Breast cancer

Breast cancer is the second most common malignancy in women. The lifetime risk of developing breast cancer for women in the US is approximately 13%. The most important risk factors are increased estrogen exposure, advanced age, and genetic predisposition (e.g., BRCA1/BRCA2 mutations). The majority of tumors are adenocarcinomas. The two most common types of breast cancer are invasive ductal carcinoma and the less aggressive invasive lobular carcinoma. In most cases, breast cancer is detected during routine mammography screening, which is recommended in women starting at 50 years of age. Mammographic abnormalities and breast masses require further radiographic evaluation, and, if there are signs of malignancy or the results are inconclusive, biopsy and subsequent histopathologic analysis. Axillary lymph node status is determined through clinical examination and biopsy of suspicious lymph nodes. Treatment primarily depends on the histopathologic classification and the cancer stage. It involves a combination of surgical resection, radiation, and systemic therapy. Surgery is either breast-conserving or involves the removal of all breast tissue on the affected side (mastectomy), or even both sides. If the tumor is positive for estrogen (ER) or progesterone (PR) receptors, it can be treated systemically with hormone therapy (e.g., tamoxifen). If the tumor is positive for HER2 receptors, it should receive targeted therapy (e.g., trastuzumab). The most important prognostic factors are cancer stage, tumor receptor status, and DNA aneuploidy. Women with a high risk of developing breast cancer (e.g., positive BRCA mutation status) should be offered risk-reducing prophylactic measures (e.g., bilateral prophylactic mastectomy).

Breast cancer is the second most common malignant disease in women. ^[1]

• Incidence
  • In 2020, an estimated 276,480 new cases of invasive breast cancer were diagnosed. ^[1]
  • ♀ >> ♂ : The female-to-male incidence ratio in the US is 125.8 to 1. ^[2]
• Peak incidence
  • Postmenopausal
  • Incidence increases with age. ^[3]
  • 50% of breast cancers are diagnosed in women ≥ 65 years of age. ^[4]
• Mortality: second leading cause of cancer death in women in the US ^[1]

One in 8 women in the US (∼ 13%) will develop invasive breast cancer during their lifetime.

Epidemiological data refers to the US, unless otherwise specified.

Predisposing factors

Hormonal risk factors

• Increased exposure to endogenous estrogen
  • First viable pregnancy after 35 years of age
  • Nulliparity and/or absence of breastfeeding ^[5]
  • Early menarche and/or late menopause
  • Obesity; in postmenopausal women (lipocytes convert androstenedione to estrone)
• Exogenous estrogen intake
  • Hormone replacement therapy after menopause ^[6]
  • Hormonal contraception ^[7]

Individual risk factors

• Sex: female
• Age: advanced age (most commonly in women ≥ 65 years) ^[4]
• Ethnicity
  • Individuals of European descent are at highest risk.
  • African Americans are at increased risk for triple-negative breast cancer.
• Lifestyle
  • Low-fiber and high-fat diet
  • Smoking
  • Alcohol consumption
• Positive medical history
  • Breast cancer in the contralateral breast
  • Breast conditions with cellular atypia (e.g., fibrocystic change, fibroadenoma)
  • Endometrial cancer , ovarian, or colorectal cancer
  • Radiation therapy during childhood ^[8]

Hereditary risk factors

• Positive family history (e.g., in first-degree relatives)

Mutations

• Tumor suppressor genes
  • BRCA1 and BRCA2: BRCA are tumor suppressor genes that code for a DNA repair protein.
    • Autosomal-dominant mutation
    • Associated with an increased risk for breast cancer and ovarian cancer
    • 5–10% of breast cancer cases are hereditary; BRCA mutations account for most of these. ^[9]
    • BRCA-positive women develop breast cancer earlier than women without the mutation.
    • An estimated 55–60% of women with BRCA1-positive status will develop invasive breast cancer before the age of 70; ; the number is 45% in BRCA2-positive women. ^[10]
    • Men with breast cancer are often positive for BRCA2.
  • PTEN, RB1, CDH1
• Oncogenes: (e.g., RAS)
• Mutations responsible for receptor overexpression
  • Estrogen/progesterone receptors
  • ERBB2 (HER2/neu)

