Breast cancer remains the most frequently diagnosed malignancy among women globally and ranks as the second leading cause of cancer-related deaths in this population. While advancements in screening and treatment have significantly improved outcomes, early and accurate diagnosis remains paramount. This educational activity is designed to equip healthcare professionals with the knowledge necessary to confidently navigate the complexities of breast cancer, with a particular focus on differential diagnosis. Understanding the nuances of differentiating breast cancer from benign breast conditions is critical for timely intervention and optimal patient management.
Objectives:
- Identify and articulate the key risk factors associated with breast cancer development.
- Distinguish between the various histological and molecular subtypes of breast cancer.
- Compare and contrast current recommended treatment strategies for breast cancer based on stage and subtype.
- Develop strategies for effective interprofessional collaboration to enhance patient care and improve outcomes for individuals affected by breast cancer, with a focus on accurate diagnosis and differential diagnosis.
Introduction
Breast cancer is a significant global health concern, representing the most common cancer in women and the second most frequent cause of cancer mortality worldwide.[1] The breast, a paired mammary gland situated superficially to the pectoralis major muscle, is composed of milk-producing lobules grouped into lobes and interspersed with adipose tissue. Milk production occurs within acini and is transported through lactiferous ducts to the nipple. Cooper’s ligaments provide structural support, anchoring the breast to the underlying muscular fascia.[2]
The majority of breast cancers originate in the ductal epithelium (ductal carcinoma), although they can also arise in the lobules (lobular carcinoma). Numerous risk factors have been consistently linked to an increased risk of breast cancer. In developed nations, screening mammography has become effective in detecting breast cancers at earlier, asymptomatic stages. However, in many developing regions, patients often present with a palpable breast mass or nipple discharge as the initial symptom.[3] The diagnostic process for breast cancer involves a combination of physical examination, breast imaging techniques, and tissue biopsy for definitive confirmation. Treatment strategies are multimodal and may include surgery, chemotherapy, radiation therapy, hormonal therapy, and targeted therapies, including immunotherapy. Treatment decisions are individualized based on factors such as tumor histology, stage, biomarker status, and genetic profiles.[1] A critical aspect of the diagnostic process is the ability to differentiate breast cancer from a range of benign breast conditions that may present with similar symptoms, highlighting the importance of a robust understanding of Breast Cancer Differential Diagnosis.
Etiology
Breast Cancer Risk Factors
Identifying and understanding breast cancer risk factors is crucial for effective risk assessment and targeted screening strategies in women. Key risk factors include:[4, 5] (See Image. Breast Cancer Risk Factors)
Age: The incidence of breast cancer increases significantly with age, making it a primary risk factor.
Gender: Being female is the most significant risk factor, although men can also develop breast cancer, albeit at a much lower rate.
Personal History: A previous diagnosis of breast cancer in one breast significantly increases the risk of developing a new primary breast cancer in the contralateral breast or a recurrence in the same breast.
Histological Factors: Certain benign breast conditions identified on biopsy are associated with an elevated risk of future breast cancer. These include atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ (LCIS).
Family History and Genetic Predisposition: A family history of breast cancer, particularly in first-degree relatives (mother, sister, daughter), increases risk. Inherited genetic mutations, most notably in BRCA1 and BRCA2 genes, are responsible for 5% to 10% of all breast cancers but can account for a higher percentage in women diagnosed at younger ages.
Reproductive History: Factors that influence lifetime estrogen exposure are linked to breast cancer risk. These include early menarche (before age 12), late first full-term pregnancy (after age 30), nulliparity (never having given birth), and late menopause (after age 55).
Exogenous Hormone Use: The use of hormone replacement therapy (HRT) and oral contraceptives, particularly those containing estrogen and progesterone, has been associated with a slightly increased risk of breast cancer.
Other Factors: Lifestyle and environmental factors such as radiation exposure (especially to the chest in young age), obesity (particularly postmenopausal), and excessive alcohol consumption are also considered risk factors.
Epidemiology
Breast cancer remains the most prevalent cancer among women globally, representing approximately 11.7% of all new cancer cases in 2020.[6] In the United States, the lifetime risk of developing breast cancer is approximately 1 in 8 for women and 1 in 1,000 for men.[7, 8, 9] The incidence rate of breast cancer rises with age, from 1.5 cases per 100,000 women aged 20 to 24 years to a peak of 421.3 cases per 100,000 in women aged 75 to 79 years. The vast majority (95%) of new breast cancer diagnoses occur in women aged 40 years or older. The median age at diagnosis is 61 years.
Initially, breast cancer incidence rates rose rapidly until around the year 2000, after which a decline was observed, particularly in women under 50. This decline is attributed to a combination of factors, including reduced use of hormone replacement therapy and increased uptake of screening mammography. Thanks to early detection and advances in treatment, breast cancer mortality rates have decreased significantly in North America and parts of Europe over the past few decades. In the US, breast cancer-related mortality decreased by 43% between 1980 and 2020. However, in many countries in Africa and Asia, breast cancer incidence and mortality rates are still on the rise.[6] Significant disparities in detection and survival rates also exist within the US, correlated with socioeconomic status and race. While incidence rates are highest among non-Hispanic white women, mortality rates are disproportionately higher among African American women. According to the American Cancer Society (ACS), breast cancer incidence rates per 100,000 women across racial and ethnic groups are:[10]
- Non-Hispanic White: 128.1
- African American: 124.3
- Hispanic/Latina: 91.0
- American Indian/Alaska Native: 91.9
- Asian American/Pacific Islander: 88.3
Pathophysiology
The majority of breast cancers (90%-95%) are sporadic, with only 5% to 10% attributed to identifiable germline genetic mutations.[11] BRCA1 and BRCA2 mutations are the most frequently implicated genetic factors. Invasive ductal carcinoma and invasive lobular carcinoma are the most common histological subtypes of invasive breast cancer. Breast carcinogenesis is a complex process involving the interplay of genetic predisposition, environmental factors, hormonal influences, and individual patient characteristics. The pathogenesis, treatment approaches, and prognosis of breast cancer are closely linked to its molecular subtypes:
- Luminal A: Hormone receptor-positive (estrogen receptor [ER] and/or progesterone receptor [PR]-positive), human epidermal growth factor receptor 2 (HER2)-negative.
