| disease | Breast Cancer |
| alias | Mammary Carcinoma |
Breast cancer (mammary carcinoma) is one of the most common malignant tumors in humans and a leading malignancy among women. The incidence of breast cancer varies significantly across countries due to differences in geographical environments and lifestyle habits. Most countries in North America and Northern Europe have high incidence rates of breast cancer in women, while some countries in South America and Southern Europe have moderate rates, and most regions in Asia, Latin America, and Africa have low rates. In developed countries such as North America and Western Europe, breast cancer ranks first among female malignancies in terms of incidence. According to estimates by the American Cancer Society, there are 120,000 new cases of breast cancer annually in the United States, with an incidence rate of 72.2 per 100,000. In 1976, 33,000 people died from breast cancer. The incidence of breast cancer also varies across different regions in China. Although China is considered a low-incidence country for female breast cancer globally, the incidence has risen significantly in recent years. Particularly, Shanghai, Beijing, Tianjin, and coastal areas are high-incidence regions for breast cancer in China, with Shanghai having the highest rate. In 1972, the incidence rate in Shanghai was 20.1 per 100,000, rising to 28 per 100,000 by 1988, making it the second most common female malignancy.
bubble_chart Etiology
Breast cancer (mammary carcinoma) is one of the most common malignant tumors in humans and a major malignancy among women. Due to differences in geographical environments and lifestyle habits, the incidence of breast cancer varies significantly across countries. Most countries in North America and Northern Europe have high incidence rates of breast cancer in women, while some countries in South America and Southern Europe have moderate rates, and most regions in Asia, Latin America, and Africa have low incidence rates. In developed countries such as North America and Western Europe, breast cancer ranks first in the incidence of malignant tumors among women. According to estimates by the American Cancer Society, there are 120,000 new cases of breast cancer annually in the United States, with an incidence rate of 72.2 per 100,000, and 33,000 deaths from breast cancer in 1976. The incidence of breast cancer also varies across different regions in China. Although China is considered a low-incidence country for breast cancer globally, the incidence has increased significantly in recent years. Particularly, Shanghai, Beijing, Tianjin, and coastal areas are high-incidence regions for breast cancer in China. Shanghai has the highest rate, with an incidence of 20.1 per 100,000 in 1972, rising to 28 per 100,000 in 1988, making it the second most common malignant tumor among women.
bubble_chart Pathological ChangesThe pathological morphology of breast cancer is complex. To comprehensively and accurately reflect the pathological features and biological behavior of breast cancer, various classification methods have been proposed. In 1978, the National Symposium on Early Diagnosis of Breast Cancer classified breast cancer into three major categories: non-invasive carcinoma, non-special type invasive carcinoma, and special type invasive carcinoma. In 1983, the National Breast Cancer Pathology Collaborative Group revised the classification into the current four categories: non-invasive carcinoma, early invasive carcinoma, invasive special type carcinoma, and invasive non-special type carcinoma. This classification better aligns with the requirements of pathological classification.
Histological Classification
1. Non-invasive carcinoma
This is the early stage of breast cancer, where the tumor is confined to the mammary ducts or acini without breaching the basement membrane.
(1) Intraductal carcinoma: Cancer cells are confined to the ducts without breaching the basement membrane. It commonly occurs in small and medium-sized ducts, rarely in larger ducts, and is usually multicentric and scattered.
(2) Lobular carcinoma in situ: This originates from the epithelial cells of the lobular ducts and terminal ducts, often seen in premenopausal women, with an onset age 5–10 years earlier than typical breast cancer. The lobules enlarge, with increased and thickened ducts and acini filled with non-polarized cancer cells. Lobular carcinoma in situ progresses slowly and has a favorable prognosis.
2. Early invasive carcinoma
(1) Early invasive lobular carcinoma: The cancerous tissue breaches the basement membrane and begins to infiltrate the lobular stroma but remains confined to the lobule.
3. Invasive special type carcinoma
(1) Papillary carcinoma: Originating from the epithelial cells of large ducts, the tumor is predominantly composed of papillary structures with or without fibrous vascular bundles. It can be non-invasive or invasive, with infiltration often occurring at the base of the papillary proliferation.
(2) Medullary carcinoma with massive lymphocyte infiltration: The cut surface often shows necrosis and hemorrhage. Microscopically, large areas of cancer cells are interspersed with abundant lymphocytes and plasma cells, more prominent at the tumor periphery, believed to represent the body's immune response to the tumor.
(3) Tubular carcinoma: Originating from duct or small duct epithelial cells, this is a low-grade malignancy with a favorable prognosis.
(4) Adenoid cystic carcinoma: Composed of basaloid cells forming irregular sheets or nests with varying numbers of uniform round lumens. The luminal surfaces and peripheral sheets show myoepithelial cells.
(5) Profuse sweating adenoid carcinoma: Cancer cells have abundant eosinophilic cytoplasm, sometimes with apical snouts, and nuclei with grade I to II atypia, forming glandular, acinar, or small papillary structures.
(6) Mucinous adenocarcinoma: Arising from mucinous metaplasia of ductal epithelium, commonly seen in perimenopausal or postmenopausal women, especially those over 60. Epithelial mucin accounts for over half of the tumor, mostly extracellular, forming mucin lakes; occasionally intracellular, appearing as signet-ring cells.
(8) Paget's disease of the nipple: Also called eczematoid carcinoma, first described by Paget (1874). Microscopically, tumor cells are large, with abundant pale or vacuolated cytoplasm, large irregular nuclei, and occasional mitotic figures.
4. Invasive non-special type carcinoma
(1) Invasive lobular carcinoma: Lobular carcinoma clearly infiltrates beyond the lobule, including small cell type invasive carcinoma.
(2) Invasive ductal carcinoma: The ductal carcinoma clearly infiltrates the stroma, but the infiltrating portion does not exceed half of the cancerous parenchyma. If it exceeds half, it is named according to the predominant morphology of the invasive carcinoma.
(3) Scirrhous carcinoma: Cancer cells are arranged in thin strands or scattered distribution, rarely forming glandular structures, with fibrous stroma accounting for more than two-thirds and being dense.
(4) Medullary carcinoma: Cancer nests are densely packed in sheets or masses, may have glandular structures, with cancer parenchyma accounting for more than two-thirds, and the stroma may contain a small number of lymphocytes and plasma cells.
