Breast cancer has become one of the most common malignant tumors worldwide, with its incidence rising annually. It is the leading malignancy in terms of incidence and mortality among women globally.

Etiology and Epidemiology

The exact etiology of breast cancer remains unknown. The breast is a target organ for many endocrine hormones, among which estrone and estradiol are directly linked to the development of breast cancer. Additionally, factors such as early onset of menarche, late menopause, infertility, and advanced age at first full-term pregnancy are associated with an increased risk of breast cancer. Women with a first-degree relative who has a history of breast cancer face a risk that is 2 to 3 times higher than that of the general population. Carriers of BRCA gene mutations also have a significantly increased risk of developing breast cancer. The relationship between benign breast diseases and breast cancer remains controversial. Moreover, factors such as overnutrition, obesity, and a high-fat diet may amplify or prolong the stimulatory effects of estrogen on breast epithelial cells, thereby increasing the risk of cancer. Environmental factors and lifestyle also contribute to the occurrence of breast cancer.

Screening and Prevention

Breast cancer screening plays an important role in the early detection of the disease and in reducing mortality rates. The recommended starting age for breast cancer screening is generally 40 years; however, for high-risk women, screening may begin earlier. Breast ultrasound and/or mammography are the primary screening methods. For younger women or those with dense breast tissue, a combination of ultrasound and mammography is advised.

Prevention strategies vary according to each individual's risk level. For women at general risk, primary strategies involve avoiding risk factors and maintaining a healthy lifestyle. For high-risk women, in addition to adopting a healthy lifestyle, preventive measures such as medication or surgical interventions may be considered to lower the likelihood of developing breast cancer.

Clinical Manifestations

In the early stages, breast cancer typically presents as a painless, solitary mass in the affected breast, often discovered accidentally. The lump is firm, with an irregular surface, poorly defined borders, and limited mobility. In 5% to 10% of cases, the initial symptom is bloody nipple discharge. As the tumor grows, localized swelling may occur. If surrounding tissues are invaded, additional signs may appear, including shortening of Cooper’s ligaments, causing skin dimpling over the tumor (known as the "dimpling sign"). Involvement of the ducts near the nipple and areola may lead to nipple displacement or retraction. As tumors enlarge further, obstruction of lymphatic drainage due to cancer cell invasion of superficial lymphatic vessels may result in lymphedema and a "peau d'orange" (orange-peel) appearance of the skin.

Certain types of breast cancer present with atypical clinical features. Inflammatory breast carcinoma is relatively rare, characterized by rapid disease progression and poor prognosis. Local skin may appear inflamed, with redness, swelling, thickening, roughness, elevated temperature, and occasional pain. Paget’s carcinoma of the breast, which affects the nipple, is also uncommon. It generally exhibits low malignancy and progresses slowly. Symptoms include itching and burning of the nipple, followed by roughness, erosion, and eczema-like changes of the nipple and areola, which may eventually ulcerate. Persistent scabbing and flaking may cyclically occur in these areas.

In advanced cases, breast cancer may invade the pectoral fascia and muscles, causing the tumor to become fixed to the chest wall, creating a "carapace-like" appearance. Cancer cells may spread widely through the subcutaneous lymphatic network, leading to the development of satellite nodules in the breast and surrounding skin. Skin ulceration may occur, often accompanied by foul odor, bleeding, or outward growth forming a cauliflower-like tumor.

Metastasis

Breast cancer metastasizes through lymphatic and hematogenous routes. Lymphatic metastasis typically presents as ipsilateral axillary lymph node enlargement. Initially, the lymph nodes are hard, painless, and mobile. Over time, they may increase in number, form a mass, and become fixed to adjacent skin or deep tissues. The primary pathways include:

Cancer cells infiltrate lymphatic vessels along the lateral edge of the pectoralis major, spreading to ipsilateral axillary lymph nodes, then to subclavian lymph nodes, and eventually to supraclavicular lymph nodes. These cells may then enter the venous circulation via the thoracic duct (left) or right lymphatic duct, leading to distant metastasis.