- Luminal B: Hormone receptor-positive, HER2-positive or HER2-negative with high proliferation markers (e.g., high Ki-67).
- HER2-enriched: HER2-positive, hormone receptor-negative.
- Basal-like: Hormone receptor-negative, HER2-negative, and often characterized by expression of basal markers (e.g., cytokeratin 5/6). Triple-negative breast cancers (TNBCs) are often basal-like, but not all TNBCs are basal-like.
Luminal A and B tumors, being hormone receptor-positive, generally exhibit less aggressive behavior and are associated with better survival rates.[12] HER2-enriched tumors are more aggressive, historically associated with poorer prognosis without targeted therapies; however, anti-HER2 targeted therapies (e.g., trastuzumab, pertuzumab) have dramatically improved outcomes.[13] Basal-like tumors, often lacking expression of hormone receptors and HER2, tend to be more aggressive and historically have had poorer survival rates, although advancements in chemotherapy and targeted therapies are improving outcomes for this subtype.[14]
Histopathology
Invasive breast cancer is defined by the infiltration of neoplastic cells beyond the basement membrane. Histologically, it is diverse, with several recognized subtypes. All invasive breast cancer specimens should undergo immunohistochemical testing for hormone receptors (ER and PR) and HER2. (See Image. Breast Estrogen Receptor Staining) Other critical pathological features evaluated include tumor grade (Nottingham grading system), pleomorphism, mitotic index (often assessed by Ki-67 labeling index), morphology, presence of tumor necrosis, multifocality, and associated precursor lesions (e.g., ductal carcinoma in situ [DCIS], LCIS). The most common histological types of invasive breast cancer include:
Invasive Ductal Carcinoma (IDC): Representing 50% to 75% of all invasive breast cancers, IDC often presents clinically as a palpable breast mass due to associated stromal fibrosis. Microscopically, IDC originates in the terminal duct-lobular unit, characterized by atypical epithelial cells invading the basement membrane. Histological features can vary, and there are no pathognomonic features specific to IDC.[1] (See Image. Invasive Ductal Carcinoma).
Invasive Lobular Carcinoma (ILC): Accounting for 10% to 15% of breast cancers, ILC characteristically infiltrates breast tissue in a single-file pattern. This infiltrative growth pattern often results in tumors that are clinically subtle, making them more challenging to detect on mammography or physical examination until the disease is more advanced. Palpable masses are less common in ILC. Multifocal and bilateral disease are more frequent with ILC compared to IDC. Immunohistochemically, ILC is typically negative for E-cadherin expression.[15] (See Image. Pleomorphic Lobular Breast Carcinoma).
Mucinous Carcinoma: Also known as colloid carcinoma, mucinous carcinoma constitutes 2% to 5% of breast cancers. These tumors are often well-circumscribed, more common in older women, and characterized by abundant extracellular mucin production.[16]
Tubular Carcinoma: Tubular carcinoma accounts for 1% to 2% of breast cancers and is microscopically defined by infiltrating tumor cells forming well-differentiated tubules with minimal nuclear atypia.[16] It is often associated with a favorable prognosis.
Medullary Carcinoma: Medullary carcinoma is a less common subtype (less than 5%) and is characterized by poorly differentiated, high-grade tumor cells with prominent lymphocytic infiltration. It is more frequently observed in BRCA1 mutation carriers and younger patients.[17] Despite its aggressive histological appearance, medullary carcinoma can have a relatively favorable prognosis compared to other high-grade breast cancers.
History and Physical Examination
The American College of Obstetricians and Gynecologists (ACOG) recommends periodic breast cancer risk assessment as part of routine patient care.[18] Risk assessment tools, available online and in clinical practice, can aid clinicians in estimating individual breast cancer risk. Most women with early breast cancer are asymptomatic, and lesions are often detected during routine breast examinations or screening mammography. As tumors enlarge, a palpable breast lump may become noticeable. Breast pain (mastalgia) is an uncommon presenting symptom, occurring in only about 5% of breast cancer cases.[19] More advanced disease may manifest with symptoms such as peau d’orange (skin edema with a pitted appearance), skin ulceration, axillary lymphadenopathy (swollen lymph nodes in the armpit), or signs of distant metastasis. Inflammatory breast cancer, an aggressive form of breast cancer, can present with clinical features mimicking a breast infection or abscess, including breast swelling, redness, warmth, and pain.[20] (See Image. Breast Cancer Axillary Lymphadenopathy)
A thorough physical examination is a critical component of breast cancer evaluation. Examination should be conducted with the patient in sitting, standing, and supine positions, with arms abducted, extended, and externally rotated to optimize breast tissue visualization and palpation. Inspection should note any skin changes (e.g., redness, thickening, peau d’orange), nipple retraction or discharge, edema, or ulceration. (See Image. Clinical Signs of Breast Carcinoma). Palpation of the breasts and regional lymph node basins (axillary, supraclavicular, infraclavicular) for lymphadenopathy is essential. While some organizations, such as the American Cancer Society, no longer recommend routine clinical breast examinations (CBEs) for asymptomatic, average-risk women due to limited evidence of significant benefit in reducing mortality, ACOG suggests that CBEs may be offered to these women, although not mandated. ACOG recommends CBEs every 1 to 3 years for women aged 25 to 39 years and annually for women aged 40 years and older if screening breast examination is performed. CBEs remain critically important for women at high risk for breast cancer and for those presenting with breast symptoms.[18] For detailed information on CBE techniques, refer to StatPearls’ companion topic, “Breast Examination Techniques.”[21]
Evaluation
Diagnostic Breast Imaging