(5) Simple carcinoma: Intermediate between scirrhous carcinoma and medullary carcinoma, meaning the proportion of cancer parenchyma and fibrous stroma is approximately equal. Cancer cells mainly form irregular solid strands or small nests, and may also have glandular structures.
(6) Adenocarcinoma: Cancer cells are relatively uniform in size, with abundant cytoplasm, possibly secretory, deeply stained nuclei, frequent mitotic figures, arranged in glandular tubules with multiple layers, disordered polarity, lacking a basement membrane, and growing invasively in the stroma. Cancer cells may also be arranged in cord-like or sheet-like masses, with glandular tubule arrangement accounting for more than half.
bubble_chart Clinical Manifestations
(1) Occult Breast Cancer refers to breast cancer that is clinically non-palpable but confirmed by pathological examination after mastectomy. It is often detected by methods such as X-ray examination or presents with axillary lymph node metastasis as the initial symptom, and should be differentiated from accessory breast cancer. In terms of treatment, it is now generally believed that once occult breast cancer is diagnosed, radical surgery should be performed if there is no supraclavicular or distant metastasis. Most reports indicate that its efficacy is better than or similar to breast cancer with axillary lymph node metastasis.
(2) Male Breast Cancer is relatively rare, accounting for 1% of all breast cancer cases and 0.1% of male malignancies. The average age of onset is 6–11 years older than that of female breast cancer.
The main symptom of male breast cancer is a painless lump under the areola. In 20% of patients, there is nipple inward invasion, crusting, or discharge. The tumor margins are often indistinct, and early skin or pectoral muscle adhesion is common, with a high rate of axillary lymph node metastasis. The pathological manifestations of male breast cancer are similar to those of female breast cancer, with the vast majority being invasive ductal carcinoma. Since male breast tissue lacks lobular structures, there are no reports of lobular carcinoma in situ pathologically. The treatment for male breast cancer is the same as for female breast cancer, but because male breast tissue is smaller and more prone to early pectoral muscle invasion, the surgical approach should primarily involve radical or extended radical mastectomy.
For advanced or recurrent cases, endocrine therapy is applied, with better outcomes than in female breast cancer. The main treatment method is bilateral orchiectomy, with an efficacy rate of 50–60%. This high efficacy is due to approximately 84% of tumor tissues being ER-positive. The average duration of effectiveness is 12 months. If the patient is unwilling to undergo orchiectomy or if the disease recurs after surgery, female hormones, male hormones, or TAM can be administered for good results. Such additive endocrine therapy can produce excellent effects in patients who have shown no response to orchiectomy. The response rate of this second-line endocrine therapy ranges between 30–50%. Chemotherapy should only be initiated after endocrine therapy, including ablative and additive methods, has failed. The drugs and administration methods are equivalent to those for female breast cancer.
(3) Inflammatory Breast Cancer is an extremely rare clinical type, often presenting as diffuse hardening and enlargement of the breast, with significant skin redness, swelling, heat, pain, and edema. The onset is explosive, closely resembling acute inflammation, hence it is also called carcinomatous mastitis. The diagnostic points for this disease are: ① Although local manifestations include redness, swelling, heat, and pain, there are no systemic inflammatory reactions such as chills or fever. ② Body temperature and white blood cell counts are mostly within the normal range. ③ Early-stage skin shows a typical violet color, with patchy edema, clear boundaries, slightly raised edges, and enlarged pores resembling orange peel. The area of redness and swelling exceeds one-third of the breast, and anti-inflammatory treatment for one week does not reduce the redness and swelling. ④ A hard, tough lump can sometimes be palpated within the inflamed breast tissue. ⑤ Firm lymph nodes are often palpable in the ipsilateral axilla. ⑥ Fine-needle aspiration cytology and pathological sections can provide diagnostic evidence.
In the past, the prognosis for inflammatory breast cancer treated with surgery or radiotherapy was very poor, with an average survival of 4–9 months, so surgery is not recommended for inflammatory breast cancer. Currently, most authors advocate a comprehensive treatment of chemotherapy and radiotherapy for inflammatory breast cancer, i.e., administering 3–4 courses of chemotherapy followed by radiotherapy, and then chemotherapy again after radiotherapy.
(4) Pregnancy-Associated and Lactational Breast Cancer accounts for approximately 0.75–31% of breast cancer cases. Due to changes in hormone levels during pregnancy and lactation, tumor growth may accelerate, and malignancy may increase. At the same time, the physiological enlargement and congestion of breast tissue during pregnancy and lactation make early detection of tumors difficult and increase the risk of dissemination.
The management principles for pregnancy-associated breast cancer are similar to those for general breast cancer, but the choice of treatment also depends on the stage of the tumor and the different stages of pregnancy. Whether to terminate the pregnancy in the early stages should be determined based on the disease stage. Termination may not be necessary for earlier stages, but for stages II or III, or cases where postoperative chemotherapy and radiotherapy are anticipated, terminating the pregnancy first can improve survival rates. Antagonism often arises because delaying surgical treatment due to pregnancy termination negatively impacts treatment outcomes.
The treatment of breast cancer during lactation should first involve cessation of breastfeeding, and postoperative adjuvant therapy is similar to that for general breast cancer. Prophylactic oophorectomy does not improve survival rates.
1. Medical History: A lump is often the first symptom of breast cancer. It is essential to inquire about the time of appearance, location, size, growth rate (fast or slow), recent changes, presence of pain, and the nature of the pain. Additionally, note the duration of nipple erosion or discharge and the characteristics of the discharge. Check for lumps in the armpit and whether the patient is pregnant or breastfeeding. Document menstrual history and family history.
2. Physical Examination: Begin with a comprehensive examination, paying attention to potential metastases in the chest, abdomen, pelvis, and skeletal system. Then, examine the breasts, starting with the healthy side before moving to the affected side. The examination should be systematic and thorough. First, inspect visually to check for symmetry between the breasts, any abnormal appearance, inflammatory changes in the skin, or signs like peau d'orange edema. For palpation, use flat fingers. When examining the breast, raise the patient's arm overhead to inspect the inner half and let it hang to examine the outer half. If a lump is detected, record its location in three zones and four quadrants, and describe its characteristics and mobility in detail. Compress the areola to check for discharge, and if present, document its nature. When examining the supraclavicular lymph nodes, pay attention to the sentinel lymph nodes deep to the origin of the sternocleidomastoid muscle. For axillary lymph node examination, lift the patient's arm with one hand while placing the other hand in the armpit, then lower the arm while supporting the elbow to palpate the axillary lymph nodes. The infraclavicular lymph nodes are difficult to assess due to pectoral muscle coverage, but multiple metastatic lymph nodes may feel full.