Genetic conditions

• Li-Fraumeni syndrome: autosomal dominant mutation of the p53 tumor suppressor gene
  • Pathophysiology
    • One abnormal copy of the TP53 gene is inherited.
    • If the second allele is somatically mutated or deleted (loss of heterozygosity), it results in unregulated cell proliferation and cancer.
  • Clinical features: multiple malignancies at an early age
    • Breast cancer
    • Osteosarcoma
    • Leukemia, lymphoma
    • Brain tumors
    • Adrenocortical carcinoma
• Peutz-Jeghers syndrome
• Klinefelter syndrome

For the characteristics of Li-Fraumeni syndrome, think BLAST53: Breast cancer/Brain tumors, Leukemia/Lymphoma, Adrenocortical carcinoma, Sarcoma, and Tp53.

Noninvasive carcinomas

Ductal carcinoma in situ (DCIS)

• Characteristics
  • No penetration of the basement membrane
  • Preceded by ductal atypia
  • Frequently appears as a pattern of grouped microcalcifications on mammography
  • Higher risk of subsequent ipsilateral invasive carcinoma

Comedocarcinoma

• Characteristics: subtype of DCIS characterized by central necrosis

Noninvasive carcinomas are characterized by the absence of stromal invasion.

Invasive carcinomas

Invasive ductal carcinoma (IDC)

• Characteristics
  • Most common type of invasive breast cancer (∼ 80%) ^[11]
  • Aggressive formation of metastases
• Localization
  • Unilateral
  • Mostly unifocal

Medullary breast cancer ^[12]

• Characteristics
  • Rare subtype of invasive ductal carcinoma
  • Most common tumor associated with the BRCA1 mutation
  • Well-circumscribed soft tumor with smooth borders (may appear benign)
  • Usually triple-negative
  • Lymphadenopathy
• Differential diagnosis: fibroadenoma

Invasive lobular carcinoma (ILC) ^[11]

• Characteristics
  • ∼ 10% of all invasive breast carcinomas
  • Less aggressive than ductal carcinoma
• Localization
  • Bilateral in ∼ 20% of cases
  • Frequently multifocal

Less common subtypes ^[11]

• Mucinous carcinoma (< 5%; more common in older women)
• Mixed carcinoma (ductal/lobular)
• Tubular carcinoma
• Papillary carcinoma of the breast
  • A rare type of invasive ductal carcinoma with a peak incidence between the ages of 60 and 70
  • More common among non-white women
  • The tumor has a very low frequency of lymph node metastasis.
  • Nearly 90% of the tumors express estrogen receptors.
• Micropapillary carcinoma

Most commonly, individuals with breast cancer develop clinical symptoms in later stages of disease.

Early stages

In early stages, affected individuals may notice a palpable mass with the following characteristics:

• Typically single, nontender, and firm
• Poorly defined margins
• Most commonly located in the upper outer quadrant (∼ 55%)

Locally advanced disease

Locally advanced disease is characterized by a number of changes affecting the appearance of the breast. These include:

• Morphology: changes in size and/or shape → asymmetric breasts
• Skin
  • Retractions or dimpling (due to fixation to the pectoral muscles, deep fascia, Cooper ligaments, and/or overlying skin)
  • Peau d'orange
• Nipple
  • Inversion
  • Blood-tinged discharge

To make skin retractions more visible, it can be helpful to gently stretch the skin or elevate the patient's arm.

Progressive disease

• Ulcerations
• Edema of the arm
• Paget disease of the nipple

Signs of metastatic disease

Lymphatic spread

• Lymphadenopathy
  • Nontender, firm, enlarged lymph nodes (> 1 cm in size), that are fixed to the skin or surrounding tissue
  • Most commonly the axillary nodes and, in later stages, the supraclavicular and/or infraclavicular nodes

Hematogenous spread

Distant metastases of breast cancer can produce a number of heterogeneous symptoms.

