- Clinical science
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)
- 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!
Epidemiological data refers to the US, unless otherwise specified.
- Breast cancer in the contralateral breast ; history of ovarian, endometrial, or colorectal cancer
- Increased estrogen exposure
BRCA1 or BRCA2 gene mutations
- Autosomal-dominant inherited gene mutation
- Associated with an increased risk for breast cancer (∼ 70%) and ovarian cancer (but also for cancer of the colon, pancreas, stomach and prostate)
- 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)
- Multiple malignancies at an early age: breast cancer, , leukemia, lymphoma, brain tumor, adrenocortical carcinoma
Most breast cancers are adenocarcinomas, arising from ductal tissue (80%) or lobular tissue (20%).
Noninvasive (in situ) carcinomas
- Ductal carcinoma in situ (DCIS)
- Lobular carcinoma in situ (LCIS)
The noninvasive carcinomas are characterized by the absence of stromal invasion!
- Invasive ductal carcinoma (most common)
- Invasive lobular carcinoma
- Less common subtypes: ductal/lobular, mucinous (< 5% ), medullary (5%), tubular (1–2% ), papillary, or micropapillary
- 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
- Definition: a ductal carcinoma (usually adenocarcinoma- either in situ or invasive) that infiltrates the nipple and areola
- Clinical features
- 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 . The condition affecting the skeletal system is covered in the learning card on .
- Definition: a rare form of advanced, invasive carcinoma, characterized by dermal lymphatic invasion of tumor cells. Most commonly a ductal carcinoma.
- Clinical features
- 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%)
|Early stage disease||Stage I + IIa|
|Locally advanced disease||Stage IIb, IIIa–IIIc|
|Advanced metastatic disease||Stage IV|| |
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|
Certain constellations of patient characteristics should raise suspicion for malignancy in a breast lump, warranting further assessment.
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- 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.
- 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)
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- 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)
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
- 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
- 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
- Bone metastasis: see “Diagnostics” under .
- Liver metastasis: abdominal CT
- Lung metastasis
- Brain metastasis: See “ ” in the learning card on .
- Advanced stages of disease (Stage III and higher) or inflammatory breast cancer: full body PET-CT or a bone scan with CT (chest, abdomen, and pelvis)
|LCIS|| || |
|Invasive ductal|| || |
|Invasive lobular|| || |
|Mucinous|| || |
|Tubular|| || |
|Inflammatory|| || |
|Breast mass||Nipple discharge||Skin changes||Ultrasound/Mammography||Biopsy|
|Benign||Nonneoplastic|| || || || |
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|Inflammatory||Mastitis|| || || |
|Fat necrosis|| || |
|Breast abscess|| |
|Eczema of the breast|| || || || || |
|Neoplastic||Fibroadenoma|| || || |
|Phyllodes tumor|| |
|Intraductal papilloma|| || |
|Malignant||Invasive carcinoma (ductal and lobular)|| || || || |
|Inflammatory breast cancer|| || |
|Paget disease of the breast|| || || |
|Other rare breast malignancies|
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.
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
- Breast-conserving therapy (BCT): lumpectomy followed by radiation therapy
Locally advanced disease
- Neoadjuvant systemic therapy + surgical resection (BCT or mastectomy) + axillary lymph node dissection
- Followed by adjuvant systemic therapy ± radiation therapy
- For patients who received neoadjuvant chemotherapy: no further chemotherapy
- For patients who did NOT receive a full course of neoadjuvant chemotherapy:
- Advanced metastatic disease: systemic treatment followed by palliative surgery and/or radiation therapy
- Gestational breast cancer
- DCIS: breast-conserving therapy or mastectomy
- LCIS: life-long surveillance and chemoprevention with hormone therapy (e.g., )
|Indications||Agents||Side effects and contraindications|
|Hormone therapy|| || |
|Targeted therapy|| || |
Metastatic disease: > > >
- Less common: ovaries, spleen
- Recurrence: up to 40% are local (chest wall, lymph nodes)
- Paraneoplastic syndrome:
- 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!
We list the most important complications. The selection is not exhaustive.
- 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!
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%
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
- 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.
- 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., , )
- 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 Raloxifene is currently not approved for primary prophylaxis against breast cancer in premenopausal women since the adverse effects of it's long-term use in premenopausal women is unknown.
- Tamoxifen or : In high risk postmenopausal women
- Aromatase inhibitors (anastrozole, exemestane): Although known to decrease risk of breast cancer, are currently not FDA approved for primary prohylaxis of breast cancer in the United States due to the unknown long-term effects of these drugs on the skeletal and cardiovascular system.
- Prophylactic surgery