3. X-ray Examination: Mammography is a common method for diagnosing breast cancer. On X-ray films, common breast diseases typically manifest as masses or nodular lesions, calcifications, skin thickening, or ductal changes. A high-density mass with spiculated margins is highly suggestive of malignancy. When the spicules exceed the diameter of the lesion, it is termed a stellate lesion. The size of the mass on X-ray is often smaller than that detected clinically, which is another malignant sign. Note the shape, size, and density of calcifications, as well as their number and distribution. Clustered calcifications, especially within a 1 cm range, strongly indicate breast cancer. More than 10 calcifications also suggest a high likelihood of malignancy.
4. Ultrasonography: Ultrasonography is non-invasive and can be repeated. It is particularly valuable for dense breast tissue but is mainly used to differentiate between cystic and solid masses. The diagnostic accuracy of ultrasound for breast cancer is 80–85%. Features such as a hyperechoic rim indicating tumor infiltration, disruption of normal breast architecture, and localized skin thickening or dimpling above the mass are important diagnostic indicators for terminating lactation.
5. Thermography: This method displays the temperature distribution on the body surface. Since cancerous tissues have rich blood supply, they generate higher surface temperatures than surrounding tissues, aiding diagnosis. However, this method lacks precise imaging standards, and the thermal abnormalities may not correspond to the tumor location, resulting in poor diagnostic accuracy. Its use has declined in recent years.
6. Near-Infrared Scanning: Near-infrared light (wavelength 600–900 μm) easily penetrates soft tissues. It produces varying shades of gray to visualize breast masses based on tissue density. Additionally, infrared light is highly sensitive to hemoglobin, clearly displaying breast vascular patterns. Breast cancer often shows increased local blood flow and proximal vessel dilation, which infrared imaging can effectively capture, aiding diagnosis.
7. CT Scan: CT can be used for preoperative localization of non-palpable breast lesions, staging confirmed breast cancer, and assessing the posterior breast region, axillary and internal mammary lymph nodes for enlargement, helping formulate treatment plans.
8. Tumor Marker Testing: During carcinogenesis, tumor cells produce, secrete, or release cellular components that exist as antigens, enzymes, hormones, or metabolites within tumor cells or host body fluids. These substances are called tumor markers.
(1) Carcinoembryonic antigen (CEA): A non-specific antigen that is elevated in many tumor and non-tumor diseases, lacking differential diagnostic value. Approximately 20-30% of operable breast cancer patients show elevated CEA levels in preoperative blood tests, while 50-70% of advanced stage and metastatic cancers exhibit high CEA values.
(2) Ferritin: Serum ferritin reflects the body's iron storage status. Elevated ferritin levels are observed in many malignant tumors such as leukemia, pancreatic cancer, gastrointestinal tumors, and breast cancer.
(3) Monoclonal Antibodies: The monoclonal antibody CA 15-3, used for breast cancer diagnosis, has a diagnostic accuracy rate of 33.3–57%.
9. Biopsy: A definitive diagnosis of breast cancer must be established before treatment can begin. Although many diagnostic methods are available, only the pathological results from a biopsy can serve as the definitive diagnostic criterion.
(1) Needle Aspiration Biopsy: Needle aspiration cytology was developed by Gutthrie in 1921 and has since evolved into fine-needle aspiration cytology.
This method is simple, rapid, and safe, and can replace some frozen tissue sections. It has a high positive rate of 80–90% and can also be used in cancer screening. If clinical findings suggest malignancy but cytology reports benign or suspicious results, surgical biopsy should be performed to confirm the diagnosis.
(2) Incisional Biopsy: This method is generally not recommended due to the risk of promoting cancer spread. It is only considered for advanced-stage cancers to determine the pathological type.
(3) Excisional Biopsy: When a malignant mass is suspected, the mass and a surrounding margin of tissue are excised for biopsy. Typically, the tumor should be completely removed with at least a 1 cm margin. The following features in the excised specimen can preliminarily indicate malignancy: ① Medullary carcinoma is soft in texture, with a grayish-white cut surface, possibly showing hemorrhage, necrosis, and cystic cavities. ② Scirrhous carcinoma has a grayish-white, contracted cut surface with a scar-like appearance, radiating outward without a membrane. ③ Intraductal carcinoma often involves multiple ducts and may extend toward the nipple. The cut surface is grayish-white, and sometimes acne-like material can be expressed. ④ Lobular carcinoma is soft and irregular in shape, with a grayish-white or pinkish cut surface. Sometimes the tumor mass is indistinct, manifesting only as thickened breast tissue.
bubble_chart Treatment Measures
1. Surgical Treatment
Surgical treatment remains one of the principal approaches for managing breast cancer. There are various surgical techniques available, yet no consensus exists regarding their selection. The overarching trend is to minimize surgical trauma and, where feasible, preserve the breast's appearance in early-stage breast cancer patients. Regardless of the chosen technique, the guiding principle must prioritize radical treatment while considering functional and cosmetic preservation as secondary objectives.
(1) Surgical Indications Halsted pioneered the radical mastectomy for carcinoma of the breast. Due to its logical approach and clear efficacy, it became the standard treatment for nearly a century. Over the past half-century, numerous exploratory modifications have been made to breast cancer surgical techniques, generally leaning toward either conservative or extensive approaches, though debates persist. Lumpectomy and total mastectomy represent conservative surgical options. Postoperative radiotherapy is required, with doses varying between 30–70 Gy. For carefully selected cases of localized early-stage cancer, favorable outcomes can be achieved. However, whether this should be the routine treatment for early-stage carcinoma of the breast and how to accurately identify such cases remain unresolved.
(2) Surgical Contraindications
1. Systemic Contraindications: ① Patients with distant metastases. ② Elderly or frail individuals unable to tolerate surgery. ③ Patients in poor general condition, presenting with cachexia. ④ Patients with impaired vital organ function who cannot withstand surgery.