• Bone metastasis
  • Bone pain
  • Pathologic fractures
  • Spinal compression
• Liver metastasis
  • Abdominal pain, distention
  • Nausea
  • Jaundice
• Lung metastasis
  • Cough
  • Hemoptysis
  • Dyspnea
  • Chest pain
• Brain metastasis
  • Headaches
  • Seizures
  • Cognitive deficits, focal neurological deficits

Paget disease of the breast ^[13]

• Definition: a rare type of breast cancer; that affects the lactiferous ducts and the skin of the nipple and areola
• Pathogenesis
  • Not fully understood
  • The following two hypotheses have been postulated: ^[14]
    • Migratory/epidermotropic theory: neoplastic ductal epithelial cells from an underlying DCIS or IDC; move through the lactiferous ducts and invade the surrounding epidermis of the nipple.
    • In situ malignant transformation of existing cells into Paget cells, meaning that the condition is a carcinoma in situ, without preexisting DCIS/IDC.
• Clinical features
  • Erythematous, scaly, or vesicular rash affecting the nipple and areola
  • Pruritus; burning sensation
  • Nipple retraction
  • Ulceration that causes blood-tinged nipple discharge
• Diagnostics
  • Punch/wedge or surface biopsy of nipple tissue: Paget cells confirm disease.
  • Imaging to look for underlying DCIS/IDC (see “Diagnostics” below)
• Differential diagnosis: mamillary eczema
• Treatment
  • Breast-conserving surgery with subsequent adjuvant whole-breast radiation (see “Treatment” below)
  • Mastectomy

Inflammatory breast cancer (IBC) ^[15]

• Definition: a rare form ; of advanced, aggressive invasive carcinoma characterized by dermal lymphatic invasion of tumor cells
• Clinical features
  • Peau d'orange
    • Erythematous, warm, and edematous skin plaques with prominent hair follicles that resemble orange peel
    • Caused by obstruction of the lymphatic channels due to tumor growth
  • Tenderness, burning sensation
  • Blood-tinged nipple discharge
  • Signs of metastatic disease (e.g., axillary lymphadenopathy) ^[16]
  • Usually no palpable mass
• Diagnostics: based on clinical features and biopsy ^[17]
  • Diagnostic criteria (all must be met)
    • Rapid onset of breast erythema, edema, warmth, and peau d'orange, with or without palpable mass on breast examination
    • Erythema involving at least one-third of the breast
    • Symptoms have been present for < 6 months
    • Core needle biopsy confirming the presence of invasive carcinoma
  • Skin punch biopsy: patients who meet the diagnostic criteria should undergo at least two full-thickness skin punch biopsies
  • Further testing
    • Imaging: bilateral mammogram and ultrasound of regional lymph node
    • Receptor and HER2 gene testing
• Differential diagnosis
  • Mastitis
  • Paget disease of the breast
  • Breast abscess
• Treatment: chemotherapy (possibly in combination with targeted therapy) PLUS radiation PLUS modified radical mastectomy
• Prognosis: 5-year survival rate is ∼ 40%.

Inflammatory breast cancer is always classified as T4 because it involves the skin.

Occult breast cancer ^[18]

• Definition: : a rare type of cancer characterized by clinically recognizable metastases originating from an undetectable primary breast tissue carcinoma
• Clinical features: axillary adenopathy (most common)
• Diagnostics
  • Biopsy of the lymph node
  • Breast ultrasound
  • Mammography
  • Breast MRI (only if ultrasound and mammography are inconclusive)
• Treatment ^[19]
  • Axillary lymph node dissection
  • Mastectomy
  • Chemotherapy and radiation
  • For further information, see “Treatment” below.

Most patients are referred for assessment after abnormalities are detected on routine mammography screening. Alternatively, young women, who are not routinely screened, may present with a mass they have found during self-examination.

Approach to suspected breast cancer

• Involves clinical assessment, radiographic imaging, and, if necessary, biopsy
• In the case of a confirmed breast cancer diagnosis, imaging of both breasts, receptor and tumor marker testing, and staging of the mass should be performed.