Mammography is the primary imaging modality for both screening and diagnosis of breast cancer.[22] Abnormal mammographic findings include masses, microcalcifications, architectural distortion, and asymmetries. When abnormalities are detected on screening mammography, diagnostic mammography, utilizing higher magnification and additional views (e.g., spot compression, magnification views), is indicated for further evaluation. Mammography has limitations in women with dense breasts, younger women (due to denser breast tissue), and individuals who cannot tolerate breast compression. Breast ultrasound or magnetic resonance imaging (MRI) with contrast enhancement can be valuable adjuncts in these situations. Breast ultrasound has comparable sensitivity to mammography in detecting breast cancer and is particularly useful in evaluating palpable masses and differentiating cystic from solid lesions. Ultrasound is also utilized for image-guided biopsies. Breast MRI is the most sensitive imaging modality for breast cancer detection but is more time-consuming, less widely available, and more expensive than mammography and ultrasound.[23] Indications for breast MRI include evaluation of axillary lymph node metastasis with an unknown primary breast tumor, assessment of Paget’s disease of the nipple, evaluation of multifocal or multicentric breast cancer, pre-operative planning, monitoring response to neoadjuvant chemotherapy, and screening in women at high risk for breast cancer (e.g., BRCA mutation carriers).[24] (See Image. Breast Mammogram)
Breast imaging findings are categorized using the Breast Imaging Reporting and Data System (BI-RADS), which assigns categories from 0 to 6 to standardize reporting, correlate imaging findings with the probability of malignancy, and guide management recommendations.[25]
Table
Tissue Biopsy
When a suspicious breast lesion is identified on imaging or physical examination, tissue biopsy is essential for definitive diagnosis. Stereotactic core needle biopsy, performed under mammographic guidance, ultrasound-guided core needle biopsy, or MRI-guided core needle biopsy, are the preferred methods for obtaining tissue samples.[26, 27, 28] Core needle biopsy is superior to fine needle aspiration (FNA) in most diagnostic scenarios as it provides histological tissue architecture and allows for assessment of invasion, receptor status, and other prognostic markers.[29] In patients with clinically palpable axillary lymph nodes suspicious for metastasis, ultrasound-guided core needle biopsy of the lymph node is indicated for staging purposes. Radiographic markers are typically placed at the biopsy site in both the breast and the axillary lymph node (if biopsied) to facilitate localization for subsequent surgical excision or radiation therapy planning. Breast tissue specimens obtained via biopsy are submitted for comprehensive pathological evaluation, including histological diagnosis, tumor grade, hormone receptor (ER, PR) status, HER2 status (by immunohistochemistry and/or in-situ hybridization), and proliferation markers (e.g., Ki-67).
Staging Imaging
Routine laboratory blood tests and imaging for distant metastases are generally not recommended for patients with clinically operable early-stage breast cancer in the absence of specific signs or symptoms suggestive of metastatic disease. However, if clinical findings suggest possible distant spread (e.g., bone pain, persistent cough, elevated liver enzymes), staging investigations may include MRI of the brain, CT scan of the chest, abdomen, and pelvis, bone scan, or PET/CT scan. Baseline complete blood count and comprehensive metabolic panel, including liver function tests, are typically obtained if neoadjuvant chemotherapy is planned. For patients presenting with clinically advanced breast cancer (e.g., inflammatory breast cancer, locally advanced disease with chest wall or skin involvement, bulky axillary lymphadenopathy), staging imaging, such as CT of the chest, abdomen, and pelvis, and bone scan or FDG-PET/CT, is often utilized to assess for distant metastases at diagnosis.[30]
Treatment / Management
Breast cancer treatment is highly individualized and depends on multiple factors, including the stage of the disease, tumor biology (histological subtype, receptor status, genetic features), patient characteristics (age, comorbidities, preferences), and available resources. Breast cancer management strategies are broadly categorized into treatment for early breast cancer, locally advanced breast cancer (LABC), and metastatic breast cancer.[30]
Early Breast Cancer
Early breast cancer encompasses tumors that are confined to the breast and may or may not involve regional lymph nodes but without distant metastasis.[30] Treatment modalities for early breast cancer include:
- Surgical Treatment: Surgical options for primary tumor excision include breast-conserving surgery (BCS), such as lumpectomy or partial mastectomy, and total mastectomy. BCS followed by radiation therapy is generally considered equivalent to mastectomy in terms of overall survival for most women with early-stage breast cancer.
- Axillary Lymph Node Management: Sentinel lymph node biopsy (SLNB) is the standard approach for axillary staging in clinically node-negative early breast cancer. If SLNB is negative, no further axillary surgery is typically required. If SLNB reveals a limited number of positive nodes (typically 1-3) without extranodal extension, axillary management may involve either completion axillary lymph node dissection (ALND) or axillary radiation therapy, depending on tumor biology and other factors. For patients with a greater number of positive nodes (>3) or extranodal extension, ALND or axillary radiation is generally indicated.
- Adjuvant Chemotherapy: Systemic adjuvant chemotherapy is considered based on the final pathologic stage, tumor size, nodal status, grade, and molecular subtype.
- In hormone receptor-positive, HER2-negative tumors, the decision to recommend chemotherapy is often guided by risk stratification using genomic assays (e.g., Oncotype DX, Mammaprint) that assess the risk of recurrence and the potential benefit of chemotherapy in addition to hormonal therapy. High-risk patients are more likely to benefit from adjuvant chemotherapy.