2. Local Lesion Contraindications (for Stage III patients exhibiting any of the following): ① Peau d'orange edema covering over half of the breast area. ② Satellite nodules on the breast skin. ③ Breast cancer invading the chest wall. ④ Clinically enlarged parasternal lymph nodes confirmed as metastatic. ⑤ Edema of the affected upper limb. ⑥ Pathologically confirmed metastasis in supraclavicular lymph nodes. ⑦ Inflammatory breast cancer. (If two or more of the following five conditions are present): ① Tumor ulceration. ② Peau d'orange edema involving up to one-third of the breast area. ③ Fixation of the tumor to the pectoralis major muscle. ④ Axillary lymph nodes with a maximum diameter exceeding 2.5 cm. ⑤ Adhesion between axillary lymph nodes or to the skin/deep tissues.
(3) Surgical Techniques
1. Radical Mastectomy: In 1894, Halsted and Meyer independently published the principles of radical mastectomy for breast cancer: ① The primary lesion and regional lymph nodes should be resected en bloc. ② The entire breast along with the pectoralis major and minor muscles must be removed. ③ Axillary lymph nodes should undergo thorough en bloc resection. Haagensen refined the radical mastectomy, emphasizing meticulous surgical execution: ① Precise dissection of skin flaps. ② After complete flap separation, the pectoralis major and minor muscles are transected from the chest wall and reflected outward. ③ During axillary dissection, the long thoracic nerve should be preserved; if no significant lymphadenopathy is present, the thoracodorsal nerve may also be spared. ④ Chest wall defects are uniformly managed with skin grafting. Intraoperative complications include: ① Axillary vein injury: Often caused by unclear dissection around the axillary vein or excessive proximity to the main trunk when dividing its branches. Clear exposure and leaving a small stump of the branch are crucial. ② Pneumothorax: May occur when transecting the costal attachments of the pectoralis muscles due to deep clamping of perforating vessels, inadvertently puncturing the intercostal muscles and pleura, leading to tension pneumothorax. Postoperative complications include: ① Subcutaneous fluid accumulation: Typically due to inadequate skin flap fixation or poor drainage. Prevention involves multiple sutures between the subcutaneous tissue and chest wall, along with continuous negative-pressure drainage. ② Skin flap necrosis: Causes include overly tight sutures or excessively thin flaps. Skin grafting is advisable for larger defects. ③ Edema of the affected upper limb and restricted elevation: Primarily due to reduced postoperative activity and scar contracture. Early functional exercise is recommended, with most patients regaining full mobility within about a month post-surgery.
2. Extended radical mastectomy for breast cancer: Extended radical mastectomy for carcinoma of the breast includes radical mastectomy (the standard radical procedure) along with internal mammary lymph node dissection, which involves removing the lymph nodes from the first to fourth intercostal spaces. During this procedure, the second, third, and fourth costal cartilages need to be excised. The surgical approaches include the intrapleural method and the extrapleural method. The former is more traumatic and associated with more complications, hence the latter is more commonly used.
3. Modified Radical Mastectomy: Primarily used for non-invasive carcinoma or stage I invasive carcinoma. It can also be selectively applied to stage II cases without clinically significant axillary lymph node enlargement.
(1) Type I: Preserves the pectoralis major and minor muscles. The skin incision and flap separation principles are the same as in radical mastectomy. First, perform a total mastectomy (including the removal of the pectoralis major muscle's surgical fascia), dissect the entire breast to the axillary side, and then proceed with axillary lymph node dissection, with the scope of clearance being essentially the same as in radical mastectomy. The anterior thoracic nerves should be preserved. Finally, the entire breast and axillary lymphoid tissue are removed en bloc.
(2) Type II: Preserves the pectoralis major muscle but removes the pectoralis minor muscle. The skin incision and other steps are the same as above. After dissecting the breast to the outer edge of the pectoralis major muscle, detach the muscle's attachment points at the 4th, 5th, and 6th ribs and flip it upward to expand the surgical field. Cut the pectoralis minor muscle's attachment point at the coracoid process of the scapula. Subsequent steps are the same as in radical mastectomy, but care must be taken to preserve the anterior thoracic nerves and accompanying blood vessels. Finally, the entire breast, pectoralis minor muscle, and axillary lymphoid tissue are removed en bloc.
4. Simple Mastectomy: As an ancient surgical procedure, it was once replaced by radical mastectomy for breast carcinoma. In recent years, with advances in the biology of breast carcinoma, total mastectomy has regained attention. Its indications are twofold: first, for non-invasive or early-stage cases without axillary lymph node metastasis, postoperative radiotherapy may be omitted. Second, for locally advanced-stage breast carcinoma, simple mastectomy followed by radiotherapy is used. From the perspective of increasing aesthetic demands, total mastectomy still requires complex breast reconstruction, making it unsuitable for early-stage cases in young and middle-aged women. Therefore, its main indications should be limited to elderly or frail patients or certain advanced-stage cases where only palliative resection is feasible.
5. Less-Than-Total Mastectomy Procedures: In recent years, due to advancements in radiotherapy equipment, earlier detection of lesions, and patients' increased demands for postoperative quality of life, many conservative surgical approaches involving less-than-total mastectomy have been reported. These procedures range from local excision to quadrantectomy, with some cases receiving postoperative radiotherapy.
Breast-conserving surgery is not suitable for all breast cancer cases, nor can it replace all radical mastectomies. It is a modified approach to breast cancer treatment, and care must be taken to avoid local recurrence. Its indications are roughly as follows: ① Small tumors, suitable for clinical T1 and some T2 (less than 4 cm) lesions; ② Peripheral tumors, those located under the areola are often unsuitable; ③ Single sexually transmitted disease lesions; ④ Tumors with clear boundaries, those without clear macroscopic or microscopic boundaries are often unsuitable; ⑤ No definite axillary lymph node metastasis. Treatment efficacy is related to the following factors: ① The tumor margin must have normal boundaries; if the margin has sufficient normal tissue, the prognosis is better; ② The size and histological grade of the primary tumor; ③ Postoperative radiotherapy; if radiotherapy is not performed, the local recurrence rate is higher.