Clinical assessment

Certain constellations of characteristics should raise suspicion for malignancy in a breast lesion and warrant further assessment.

If the cancerous lesion is detectable by palpation, a stage II tumor or higher (size > 2 cm) is very likely.

Radiographic imaging

• Women < 30 years of age should undergo breast ultrasound; higher breast tissue density makes detection of breast abnormalities with mammography more difficult.
• Women ≥ 30 years of age should undergo mammography.

Breast ultrasound ^[21]

• Allows solid lesions to be differentiated from benign cysts
• Includes the evaluation of axillary, supraclavicular, and infraclavicular lymph nodes

Mammography

• Two low-dose x-rays of the breast are obtained (mediolateral oblique and craniocaudal) to screen for breast abnormalities.
• Used for early detection of breast abnormalities: Mammography detects the majority of cancers and can detect lesions ∼ 2 years before they are clinically evident.

In postmenopausal women and women ≥ 30 years of age with a suspicious breast mass, mammography is preferred over ultrasound. In premenopausal women < 30 years of age, ultrasound is preferred, because the higher density of breast tissue decreases the diagnostic power of mammography.

Mammography has greatly improved the rate of early detection of noninvasive carcinomas.

Mammography during pregnancy

• In general, mammograms are considered safe during pregnancy because they only involve a small amount of radiation.
• Radiation is focused on the breast tissue and a lead shield is placed over the belly to prevent radiation exposure.

Biopsy

Fine-needle aspiration (FNA)

• Description: a procedure in which a thin, hollow needle is repeatedly inserted into a suspicious lesion to collect cell samples for analysis
• Indication
  • Preferred tool for assessing a breast mass with a low probability of being malignant
  • May also be used for follow-up and assessment of response to treatment
  • See “Benign breast conditions.”
• Advantages
  • Simple and fast technique
  • Minimally invasive
  • Especially suited for lesions close to the skin
  • No anesthesia required
  • Low risk of complications
• Disadvantages
  • Small sample are associated with a high false-positive rate.
  • Cannot be used to distinguish between noninvasive and invasive carcinoma
  • If cytology results indicate a potential for malignancy, a core needle biopsy is required to confirm the diagnosis. ^[22]

Core needle biopsy (CNB)

• Description: a type of biopsy performed with a larger needle under image guidance using sonography, mammography, or MRI ^[23]
• Indication: preferred tool for assessing a suspicious breast mass on ultrasound or mammography
• Advantages
  • Can be used to confirm the diagnosis (preferred test)
  • Used to distinguish between noninvasive and invasive carcinoma based on histology (see “Pathology” below)
  • Allows testing for receptor status
• Disadvantages
  • Invasive procedure
  • Local anesthesia required
  • Higher risk of complications (e.g., hematoma, pain) compared to FNA ^[22]

Surgical biopsy

• Description
  • Incisional biopsy: surgical removal of a part of the suspicious mass
  • Excisional biopsy: The entire mass and potentially a safety margin with healthy tissue is surgically removed.
• Indication
  • Should only be used if CNB is not feasible or results of CNB are inconclusive
  • Full-thickness skin biopsy (punch biopsy) should be performed if inflammatory breast cancer or Paget disease of the breast is suspected.
• Advantages
  • Provides a larger tissue sample for a more accurate diagnosis
  • Immediate resection of the tumor is possible.
• Disadvantages
  • Highly invasive procedure
  • General anesthesia required
  • Highest risk of complications (e.g., bleeding, surgical site infection) compared to FNA or CNB

Receptor testing ^[24]

Overview

• Refers to the determination of receptor overexpression in breast cancer biopsy samples
• Receptor status is crucial in the development of treatment strategies because tumors with overexpression can be targeted directly with hormone therapy or biologics (see “Treatment” below).

Hormone receptors

• Analysis involves immunohistochemical staining.
• 80% of breast cancers are positive for overexpression of at least one hormone receptor:
  • ∼ 75% of breast cancers are estrogen receptor-positive (ER-positive).
  • ∼ 65% of breast cancers are progesterone receptor-positive (PR-positive).
  • ∼ 65% of breast cancers are positive for both receptors.
  • ∼ 20% of breast cancers are negative for both receptors.