- All HER2-positive early breast cancers larger than 1 cm typically warrant adjuvant anti-HER2 targeted therapy (e.g., trastuzumab, pertuzumab) in combination with chemotherapy.
- Triple-negative breast cancers (TNBCs) larger than 1 cm generally require adjuvant chemotherapy.
- Radiation Therapy: Radiation therapy is a crucial component of BCS, typically delivered to the whole breast with a boost to the tumor bed to reduce the risk of local recurrence. In patients undergoing mastectomy, post-mastectomy radiation therapy (PMRT) is generally not routinely indicated unless specific high-risk features are present, such as large tumor size (>5 cm), positive surgical margins, chest wall invasion, skin involvement, multifocal disease, or ≥4 positive axillary lymph nodes.
- Adjuvant Hormonal Therapy: Anti-estrogen therapy (e.g., tamoxifen) or aromatase inhibitors (e.g., anastrozole, letrozole, exemestane) are indicated for all hormone receptor-positive breast cancers. The duration of adjuvant hormonal therapy is typically 5 to 10 years.
Neoadjuvant chemotherapy (NAC), administered before surgery, is increasingly utilized, particularly for locally advanced breast cancers and certain subtypes of early breast cancer, such as triple-negative and HER2-positive tumors. NAC offers several advantages, including tumor downstaging to facilitate breast-conserving surgery, assessment of tumor response to chemotherapy in vivo, and potential eradication of micrometastatic disease.[31, 32]
Locally Advanced Breast Cancer (LABC)
Locally advanced breast cancer (LABC) typically includes tumors larger than 5 cm in diameter or tumors with clinically evident regional lymph node involvement but without distant metastases. Neoadjuvant chemotherapy (NAC) is the standard initial treatment for most patients with LABC, followed by surgery and radiation therapy.[30]
Prior to initiating NAC, baseline staging, including breast MRI, is usually performed. Radiographic markers are placed in the primary tumor and clinically involved lymph nodes to facilitate localization after NAC, as tumors may significantly shrink or even achieve pathologic complete response.
Chemotherapy regimens for NAC in LABC are selected based on tumor biology (hormone receptor status, HER2 status, TNBC), patient characteristics, and institutional preferences. Following completion of NAC, restaging imaging (mammography, ultrasound, MRI) is performed to assess tumor response and guide subsequent surgical management.
- Surgical Treatment: Surgical options after NAC include BCS or mastectomy. Contraindications to BCS may include persistent large tumor size, chest wall or skin involvement, multifocal disease, inability to undergo radiation therapy, or an unfavorable tumor size to breast size ratio.
- Axillary Lymph Node Management: In patients with clinically node-positive disease at presentation, axillary lymph node dissection (ALND) is typically performed regardless of response to NAC. In patients who were clinically node-negative initially but underwent NAC, sentinel lymph node biopsy (SLNB) may be considered at the time of surgery. If residual disease is present in axillary lymph nodes after NAC and surgery, completion ALND or axillary radiation therapy may be indicated.
- Post-Neoadjuvant Systemic Therapy: Patients with residual disease in the breast or lymph nodes after NAC may benefit from additional systemic therapy, which may include adjuvant chemotherapy, targeted therapy, or hormonal therapy, depending on the initial tumor subtype and response to NAC.
- Radiation Therapy: Radiation therapy is typically administered after surgery following NAC, particularly in patients who undergo BCS or those with high-risk features after mastectomy.
- Adjuvant Hormonal Therapy: Hormonal therapy is indicated for hormone receptor-positive LABC following completion of chemotherapy and radiation therapy, typically for 5 to 10 years.
Metastatic Breast Cancer
Metastatic breast cancer (MBC), also known as stage IV breast cancer, is characterized by distant spread of the disease to organs beyond the breast and regional lymph nodes (e.g., bone, lung, liver, brain). The primary goal of treatment for MBC is to prolong survival, control symptoms, and maintain quality of life. Systemic therapy is the mainstay of treatment for MBC. Treatment decisions are highly individualized, considering factors such as hormone receptor status, HER2 status, sites of metastasis, disease-free interval, prior treatments, patient preferences, and comorbidities. Systemic therapy options include chemotherapy, hormonal therapy, targeted therapies (e.g., HER2-targeted agents, CDK4/6 inhibitors, PI3K inhibitors, PARP inhibitors), and immunotherapy (in specific subsets, such as PD-L1 positive triple-negative MBC). Palliative radiation therapy may be used to manage localized symptoms from metastatic lesions, such as bone pain, spinal cord compression, or brain metastases. Surgery is generally not indicated for the primary breast tumor in the setting of de novo MBC, except in select palliative situations for symptom control or to address local complications.[33]
Differential Diagnosis
The differential diagnosis of breast cancer is broad and includes a variety of benign breast conditions that can mimic breast cancer clinically or radiologically. Accurate differential diagnosis is essential to avoid unnecessary anxiety and interventions for benign conditions while ensuring timely diagnosis and treatment for breast cancer. Key conditions to consider in the differential diagnosis include:
- Mastitis and Breast Abscess: Infections of the breast (mastitis) and breast abscesses can present with breast pain, redness, swelling, and warmth, mimicking inflammatory breast cancer. Mastitis is often associated with breastfeeding but can also occur in non-lactating women. Breast abscesses are localized collections of pus within the breast tissue, often developing as a complication of mastitis. Clinical features, response to antibiotics, and imaging (ultrasound) can help differentiate mastitis/abscess from inflammatory breast cancer. Inflammatory breast cancer typically does not respond to antibiotics, and skin changes are more persistent and characteristic of peau d’orange. Persistent inflammation or cellulitis unresponsive to antibiotic therapy should prompt further investigation to rule out inflammatory breast cancer.
