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Breast Cancer

Anne Campbell Larkin, MD and Frank J. Domino, MD Reviewed 05/2023



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Most commonly diagnosed cancer (CA) in women and the second most common cause of CA death for U.S. women. Females have a ~2.6% or 1 in 39 chance of dying from breast cancer in the U.S. 


  • Malignant neoplasm of cells native to the breast—epithelial, glandular, or stroma

  • Types: ductal carcinoma in situ (DCIS), infiltrating ductal carcinoma, infiltrating lobular carcinoma, Paget disease, phyllodes tumor, inflammatory breast cancer (BC), angiosarcoma

  • Molecular subtypes: luminal A (HR+/HER2−), triple negative (HR−/HER2−), luminal B (HR+/HER2+), HER2-enriched (HR−/HER2+)



Female ductal carcinoma in situ: 49,290; invasive BC: 281,550 in 2021, BC have increased by 0.5% per year 


3.8 million breast cancer survivors in the U.S. (1). 


  • Genes such as BRCA1 and BRCA2 function as tumor suppressor genes, and mutation leads to cell cycle progression and limitations in DNA repair.

  • 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.


  • Criteria for additional risk evaluation/gene testing in affected BC individual

    • 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

      • ≥2 family members with BC or pancreatic CA any age

      • Population at increased risk (e.g., Ashkenazi Jewish descent with BC or ovarian CA at any age)

    • Triple-negative BC (ER−, PR−, HER2−)

    • Two BC primaries, ovarian/fallopian tube/primary peritoneal CA

    • ≥1 family member with BC and CA of thyroid, adrenal cortex, endometrium, pancreas, central nervous system, diffuse gastric, aggressive prostate (Gleason >7), leukemia, lymphoma, sarcoma, dermatologic manifestations, and/or macrocephaly, gastrointestinal (GI) hamartomas

    • Male BC

  • Criteria for additional risk evaluation/gene testing in unaffected BC individual

    • 1st- or 2nd-degree relative with BC ≤45 years of age

    • ≥2 breast primaries in one individual

    • ≥1 ovarian/fallopian tube/primary peritoneal CA from same side of family

    • ≥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, leukemia, lymphoma, sarcoma, dermatologic manifestations, and/or macrocephaly, GI hamartomas

    • Ashkenazi Jew with BC/ovarian CA at any age

    • Male BC

  • BRCA1 and BRCA2 are inherited in an autosomal fashion and account for 5–10% of female and 5–20% male CAs; 15–20% familial BCs

  • Syndromes associated with BC: Cowden syndrome (PTEN), Li-Fraumeni syndrome (TP53), ataxia-telangiectasia (ATM), and Peutz-Jeghers (STK11)


  • National Cancer Institute BC Risk calculator:

  • Hormone Replacement Therapy (combination estrogen-progesterone and estrogen only agents [but not vaginal estrogen]) during perimenopause increases breast cancer risk for 10 years after medication is discontinued.

  • Age >65 years, biopsy confirmed atypical hyperplasia, DCIS, lobular carcinoma in situ (LCIS)

  • BRCA mutation, Ashkenazi Jewish descent

  • Personal history of BC <40 years

  • 1st-degree relatives diagnosed at an early age

  • Post-menopausal

  • History of radiation

  • Increased alcohol use

  • Diethylstilbestrol exposure

  • Early menarche (<12 years), late menopause (>55 years), 1st pregnancy at >30 years

  • Proliferative breast disease without atypia (fibroadenoma or ductal hyperplasia)

  • Dense breasts (>50%)

  • Nulliparous/no history of full-term pregnancy/no history of breastfeeding

  • Obesity

  • History of endometrial or ovarian CA

  • Hormone replacement therapy


  • Maintain healthy weight—obesity increases BC risk.

  • Limit alcohol use—≤1 serving of alcohol per day is recommended.

  • High serum 25-OH Vitamin D levels correlate with lower breast cancer risk; vitamin D supplementation.