Human epidermal growth factor receptor 2 (HER2/neu, c-erbB2) ^[25]

• An epidermal growth factor receptor with intracellular tyrosine-kinase activity that promotes cell growth and differentiation and inhibits apoptosis.
• ∼ 20% of breast cancers are HER2-positive.
• Analysis involves immunohistochemical staining for HER2/neu and, in some cases, FISH.
• HER2-positive breast cancer can be treated with therapeutic receptor inhibition, which can help to slow cancerous growth and decrease cancer mass (see “Trastuzumab” below).

Triple-negative breast cancer ^[26]

• ∼ 10–15% of breast cancers are hormone receptor-negative and HER2-negative. ^[27]
• Most commonly seen in African American women
• Typically more aggressive, high-grade tumors
• Treated with chemotherapy (see “Chemotherapy” below)

Tumor markers ^[28]

• CEA
• CA 15-3
• CA 27-29

Metastasis

Lymph node status

Lymph node status is assessed via physical examination, ultrasonography, and/or CT scan. For more detailed information, see “Intraoperative lymph node evaluation.”

• Clinically suspicious lymph nodes
  • Nontender, firm, immobile, size > 1 cm
  • Require workup with CNB prior to surgical management
• Lymph nodes that appear normal: assessed during surgery (sentinel lymph node biopsy)

Distant metastasis

• Imaging usually involves the following:
  • Chest x-ray
  • CT of the chest, abdomen, and pelvis
  • MRI of the brain
• Individuals with advanced disease or inflammatory breast cancer should undergo a full body PET-CT or a bone scan with CT (chest, abdomen, and pelvis).
• Laboratory results may show ↑ ESR, ↑ ALP, and/or ↑ calcium.

Bone metastasis

• Contrast-enhanced MRI
  • In patients with localized bone pain or ↑ ALP
  • Classically shows mixed lytic and blastic lesions in the vertebrae (most common site), pelvic bone, and/or long bones
• If MRI detects a metastatic lesion, a bone scan should be performed to identify additional occult lesions.
• See “Secondary malignancies of the bone (bone metastasis).”

Liver metastasis

• Abdominal CT showing metastatic lesions and/or ascites

Lung metastasis

• Chest x-ray or chest CT
  • Usually multiple lesions
  • Mostly unilateral pleural effusion
• Thoracocentesis in cases of pleural effusion to detect malignant cells in the fluid

Brain metastasis

• MRI with contrast shows well-circumscribed tumors at the junction of gray and white matter and/or watershed areas of the arterial system.
• See “Brain metastasis.”

Noninvasive carcinomas

DCIS

• Enlarged ducts lined with atypical epithelium
• Neoplastic cells within ductal lumen
• Intact basal membrane
• Microcalcifications

Comedocarcinoma

• Cells with high-grade nuclei
• Extensive central caseous necrosis
• Dystrophic calcifications

Invasive carcinomas

Invasive ductal

• Findings
  • Disorganized, small, duct-like glandular cells with stromal invasion (desmoplastic stroma)
  • Fibrosis of surrounding tissue
  • Microcalcifications
• Subtypes
  • Tubular
    • Well-differentiated tubular structures without myoepithelium
    • Stromal invasion (radial pattern)
  • Mucinous
    • Well circumscribed tumor
    • Copious extracellular mucus

Medullary carcinoma

• Well circumscribed, rapidly growing tumor (can mimic fibroadenoma)
• Large, poorly differentiated cells with syncytial growth involving lymphocytic and plasma cell infiltration

Invasive lobular

• Malignant cells in lobules
• Monomorphic cells in a single file pattern due to a decrease in E-cadherin expression
• Absence of new duct formation
• Often without desmoplastic response

In INvasive Lobular carcinoma, neoplastic cells arranged IN Lines.

