- 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
- Breast cancer in the contralateral breast ; history of ovarian, endometrial, or colorectal cancer
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Increased estrogen exposure
- High number of total menstrual cycles
- Exogenous estrogen intake: hormone replacement therapy after menopause
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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
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Li-Fraumeni syndrome (Sarcoma, Breast, Leukemia and Adrenal Gland cancer syndrome (SBLA))
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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
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Autosomal dominant inherited mutation of the p53 tumor suppressor gene (TP53)
- Peutz-Jeghers syndrome
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
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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)
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Lobular carcinoma in situ (LCIS)
- 1–5% of all newly diagnosed breast cancers
- Mean age at diagnosis: 44–46 years
- Localization: multifocal
- Microcalcifications are rare
- Lower risk of subsequent invasive carcinoma (ipsilateral and/or contralateral)
The noninvasive carcinomas are characterized by the absence of stromal invasion!
Invasive carcinomas
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Invasive ductal carcinoma (most common)
- 70–80% of all invasive breast carcinomas
- Unilateral localization
- Mostly unifocal tumors
- More aggressive, early metastases
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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: ductal/lobular, mucinous (< 5% ), medullary (5%), tubular (1–2% ), papillary, or micropapillary
- Inflammatory breast cancer
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
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Skin changes
- Retractions or dimpling (due to tightening of the Cooper ligaments)
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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
- Tumor location
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
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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
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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
- Definition: a rare form of advanced, invasive carcinoma, characterized by dermal lymphatic invasion of tumor cells. Most commonly a ductal carcinoma.
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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%)
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 | |
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Early stage disease | Stage I + IIa |
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Locally advanced disease | Stage IIb, IIIa–IIIc |
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Advanced metastatic disease | Stage IV |
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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 |
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Clinical assessment
Certain constellations of patient characteristics should raise suspicion for malignancy in a breast lump, warranting further assessment.
Nonsuspicious | Suspicious |
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Radiographic imaging
Mammography
Although mammography does not confirm the diagnosis, it is primarily useful for early detection of breast abnormalities!
Benign | Malignant |
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Galactography
- Procedure: Contrast material is injected into the milk duct system and visualized by subsequent mammogram.
- Indication: pathologic nipple discharge
- This procedure is infrequently used these days.
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 |
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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.
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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
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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
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Triple-negative breast cancer = Estrogen-negative + progesterone-negative + HER2-negative
- Approx. 10% of cases
- Typically more aggressive, high-grade tumors
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Tumor markers
- CA 15-3
- CA 27-29
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(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.
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Further tests
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Bone metastasis: see “Diagnostics” under secondary malignancies of the bone (bone metastasis).
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1st: contrast-enhanced MRI (in patients with localized bone pain or elevated AP)
- Mixed lytic and blastic lesions
- Vertebrae, pelvic bone, and long bones
- 2nd bone scan: if MRI detects metastatic lesion to identify additional occult lesions
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1st: contrast-enhanced MRI (in patients with localized bone pain or elevated AP)
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Liver metastasis: abdominal CT
- Metastatic lesions, ascites
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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.
- 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)
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Bone metastasis: see “Diagnostics” under secondary malignancies of the bone (bone metastasis).
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 |
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DCIS |
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LCIS |
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Invasive carcinomas
Type | Characteristics | Growth pattern |
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Invasive ductal |
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Invasive lobular |
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Medullary |
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Mucinous |
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Tubular |
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Inflammatory |
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References:[26]
Differential diagnoses
Breast mass | Nipple discharge | Skin changes | Ultrasound/Mammography | Biopsy | |||
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Benign | Nonneoplastic | Fibrocystic breast changes |
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Gynecomastia |
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Inflammatory | Mastitis |
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Fat necrosis |
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Breast abscess |
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Eczema of the breast |
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Neoplastic | Fibroadenoma |
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Phyllodes tumor |
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Intraductal papilloma |
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Malignant | Invasive carcinoma (ductal and lobular) |
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Inflammatory breast cancer |
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Paget disease of the breast |
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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
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Early stage disease
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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
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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
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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)
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Breast-conserving therapy (BCT): lumpectomy followed by radiation therapy
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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
- Hormone and targeted biologic therapy in all ER/PR+ or HER2+ patients
- Radiation therapy is generally recommended for women who have residual disease in their nodes or breast after neoadjuvant therapy.
- For patients who did NOT receive a full course of neoadjuvant chemotherapy:
- Hormone and targeted biologic therapy in all ER/PR+ or HER2+ patients.
- Chemotherapy based on the guidelines above for early stage disease.
- Radiation therapy generally recommended for women with positive lymph nodes or positive mastectomy margins.
- For patients who received neoadjuvant chemotherapy: no further chemotherapy
- Advanced metastatic disease: systemic treatment followed by palliative surgery and/or radiation therapy
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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
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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)
- Alternative: hormone therapy (may also be considered to prevent recurrence in women with hormone receptor-positive DCIS who received BCT or a unilateral mastectomy. )
- LCIS: life-long surveillance and chemoprevention with hormone therapy (e.g., tamoxifen)
Systemic therapy
Indications | Agents | Side effects and contraindications | |
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Chemotherapy |
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Hormone therapy |
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Targeted therapy |
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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
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Metastatic disease: bone metastasis > liver metastasis > lung metastasis > brain metastasis
- Less common: ovaries, spleen
- 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
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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.
Prognosis
Prognostic factors
- Axillary lymph node status (most important prognostic factor)
- Tumor size
- Patient's age
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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
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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
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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.
- 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 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 Raloxifene: 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
References:[6][28][36][37][38]