II. Radiotherapy
Radiotherapy is a major component of breast cancer treatment and one of the local treatment modalities. Compared to surgery, it is less restricted by anatomical or patient constitution factors. However, the efficacy of radiotherapy is influenced by the biological effects of radiation. With current commonly used radiotherapy facilities, it is difficult to achieve the goal of "complete eradication" of the tumor, making its efficacy inferior to surgery. Therefore, most scholars currently do not advocate radiotherapy alone for curable breast cancer. Radiotherapy is mostly used in comprehensive treatment, including as an adjuvant therapy before or after radical mastectomy, or as palliative treatment for advanced-stage breast cancer. Over the past decade, comprehensive treatments centered on local excision for earlier-stage breast cancer have become increasingly common, with efficacy not significantly different from radical mastectomy. Radiotherapy has played an important role in reducing the scope of surgery.
(1) Preoperative Radiotherapy
1. Indications
(1) Large primary lesions where direct surgery is estimated to be difficult.
(2) Rapidly growing tumors with significant short-term progression.
(3) Primary lesions with significant skin edema or pectoral muscle adhesion.
(4) The axillary lymph nodes are large or show significant adhesion to the skin and surrounding tissues.
(5) Cases with unsatisfactory tumor regression after preoperative chemotherapy.
(6) Inflammatory breast cancer patients aiming for surgical resection.
2. The Role of Preoperative Radiotherapy
(1) It can improve the surgical resection rate, allowing some inoperable patients to regain the opportunity for surgery.
(2) By inhibiting the activity of tumor cells, radiotherapy can reduce postoperative recurrence and metastasis rates, thereby improving survival rates.
(3) Radiotherapy extends the preoperative observation period, potentially preventing unnecessary surgery in some cases with subclinical distant metastases.
3. Disadvantages of Preoperative Radiotherapy
It increases surgical complications and may affect accurate postoperative staging and hormone receptor measurements.
4. Methods of Preoperative Radiotherapy
Preoperative radiotherapy should ideally use high-energy radiation to better protect normal tissues and reduce complications. In terms of radiation techniques, conventional fractionation with moderate doses is commonly used. Rapid or hyperfractionated radiation is generally not employed. Surgery is ideally performed 4–6 weeks after completing radiotherapy.
(II) Postoperative Radiotherapy
Whether radiotherapy is necessary after radical surgery has long been a highly debated issue in breast cancer treatment. In recent years, more authors acknowledge that postoperative radiotherapy can reduce local and regional recurrence rates. Since Fisher proposed new perspectives on breast cancer, treatment has gradually shifted from localized therapy to comprehensive therapy. With the widespread use of postoperative adjuvant chemotherapy, postoperative radiotherapy is no longer a routine treatment after radical surgery but is applied selectively.
1. Indications
(1) After simple mastectomy.
(2) Post-radical surgery cases with pathological reports showing metastasis in the middle or upper axillary lymph nodes.
(3) Post-radical surgery cases where pathology confirms metastatic lymph nodes account for more than half of the examined lymph nodes or involve four or more lymph nodes.
(4) Cases with pathologically confirmed internal mammary lymph node metastasis (irradiate the supraclavicular area).
(5) Cases where the primary lesion is located in the central or medial breast and underwent radical surgery, especially those with axillary lymph node metastasis.
2. Principles of Radiotherapy
(1) For stage I or II breast cancer after radical or modified radical surgery, if the primary lesion is in the outer quadrant of the breast and axillary lymph node pathology is negative, no postoperative radiotherapy is needed. If axillary lymph nodes are positive, irradiate the internal mammary area and supraclavicular regions. If the primary lesion is in the central or medial quadrant and axillary lymph node pathology is negative, irradiate only the internal mammary area; if positive, add the supraclavicular regions.
(2) For stage III breast cancer after radical surgery, regardless of axillary lymph node status, irradiate the internal mammary area and supraclavicular regions. Depending on the number of positive axillary lymph nodes and chest wall involvement, consider whether to add chest wall irradiation.
(3) After radical breast cancer surgery, if axillary lymph nodes have been cleared, the axillary area is generally not irradiated unless the surgical clearance was incomplete or residual lesions are present.
(4) Radiotherapy should ideally begin within 4–6 weeks post-surgery, or up to 8 weeks for cases with skin grafts.
(III) Radiotherapy as the Primary Treatment
In the past, radiation therapy for locally advanced tumors without surgical indications was often palliative. In recent years, with the improvement and advancement of radiation equipment and techniques, as well as progress in radiobiological research, radiation can now deliver a higher dose to the local tumor while causing less injury to surrounding normal tissues, significantly improving treatment outcomes. Currently, studies are being conducted on combining minor surgery with radiation therapy for early-stage breast cancer, shifting the role of radiation therapy in breast cancer treatment from palliative to curative. Most authors suggest that patients with primary lesions smaller than 3cm and N0 or N1 may be considered for minor surgery plus radiotherapy. For locally advanced breast cancer, radiation therapy remains an effective local treatment modality, and complete tumor resection or simple mastectomy prior to radiation can enhance therapeutic efficacy.
(IV) Radiotherapy for Recurrent and Metastatic Lesions
Postoperative recurrence of breast cancer is an unfavorable sign, but not without hope.
Appropriate local treatment can improve quality of life and prolong survival. In terms of irradiation, large-field irradiation is more effective than small-field irradiation and should be adopted whenever possible. For recurrent cases, combined radiotherapy and chemotherapy should be used, especially for rapidly progressing recurrences. When distant metastasis occurs in carcinoma of the breast, chemotherapy should be considered first, with appropriate radiotherapy to alleviate symptoms and reduce patient suffering. For example, pain in patients with bone metastases can be reduced or eliminated after radiotherapy. For patients with thoracic or lumbar vertebral metastases, radiotherapy can prevent or delay the onset of paralysis.
III. Relationship Between Hormone Receptor Assays and Endocrine Therapy
Hormone receptor assays have a clear relationship with the efficacy of breast cancer treatment: ① The response rate to endocrine therapy is 50–60% for estrogen receptor-positive patients, while it is less than 10% for receptor-negative patients. Simultaneous measurement of progesterone receptors can more accurately predict the efficacy of endocrine therapy, with a response rate exceeding 77% for patients positive for both receptors. The level of receptor content is positively correlated with efficacy—the higher the content, the better the therapeutic outcome. ② Receptor-negative cells are often poorly differentiated. Receptor-negative patients are more prone to postoperative recurrence. Regardless of lymph node involvement, receptor-negative patients have a worse prognosis than receptor-positive ones. Recurrences in receptor-positive patients tend to involve the skin, soft tissues, or bones, whereas receptor-negative patients are more likely to develop visceral metastases. ③ Hormone receptor assays are now used to formulate postoperative adjuvant treatment plans. Receptor-positive patients, especially postmenopausal cases, can receive endocrine therapy as adjuvant treatment, while premenopausal or receptor-negative patients are primarily treated with adjuvant chemotherapy.