  • Medication: The U.S. Preventative Services Task Force(USPSTF) recommends that clinicians offer to prescribe risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women who have a >3% risk for breast cancer and low risk for adverse medication effects (B recommendation).

  • Breast self-exams (BSE): no longer recommend.

  • Clinical breast exam (CBE): USPSTF: insufficient evidence to assess clinical benefits and harms; American Cancer Society (ACS): no clear benefit 

  • Mammography:

    • USPSTF: women should undergo biennial mammogram starting at age 50 until age 74

    • ACS: Women annual mammograms starting at age 45 to 54, then women >55 biennial mammograms or yearly screening if desired  (1).


  • Li-Fraumeni, and Cowden disease

  • History of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and LCIS

  • Obesity



  • Painless lump in breast or axilla; swelling, thickening, redness, or dimpling of the skin

  • Nipple discharge (bloody), erosion, or retraction


  • Visualize breasts sitting and supine looking for skin dimpling, peau d’orange, and asymmetry.

  • Palpation of all four breast quadrants and regional lymph node exam: cervical, supraclavicular, infraclavicular, axillary


  • Benign breast disease:

    • Fibrocystic disease, fibroadenoma

    • Intraductal papilloma (bloody nipple discharge), duct ectasia

    • Simple cyst

    • Sclerosing adenosis, fat necrosis (history of serial/parallel breast trauma)

  • Infection: Abscess, cellulitis, mastitis


Initial Tests (lab, imaging)

  • Mammography (MMG) BI-RADS: Breast Imaging–Reporting and Data System is a quality assurance (QA) method published by the American Radiology Society.

    • BI-RADS has been extended to breast US and MRI interpretation as well.

    • Components of BI-RADS report:

      • Overall breast composition, including breast density

        • A—Breasts are almost entirely fatty tissue; B—Scattered areas of fibroglandular density; C—Heterogenously dense; D—Extremely dense

    • Final BI-RADS assessment category:

      • BI-RADS 0: incomplete; additional imaging evaluation needed

        • Commonly occurs on screening studies

      • BI-RADS 1: negative

        • Continue with current screening guidelines

      • BI-RADS 2: benign

        • No further action needed

      • BI-RADS 3: probably benign, possibility of malignancy is <2%

        • Follow-up imaging should occur in 6-months for one year; consider imaging every 6-12 months for 2-3 years.

        • Can consider biopsy if patients is anxious or follow-up is uncertain

      • BI-RADS 4: suspicious

        • Patient and clinician should discuss possible management plans and likely a biopsy.

      • BI-RADS 5: highly suggestive of malignancy

        • Diagnostic imaging needed with follow-up and biopsy

      • BI-RADS 6: known biopsy—proven malignancy

        • Includes patients with biopsy-proven cancers that have yet to be surgically removed

  • Calcifications on screening mammography requires diagnostic mammogram (Dx MMG) and stereotactic guided biopsy.

  • Palpable masses on exam should be evaluated with Dx MMG and US ± biopsy.

    • Palpable mass ≥30 yr: Obtain Dx MMG and US to determine cystic versus solid.

      • If BI-RADS 1 to 3, then get US ± biopsy. If BI-RADS 4 to 6, then get core needle biopsy ± surgical excision.

  • Palpable mass <30 yr: Obtain US ± Dx MMG ± biopsy; if low clinical suspicion, observe for 1 to 2 menstrual cycles for resolution.

  • Spontaneous, reproducible nipple discharge: Obtain Dx MMG ± US; If negative, then consider ductogram or MRI ± surgical excision.

  • Asymmetric thickening/nodularity <30 yr: obtain US ± Dx MMG ± biopsy.

  • Asymmetric thickening/nodularity ≥30 yr: obtain Dx MMG+ US ± biopsy.

  • Skin changes, peau d’orange: Obtain Dx MMG ± US ± biopsy for underlying mass; if no mass, then perform punch biopsy of skin change.

  • Palpable lymph nodes: Obtain CT chest, abdomen/pelvis and bone scan.

  • All newly diagnosed BC should be offered multidisciplinary care including genetic and fertility counseling.

