Breast cancer

Breast cancer is the most common malignancy in women. The lifetime risk of developing breast cancer for women in the USA is approx. 12%. The most important risk factors include increased estrogen exposure, advanced age, and genetic predisposition (BRCA1/BRCA2 mutations). Most breast cancers are adenocarcinomas. Histopathologic classification differentiates between ductal and lobular carcinomas. The two most common types of breast cancer are invasive ductal carcinoma, which accounts for 70–80% of all cases, and the less aggressive invasive lobular carcinoma. Both types typically develop from noninvasive carcinomas, i.e., ductal carcinoma in situ (DCIS), and lobular carcinoma in situ (LCIS), respectively.

The majority of breast cancers are detected during routine mammography screening, which is recommended every two years in women aged 50–74 years. Alternatively, women may present with a self-palpated breast lump. Mammographic abnormalities and breast masses require further radiographic evaluation, and, if there are signs of malignancy or the results are inconclusive, histopathologic analysis (biopsy). The axillary lymph node status is determined through clinical examination and biopsy of a suspicious lymph node or sentinel lymph node.

The treatment approach primarily depends on the histopathologic classification and the disease stage and involves a combination of surgical management, radiation therapy, and systemic therapy. Surgical management is either breast-conserving therapy (BCT) or mastectomy. Systemic therapy has significantly improved in recent years with the development of hormone therapy (tamoxifen) and targeted therapy (trastuzumab). The most important prognostic factors are lymph node status, tumor size, patient's age, and tumor receptor status (hormone receptors and HER2).

Women with a high risk of developing breast cancer (i.e., positive BRCA mutation status) should be offered genetic counseling and risk-reducing prophylactic surgery.

• Incidence: most common malignant disease in women (∼ 30% of all malignancies in women)
• Peak incidence: postmenopausal
• Mortality: second leading cause of cancer death in women in the US

One in 8 women in the USA (∼12 %) will develop invasive breast cancer during their lifetime!

References:^[1][2][3]

Epidemiological data refers to the US, unless otherwise specified.

Predisposing factors

• Breast cancer in the contralateral breast ; history of ovarian, endometrial, or colorectal cancer
• Increased estrogen exposure
  • High number of total menstrual cycles
    • Early menarche, late menopause
    • Nulliparity
    • First full-term pregnancy after age 35 years
  • Exogenous estrogen intake: hormone replacement therapy after menopause
• BRCA1 or BRCA2 gene mutations
  • Autosomal-dominant inherited gene mutation
  • Associated with an increased risk for breast cancer (∼ 70%) and ovarian cancer
    • BRCA-positive women develop breast cancer approx. 15–20 years earlier than women without the mutation.
    • BRCA mutations are found in 5–10% of all women with breast cancer.
• Positive family history (e.g. affected first-degree relatives)
• Positive history of breast conditions (e.g., fibrocystic change, fibroadenoma) with cellular atypia
• Previous radiation treatment in childhood
• Lifestyle factors: low-fiber and high-fat diet, smoking, alcohol consumption, obesity in postmenopausal women

Associated genetic diseases

• Li-Fraumeni syndrome (Sarcoma, Breast, Leukemia and Adrenal Gland cancer syndrome (SBLA))
  • Autosomal dominant inherited mutation of the p53 tumor suppressor gene (TP53)
    • Loss of heterozygosity: one abnormal copy of the TP53 gene is inherited → second allele is somatically mutated or deleted → unregulated cell proliferation and cancer
  • Multiple malignancies at an early age: breast cancer, osteosarcoma, leukemia, lymphoma, brain tumor, adrenocortical carcinoma
• Peutz-Jeghers syndrome

References:^{[1][4][5][6][7][8][9][10]}

Most breast cancers are adenocarcinomas, arising from ductal tissue (80%) or lobular tissue (20%).