IV. Endocrine Therapy
Endocrine therapy for carcinoma of the breast is non-curative but can achieve varying degrees of palliative effects in hormone-dependent carcinoma of the breast. The higher the estrogen receptor (ER) content in the cytoplasm and nucleus of cancer cells, the stronger their hormone dependence. It is also important to remember that carcinoma of the breast occurring before amenorrhea differs in treatment from that occurring after amenorrhea.
(I) Treatment for Premenopausal Patients (or Within 1 Year After Amenorrhea)
1. Castration Therapy
Includes surgical castration and radiation castration. The former is used for patients in good general condition who urgently need endocrine therapy to take effect; the latter is for patients in poor general condition who cannot tolerate surgery. The response rate for unselected cases undergoing ovarian ablation is 30–40%, while for hormone receptor-positive cases, it can reach 50–60%. Currently, prophylactic ovarian ablation is mainly used for premenopausal (especially ages 45–50) high-risk recurrence cases with extensive lymph node metastases and positive hormone receptor assays. It is not suitable for postmenopausal or young patients.
2. Endocrine Drug Therapy
(1) Testosterone Propionate: 100 mg, intramuscular injection, once daily for 5 doses, then reduced to 3 times per week. The dosage may be further reduced based on symptom relief and systemic reactions, continuing for about 4 months. If no effect is observed after 6 weeks, discontinue use.
(2) Fluoxymesterone: Similar to testosterone propionate but with relatively fewer androgenic effects. It can be taken orally, with a dose of 10–30 mg/day. The drug is available in three dosage forms: 2 mg, 5 mg, and 10 mg.
(3) Dromostanolone: A testosterone derivative, 2.5 times more potent than testosterone propionate. It can be taken orally at 150–300 mg/day.
(II) Treatment for Postmenopausal Patients (Amenorrhea for More Than 1 Year): The following drugs may be selected.
1. Tamoxifen (TAM): It is an anti-estrogen drug that binds to the estrogen receptors of cancer cells, inhibiting their proliferation. The usual dose is 10mg, taken orally, twice daily. Increasing the dose does not enhance efficacy. The main side effects include: ① Gastrointestinal reactions: loss of appetite, nausea, and occasionally vomiting and diarrhea; ② Reproductive system: amenorrhea, vaginal bleeding, and vulvar cutaneous pruritus; ③ Neuropsychiatric symptoms: headache, vertigo, and depression; ④ Skin: facial flushing and rash; ⑤ Blood counts: occasional leukopenia and thrombocytopenia—use with caution in patients with low blood counts; ⑥ Abnormal liver function in some patients; ⑦ Effects on the fetus—contraindicated during pregnancy and lactation; ⑧ Damage to the retina, which may affect vision.
2. Aminoglutethimide: 125mg, orally, 4 times/day, combined with hydrocortisone 25mg orally, 2 times/day, or prednisone 5mg, 2 times/day. After one week, increase aminoglutethimide to 250mg, 2 times/day, hydrocortisone 25mg, 4 times/day, or prednisone 5mg, 3 times/day.
3. Medroxyprogesterone acetate 200–300mg intramuscular injection, 2 times/day.
4. Diethylstilbestrol 1–2mg, orally, 3 times/day.
5. Ethinylestradiol (ethinyl estradiol): This is a synthetic estrogen with strong activity. 0.5–1mg, orally, 3 times/day.
V. Chemotherapy
(I) Principles of Adjuvant Chemotherapy Numerous experimental studies and clinical observations have confirmed that most breast cancers are systemic diseases. When breast cancer grows larger than 1cm and becomes clinically palpable, it is often already a systemic disease, with possible distant micrometastases that current diagnostic methods cannot yet detect. The goal of surgical treatment is to achieve maximum local control of the primary tumor and regional lymph nodes, reduce local recurrence, and improve survival rates. However, residual tumor cells may still remain in the body after tumor resection. Based on the concept that breast cancer is already a systemic disease at diagnosis, the purpose of systemic chemotherapy is to eradicate residual tumor cells in the body to improve the cure rate of surgical treatment.
(II) Preoperative Adjuvant Chemotherapy
1. Significance of Preoperative Chemotherapy
(1) Early control of micrometastases.
(2) Induce regression or partial elimination of the primary cancer and surrounding disseminated cancer cells to reduce postoperative recurrence and metastasis.
(3) Advanced carcinoma of the breast and inflammatory carcinoma of the breast may limit the feasibility of surgical treatment. Preoperative chemotherapy can shrink the tumor to facilitate surgical resection.
(4) The effectiveness of preoperative chemotherapy can be evaluated based on the resected tumor specimen, serving as a reference for selecting postoperative or recurrence chemotherapy regimens.
2. Methods of Preoperative Chemotherapy
(1) Preoperative systemic chemotherapy: Since 1978, the Cancer Hospital of Shanghai Medical University administered oral pyrimidine mustard (45mg total over intermittent dosing) to 96 breast cancer patients before surgery. Compared to 94 controls, the 5-year survival rate for Stage III patients was 56.3% in the treatment group versus 39.3% in the control group.
(2) Preoperative stirred pulse perfusion chemotherapy: Includes intrathoracic stirred pulse catheterization and subclavian stirred pulse catheterization.
(III) Postoperative Adjuvant Chemotherapy
1. Indications for Postoperative Adjuvant Chemotherapy
(1) Premenopausal women with axillary lymph node stagnation of yang, regardless of estrogen receptor status, should receive standardized combination chemotherapy as the standard treatment protocol.
(2) Postmenopausal women with axillary lymph node stagnation of yang and estrogen receptor-positive status should prioritize anti-estrogen therapy.
(3) Postmenopausal women with axillary lymph node stagnation of yang and estrogen receptor-negative status may consider chemotherapy, but it is not recommended as a standard protocol.