Cancer cells utilize medial lymphatic vessels to drain through the intercostal perforating branches into internal mammary lymph nodes, progressing to supraclavicular lymph nodes, and subsequently invading the bloodstream through similar routes.

Breast cancer is systemic in nature, and hematogenous metastasis can occur even in the early stages. Cancer cells directly infiltrate the bloodstream, leading to distant metastasis in common sites such as the bones, lungs, and liver, often resulting in associated clinical symptoms.

Diagnosis

The clinical diagnosis of breast cancer relies on medical history, physical examination, and imaging techniques such as breast ultrasound, mammography, or magnetic resonance imaging (MRI). A definitive diagnosis requires a pathological evaluation obtained through tissue biopsy. Additional diagnostic tools, including ductoscopy, fine-needle aspiration cytology, tumor marker detection, and nuclear medicine imaging, can provide supplementary diagnostic information. Histological differentiation is necessary to distinguish breast cancer from benign conditions such as fibroadenoma, cystic hyperplasia, or mastitis.

Staging

Breast cancer staging is undertaken using various systems, with the TNM classification recommended by the International Union Against Cancer being the most commonly used. This method evaluates the primary tumor (T), regional lymph nodes (N), and distant metastasis (M) as follows:
T (Primary tumor)
T₀: No identifiable primary tumor.
T_is: Carcinoma in situ (non-invasive cancer or Paget’s disease without underlying tumor).
T₁: Tumor diameter ≤2 cm.
T₂: Tumor diameter >2 cm but ≤5 cm.
T₃: Tumor diameter >5 cm.
T₄: Tumor of any size with extension to the skin or chest wall (including ribs, intercostal muscles, or serratus anterior). Inflammatory breast cancer is also included in this category.
N (Regional lymph nodes)
N₀: No regional lymph node enlargement.
N₁: Enlarged ipsilateral axillary lymph nodes that remain mobile.
N₂: Enlarged ipsilateral axillary lymph nodes that are matted or adherent to surrounding tissues.
N₃: Metastasis to ipsilateral internal mammary or supraclavicular lymph nodes.
M (Distant metastasis)
M₀: No distant metastasis.
M₁: Presence of distant metastasis.

Based on combinations of the TNM categories, breast cancer can be classified into the following clinical stages:

Stage 0: T_isN₀M₀
Stage I: T₁N₀M₀
Stage II: T_0–1N₁M₀, T₂N_0–1M₀, T₃N₀M₀
Stage III: T_0–2N₂M₀, T₃N_1–2M₀, T₄ (any N)M₀, or (any T)N₃M₀
Stage IV: Any T or N with M₁

Pathological and Molecular Subtypes

Breast cancer is a heterogeneous disease with multiple subtypes, as elucidated by pathological and molecular biology research. Subtyping is closely associated with treatment decisions and clinical outcomes. Classification methods include:

Pathological Subtypes

Non-Invasive Carcinomas

This group includes ductal carcinoma in situ (cancer cells that have not breached the basement membrane of ductal walls), lobular carcinoma in situ (cancer cells confined to the terminal duct lobular unit without invasion of the basement membrane), and Paget’s disease of the breast (without associated invasive cancer). These cancers are typically early-stage with a favorable prognosis.

Special Invasive Carcinomas

These subtypes include papillary carcinoma, medullary carcinoma (with significant lymphocytic infiltration), tubular carcinoma (highly differentiated adenocarcinoma), adenoid cystic carcinoma, mucinous carcinoma, apocrine carcinoma, squamous cell carcinoma, and more.

Non-Special Invasive Carcinomas

This common group includes invasive ductal carcinoma, invasive lobular carcinoma, scirrhous carcinoma, medullary carcinoma (without prominent lymphocytic infiltration), simple carcinoma, and adenocarcinoma. Prognosis prediction in this category requires consideration of other contributing factors.

