Breast Cancer

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+)

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: https://bcrisktool.cancer.gov

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

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.

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

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.

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

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

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

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.