Follow-Up Tests & Special Considerations

  • Advanced disease (stage IIIA or higher): Chest 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 if: Localized bone pain or elevated alkaline phosphate

  • Abdominal ± pelvis CT if: Abdominal symptoms, elevated alkaline phosphate, abnormal LFTs

  • Chest CT if: Pulmonary symptoms present

  • Brain/spine MRI if: CNS/spinal cord symptoms

Diagnostic Procedures / Other

  • Primary tumor: Fine-needle aspiration (FNA), US-guided core needle biopsy, stereotactic-guided core needle biopsy, MRI-guided biopsies for abnormalities only visualized on breast MRI

  • US of axillary lymph nodes during work-up and core-needle biopsy or FNA if suspicious nodes are identified.

Test Interpretation

Surgical pathology results should note: Ductal/lobular/other, tumor size, inflammatory component, invasive/noninvasive, margins, nodal involvement and tumor receptor status: ER, PR, HER2 assay 



  • Neoadjuvant chemotherapy: Locally advanced (large tumor and/or positive lymph nodes), early operable BC to facilitate breast conservation surgery, triple negative BC and tumor size >0.5 cm, HER2 (+) tumors ≥2 cm with positive lymph nodes

  • Consider 21-gene PT-PCR assay in ER/PR(+) tumors with (−) nodes to potentially assess risk of recurrence; not validated to predict chemotherapy response; can determine if chemotherapy indicated in the adjuvant setting

  • Cytotoxic therapy: anthracyclines, taxanes, alkylating agents, antimetabolites: Higher risk patients with nonmetastatic operable tumors, Patients with high risk of recurrence after local treatment (s/p surgery ± radiation)

  • Dose-dense chemotherapy demonstrates overall survival advantage in early BC​​​​​​: Doxorubicin /cyclophosphamide (AC) weekly or every 2 weeks paclitaxel for HER2 negative BC

  • Anti-HER2/neu antibody (e.g., trastuzumab with or without pertuzumab) in HER2/neu-positive patients; given with other chemotherapy agents in the neoadjuvant or adjuvant setting


Cardiology for trastuzumab-induced cardiomyopathy 


  • Radiation Therapy (RT)

    • Upon completion of surgery ± chemotherapy, whole breast radiation should be offered for patients undergoing breast conservation therapy (BCT) prior to starting endocrine therapy.

    • Postmastectomy RT is offered if tumor >5 cm, ≥1 lymph nodes are involved, chest wall/skin involvement, unable to obtain clear margins.

  • ASA once per week

  • General prevention for high-risk lesions (LCIS, ALH, ADH); Tamoxifen 20 mg QD for 5 years

  • Hormone therapy for ER+ tumors

    • DCIS:

      • Tamoxifen 200 mg QD for 5 years

      • Age <60 and postmenopausal: may consider use of aromatase inhibitors (AI)

      • Age >60: selective estrogen receptor modulator (SERM) or AI equally effective

    • Invasive cancer:

      • SERM (tamoxifen 20 mg QD): 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.

      • Aromatase inhibitors (anastrozole 1mg QD, letrozole 2.5 mg QD, and exemestane 25 mg QD): postmenopausal women, 5-year treatment following endocrine therapy for 4.5 to 6 years, or endocrine therapy for up to 10 years

      • Ovarian ablation or suppression with luteinizing hormone–releasing hormone agonists: premenopausal women

  • Advanced disease

    • Hormone and cytotoxic therapy, bisphosphonates, antivascular endothelial growth factor (VEGF) antibody, anti-HER2/neu antibody in select HER2/neu-positive patients

Pregnancy Considerations
  • Mastectomy or breast conservation: BCT can be offered at any point in pregnancy, but may require delay in adjuvant radiation therapy with Sentinel lymph node biopsy (SLNB):

  • Lymphoscintigraphy is safe in pregnancy with radioactive colloid alone

  • Chemotherapy: appropriate in 2nd and 3rd trimesters; trastuzumab contraindicated; RT: Avoid until after delivery.