Other Rare Carcinomas

Molecular Subtypes

Molecular subtypes are determined using immunohistochemical analysis of four biomarkers: estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and the proliferation index marker (Ki-67). These subtypes include the following:

Luminal A
Luminal B
HER2-positive
Triple-negative

Each molecular subtype exhibits distinct biological characteristics, clinical outcomes, and treatment approaches.

Treatment

The treatment of breast cancer involves a multidisciplinary approach with surgery serving as the cornerstone. Patients with early-stage breast cancer are primarily managed with surgical intervention, though surgery is contraindicated for those with poor general health, severe organ dysfunction, or significant frailty due to advanced age.

Surgical Treatment

Recent studies have demonstrated that breast cancer is a systemic disease from its onset, making it increasingly important to reduce surgical intervention and enhance systemic adjuvant therapies.

Radical Mastectomy and Modified Radical Mastectomy

Radical mastectomy involves en bloc removal of the entire breast, pectoralis major and minor muscles, and levels I, II, and III axillary lymph nodes. This approach is used when tumors invade the pectoralis major or minor muscles. Modified radical mastectomy, which preserves the pectoralis major and minor muscles, provides better postoperative cosmetic outcomes and is currently one of the most widely adopted techniques.

Breast-Conserving Surgery

This option is suitable for patients in clinical stages I and II with adequately sized breasts that allow for satisfactory cosmetic results after surgery. Breast-conserving surgery is contraindicated in cases where negative surgical margins cannot be secured. The primary tumor and a surrounding tissue margin of 1–2 cm are resected to ensure no tumor cells are present at the specimen's margin. Adjuvant radiotherapy is required following this procedure. With advancements in oncoplastic techniques and increasing patient demand for better aesthetic outcomes, the implementation of breast-conserving surgery is growing in popularity.

Sentinel Lymph Node Biopsy and Axillary Lymph Node Dissection

Axillary lymph node dissection remains a standard intervention for clinically positive axillary lymph nodes, involving the removal of levels I and II axillary lymph nodes. For clinically negative axillary lymph nodes, sentinel lymph node biopsy is performed. Sentinel lymph nodes, which are the first draining lymph nodes from the tumor, are visualized using tracers and subsequently excised for biopsy. The pathological findings from the sentinel lymph nodes determine whether tumor metastasis has occurred in the axillary lymph nodes. Routine axillary lymph node dissection can be avoided in cases with negative sentinel lymph node findings.

Endoscopic Surgery

Endoscopic breast surgery offers advantages such as hidden and minimal incisions. Procedures include subcutaneous partial or total mastectomy, sentinel or axillary lymph node dissection, removal of the internal mammary lymph node chain, and breast reconstruction using implants or autologous tissue.

Oncoplastic and Reconstructive Surgery

In recent years, breast cancer surgery has evolved from solely focusing on survival to preserving function and cosmetic outcomes through reconstructive techniques. Breast reconstruction can be categorized into immediate reconstruction, performed during the same surgery as mastectomy, or delayed reconstruction, performed months or years later when conditions are appropriate. Reconstruction methods primarily involve implant-based reconstruction or autologous tissue reconstruction.

Chemotherapy

Breast cancer is one of the most responsive solid tumors to chemotherapy, which plays a pivotal role in its management. The goal of adjuvant chemotherapy after surgery is to eliminate potential subclinical metastatic foci and is typically indicated for patients at a high risk of recurrence and metastasis. For invasive breast cancer with axillary lymph node involvement, adjuvant chemotherapy is recommended. Even with negative axillary lymph nodes, patients with high-risk factors—such as tumor size larger than 2 cm, poor histological differentiation, estrogen and progesterone receptor negativity, or HER2 overexpression—are considered candidates for adjuvant chemotherapy.

For poorly differentiated, advanced-stage tumors, combination regimens of anthracyclines and taxanes are commonly employed, such as EC (epirubicin and cyclophosphamide) followed by T (docetaxel or paclitaxel). For well-differentiated, early-stage tumors, regimens based on either taxanes or anthracyclines may be used, such as the TC or EC regimen.