Noninvasive (in situ) carcinomas

• Ductal carcinoma in situ (DCIS)
  • ∼ 25% of all newly diagnosed breast cancers
  • Localization: unifocal
  • Frequently has a pattern of grouped microcalcifications
  • Higher risk of subsequent invasive carcinoma (ipsilateral)
• Lobular carcinoma in situ (LCIS)
  • 1–5% of all newly diagnosed breast cancers
  • Localization: multifocal
  • Microcalcifications are rare
  • Lower risk of subsequent invasive carcinoma (equal predisposition in both breasts)

The noninvasive carcinomas are characterized by the absence of stromal invasion!

Invasive carcinomas

• Invasive ductal carcinoma (most common)
  • 70–80% of all invasive breast carcinomas
  • Unilateral localization
  • Mostly unifocal tumors
  • More aggressive, early metastases
• Invasive lobular carcinoma
  • 10–15% of all invasive breast carcinomas
  • Unilateral or bilateral
  • Frequently multifocal
  • Less aggressive than ductal carcinoma
  • Slower metastasis than ductal carcinoma
• Less common subtypes: mucinous (< 5% ), medullary (5%), tubular (1–2% )
• Inflammatory breast cancer

References:^{[1][4][6][11][12][13]}

Patients with breast cancer develop clinical symptoms rather late at advanced tumor stages. Typical signs may include:

• Changes in breast size and/or shape; asymmetric breasts
• Palpable mass: typically a single, nontender, firm mass with poorly defined margins; , most commonly in the upper outer quadrant
• Skin changes
  • Retractions or dimpling (due to tightening of the Cooper ligaments)
  • Peau d'orange: skin resembling an orange peel (due to obstruction of the lymphatic channels)
    • Redness, edema, and pitting of the hair follicles
• Nipple changes: inversion, blood-tinged discharge
• Axillary lymphadenopathy: firm, enlarged lymph nodes (> 1 cm in size), that are fixed to the skin or surrounding tissue
• In advanced stages: ulcerations

References:^[4][5][6]

Paget disease of the breast

• Definition: a ductal carcinoma (usually adenocarcinoma- either in situ or invasive) that infiltrates the nipple and areola
• Clinical features
  • Erythematous, scaly, or vesicular rash affecting the nipple and areola
  • Pruritus, burning sensation, nipple retraction
  • The lesion eventually ulcerates → blood-tinged nipple discharge
• Diagnostics
  • Nipple scrape cytology: large, round cells with prominent nuclei
  • Punch or wedge biopsy
• Differential diagnosis: mamillary eczema
• Treatment: surgical treatment, if possible using a breast-conserving procedure (see “Treatment” below).

Inflammatory breast cancer

• Definition: a rare form of advanced, invasive carcinoma, characterized by dermal lymphatic invasion of tumor cells. Most commonly a ductal carcinoma.
• Clinical features
  • Erythematous and edematous (peau d'orange) skin plaques over a rapidly growing breast mass
  • Tenderness, burning sensation, blood-tinged nipple discharge
  • Axillary lymphadenopathy
  • 25% of patients have metastatic disease at the time of presentation
• Differential diagnosis: mastitis, breast abscess, Paget disease of the breast
• Treatment: chemotherapy + radiotherapy + radical mastectomy
• Poor prognosis: 5-year survival with treatment: ∼ 50% (without treatment: < 5%)

References:^{[1][4][14][15]}

Approach to suspected breast cancer

Most patients present with abnormalities detected during routine mammography screening. Alternatively, young women in particular (who are not routinely screened) present with a self-palpated breast mass. The diagnostic approach involves clinical assessment, radiographic imaging, and biopsy.

Clinical scenario	First step
Women < 30 years with a self-palpated breast lump	Clinical assessment Ultrasound in women with a high probability of malignancy In women with low probability of malignancy (if there are no obvious signs of malignancy) reexamine within 3–10 days after the onset of their menstrual period for reexamination!
Women > 30 years with self-palpated breast lump or mammographic abnormalities detected during breast cancer screening	Clinical assessment and mammography (ultrasound if mammography is inconclusive)

Clinical assessment

Certain constellations of patient characteristics should raise suspicion for malignancy in a breast lump, warranting further assessment.