(4) Premenopausal women with axillary lymph node stagnation of yin are not universally recommended for adjuvant therapy, but certain high-risk patients should consider adjuvant chemotherapy.
(5) Postmenopausal women with axillary lymph node stagnation of yin, regardless of estrogen receptor levels, do not have an indication for adjuvant chemotherapy, but certain high-risk patients should consider it.
High-risk recurrence factors for lymph node stagnation of yin breast cancer include: ① Negative hormone receptors (ER, PR). ② High percentage of S-phase tumor cells. ③ Aneuploid tumors. ④ Overexpression or amplification of the oncogene CerbB-2.
2. Modern Perspectives on Adjuvant Chemotherapy
(1) Adjuvant chemotherapy should be administered early postoperatively, ideally within 2 weeks, and no later than one month after surgery. Delaying until obvious lesions appear will reduce efficacy.
(2) In adjuvant chemotherapy, combination chemotherapy is more effective than single-agent chemotherapy.
(3) Adjuvant chemotherapy needs to reach a certain dose, and the effect is better when 85% of the original planned dose is achieved.
(4) The treatment period should not be too long. For postoperative breast cancer, six consecutive courses of chemotherapy are recommended.
3. Recommended chemotherapy regimens
(1) CMF regimen: a classic chemotherapy regimen for carcinoma of the breast
Cyclophosphamide (CTX) 400mg/m2 IV d1d8
Methotrexate (MTX) 200mg/m2 IM d1d8
Fluorouracil (5-Fu) 400mg/m2 IV drip dl-5
Repeat every three weeks
(2) CAF regimen
Cyclophosphamide (CTX) 400mg/m2 IV d1d8
Adriamycin (ADM) 300mg/m2 IV d1
Fluorouracil (5-Fu) 400mg/m2 IV drip d1-s
Repeat every three weeks
(3) Cooper regimen
Cyclophosphamide 2.5mg/kg daily, orally
Methotrexate 0.7mg/kg weekly, IV for 8 weeks.
5-Fluorouracil 12mg/kg weekly, IV, then every other week
Vincristine 34mg/kg weekly for 4–5 weeks.
Prednisone 0.75mg/kg daily, then half dose for 10 days, 5mg/d for 3 weeks
4. Second-line chemotherapy regimens for breast cancer
(1) CEF regimen
Cyclophosphamide 500mg/m2 IV d1d8
Epirubicin 50mg/m2 IV d1
5-Fluorouracil 500mg/m2 IV d1-3;
(2) DCF regimen
Mitoxantrone 10mg/m2 IV dl
Cyclophosphamide 500mg/m2 IV d1
5-Fluorouracil 1000mg/m2 IV d1
(IV) Chemotherapy for bone metastases: Combination chemotherapy is more effective for soft tissue metastases (e.g., brain, liver, lung) than for bone metastases. However,
there are reports of bone metastases completely disappearing with intensive combination chemotherapy. Mithramycin (MTH) inhibits bone resorption and is clinically used to treat hypercalcemia caused by osteolytic bone metastases. A commonly used regimen is the AMO regimen: Adriamycin (ADM) 40mg/m2 IV on days 1 and 8; Vincristine 1.4mg/m2 IV on days 1 and 8; Mithramycin (MTH) 2mg dissolved in 200ml of 5% glucose solution, infused over 2 hours on days 1, 8, 15, and 22; repeat every 28 days for three courses. For localized lesions, radiotherapy may be combined.
(V) Chemotherapy for central nervous system metastases
1. If there is no brain edema, X-ray tomography can be used for localization, followed by radiotherapy. For patients with brain edema, diuretics (e.g., mannitol) and high-dose corticosteroids should be used first to control the edema.
2. For widespread or unlocalizable lesions, lipophilic chemotherapeutic drugs that easily cross the blood-brain barrier can be used, such as CCNU 100mg orally every 3–4 weeks or MeCCNU 125mg orally every 4–6 weeks.
(VI) Chemotherapy for cancerous pleural effusion: Drain the pleural fluid as much as possible, then inject one of the following chemotherapeutic drugs into the pleural cavity: ① Nitrocaphane 40–60mg; ② Nitrogen mustard 10mg; ③ Thiotepa 30mg; ④ Mitomycin 6–8mg; ⑤ Fluorouracil 1000mg; ⑥ Cisplatin 90–120mg. Except for cisplatin, which is injected every 3 weeks (with systemic hydration), the other drugs are generally injected into the pleural cavity once a week.
bubble_chart Follow-up Consultation
Local recurrence mostly occurs within the first few years after treatment (85% within five years). Among these, 1-2% first appear after 10 years of disease-free survival. Therefore, regular follow-up examinations, including mammography, are crucial measures for the early diagnosis of contralateral breast cancer in 15-20% of patients. Some patients undergo conservative surgery, such as lumpectomy, and even if recurrence occurs, it is not difficult to cure. These patients are worth close follow-up and monitoring.
There are many factors related to the prognosis of breast cancer, among which the main ones are the extent of tumor invasion and its pathobiological characteristics.
(1) Extent of Tumor Invasion
1. Tumor size: In the absence of regional lymph node metastasis and distant metastasis, the larger the primary lesion and the more severe the local infiltration, the worse the prognosis.
2. Axillary lymph node metastasis: The prognosis is good when there is no axillary lymph node metastasis, and poor when metastasis is present. Moreover, the greater the number of metastases, the worse the prognosis. Higher metastasis location also indicates a poorer prognosis.
3. Distant metastasis: Most cases result in death within about one year.
(2) Pathological Type and Differentiation Degree of the Tumor The pathological type and differentiation degree of the tumor, its invasiveness, and the host's immune response to the tumor are important factors affecting prognosis. Special types of breast cancer have a better prognosis than non-special types. Among non-special types, non-invasive carcinomas have a better prognosis than invasive carcinomas, and well-differentiated tumors have a better prognosis than poorly differentiated ones. Some tumors are highly malignant and may develop necrosis during rapid growth. Severe tumor necrosis indicates strong invasiveness and a poorer prognosis.
(3) Clinical Staging The TNM staging system is familiar to clinicians, and higher stages indicate a poorer prognosis. However, two points should be noted: first, within the same stage, the presence or absence of axillary lymph node metastasis is more important than tumor size; second, clinical examination for axillary lymph node metastasis is often prone to errors.