- Fat Necrosis: Fat necrosis is a benign condition resulting from trauma to the breast, surgery, or radiation therapy, leading to damage and breakdown of fat tissue. Fat necrosis can present as a palpable breast mass, often firm and irregular, mimicking breast cancer on physical exam and mammography. Calcifications associated with fat necrosis can also be suspicious on mammography. Ultrasound and biopsy may be necessary to differentiate fat necrosis from breast cancer. Biopsy of fat necrosis typically shows benign findings with fat necrosis, inflammation, and fibrosis.
- Fibroadenoma: Fibroadenomas are common benign breast tumors, particularly in younger women. They typically present as smooth, well-circumscribed, mobile breast masses that are often described as “rubbery.” While fibroadenomas are usually easily distinguishable from breast cancer on physical exam and imaging, complex fibroadenomas or larger fibroadenomas (>2 cm) may warrant further evaluation to exclude coexisting breast cancer. Core needle biopsy can confirm the diagnosis of fibroadenoma and rule out malignancy.
- Fibrocystic Changes: Fibrocystic changes are a spectrum of benign breast conditions characterized by breast pain, tenderness, and lumpiness, often fluctuating with the menstrual cycle. Cysts are fluid-filled sacs within the breast tissue that can be palpable. Fibrocystic changes are very common and are not associated with an increased risk of breast cancer. However, nodularity and cysts can sometimes make clinical breast examination and mammography interpretation more challenging. Ultrasound is helpful in evaluating cystic lesions. Aspiration of cysts can relieve pain and confirm their benign nature.
- Radial Scar: Radial scars are benign breast lesions that can mimic breast cancer on mammography due to their spiculated appearance and architectural distortion. They are often detected incidentally on screening mammography. Radial scars are associated with a slightly increased risk of breast cancer and are typically surgically excised to rule out associated malignancy and for definitive diagnosis.
- Intraductal Papilloma: Intraductal papillomas are benign tumors that grow within the breast ducts, often near the nipple. They can present with nipple discharge, which may be bloody. While intraductal papillomas are benign, they are associated with a slightly increased risk of breast cancer. Excision is typically recommended, particularly for larger papillomas or those with atypical features, to rule out malignancy and address symptoms.
Distinguishing breast cancer from these benign conditions requires a comprehensive approach, integrating clinical findings, imaging characteristics, and pathological evaluation when necessary. A thorough history, careful physical examination, appropriate breast imaging (mammography, ultrasound, MRI), and image-guided biopsy when indicated are essential for accurate differential diagnosis and optimal patient management.
Surgical Oncology
Surgery plays a central role in the management of breast cancer, both for local disease control and staging purposes.[30] Advances in systemic therapies (chemotherapy, targeted therapy, hormonal therapy) have led to less extensive surgical approaches while maintaining or improving survival outcomes. In contemporary practice, surgery aims to remove the primary tumor and provide accurate staging information, particularly regarding axillary lymph node involvement. Breast-conserving surgery (BCS) is a viable option for many women with early-stage breast cancer.[34] The primary surgical procedures for breast cancer and axillary management include:
Partial Mastectomy or Lumpectomy:
Partial mastectomy, also known as lumpectomy, involves the surgical removal of the tumor along with a margin of surrounding normal breast tissue.[35] The incision type and location are tailored to tumor location and desired cosmetic outcome, often utilizing circumareolar, radial, or inframammary crease incisions. Partial mastectomy is the cornerstone of BCS, allowing for preservation of the majority of the breast. Cosmetic outcomes depend on the volume of breast tissue excised relative to the remaining breast volume and nipple preservation. For non-palpable lesions detected on imaging, preoperative localization using a wire or radioactive seed is necessary to ensure complete tumor removal.
Simple Mastectomy and Nipple-Sparing Mastectomy:
Simple mastectomy involves the removal of the entire breast tissue, including the nipple-areola complex, and overlying skin. [34] The underlying pectoralis major fascia is also typically removed. The extent of skin removal depends on whether immediate breast reconstruction is planned and the type of reconstruction. Nipple-sparing mastectomy (NSM) is a modification of simple mastectomy where the nipple-areola complex is preserved, and breast tissue is removed through a small incision, often circumareolar. NSM offers superior cosmetic outcomes in breast reconstruction compared to conventional mastectomy, with oncologic outcomes considered acceptably similar in appropriately selected patients.
Modified Radical Mastectomy:
Modified radical mastectomy (MRM) combines simple mastectomy with axillary lymph node dissection (ALND). The mastectomy incision is often extended into the axilla to allow for removal of axillary lymph node levels I and II. Radical mastectomy, which historically involved removal of pectoralis muscles and sacrifice of nerves, is rarely performed in modern practice.
Axillary Sentinel Lymph Node Biopsy and Axillary Lymph Node Dissection:
Axillary sentinel lymph node biopsy (SLNB) is the standard staging procedure for the axilla in clinically node-negative breast cancer. A radiotracer and/or blue dye is injected near the primary tumor. The sentinel lymph node(s), defined as the first lymph node(s) to receive lymphatic drainage from the tumor, are identified by radiotracer uptake and/or blue dye staining and excised. Typically, 1 to 3 sentinel lymph nodes are removed and pathologically evaluated. If SLNB is performed in conjunction with lumpectomy, the axillary incision may be incorporated into the lumpectomy incision or made as a separate incision in the axillary hairline. Axillary lymph node dissection (ALND) involves the surgical removal of axillary lymph node levels I, II, and often level III (depending on surgical extent), along with surrounding fibrofatty tissue. ALND aims to remove all lymph nodes in these levels while preserving the long thoracic nerve and thoracodorsal nerve to minimize morbidity.[36, 37] ALND is indicated in patients with clinically node-positive disease at presentation, those with positive sentinel lymph nodes in certain high-risk scenarios, or those with persistent axillary disease after neoadjuvant chemotherapy.