Nonsuspicious	Suspicious
Age < 35 years No family history Soft, movable mass Size changes with menstruation cycle	Age > 35 years Positive family history Firm, rigid mass with irregular borders Skin changes Axillary adenopathy Asymmetry to the contralateral breast, fixation to the skin or chest wall

Radiographic imaging

Mammography

Although mammography does not confirm the diagnosis, it is primarily useful for early detection of breast abnormalities!

Benign	Malignant
Well-defined, circumscribed mass Radiolucent ring surrounding the lesion (halo sign) Diffuse microcalcification or coarse calcification	Focal mass or density with poorly defined margins Spiculated margins Clustered microcalcifications

Breast ultrasound

• Distinguish between solid lesions and benign cysts
• Evaluate axillary, supraclavicular, and infraclavicular lymph nodes
• Provide guidance in interventional procedures (fine needle aspiration, core needle biopsy)

Biopsy

Core needle biopsy (CNB) : confirms the diagnosis (preferred test) and can distinguish between noninvasive and invasive carcinoma based on histology; indicated for a suspicious breast mass on ultrasound or mammography.

• Fine needle aspiration
  • Preferred tool for assessing a breast mass with a low probability of being malignant → See “benign breast conditions” for details.
  • FNA cannot distinguish between noninvasive and invasive carcinomas → if cytology is suspicious for malignancy, a core needle biopsy is required to confirm the diagnosis.
• Surgical excision
  • If CNB is not feasible
  • Results of CNB are inconclusive

Workup of diagnosed breast cancer

• Receptor testing of biopsy samples
  • Immunohistochemical staining for estrogen and progesterone receptor status (positive in 70% of cases)
  • FISH or immunohistochemical staining for HER2/neu positive (overexpression) in approx. 20% of cases
  • Triple-negative breast cancer = Estrogen-negative + progesterone-negative + HER2-negative
    • Approx. 10% of cases
    • Typically more aggressive, high-grade tumors
• Tumor markers
  • CA 15-3
  • CA 27-29
• (Axillary) lymph node status: : clinically suspicious lymph nodes require workup with CNB prior to surgical management of the breast cancer
  • See “Management of breast cancer” below for details regarding workup of clinically nonsuspicious lymph nodes.
• Further tests
  • Bone metastasis: see “Diagnostics” under secondary malignancies of the bone (bone metastasis).
    • 1^st: contrast-enhanced MRI (in patients with localized bone pain or elevated ALP)
    • 2^nd bone scan: if MRI detects metastatic lesion to identify additional occult lesions
  • Liver metastasis: abdominal CT
  • Lung metastasis
    • CXR or chest CT: usually multiple lesions, mostly unilateral pleural effusion
    • Thoracocentesis in the case of pleural effusion: malignant cells in the fluid (blood-tinged)
  • Brain metastasis: See “Differential diagnoses of brain tumors” in the learning card on brain tumors.

Axillary lymph node involvement suggests that hematogenic spread has already occurred!

References:^{[1][4][5][17][18][19][6][20][21][22][23][24][25]}

Noninvasive carcinomas

Type	Characteristics	Growth pattern
DCIS	Macroscopic: firm mass may be visible Microscopic Enlarged ducts lined with atypical epithelium Intact basal membrane Microcalcifications are noted occasionally.	Two growth patterns Comedo necrosis: DCIS with central necrosis ; associated with an increased risk of malignancy Noncomedo (cribriform, papillary, solid)
LCIS	Macroscopic: not visible Microscopic The lobules are filled with monomorphic cells. Intact basal membrane	Diffuse

