About Breast Cancer

Breast cancer is a disease that occurs due to the uncontrolled proliferation of cells, disrupting the organ’s structure and function. Fifty years ago, one in every 13 women would be diagnosed with breast cancer. Today, this rate has dropped to one in every eight women.

Breast cancer can also occur in men, but it is rare. As with all cancers, early detection is crucial in breast cancer. In advanced cases, the cancer first spreads to the lymph nodes and then to other organs.

Breast cancer is a life-threatening disease for women and is one of the leading causes of death. Increasing public awareness and interest in breast cancer, as well as advancements in imaging methods, have had a positive impact on the recognition and screening of breast cancer.

Breast cancer treatment includes surgery, radiotherapy (RT), and chemotherapy (CT) for localized disease, or a combination of these. It also involves systemic treatments such as endocrine therapy, biological therapy, or their combinations. Primary conventional surgery is no longer the most suitable treatment for some patients. The need for various local or systemic treatments and their selection depends on various prognostic and predictive factors.

What are Breast Cancer Factors?

These factors include tumor histology, clinical and pathological features of the tumor, involvement of axillary lymph nodes, hormone receptors, human epidermal growth factor receptor 2 (HER2) status, multi-gene testing, presence or absence of detectable metastatic disease, patient comorbidities, age and menopausal status (1). Neoadjuvant therapy has become a widely used option in triple negative (TN) and HER2 positive early stage breast cancer (2). Depending on the molecular subtype of breast cancer, therapeutic treatments include endocrine therapy, anti-HER2 targeted therapy and CT. The goals of treatment in metastatic breast cancer are to prolong survival and maintain quality of life (3). In this review, anatomy of the breast, epidemiology of breast cancer, histopathologic subtypes of breast cancer, diagnostic methods, stages of breast cancer, treatment methods and follow-up are discussed.

What is the Incidence of Breast Cancer?

Breast cancer is the most common cancer in women worldwide and the second most common cancer overall. According to the Global Cancer Observatory (GLOBOCAN) 2020 data, 19,292,789 people were newly diagnosed with cancer and 2,261,419 of these were new breast cancer diagnoses (4). The number of newly diagnosed breast cancers in Turkey in 2020 was calculated as 24,175 (5). It is the second leading cause of cancer-related deaths after lung cancer. The probability of a woman dying from breast cancer is approximately 2.6%. Since 2007, breast cancer mortality rates have been stable in women under 50 years of age, while continuing to decline in older women. From 2013 to 2017, the death rate decreased by 1.3% per year (6). This decrease is believed to be a result of early screening programs, increased awareness and finding better treatments for breast cancer.

What is the Anatomy of the Breast and Axilla?

The breast parenchyma extends from the 2nd or 3rd ribs downward to approximately the 6th or 7th ribs in the vertical plane and from the sternum medially to the mid-axillary line laterally in the transverse plane. The adult female breast is located between the superficial and deep layers of the superficial fascia of the anterior chest wall. The gland of the breast contains 12-20 lobes that divide into smaller lobules. Each lobe consists of 20-40 terminal ductal lobular units (TDLU). These lobes and lobules are connected by milk ducts through which secretory products reach the nipple. The lactiferous duct is formed by the union of the terminal ducts of several lobules. Under the nipple, lactiferous ducts expand as lactiferous sinuses and open to this region (7). Montgomery, sweat and sebaceous glands are found around the areola in the nipple (8). In some parts of the breast, connective tissue condenses and forms ligaments supporting the breast tissue and extends from the dermis of the skin on the surface to the deep fascia. These suspensory ligaments called Cooper ligament support the breast on the chest wall (9).

What is the Structure of the Breast and Axilla?

The arterial blood supply of the breast is rich and is provided by three main arteries: perforating branches of the internal thoracic artery, lateral branches of the posterior intercostal artery and branches of the axillary artery. The branches of the axillary artery supply the lateral part of the breast. These are the superior thoracic, thoracoacromial, lateral thoracic and subscapular arteries. The branches of the internal thoracic artery provide blood supply to the medial part of the breast. The perforating branches of the 2nd-4th intercostal arteries contribute to the nutrition of the entire breast. The venous blood supply of the breast follows the mentioned arteries. They open to the axillary, internal thoracic and 2nd-4th intercostal veins (10). Lymphatics from the nipple and areola areas drain into the subareolar plexus (Sappey plexus). Approximately 75% of the lymphatics from here drain to the pectoral lymph nodes and then to the axillary lymph nodes. The remaining lymphatic drainage is to the parasternal lymph nodes (11).