Subtypes and variants

Inflammatory carcinoma

• Dermal lymphatic invasion and angioinvasion
• Rapid growth
• No mass formation

Paget disease of the breast

• Paget cells (large, round cells with clear halo and prominent nuclei) form an intraepithelial adenocarcinoma.
• Extend up the lactiferous ducts and into the skin of the nipple

• See “Differential diagnoses of a palpable breast mass.”
• See “Overview of common breast conditions.”

The differential diagnoses listed here are not exhaustive.

Approach

• Depends on the histopathologic classification and cancer stage
• Involves a combination of surgical management and systemic therapy (chemotherapy, hormone therapy, targeted therapy)
• Patient preference for more or less aggressive management plays a significant role in selecting the treatment approach.

Surgical tumor removal

Breast-conserving surgery (BCT)

• Definition: a type of surgery that focuses on the removal of cancerous breast tissue only, in contrast to full-breast mastectomy
• Contraindications
  • Large tumor-to-breast volume ratio
  • Multifocal tumors
  • Fixation to the chest wall
  • Involvement of the skin or nipple
  • Subareolar location
  • History of chest radiation
  • Excision with negative tumor margins (> 2 mm) not guaranteed
  • Clustered microcalcifications on imaging

Mastectomy

A mastectomy involves the removal of the entire breast and, depending on the specific procedure, possibly other structures, such as lymph nodes and muscles.

• Total mastectomy
  • Removal of the entire breast and nipple-areolar complex with sparing of pectoral muscles
  • Sentinel lymph node biopsy; no dissection of lymph node levels I and II
• Skin-sparing mastectomy
  • Removal of breast tissue, nipple, and areola while leaving the majority of skin intact
  • Allows for (simultaneous) breast reconstruction via implants or their own tissue
  • Not suited for large tumors or those that already involve the skin (e.g., inflammatory carcinoma)
• Nipple-sparing mastectomy
  • Variation of skin-sparing mastectomy: Only the breast tissue is removed, while the skin and nipple are spared.
  • Allows for (simultaneous) breast reconstruction via implants or tissue
  • Indicated for early stages of breast cancer
• Radical mastectomy
  • Excision of the breast, pectoralis major, pectoralis minor, and axillary lymph nodes
  • Has been largely replaced by less extensive procedures
• Modified radical mastectomy
  • Excision of the entire breast, underlying pectoralis fascia, and level I and II axillary lymph nodes
  • The pectoralis muscle and level III axillary lymph nodes are spared.
  • Preferred over radical mastectomy because there are equivalent survival outcomes but decreased morbidity
• Double mastectomy
  • Simultaneous removal of both breasts
  • Indicated in women with increased risk for breast cancer (e.g., due to BRCA gene mutation) or as part of breast cancer treatment

Intraoperative lymph node evaluation

Sentinel lymph node biopsy (SNLB)

• Used to assess whether cancer cells have spread to the axillary lymph nodes and helps to identify the axillary lymph node that initially drains the tumorous breast tissue
• Indicated for all patients with no clinical signs of axillary lymph node infiltration
• Must be performed during breast-conserving surgery and mastectomy
• If the sentinel lymph node is negative, the likelihood of other nodes in this group being involved is very low.

Axillary dissection

• Removal of ≥ 10 lymph nodes during surgery with subsequent histopathologic examination
• Indicated for patients with clinical signs of axillary lymph node infiltration
• Can be performed during primary surgery (e.g., mastectomy) or after ^[29]

Radiation

• Classically follows surgery
• Indicated for patients with a high risk of local recurrence (e.g., positive lymph nodes, cancer in deep margin)

Chemotherapy

• Overview
  • Can be given as neoadjuvant or adjuvant chemotherapy
  • Usually combination therapy
• Indications
  • Tumor size > 2 cm
  • Triple-negative breast cancer and tumor size ≥ 0.5 cm
  • HER-2 positive breast cancer and tumor size > 1 cm
  • Positive lymph nodes
  • Aggressive tumor histology
• Regimens
  • FEC-D: 5-fluorouracil PLUS epirubicin PLUS cyclophosphamide, followed by docetaxel
  • CMF: cyclophosphamide PLUS methotrexate PLUS fluorouracil
• Contraindication: pregnancy (first trimester)

Hormone therapy

• Indication: all ER/PR-positive tumors
• Goal: suppression of extraovarian hormone production and blockade of estrogen receptors in order to decrease the risk of breast cancer recurrence
• Contraindication: pregnancy

Hormone-containing contraceptives are contraindicated in patients with breast cancer. Copper IUDs contain no hormones and are therefore the preferred contraceptive option.

