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Breast cancer

Last updated: March 4, 2021

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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]

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

Individual risk factors

Hereditary risk factors

Mutations

Genetic conditions

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)

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]

Invasive lobular carcinoma (ILC) [11]

  • Characteristics
  • Localization
    • Bilateral in ∼ 20% of cases
    • Frequently multifocal

Less common subtypes [11]

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:

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

Progressive disease

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.

Paget disease of the breast [13]

Inflammatory breast cancer (IBC) [15]

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

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.

Differentiating between suspicious and benign lesions
Most likely benign Suspicious
Age
  • < 35 years
  • > 35 years
Family history
Features of the lump
Additional findings
  • None
Further management
  • Reassurance and follow-up
  • If necessary, reexamine 3–10 days after the onset of menstruation. [17]

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

Radiographic imaging

Breast ultrasound [18]

  • Allows solid lesions to be differentiated from benign cysts
  • Includes the evaluation of axillary, supraclavicular, and infraclavicular lymph nodes
Ultrasound findings of benign and malignant breast lesions
Benign lesion Malignant lesion
Appearance
  • Homogeneous texture or echo-free space
  • Heterogeneous texture
  • Hypoechoic

Structure

  • Firm, rigid
Margins
  • Well-circumscribed lesion with smooth margins
  • Irregular mass with poorly defined, spiculated margins
Further findings
Further management
  • Regular check-ups
  • Possibly surgical excision

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.
Mammography findings of benign and malignant breast lesions
Benign lesion Malignant lesion
Appearance of the lesion
  • Well-defined, circumscribed mass
  • Focal mass or density
Margins
  • Poorly defined, spiculated margins
Calcifications
  • Diffuse microcalcification or coarse calcification
  • Clustered microcalcifications
Further management
  • Regular check-ups
  • Possibly surgical excision

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
  • Advantages
    • Simple and fast technique
    • Minimally invasive
    • Especially suited for lesions close to the skin
    • No anesthesia required
    • Low risk of complications
  • Disadvantages

Core needle biopsy (CNB)

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
  • Advantages
    • Provides a larger tissue sample for 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 [21]

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.
Distribution of hormone receptor status in breast cancer
Receptor status ER+ ER-
PR+ 63% 3%
PR- 13%

21%

Human epidermal growth factor receptor 2 (HER2/neu, c-erbB2) [22]

Triple-negative breast cancer [23]

  • ∼ 10–15% of breast cancers are hormone receptor-negative and HER2-negative. [24]
  • Most commonly seen in African American women
  • Typically more aggressive, high-grade tumors
  • Treated with chemotherapy (see “Chemotherapy” below)

Tumor markers [25]

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.”

Distant metastasis

  • Imaging usually involves the following:
  • 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

Liver metastasis

Lung metastasis

Brain metastasis

TNM classification of breast cancer
Stage Tumor spread
Primary tumor
Tis
T1
  • Tumor size ≤ 2 cm
    • T1mi: microinvasion ≤ 0.1 cm
    • T1a: ≤ 0.5 cm
    • T1b: > 0.5 cm and ≤1 cm
    • T1c: > 1 cm and ≤ 2 cm
T2
  • Tumor size > 2 cm and ≤ 5 cm
T3
T4
Lymph node involvement (clinical)
N1
N2
N3
Distant metastases
M

Noninvasive carcinomas

DCIS

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

Comedocarcinoma

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

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

Differential diagnoses of benign and malignant breast lesions
Conditions Clinical features Nipple discharge Skin changes Ultrasound/mammography Biopsy
Benign Nonneoplastic Fibrocystic breast changes
  • Clear or slightly milky
  • None
  • Normal appearance
  • Clear borders
  • Possibly focal regions of thick parenchyma, cysts, or dispersed calcifications
Gynecomastia
  • Firm, concentric, sometimes tender mass
  • Located at the nipple-areolar complex
  • None
  • Not indicated
Inflammatory Mastitis
  • Milky
  • Bloody
Fat necrosis
  • Irregularly defined and dense periareolar breast mass
  • None
  • Fluid-filled cyst
  • Course rim calcification
Breast abscess
  • In some cases, red streaks above the mass
  • Indistinct mass with internal septations
  • Drainage and culture [26]
Eczema of the breast
  • None
  • Eczematous rash with poorly defined margins
  • No infiltration
  • Not indicated
Neoplastic Fibroadenoma
  • Solitary, well-defined, nontender, rubbery, and mobile mass
  • None
  • Well-defined mass
  • In some cases, popcorn-like calcifications
Phyllodes tumor
  • Painless, smooth, multinodular lump with variable growth rate
Intraductal papilloma
  • Solitary lesions: palpable breast tumor close to or behind the nipple
  • Multiple lesions: usually asymptomatic
  • Bloody
Malignant Invasive ductal carcinoma
  • Focal mass or density with poorly defined margins
  • Spiculated margins
  • Clustered microcalcifications
  • Malignant cells in duct
  • Stromal invasion
  • Microcalcifications
  • Fibrosis in surrounding tissue
Invasive lobular carcinoma
  • Malignant cells in lobules
  • Monomorphic cells in a single file pattern ("single file" pattern)
Inflammatory breast cancer
  • Blood-tinged
  • Dermal lymphatic invasion, angioinvasion
Paget disease of the breast
  • Possibly a firm, rigid mass with irregular borders
  • Blood-tinged
  • Paget cells

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.

Intraoperative lymph node evaluation

Sentinel lymph node biopsy (SNLB)

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 [28]

Radiation

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

Chemotherapy

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

Targeted therapy

Trastuzumab

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 [29]

Stage I [30]

Stage II [30]

Stage III [30]

  • 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

Stage IV [31]

Special patient groups: gestational breast cancer

Cancer-associated complications

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

Treatment-associated complications

Secondary lymphedema of the arm [34]

Secondary malignancies

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

Prognostic factors [35]

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

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

Survival

Survival of breast cancer patients
SEER stage AJCC/UICC Description 5-year survival rate
Localized
  • Stage I
  • Stage IIa
  • Localized tumor (< 5 cm)
  • ≤ 3 nodes involved, including the sentinel lymph node
  • 99%
Regional
  • Stage IIb
  • Stages IIIa–IIIc
  • 86%
Distant
  • Stage IV
  • 27%

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.
Screening recommendations for women with an average risk of breast cancer [36][37]
Age USPSTF [38] American Cancer Society [39] ACOG [40]
40–49 years
  • The decision should be an individual one.
  • If the potential benefits (e.g., early diagnosis) outweigh the potential harms (e.g., radiation exposure)
  • 40–44 years: can choose to start annual mammography screening
  • 45–49 years: should start annual mammography screening
50–75 years
  • > 55 years: mammography screening every 2 years or continue annual screening if desired
> 75 years
  • No sufficient data if benefits outweigh harm in this patient group
  • Continue screening as long as the patient is physically well and expected to live for > 10 years.
Screening recommendations for women with a high risk of breast cancer
N/A
  • Begin screening at ∼ 40 years of age

Prevention measures for high-risk individuals


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