Neoadjuvant chemotherapy, or preoperative chemotherapy, is frequently utilized for triple-negative and HER2-positive breast cancer with larger tumors. The objectives of neoadjuvant chemotherapy are to reduce the size of the primary tumor and/or regional lymph node metastasis, improve surgical outcomes, and assess tumor responsiveness to therapeutic agents. Any regimen suitable for adjuvant chemotherapy can also be used for neoadjuvant purposes.

Endocrine Therapy

Approximately 70% of breast cancer cases exhibit positivity for estrogen receptor (ER) and progesterone receptor (PR), making them responsive to anti-estrogen therapy and classified as hormone-dependent tumors. In contrast, ER-negative breast cancers are less responsive to anti-estrogen therapy and are classified as hormone-independent tumors. For patients with hormone receptor-positive tumors, the use of anti-estrogen therapy represents endocrine therapy.

The primary goal of endocrine therapy is to reduce the binding of estrogen to estrogen receptors on the surface of breast cancer cells. Commonly used drugs include selective estrogen receptor modulators such as tamoxifen, aromatase inhibitors that reduce the conversion of androgens to estrogens, and luteinizing hormone-releasing hormone agonists (LHRHa) that suppress ovarian function.

Tamoxifen is the most widely used anti-estrogen drug, and it functions by competitively binding to estrogen receptors, thereby blocking estrogen from entering tumor cells and inhibiting their growth. This reduces the risk of postoperative recurrence and metastasis, as well as the incidence of contralateral breast cancer. Aromatase inhibitors are more effective than tamoxifen for postmenopausal patients. These drugs inhibit the aromatization process by which adrenal androgens are converted to estrogens, ultimately reducing estradiol production and achieving the therapeutic goal of breast cancer treatment. Ovarian suppression, either through pharmacological or surgical intervention, is an additional method to lower systemic estrogen levels. This approach is suitable for premenopausal patients with a high risk of recurrence.

Radiotherapy

Radiotherapy serves as one of the local treatment modalities for breast cancer. For early-stage breast cancer, whole-breast radiotherapy with an appropriate dose is recommended after breast-conserving surgery to reduce the risk of local recurrence. Following mastectomy, radiotherapy is indicated for patients with specific risk factors, such as a primary tumor diameter ≥5 cm, the presence of ≥4 axillary lymph node metastases, or 1–3 lymph node metastases accompanied by high-risk factors.

Targeted Therapy

Current targeted therapies for breast cancer primarily focus on the HER2 receptor and its downstream signaling pathways. Commonly used agents include monoclonal antibodies such as trastuzumab and pertuzumab, small-molecule tyrosine kinase inhibitors, and antibody-drug conjugates.

Immunotherapy

Immunotherapy for tumors can exert antitumor effects independently or achieve enhanced efficacy when combined with conventional radiotherapy, chemotherapy, or targeted therapy. Presently, immunotherapy for tumors mainly includes three categories: immune checkpoint inhibitors, cellular immunotherapy, and tumor vaccines. Immune checkpoint inhibitors primarily target the PD-1/PD-L1 pathway with therapeutic monoclonal antibodies.

Other Treatments

Bone metastases in breast cancer patients generally do not pose immediate life-threatening risks. Treatment in such cases focuses on preventing and managing bone-related events, improving quality of life, and controlling tumor progression. Systemic therapy serves as the mainstay of treatment, supplemented by the rational use of bone-modifying agents such as bisphosphonates (e.g., zoledronic acid and ibandronate) and denosumab.

Given that breast cancer is a systemic disease, emphasis is placed on understanding its biological behavior. Predictive models based on multiple risk genes (including both coding genes and small non-coding RNA) are being developed to enable individualized predictions of recurrence risk and treatment sensitivity. This approach aims to optimize comprehensive treatment strategies and improve survival rates.