dense chemotherapy demonstrates overall survival advantage in early BC (4)[A].
  • Advanced disease
    • Hormone therapy
    • Cytotoxic therapy
    • Bisphosphonates to decrease skeletal complications
    • Antivascular endothelial growth factor antibody
    • Anti-HER2/neu antibody in select HER2/neu-positive patients
  • Metastatic disease
    • Monitoring metastatic disease: system assessment, physical examination, performance status, weight, LFT/CBC, CT scan/chest/abdomen/pelvis, bone scan, PET/CT, tumor markers
SURGERY/OTHER PROCEDURES
Secondary prevention
  • Risk-reducing mastectomy and bilateral salpingo-oophorectomy for breast and ovary CA syndromes
  • Breast-conserving partial mastectomy/lumpectomy, if possible
  • Negative margins; tumor usually <5 cm
  • No prior breast radiation, relative contraindication: connective tissue disease (lupus, scleroderma)
  • Modified radical mastectomy
  • Large tumors; multicentric disease; young women with known BRCA; consider immediate or delayed reconstruction
  • RT should be initiated without delay
  • After breast-conserving therapy (BCT), stage I, IIA, IIB treatable with BCT + radiation
  • Postmastectomy in select high-risk patients; palliation of metastatic disease; cord compression
Pregnancy Considerations
  • TREATMENT varies on trimester
  • Surgical: mastectomy or breast conservation: mastectomy preferred due to limitations of radiation during pregnancy.
  • Sentinel lymph node biopsy: safe to use with lymphoscintigraphy
  • Chemotherapy: appropriate in 2nd and 3rd trimesters, trastuzumab contraindicated
  • RT: Avoid until after delivery.
INPATIENT CONSIDERATIONS
Discharge Criteria
Postmastectomy
  • Complications: seroma, phantom breast syndrome, cellulitis, chest wall/axilla/arm pain, long thoracic nerve damage leading to winged scapula sign
  • Lymphedema; avoid having BP taken on side of surgery
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Every 4 to 6 months for 5 years, then annually
  • No evidence to support the use of routine CBC, LFTs, “tumor markers”, bone scan, CXR, liver ultrasound, CT scans, MRI, PET
  • Mammogram/imaging 1 year after initial mammogram but 6 to 12 months postradiation, then annually
  • Annual gynecologic exam for women on tamoxifen; bone mineral density at baseline and follow-up for women on aromatase inhibitors or with ovarian failure secondary to treatment
PROGNOSIS (5)

Stage

5-year Relative Survival Rate

0

100%

I

100%

II

93%

III

72%

IV

22%

REFERENCES
1. American Cancer Society. Breast Cancer Facts & Figures 2015-2016. Atlanta, GA: American Cancer Society; 2015. http://www.cancer.org.
2. National Comprehensive Cancer Network. NCCN Guidelines: Breast Cancer (Version 3.2015) © 2015. Breast Cancer National Comprehensive Cancer Network, Inc. http://www.nccn.org.
3. U.S. Preventive Services Task Force. Breast Cancer: Screening 2009. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/breast-cancer-screening?ds=1&s=breastcancer.
4. Lyman GH, Barron RL, Natoli JL, et al. Systematic review of efficacy of dose-dense versus non-dose-dense chemotherapy in breast cancer, non-Hodgkin lymphoma, and non-small cell lung cancer. Crit Rev Oncol Hematol. 2012;81(3):296-308.
5. American Cancer Society. Breast Cancer Survival by stage. http://www.cancer.org.
Additional Reading
Rothwell PM, Wilson M, Price JF, et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379(9826):1591-1601.
Codes
ICD10
  • C50.919 Malignant neoplasm of unsp site of unspecified female breast
  • D05.90 Unspecified type of carcinoma in situ of unspecified breast
  • Z12.31 Encntr screen mammogram for malignant neoplasm of breast
Clinical Pearls
  • BC is most common CA death in U.S. women, lifetime risk of 1 in 8.
  • High alcohol use, high body mass index (BMI), and physical inactivity are modifiable risk factors.
  • Pursue/refer all abnormal breast physical examination/imaging findings.
  • If patient ≥30 years of age with palpable mass, obtain mammogram, if <30 years of age obtain ultrasound.
  • Normal mammography does not exclude possibility of CA with a palpable mass.