Agents

• Premenopausal
  • Tamoxifen (see “Selective estrogen receptor modulators”)
  • GnRH agonists
• Postmenopausal: aromatase inhibitors
• Preventive: raloxifene (see “Selective estrogen receptor modulators”)

Targeted therapy

Trastuzumab

• Definition: humanized monoclonal antibody against the HER2 tyrosine kinase receptor; that is used in the treatment of HER2-positive breast and gastric cancer
• Mechanism of action: targets HER2/neu (c-erbB2) tyrosine kinase receptor → ↓ of HER2 initiated cellular signaling and ↑ antibody-dependent cytotoxicity → ↓ tumor growth
• Indication: all HER2-positive tumors
• Side effects
  • Cardiotoxicity; (e.g., dilated cardiomyopathy with systolic CHF): An echocardiogram is recommended prior to initiating treatment to evaluate cardiac function.
  • Gastrointestinal symptoms (e.g., diarrhea, nausea)
• Contraindication: pregnancy

Trastuzumab causes dilated cardiomyopathy: If you trust trustuzumub, it might break your heart.

For the most important indication of trastuzumab (breast cancer) and its target (HER2), think: Her two (HER2) breasts can be treated with trastwozumab.

Treatment by stage

Stage 0: DCIS ^[30]

• Surgery
  • Most commonly BCT, potentially including SNLB
  • Simple mastectomy when DCIS is too large for BCT, potentially including SNLB
• Radiation therapy: : following BCT
• Systemic therapy: adjuvant hormone therapy if DCIS is hormone receptor-positive

Stage I ^[31]

• Surgery: BCT or mastectomy, in combination with either SNLB or axillary lymph node dissection
• Radiation therapy: following BCT
• Systemic therapy
  • Adjuvant hormone therapy for hormone receptor-positive breast cancer
  • Adjuvant chemotherapy for tumors larger than 1 cm in diameter and/or breast cancer that is hormone receptor-negative/HER2-positive
  • Adjuvant targeted therapy for HER2-positive breast cancer

Stage II ^[31]

• Surgery: BCT or mastectomy, in combination with either SNLB or axillary lymph node dissection
• Radiation therapy
  • Following BCT
  • After mastectomy, when lymph node status is positive or margins are not tumor-free after mastectomy
• Systemic therapy: Depending on the individual case, hormone therapy, chemotherapy, and targeted therapy can be either neoadjuvant, adjuvant, or both.

Stage III ^[31]

• Neoadjuvant approach
  • In most cases, treatment of stage III begins with neoadjuvant chemotherapy, potentially in combination with targeted therapy for HER2-positive breast cancer to shrink the tumor.
  • Afterwards, either BCT or mastectomy is performed, usually in combination with ALND.
  • This is usually followed by radiation and, in some cases, chemotherapy and/or targeted therapy.
  • Individuals with hormone receptor-positive breast cancer will receive adjuvant hormone therapy.
• Surgical approach
  • In most cases, mastectomy for locally advanced cancer, together with ALND
  • Surgery is followed by radiation, adjuvant chemotherapy, and, depending on receptor status, hormone therapy and/or targeted therapy.

Stage IV ^[32]

• Palliative therapy in stage IV consists of systemic treatment (chemotherapy, hormone therapy, targeted therapy, and possibly immunotherapy), possibly in combination with radiation therapy.
• Additionally, drugs to relieve symptoms of metastatic disease can be given (e.g., bisphosphonates, pain medication, antiemetics).
• In some cases, palliative surgery can be done to control local symptoms (e.g., mastectomy).