Invasive carcinomas

Type	Characteristics	Growth pattern
Invasive ductal	Macroscopic: firm tumor, fibrous, grayish-white cut surface Microscopic: disorganized, small duct-like glandular cells with stromal invasion, microcalcifications, and fibrosis in surrounding tissue	Unilateral
Invasive lobular	Macroscopic: solid Microscopic Malignant cells in lobules Monomorphic cells in a single file pattern ("Indian file" pattern	Unilateral or bilateral
Medullary	Well circumscribed tumor Poorly differentiated cells with syncytial growth with lymphocytic infiltrates	Rapid growth
Mucinous	Well circumscribed tumor Extracellular mucus	Slow growth
Tubular	Well-differentiated tubular structures, stromal invasion (radial pattern)	Slow growth
Inflammatory	Dermal lymphatic invasion, angioinvasion	Rapid growth

References:^[26]

			Breast mass	Nipple discharge	Skin changes	Ultrasound/Mammography	Biopsy
Benign	Nonneoplastic	Fibrocystic breast changes	Premenstrual bilateral breast pain Tender breast nodules	Clear or slightly milky	None	Normal appearance or focal regions of thick parenchyma Clear borders +/- cysts +/- dispersed calcifications	Stromal fibrosis Cysts Papillary apocrine changes Mild epithelial hyperplasiaorcalcifications
		Gynecomastia	Firm, concentric, sometimes tender mass at the nipple areolar complex	None	None	Mammogram only required in doubtful or persistent cases)	Unnecessary
	Inflammatory	Mastitis	Tender, firm, swollen, erythematous breast (generally unilateral) Flu-like symptoms, malaise, fever, and chills Possible reactive lymphadenopathy	Milky Bloody	Signs of inflammation (swelling, warmth, erythema)	Unnecessary	Unnecessary Milk sampling + culture only if initial treatment fails
		Fat necrosis	Irregularly defined and dense periareolar breast mass		Skin retraction, erythema, and ecchymosis	Fluid-filled cyst Course rim calcification	Foam cells, multinucleated giant cells, hemosiderin deposition, and chronic inflammation
		Breast abscess	Fluctuant mass
		Eczema of the breast	None	None	Eczematous rash with poorly defined margins and no infiltration	Unnecessary	Only if diagnosis is inconclusive or malignancy is suspected
	Neoplastic	Fibroadenoma	Solitary, well-defined, non-tender, rubbery and mobile mass			Well-defined mass Possibly popcorn-like calcifications	Fibrous and glandular tissue
		Phyllodes tumor	Painless, smooth, multinodular lump Variable growth rate Generally > 3 cm			Similar findings to fibroadenoma, but phyllodes tumors tend to be larger and grow faster than fibroadenoma	Leaf-like architecture with papillary projection of epithelium-lined stroma and varying degrees of atypia and hyperplasia
		Intraductal papilloma	Solitary lesions: palpable breast tumor close to or behind the nipple Multiple lesions: usually asymptomatic	Bloody (most common cause)	None		Fibrovascular tissues surrounded by epithelial cells within lactiferous ducts
Malignant		Invasive carcinoma (ductal and lobular)	Firm, rigid mass with irregular borders Asymmetry to the contralateral breast Fixation to the skin or chest wall Axillary adenopathy	Bloody	Thickening Retraction Dimpling	Focal mass or density with poorly defined margins Spiculated margins Clustered microcalcifications	Ductal: malignant cells in duct, stromal invasion, microcalcifications, fibrosis in surrounding tissue Lobular: malignant cells in lobules; monomorphic cells in a single file pattern ("Indian file" pattern)
		Inflammatory breast cancer	A rapidly growing breast mass Tenderness, burning sensation Axillary lymphadenopathy	Blood-tinged	Erythematous and edematous (peau d'orange) skin plaques directly above the breast mass		Dermal lymphatic invasion, angioinvasion
		Paget disease of the breast	Possibly a firm, rigid mass with irregular borders (similar to invasive ductal carcinoma)	Blood-tinged (when the lesion ulcerates)	Erythematous, scaly, or vesicular rash affecting the nipple and areola Pruritus, burning sensation, nipple retraction		Nipple scrape cytology: large, round cells with prominent nuclei
		Other rare breast malignancies	Breast sarcoma Breast lymphoma

References:^[27]

The differential diagnoses listed here are not exhaustive.