Radiation Oncology
Radiation therapy is a critical component of breast cancer management, primarily for local and regional disease control, typically in the adjuvant setting after surgery, and also in palliative settings to manage symptoms from metastases. Adjuvant radiation therapy after breast-conserving surgery has been shown to reduce the risk of local breast cancer recurrence by approximately 50%.[38, 39] While adjuvant radiation therapy in early-stage breast cancer after BCS has not consistently demonstrated improvement in overall survival, it significantly reduces local recurrence risk and the need for subsequent mastectomy for local recurrence. Modalities for adjuvant radiation therapy delivery include external beam radiation therapy (EBRT), brachytherapy, or a combination of both.[40, 41]
Radiation Therapy Delivery Techniques
Accelerated Partial Breast Irradiation (APBI)
Accelerated partial breast irradiation (APBI) is a technique that delivers radiation therapy to a limited portion of the breast surrounding the tumor bed, rather than the whole breast, over a shorter period. APBI is suitable for select patients with early-stage breast cancer who meet specific criteria. The American Society for Radiation Oncology (ASTRO) guidelines define suitable, cautionary, and unsuitable candidates for APBI.[42] APBI can be delivered using brachytherapy techniques, such as multicatheter interstitial brachytherapy or balloon brachytherapy, or with external beam radiation therapy. Brachytherapy APBI involves temporary placement of catheters or balloons into the surgical cavity, through which radioactive sources (typically Ir-192 high-dose-rate afterloader) are inserted to deliver highly conformal radiation to the tumor bed. (See StatPearls’ companion topic, “Brachytherapy,” for additional information.) External beam APBI utilizes specialized external beam radiation techniques to target the partial breast volume. APBI regimens typically involve delivering 34 to 38.5 Gy in 10 fractions delivered twice daily over 5 days. The main advantage of APBI is the shorter treatment duration (1 week vs. 3-6 weeks for whole breast radiation). However, brachytherapy APBI requires catheter or balloon placement, which may involve additional procedures. Long-term outcomes with APBI in appropriately selected patients have shown comparable local control rates to whole breast radiation. The 10-year cumulative incidence of breast cancer recurrence for patients treated with APBI has been reported to be approximately 4.6%.[43]
Whole Breast Radiation Therapy (WBRT)
Whole breast radiation therapy (WBRT) is the standard radiation technique for most patients undergoing breast-conserving surgery for early-stage breast cancer. WBRT involves delivering radiation to the entire breast tissue volume. WBRT is typically delivered in the adjuvant setting after BCS or after completion of adjuvant chemotherapy. Radiation treatment planning for WBRT involves CT simulation to define the breast tissue volume to be treated. Three-dimensional conformal radiation therapy (3D-CRT) planning is commonly used for WBRT, allowing for shaping of the radiation beams to conform to the breast while minimizing dose to surrounding organs, such as the ipsilateral lung and heart. Standard WBRT fractionation regimens involve delivering 40.05 to 50.4 Gy in 15 to 25 daily fractions over 3 to 5 weeks. The 10-year ipsilateral breast recurrence rate following WBRT for early-stage breast cancer is approximately 3.9%.[43]
Boost Radiation Therapy:
A radiation boost, an additional dose of radiation delivered specifically to the surgical cavity after WBRT, is often recommended to further reduce the risk of local recurrence. Several randomized trials have demonstrated improved local control with the addition of a boost. Early-stage breast cancer patients receiving a boost of 10 Gy to the surgical cavity after WBRT have shown a 5-year local recurrence rate of 3.6% compared to 4.5% without a boost. The EORTC trial reported a 10-year local control rate of 6% with boost versus 10% without boost.[44] The benefit of a radiation boost appears to be more pronounced in younger women (age ≤50 years).[44] Boost doses typically range from 10 to 16 Gy delivered in daily fractions over 1 to 2 weeks. Potential drawbacks of boost radiation include an increased risk of breast fibrosis, which may impact cosmesis. The EORTC trial reported a 4.4% rate of severe breast fibrosis in patients receiving a boost compared to 1.6% without boost.[44]
Post-Mastectomy Radiation Therapy (PMRT)
Post-mastectomy radiation therapy (PMRT) is indicated in certain high-risk scenarios after mastectomy, including patients with positive axillary lymph nodes (node-positive disease), positive surgical margins after mastectomy, and primary breast tumors larger than 5 cm. PMRT may also be considered in patients with other high-risk pathologic features, such as central or medial tumors ≥2 cm with lymphovascular invasion, high tumor grade (grade 3), or hormone receptor-negative status. PMRT typically targets the chest wall and may include regional lymphatics (axillary, supraclavicular, internal mammary nodes). Prospective randomized trials have demonstrated the benefit of PMRT in high-risk patients, particularly in terms of reducing locoregional recurrence, breast cancer mortality, and improving overall survival. The Danish 82bc trials, with long-term follow-up, have shown persistent benefits of PMRT in premenopausal and postmenopausal high-risk patients (tumor size >5 cm, locally invasive tumors, or node-positive disease) in terms of 30-year overall survival, breast cancer mortality, and locoregional recurrence.[45]
Comprehensive Nodal Irradiation (CNI)
Comprehensive nodal irradiation (CNI) involves radiation therapy to all regional lymph node basins draining the breast and chest wall, including axillary levels I-III, supraclavicular nodes, and internal mammary nodes. CNI may be incorporated into WBRT or PMRT and is typically indicated in patients with node-positive breast cancer, either based on sentinel lymph node biopsy or axillary lymph node dissection. In patients undergoing ALND, radiation therapy typically includes undissected nodal areas and regions at risk for nodal involvement. CNI is technically more complex than WBRT alone, often requiring additional radiation fields (e.g., 3-field or 4-field plans). CNI also increases radiation dose to uninvolved structures such as the lungs and heart. Meeting heart dose constraints can be particularly challenging when treating left-sided breast cancer. Techniques such as deep inspiratory breath hold (DIBH) or intensity-modulated radiation therapy (IMRT) may be utilized to minimize heart dose in these cases. CNI has been prospectively compared to axillary dissection in patients with 1 to 3 positive sentinel lymph nodes and shown to have similar axillary control rates (0.93% vs. 1.82%).[46] CNI has also been shown to improve 10-year disease-free survival in high-risk patients without a clear overall survival benefit in some studies.[47] Potential risks associated with CNI include an increased risk of lymphedema due to radiation to regional lymphatics and a higher risk of radiation pneumonitis due to increased lung tissue irradiation.