  • Breast-conserving therapy (lumpectomy) offered if negative margins, will also receive adjuvant RT.

  • Mastectomy indicated for multicentric disease, large tumor to breast size ratio, inflammatory BC, T4 disease, contraindication to RT, patient preference.

  • Axillary nodes: preoperative US and biopsy for all patients with axillary nodes. If positive, axillary node dissection.​​​​



  • Every 4 to 6 months for 5 years and then annually

  • No evidence for routine complete blood count, LFTs, “tumor markers,” bone scan, chest x-ray, liver US, CT scans, MRI, PET

  • Mammogram 6 months postradiation then annually

  • Annual gynecologic exam on endocrine therapy; bone mineral density at baseline and follow-up when on aromatase inhibitors or with ovarian failure secondary to treatment


  • 5 year survival (SEER 18, all races, females)

    • Localized 98.8%, regional 85.5%, distant 27.4%, unknown 54.5%, all stages 89.9%


  • Surgery: lymphedema, wound infections, seroma, hematoma, chronic pain, limited range of motion, poor cosmesis

  • Chemotherapy: immunosuppression, neuropathy, cardiotoxicity

  • Radiation: skin breakdown, fibrosis, chronic pain, long term increased risk of sarcoma

  • Endocrine therapy: osteoporosis, endometrial cancer and deep venous thrombosis


American Cancer Society. About Breast Cancer. Atlanta, GA: American Cancer Society; 2021.



  • C50.52 Malignant neoplasm of lower-outer quadrant of breast, male

  • C50.929 Malignant neoplasm of unspecified site of unspecified male breast

  • C50.812 Malignant neoplasm of overlapping sites of left female breast

  • C50.529 Malignant neoplasm of lower-outer quadrant of unspecified male breast

  • C50.211 Malignant neoplasm of upper-inner quadrant of right female breast

  • C50.821 Malignant neoplasm of overlapping sites of right male breast

  • C50.329 Malignant neoplasm of lower-inner quadrant of unspecified male breast

  • C50.312 Malignant neoplasm of lower-inner quadrant of left female breast

  • C50.621 Malignant neoplasm of axillary tail of right male breast

  • C50.421 Malignant neoplasm of upper-outer quadrant of right male breast

  • C50.921 Malignant neoplasm of unspecified site of right male breast

  • C50.022 Malignant neoplasm of nipple and areola, left male breast

  • C50.221 Malignant neoplasm of upper-inner quadrant of right male breast

  • C50.11 Malignant neoplasm of central portion of breast, female

  • C50.02 Malignant neoplasm of nipple and areola, male

  • C50.629 Malignant neoplasm of axillary tail of unspecified male breast

  • C50.129 Malignant neoplasm of central portion of unspecified male breast

  • C50.512 Malignant neoplasm of lower-outer quadrant of left female breast

  • C50.319 Malignant neoplasm of lower-inner quadrant of unspecified female breast


  • 372064008 Malignant neoplasm of female breast

  • 188153009 Malignant neoplasm of lower-inner quadrant of female breast

  • 188152004 Malignant neoplasm of upper-inner quadrant of female breast

  • 188151006 Malignant neoplasm of central part of female breast

  • 188156001 Malignant neoplasm of axillary tail of female breast

  • 188147009 Malignant neoplasm of nipple and areola of female breast

  • 372095001 Malignant neoplasm of male breast

  • 188155002 Malignant neoplasm of lower-outer quadrant of female breast

  • 188154003 Malignant neoplasm of upper-outer quadrant of female breast

  • 286896005 Carcinoma breast - lower, outer quadrant

  • 286895009 Carcinoma of breast - upper, outer quadrant

  • 286894008 Carcinoma of breast - lower, inner quadrant

  • 286893002 Carcinoma of breast - upper, inner quadrant

  • 189336000 Carcinoma in situ of breast


  • U.S. women; lifetime risk of 1 in 8

  • Excessive alcohol use, high body mass index (BMI), and physical inactivity are modifiable risk factors.

  • Normal mammography does not exclude the possibility of CA with a palpable mass.