The treatment approach primarily depends on the histopathologic classification and disease stage and involves a combination of surgical management and systemic therapy (chemotherapy, hormone therapy, targeted therapy). Patient preference for more or less aggressive management also plays a significant role in selecting the treatment approach.

Invasive carcinoma

• Early stage disease
  • Breast-conserving therapy (BCT): lumpectomy followed by radiation therapy
    • Contraindications: large tumor-to-breast ratio, multifocal tumors, fixation to the chest wall, excision with negative tumor margins (> 2 mm) not guaranteed, clustered microcalcifications on imaging, involvement of the skin or nipple, a history of chest radiation
    • Surgical margins need to be tumor free . Otherwise, repeat resection or consider mastectomy.
    • Consider mastectomy for anyone unable to undergo BCT or who requests a more aggressive management.
  • Intraoperative lymph node evaluation
    • Sentinel lymph node biopsy: assesses potential lymphatic spread of cancer cells to the axillary lymph nodes ; indicated for all patients with clinically negative preoperative axillary lymph nodes
    • Axillary dissection; : for patients with clinically positive preoperative axillary lymph nodes
  • Adjuvant systemic therapy
    • Hormone and targeted biologic therapy in all ER/PR+ or HER2+ patients
    • Chemotherapy in high-risk patients (see table under "Systemic therapy” below)
• Locally advanced disease
  • Neoadjuvant systemic therapy + surgical resection (BCT or mastectomy) + axillary lymph node dissection
  • Followed by adjuvant systemic therapy ± radiation therapy
• Advanced metastatic disease: systemic treatment followed by palliative surgery and/or radiation therapy
• Gestational breast cancer
  • Surgery is the treatment of choice (radiation therapy is contraindicated during pregnancy)
  • Adjuvant chemotherapy only in the second and third trimester.

Noninvasive carcinoma

• DCIS: breast-conserving therapy or mastectomy
  • Mastectomy plus sentinel lymph node biopsy (SNLB) if lumpectomy is not feasible (see "Contraindications” under breast-conserving therapy above)
• LCIS: life-long surveillance and chemoprevention with hormone therapy (e.g., tamoxifen)
  • Indications for prophylactic bilateral mastectomy
    • A strong family history of breast cancer
    • Positive for mutations of BRCA 1 or BRCA 2
    • Patients who do not wish to take chemoprevention/hormone therapy

Systemic therapy

	Indications	Agents	Side effects and contraindications
Chemotherapy	High-risk patients: Tumor size > 2 cm Positive lymph nodes Aggressive tumor histology Triple negative breast cancer	Anthracycline and taxane regimen	Myelosuppression Alopecia Hypersensitivity Cardiotoxicity Contraindicated during the first trimester of pregnancy
Hormone therapy	ER or PR positive tumors	Premenopausal First-line treatment: tamoxifen Selective estrogen receptor modulator (SERM) that acts as an antagonist on the estrogen receptors of the breast Acts as an agonist on estrogen receptors in bone and uterus.	↑ Risk of endometrial cancer: with Tamoxifen ↑ Risk of uterine sarcoma Hot flashes Nausea Skin rash ↑ Risk of thromboembolic events Musculoskeletal pain, weakness Decreases the risk of osteoporosis and fractures Cataract Contraindicated during pregnancy
		Postmenopausal Aromatase inhibitors, e.g., anastrozole, letrozole, exemestane Tamoxifen + aromatase inhibitor Alternative: raloxifene (a SERM that is particularly beneficial in older patients with osteoporosis)	Hot flashes, night sweats Arthralgia Aromatase inhibitors: increase the risk of osteoporosis Cardiovascular disease Hypercholesterolemia ↓ Libido, vaginal dryness Fatigue, cognitive dysfunction Raloxifene: does not increase the risk of endometrial hyperplasia and carcinoma; has a lower risk of thromboembolic events and cataracts than tamoxifen
Targeted therapy	HER2-positive tumors	Trastuzumab	Cardiotoxic (e.g., dilated cardiomyopathy with systolic CHF): an echocardiogram is recommended prior to initiating treatment to evaluate cardiac function. Contraindicated during pregnancy

Tamoxifen acts as an agonist on endometrial estrogen receptors, thereby increasing the risk of endometrial cancer.