Intensity-Modulated Radiation Therapy (IMRT)
Breast intensity-modulated radiation therapy (IMRT) is a more advanced radiation technique that allows for modulation of radiation beam intensity across the treatment field, enabling more conformal dose delivery to the target volume and better sparing of surrounding normal tissues compared to conventional 3D-CRT. IMRT may be used as an alternative to 3D-CRT in certain clinical scenarios, such as when achieving heart dose constraints is challenging, particularly in left-sided breast cancer, or to improve dose homogeneity within the breast and reduce skin toxicity. Several prospective randomized trials have compared 3D-CRT to IMRT in breast radiation therapy. These studies have consistently demonstrated that grade 2 or higher radiation dermatitis is significantly reduced with IMRT compared to 3D-CRT.[48, 49] However, no significant differences in local recurrence rates or survival outcomes have been observed between IMRT and 3D-CRT.
Radiation Therapy Complications
Radiation therapy to the breast and regional lymph nodes can be associated with both acute and late complications. Common radiation therapy complications include:
Cardiac Toxicity:
Long-term cardiac toxicity is a well-documented potential complication of breast irradiation. Radiation exposure to coronary arteries can accelerate atherosclerosis, leading to an increased risk of major coronary events years after radiation therapy. Population-based case-control studies have shown a linear increase in the risk of major coronary events with increasing radiation dose to the heart, with an estimated 7.4% increase in relative risk per gray of mean heart dose without an apparent threshold.[50] Women with pre-existing cardiac risk factors may be at even higher risk.[50]
Pneumonitis:
Radiation pneumonitis, inflammation of the lung tissue due to radiation exposure, can occur in patients receiving adjuvant radiation therapy for breast cancer. The incidence of radiation pneumonitis ranges from 0.8% to 2.9%.[51] Radiation pneumonitis typically develops within 1 year post-radiation and can range in severity from mild, asymptomatic cases to more severe cases requiring steroid treatment, oxygen therapy, and, in rare instances, intubation. The risk of pneumonitis increases with the volume of lung tissue irradiated. Patients receiving comprehensive nodal irradiation (CNI) have a higher risk of pneumonitis. Concurrent use of taxane chemotherapy agents, such as paclitaxel, commonly used in breast cancer chemotherapy regimens, may significantly increase the risk of radiation pneumonitis in patients receiving radiation therapy.[52] Meticulous radiation treatment planning and adherence to published lung dose constraints are crucial preventative measures.
Breast Fibrosis:
Breast fibrosis, the development of scar tissue within the breast, is a relatively common late complication of adjuvant breast radiation therapy. Onset typically occurs 4 to 12 months post-treatment. Symptoms of breast fibrosis include breast shrinkage, firmness, pain, and impaired wound healing. Breast fibrosis can significantly impact breast cosmesis. The reported incidence of breast fibrosis in the literature ranges from 10% to 15%.[53] Risk factors for breast fibrosis include whole breast radiation dose, beam energy, dose heterogeneity, boost radiation to the surgical cavity, and concurrent chemotherapy. A nomogram has been developed based on data from the EORTC “Boost Versus No Boost” trial to predict the risk of moderate to severe breast fibrosis after whole breast radiation.[54] Preventative measures include carefully weighing the risks and benefits of boost radiation, using lower beam energies when appropriate, and limiting dose hotspots within the breast. Once breast fibrosis develops, it is often irreversible. Management is primarily symptomatic, including NSAIDs, SNRIs, and anticonvulsants like gabapentin for pain management.
Lymphedema:
Lymphedema, chronic swelling of the arm on the treated side, can develop months to years after breast cancer treatment, including surgery and radiation therapy. Patients may experience progressive arm swelling, heaviness, tightness, pain, impaired wound healing, and increased risk of infection. The risk of lymphedema depends on the extent of disruption to regional lymphatics. Risk factors include the number of lymph nodes removed during axillary surgery, body mass index (BMI), and the volume of regional lymphatics irradiated. [56] A nomogram developed by Gross et al. in 2019 can help quantify lymphedema risk.[56] Patients undergoing sentinel lymph node biopsy have a lower risk of lymphedema (approximately 5.6%) compared to those undergoing full axillary lymph node dissection (approximately 19.9%).[57] The AMAROS trial reported a 5-year lymphedema rate of 25% in patients receiving axillary dissection versus 12% in those receiving regional nodal radiation alone.[58] Patients undergoing both axillary dissection and regional nodal radiation therapy are at the highest risk. Evidence for lymphedema prevention is limited but may include weight-bearing exercise and maintaining a healthy body weight. Management of established lymphedema includes fitted compression garments, arm elevation, manual lymphatic drainage, and exercise therapy.