Special patient groups: gestational breast cancer

• Surgery is the treatment of choice.
• Radiation therapy is contraindicated during pregnancy.
• Adjuvant chemotherapy only in the second and third trimester

Cancer-associated complications

• Malignant pleural effusion: affects 7–11% of all individuals with breast cancer ^[33]
• Paraneoplastic syndromes
• Recurrence occurs in ∼ 40% of all cases. ^[34]

Recurrence typically occurs in the first five years after completion of treatment.

Treatment-associated complications

• Long thoracic nerve damage
  • Intraoperative complication during radical mastectomy
  • Causes winged scapula, which may lead to muscle disorders and shoulder, neck, and upper back pain

Secondary lymphedema of the arm ^[35]

• Etiology
  • Surgical intervention and/or radiation in the axillary region
  • The frequency of lymphedema varies depending on the treatment modality.
    • Lumpectomy alone: 3%
    • Total mastectomy PLUS axillary radiation: ∼ 15%
    • Axillary lymph node dissection PLUS axillary radiation: 21–51%
• Risk factors
  • Location of the tumor in the upper outer quadrant
  • Axillary lymph node dissection
  • Radiation after ALND
• Clinical features
  • Immobility of the limb, swelling, feeling of tightness
  • ↑ Risk of infection
  • ↓ Wound healing
  • Cosmetic disfigurement
• Diagnostics: clinical diagnosis
  • Review of medical and surgical history
  • Skin inspection and palpation; assessment of tissue consistency and skin mobility
  • Measurement of volume and girth
• Treatment
  • Hyperbaric oxygen therapy
  • Low-level laser therapy
  • Microsurgical lymphatic-venous anastomoses
  • Complete decongestive therapy
  • Manual lymph drainage
  • Compression
• Complications: angiosarcoma of the breast (see below)

Secondary malignancies

• Angiosarcoma of the breast
  • Rare malignancy that is sometimes referred to as lymphangiosarcoma or hemangiosarcoma, depending on whether it arises from lymphatic or capillary endothelial cells
  • Results from chronic lymphedema in patients who have undergone lymphadenectomy and/or radiation therapy
  • Manifests with multiple blue/purple, macular, and papular lesions in the area of the breast, chest wall, and/or upper extremity
• Endometrial cancer: risk increased by tamoxifen therapy

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

Prognostic factors ^[36]

Stage at diagnosis

The most important prognostic factor is the breast cancer stage at time of diagnosis. Earlier stages have a significantly better prognosis than late stages.

• Tumor size
  • Large tumors have a less favorable prognosis because they are associated with higher rates of recurrence.
  • Positive correlation between tumor size and number of involved lymph nodes
• Lymphatic spread: Axillary lymph node status is the one of most important prognostic factors.
• Histological tumor grade: High-grade tumors are associated with aggressive progression.
• Receptor status
  • Hormone-negative breast cancer has a poorer prognosis than hormone-positive breast cancer.
  • HER2-positive tumors show aggressive growth and metastasize quickly compared to HER2-negative tumors.
  • Triple-negative disease is associated with a poor prognosis.

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

Other risk factors

• Advanced age
• Aneuploidy

Survival

Breast cancer screening

• Women with first-degree relatives with breast cancer should begin screening 10 years before the age of the earliest diagnosis in the family.
• Physical examination plays a minor role in screening for breast cancer.

• Individuals with the following risk factors are considered at high risk:
  • Known BRCA mutation
  • First-degree relative with a BRCA mutation
  • Lifetime risk for breast cancer of about 20–25%
  • Women who have a family history of breast cancer
  • Women with a history of chest radiation therapy (between 10–30 years of age)
  • Women with a 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

Prevention measures for high-risk individuals

• Prophylactic surgery
  • Bilateral prophylactic mastectomy
  • Bilateral salpingo-oophorectomy (BSO) by age 35–40 years and/or when childbearing is no longer desired
• Alternative: chemoprevention with selective estrogen receptor modulator
  • In high-risk premenopausal women: tamoxifen
  • In high-risk postmenopausal women
    • Tamoxifen or raloxifene
    • Aromatase inhibitors (e.g., anastrozole, exemestane): monotherapy or in sequence with SERM