References:^{[1][4][6][28][29][11][30][31][32][33][16]}

• Metastatic disease: bone metastasis > liver metastasis > lung metastasis > brain metastasis
• Recurrence: up to 40% are local (chest wall, lymph nodes)
• Paraneoplastic syndrome: hypercalcemia of malignancy
• Treatment-associated complications:
  • Lymphedema of the arm : results in immobility of the limb, increased risk of infection, impaired wound healing, and cosmetic disfigurement
  • Angiosarcoma of the breast
    • Sometimes referred to as lymphangiosarcoma or hemangiosarcoma, depending on whether it arises from lymphatic or capillary endothelial cells
    • Rare, secondary malignancy that results from chronic lymphedema in patients who underwent radiation therapy and/or lymphadenectomy after mastectomy
    • Presents with multiple blue/purple, macular, and papular lesions in the area of the breast, chest wall, or upper extremity
  • Endometrial cancer is promoted by tamoxifen therapy.

Relapse typically occurs within the first five years after completion of treatment!

References:^{[1][4][5][6][16][34][35]}

We list the most important complications. The selection is not exhaustive.

Prognostic factors

• Axillary lymph node status (most important prognostic factor)
• Tumor size
• Patient's age
• Receptor status (ER/PR-negative and triple-negative disease are associated with a worse prognosis)
  • Histologic grade and subtype

HER2-positive cancers demonstrate a more aggressive tumor growth and higher recurrence rates and therefore are associated with a poor prognosis. Since the development of targeted therapy with trastuzumab, the prognosis for patients with HER2-positive cancers has improved!

Survival

• Early-stage disease without lymph node involvement
  • 10-year survival rate: 70%
• Node-positive disease: high risk of recurrence
• Metastatic disease: 3-year survival rate of 48–71%

References:^[4][6][22]

Breast cancer screening

• Mammography: every 2 years in average-risk women aged 50–74 years
  • Two views of the breast are obtained: mediolateral oblique and craniocaudal
• Physical examination plays a minor role in screening for breast cancer.

If the cancerous lesion is detectable by palpation, a stage II tumor or higher (size > 2 cm) is very likely!
Mammography has greatly improved early detection of noninvasive carcinomas! While DCIS can occasionally be detected as a palpable lump, LCIS cannot be detected by clinical examination.

• Protective factors:
  • Early first pregnancy, several pregnancies before the age of 30 years
  • Breastfeeding
  • Physical activity

Prevention in high-risk women

• High risk women
  • BRCA1/BRCA2 mutation-positive women
  • Women with a first-degree relative with a BRCA1/BRCA2 gene mutation
  • Women who have a family history of breast cancer
  • Women with a history of chest radiation therapy (between age 10–30 years)
  • Women with personal or family history of familial cancer syndromes (e.g., Li-Fraumeni syndrome, Cowden syndrome)
  • Women ≥ 35 years of age with previous invasive breast cancer or carcinoma in situ
• All women should be offered
  • Genetic counseling
  • Annual mammography and MRI
  • Prevention measures:
    • Prophylactic surgery
      • Bilateral prophylactic mastectomy
      • Bilateral salpingo-oophorectomy (BSO) by age 35–40 years and/or when childbearing is no longer desired
    • Alternative: selective estrogen receptor modulator
      • Tamoxifen: In high risk premenopausal women
      • Tamoxifen or Raloxifene: In high risk postmenopausal women

References:^{[6][28][36][37][38]}