Brachial Plexopathy:
Brachial plexopathy, damage to the brachial plexus nerves in the shoulder and arm, is a rare late complication of radiation therapy to regional lymph nodes. Symptoms include hand and arm paresthesia, weakness, and pain in the affected arm and shoulder, typically developing 8 to 12 months after treatment. Brachial plexopathy affects approximately 1% of patients receiving breast radiation therapy. Risk factors may include high radiation doses (>50 Gy) and concurrent chemotherapy.[59] Primary prevention involves limiting radiation dose to the brachial plexus during treatment planning.
Rib Fracture:
Rib fractures are another rare late complication of breast radiation therapy, occurring in 0.3% to 1.8% of patients.[59, 60] The median time to onset is approximately 12 months post-radiation. Risk factors include lower radiation beam energies and higher radiation doses. Treatment is typically conservative, focusing on pain management.
Secondary Malignancy:
Radiation therapy can induce DNA damage in both cancerous and normal tissues, potentially leading to the development of radiation-induced secondary malignancies years after treatment. Large meta-analyses have shown a slightly increased long-term risk of non-breast cancers, including sarcomas, lung cancer, and esophageal cancer, in patients treated with radiotherapy for breast cancer.[61] However, the absolute risk of developing a secondary malignancy is low, estimated at 1% to 2% at 10 years after radiation therapy.[62] Risk factors for radiation-induced secondary malignancies include younger age at radiation exposure, female gender, larger radiation field sizes, and higher radiation doses.[63]
Medical Oncology
Medical oncology treatments, including chemotherapy, hormonal therapy, targeted therapy, and immunotherapy, are integral to breast cancer management, particularly for systemic disease control.
Cytotoxic Chemotherapy
Cytotoxic chemotherapy remains a cornerstone of systemic therapy for breast cancer in both neoadjuvant and adjuvant settings. Chemotherapy is most effective against rapidly dividing tumor cells, such as those in high-grade, poorly differentiated tumors like triple-negative and HER2-positive breast cancers. Chemotherapy regimens are selected based on tumor characteristics (subtype, stage), patient factors (performance status, comorbidities), and potential benefits and risks.[64]
Adjuvant chemotherapy, administered after surgery, has been shown to improve overall survival, disease-free survival, and reduce the risk of local and distant recurrence in appropriate patients.[65] Early adjuvant chemotherapy regimens included cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). More contemporary regimens utilize anthracyclines (e.g., doxorubicin, epirubicin) and taxanes (e.g., paclitaxel, docetaxel) in combinations such as AC (adriamycin and cyclophosphamide), TC (docetaxel and cyclophosphamide), or TAC (docetaxel, adriamycin, and cyclophosphamide). Adjuvant chemotherapy is generally recommended for most patients with triple-negative and HER2-positive breast cancers larger than T1 stage. Recommendations for adjuvant chemotherapy in hormone receptor-positive, HER2-negative breast cancer are more nuanced and often guided by genomic assays (e.g., Oncotype DX, Mammaprint) that assess recurrence risk and predict chemotherapy benefit.[66, 67] Neoadjuvant chemotherapy (NAC), administered before surgery, is increasingly used for locally advanced breast cancer and certain subtypes of early breast cancer, particularly triple-negative and HER2-positive tumors. NAC can lead to tumor downstaging, increasing the likelihood of breast-conserving surgery, and allows for assessment of tumor response to chemotherapy, providing prognostic information.[68, 69]
Targeted Therapy
Targeted therapies are drugs that specifically target molecules involved in cancer cell growth and survival. Several targeted therapies are approved for breast cancer, depending on the molecular characteristics of the tumor.
HER2-Targeted Therapy:
HER2-positive breast cancers overexpress the HER2 protein, which promotes cancer cell growth. HER2-targeted therapies, such as trastuzumab, pertuzumab, ado-trastuzumab emtansine (T-DM1), and fam-trastuzumab deruxtecan-nxki (Enhertu), are monoclonal antibodies or antibody-drug conjugates that specifically target HER2. These agents have significantly improved outcomes for HER2-positive breast cancer when used in combination with chemotherapy in both early-stage and metastatic settings.
Hormonal Therapy:
Hormonal therapy is a crucial treatment modality for hormone receptor-positive (ER-positive and/or PR-positive) breast cancers. Hormonal therapies work by blocking or reducing the effects of estrogen and/or progesterone, which can fuel the growth of hormone receptor-positive breast cancers. Selective estrogen receptor modulators (SERMs), such as tamoxifen, and aromatase inhibitors (AIs), such as letrozole, anastrozole, and exemestane, are the main classes of hormonal therapy. Tamoxifen is effective in both premenopausal and postmenopausal women, while AIs are primarily used in postmenopausal women. Hormonal therapy is typically administered for 5 to 10 years after surgery for early-stage hormone receptor-positive breast cancer and is also a mainstay of treatment for metastatic hormone receptor-positive breast cancer.[69, 31] Premenopausal women with hormone receptor-positive breast cancer may also benefit from ovarian suppression or ablation to reduce estrogen production, using luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide) or surgical oophorectomy (ovary removal).[75]
Staging
Breast cancer staging is a critical process used to define the extent of disease, determine prognosis, and guide treatment decisions. Breast cancer staging is based on the TNM (Tumor, Node, Metastasis) classification system developed by the American Joint Committee on Cancer (AJCC). Staging is determined both clinically (clinical staging, cTNM) based on physical examination and imaging findings prior to treatment and pathologically (pathologic staging, pTNM) based on pathological examination of the surgically removed primary tumor and regional lymph nodes after definitive surgery. The TNM system categorizes breast cancer into stages 0, I, II, III, and IV, with stage IV representing metastatic breast cancer.
Primary Tumor (T)
Tis: Carcinoma in situ (DCIS or LCIS), Paget disease of the nipple without an associated invasive tumor.
