• Clinical science

Breast cancer

Abstract

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.

Epidemiology

  • Incidence: most common malignant disease in women (∼ 30% of all malignancies in women)
  • Sex: >> (100:1)
  • 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.

Etiology

Predisposing factors

Associated genetic diseases

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

Overview

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

Noninvasive (in situ) carcinomas

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

Invasive carcinomas


References:[1][4][6][11][12][13]

Clinical features

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
  • 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
  • Tumor location
    • ∼ 55%: upper outer quadrant
    • ∼ 10–15%: upper inner quadrant
    • ∼ 10–15%: nipple
    • ∼ 10–15%: lower outer quadrant
    • ∼ 5%: lower inner quadrant
    • ∼ 5–25%: multicentric location in one breast
    • ∼ 1–3%: initial bilateral

References:[4][5][6]

Subtypes and variants

Paget disease of the breast

  • Definition: a ductal carcinoma (usually adenocarcinoma- either in situ or invasive) that infiltrates the nipple and areola
  • Clinical features
  • 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).
  • The extramammary Paget disease, which is a vulvar malignancy, can be found in the learning card on vulvar cancer. The condition affecting the skeletal system is covered in the learning card on Paget disease of bone.

Inflammatory breast cancer

Inflammatory breast cancer is an advanced stage breast cancer (T4 lesion) by default according to TNM classification!
References:[1][4][14][15]

Stages

Stages Description
Early stage disease Stage I + IIa
  • Localized tumor (< 5 cm)
  • ≤ 3 nodes involved, including the sentinel lymph node
Locally advanced disease Stage IIb, IIIa–IIIc
Advanced metastatic disease Stage IV

References:[16]

Diagnostics

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

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

Galactography

Pneumocystography

  • Procedure: Air is insufflated into a cyst under sonographic guidance and visualized with subsequent mammogram.
  • Indication: to improve visualization of cystic wall and surrounding structures
  • This procedure has mostly been abandoned.

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)
Benign Malignant
  • Homogenic texture or echo-free space
  • Heterogenous texture
  • Well-circumscribed process with smooth margins
  • Irregular mass with poorly defined margins, alternating hyperechoic and hypoechoic lines ("sonographic spiculation")
  • Posterior enhancement (cyst) or thin echogenic rim with pseudocapsules (fibroadenoma)
  • Posterior shadowing
  • Fluctuant
  • Firm, rigid

Contrast-enhanced MRI

  • Not part of routine diagnostics.
  • Indications include:
    • If mammographic and ultrasound findings are inconclusive
    • Women with a high risk of breast cancer (e.g., BRCA mutation carriers)

Biopsy

Core needle biopsy (CNB) : confirms the diagnosis (preferred test) and can distinguish between noninvasive and invasive carcinoma based on histology; (see “Pathology” below); 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

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]

Pathology

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]

Differential diagnoses

Breast mass Nipple discharge Skin changes Ultrasound/Mammography Biopsy
Benign Nonneoplastic Fibrocystic breast changes
  • 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
  • Milky
  • Bloody
  • Unnecessary
  • Unnecessary
  • Milk sampling + culture only if initial treatment fails
Fat necrosis
  • Irregularly defined and dense periareolar breast mass
  • Fluid-filled cyst
  • Course rim calcification
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
Phyllodes tumor
  • Painless, smooth, multinodular lump
  • Variable growth rate
  • Generally > 3 cm
  • 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
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
  • Blood-tinged
  • Dermal lymphatic invasion, angioinvasion
Paget disease of the breast
  • Blood-tinged (when the lesion ulcerates)
  • Nipple scrape cytology: large, round cells with prominent nuclei
Other rare breast malignancies


References:[27]

The differential diagnoses listed here are not exhaustive.

Treatment

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. followed by breast reconstruction
    • Intraoperative lymph node evaluation
    • 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

Systemic therapy

Indications Agents Side effects and contraindications
Chemotherapy
  • Myelosuppression
  • Alopecia
  • Hypersensitivity
  • Cardiotoxicity
  • Contraindicated during the first trimester of pregnancy
Hormone therapy
  • ER or PR positive tumors
Targeted therapy
  • HER2-positive tumors

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]

Complications

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.

Prognosis

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; (G1–G3: well, moderately, or poorly differentiated) 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; 1–3 lymph nodes → 5-year recurrence rate of 30–40%
  • Metastatic disease: 3-year survival rate of 48–71%


References:[4][6][22]

Prevention

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 The risk can be calculated using the Gail model, which uses current age, age at menarche, age at first live birth, the number of first-degree relatives with breast cancer, and breast biopsy reports to calculate the probability of breast cancer over time.
  • 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


References:[6][28][36][37][38]