(4) Steroid Hormone Receptors and Prognosis Steroid hormone receptor testing can not only serve as a reference for selecting hormone therapy but also as an indicator for estimating prognosis. Patients with receptor-positive status have a better prognosis than those with negative status, with a difference of about 10%, especially in cases with positive lymph node metastasis. Among estrogen receptors and progesterone receptors, progesterone receptors are more significant. Patients with both receptors positive have a better prognosis than those with only one positive or both negative.
Early Detection of Breast Carcinoma It is well known that cancer is not an "incurable disease." The key lies in early detection and treatment. Years of clinical practice have confirmed that for most cancers, relying solely on improved treatment methods has yielded unsatisfactory results in terms of increasing cure rates. Taking breast cancer as an example, despite various advancements in treatment methods over the past few decades, the mortality rate has not significantly declined. The primary reason for this is the late stage at which patients seek medical attention, with the majority of treated cases being in the advanced stage. This underscores the need to promote the detection of early-stage cancer to reduce the occurrence of advanced-stage cases, which would be an effective way to improve the survival rate of breast cancer.
The modern definition of early-stage breast cancer should include microcarcinomas (diameter ≤ 0.5 cm) and clinically non-palpable T0 cancers, as these types rarely metastasize. After surgical treatment, the 10-year survival rate for such cases generally exceeds 90%. Detecting a large number of these cancers could significantly improve survival rates. To achieve this, the following points are proposed:
1. **Establishing a New Concept of Early-Stage Cancer**: Early-stage cancers are not uncommon in routine examinations and should theoretically outnumber the more commonly seen advanced-stage cancers, as the preclinical phase accounts for about two-thirds of the natural progression of breast cancer. However, early-stage cancers are rarely detected, indicating that most are missed during examinations. The main reason is the lack of sufficient awareness among examiners. To this day, most diagnosticians still adhere to the traditional concept of using a "breast lump" as the primary sign for diagnosing breast cancer. Yet, the aforementioned early-stage cancers may not always form noticeable lumps. Under this outdated concept, early-stage cancers are inevitably overlooked. Therefore, it is essential to redefine the concept of early-stage cancer.
2. **Carefully Investigating Risk Factors for Breast Cancer**: There are many risk factors for breast cancer, including the following: - (1) Family history of breast carcinoma, especially whether the examinee’s mother or sisters have had the disease; - (2) Early menarche (before age 12) or late menopause (after age 50); - (3) Nulliparity after age 40; - (4) A history of cancer in one breast, making the other breast a high-risk site. Individuals with these factors should be considered at high risk and prioritized for examination.
3. **Investigating Any Breast Abnormalities**:
- (1) **Nipple discharge**, especially bloody discharge, is often associated with breast carcinoma. In women over 50, bloody discharge has a malignancy rate of over 50%.
- (2) **Localized thickening of breast tissue** is a common but often overlooked sign. In premenopausal women, especially if the thickening varies with the menstrual cycle, it is usually physiological. However, if the thickening persists, is unrelated to the menstrual cycle, or worsens over time—particularly in postmenopausal women—it must be taken seriously.
- (3) **Persistent nipple erosion unresponsive to local treatment** should raise suspicion of Paget’s disease. Cytological smears have a high positive rate, and timely diagnosis is crucial.
- (4) **Breast pain** in premenopausal women, especially if it fluctuates with the menstrual cycle, is often physiological. However, if the pain is localized, fixed, unrelated to the menstrual cycle, or occurs in postmenopausal women, the cause must be investigated.
- (5) **Unexplained areolar edema, nipple retraction, or localized skin dimpling** should be thoroughly evaluated.
In conclusion, early detection and treatment are undoubtedly the future direction of breast carcinoma prevention and control. What is urgently needed now is widespread education on early detection, large-scale breast cancer screening programs, and encouraging women to perform self-examinations, all aimed at improving survival rates and reducing mortality.
bubble_chart Metastasis and Spread
Similar to a few types of tumors, such as stony goiter (thyroid carcinoma), the natural course of breast cancer is usually very long. The doubling time of breast cancer cells averages 90 days. Starting from the first malignant transformation of a cell, it takes more than 30 doublings for the tumor to reach a spherical diameter of 1 cm, which requires 7 to 8 years. The disease cause of breast cancer is not yet fully understood, and the best way to reduce mortality is early detection and early treatment. Before metastasis occurs, the vast majority of cases can be cured with surgery and radiotherapy alone. Once metastasis occurs, aggressive treatment can only cure a small portion of patients. Therefore, understanding the natural progression of breast cancer helps in selecting the best treatment plan.
The spread of breast cancer can occur directly to surrounding tissues or through lymphatic and blood vessels. Lymph nodes should theoretically act as the first barrier preventing cancer cells from escaping the primary tumor. If cancer cells bypass the lymph node barrier, they usually invade the supraclavicular lymph nodes and then enter the veins to spread through the bloodstream. In addition to metastasizing to axillary lymph nodes, breast cancer can also involve the parasternal lymph nodes, particularly those in the second, third, and fourth intercostal spaces. This is more common when the tumor is located in the inner half of the breast or the areolar region, from where the cancer can further invade the mediastinal lymph nodes. Breast cancer cells can also directly invade blood vessels, leading to distant metastasis. The intercostal branches can enter the internal thoracic vein and then the ipsilateral innominate vein, eventually reaching the pulmonary circulation. The deep tissues of the breast, pectoral muscles, and chest wall veins drain into the axillary vein, which connects to the subclavian vein and innominate vein, serving as an important pathway for lung metastasis. The intercostal veins flow into the azygos and hemiazygos veins, ultimately entering the lungs via the superior vena cava. The azygos system connects with the vertebral veins, the external vertebral venous plexus, and the internal vertebral venous plexus. The vertebral venous system and the caval venous system can exchange blood flow when intra-abdominal pressure changes. Therefore, some patients may develop metastases in the skull, spine, or pelvis before metastases appear in the caval venous system (e.g., the lungs).
For a long time, it has been observed that breast cancer may already have distant metastases at the time of diagnosis, even if they are clinically undetectable. This forms the theoretical basis for conservative chemotherapy. Today, the risk of distant micrometastases can be preliminarily estimated based on tumor size, the number of affected lymph nodes, and various other biological characteristics.