Location of the Axillary Lymph Node in the Body

The axillary space resembles a pyramid and knowing its boundaries guides the surgeon, especially during axillary dissection. The upper border is the axillary vein; the lower border is the intersection of the serratus anterior and latissimus dorsi muscle. The lateral border is the latissimus dorsi muscle; the medial border is the thoracic wall. The pectoralis major and pectoralis minor muscles form the anterior border; the subscapular muscle forms the posterior border.

Axillary lymph nodes are examined in three levels according to their location in relation to the pectoralis minor muscle. In general, the first and second level lymph nodes are removed during classical axillary dissection. Level 1 lymph nodes (axillary vein group, external mammarian group, subscapular group) are lateral to the pectoralis minor muscle, level 2 lymph nodes (central group, interpectoral group) are behind the pectoralis minor muscle and level 3 lymph nodes (subclavicular group) are medial to the pectoralis minor muscle.

Axilla Injury

There are several nerves in the axilla that require great care to avoid injury. The thoracodorsal nerve and the thoracicus longus nerve are two important branches of the brachial plexus in the axilla. The thoracicus longus nerve innervates the serratus anterior muscle; if injured, it results in a wing scapula (scapula alata) and patients may complain of upper limb weakness or decreased shoulder range of motion. The thoracodorsal nerve innervates the latissimus dorsi muscle and if injured, the latissimus dorsi muscle atrophies and the patient may lose the chance of autologous reconstruction with the latissimus dorsi muscle. The most commonly injured nerve is the intercostobrachial nerve and it causes paresthesia in the medial upper arm (12).

Histopathology Subsamples

Breast cancer is divided into non-invasive or invasive breast cancer according to whether the tumor is confined to the epithelial component of the breast or invades the stroma (Table 1). Both tumor types, both ductal and lobular, originate from TDLU. Those that have not invaded the basement membrane in the lobule and duct from which they originate are called in situ; those that invade the basement membrane and spread to the stroma and adjacent tissues are called invasive breast cancer (13).

What is Non-invasive Breast Cancer?

Ductal carcinoma in situ (DCIS): A neoplastic proliferation of epithelial cells confined to ducts or lobules, characterized by the presence of cellular and nuclear atypia, potential malignancy and subsequent tendency to develop invasive breast cancer. The myoepithelial cells of the outer layer of the ductus are usually preserved but may be reduced in number. It is multicentric in approximately 40-80% of cases and bilateral in approximately 10-20%. The spread of DCIS from the ductus to the lobular acini is called lobular carcinogenesis. With the widespread use of screening mammography and increased awareness of breast cancer in the general population, there has been a significant increase in the detection of these lesions. Mortality due to DCIS is extremely rare, but mortality can occur after the initial diagnosis of DCIS, either because of an undetected invasive component or because of recurrence of the invasive lesion after treatment (14).

What are the Histologic Subsamples of DCIS?

There are 5 histologic subtypes of DCIS: Papillary, micropapillary, cribriform, solid and comedo. Generally, DCIS is divided into 3 types: low, intermediate and high grade, according to the degree of nuclear atypia, intraluminal necrosis and, to a lesser extent, mitotic activity and calcification. Solid and comedo types tend to be higher grade. The risk of developing invasive carcinoma is directly proportional to the grade of DCIS.

 

 

What is Lobular Carcinoma In Situ (LCIS)?

Lobular carcinoma in situ (LCIS) is the proliferation of cells in the milk glands without protrusion. It is an intralobular proliferation of small, highly uniform and cohesive cells arising from the TDLU, with or without pagetoid involvement of the terminal ducts. Long-term follow-up results in women with LCIS have shown that it is a risk factor and may be a precursor to the subsequent development of invasive carcinoma. Both ductal and lobular breast carcinomas can arise from LCIS. They are indistinguishable on general examination and are usually detected incidentally in breast specimens or biopsies performed for other reasons. It is multicentric in about 60-80% of cases and bilateral in about 20-60%. Atypical changes such as pleomorphism, mitosis and necrosis are absent or rarely present. Intracellular mucin droplets are usually seen (15).

LKIS Distinctiveness

There are two immunohistochemical markers that distinguish LKIS: lack of E-cadherin and β-catenin expression and positivity for high molecular weight (HMW) keratin. The loss of E-cadherin in LKIS is due to gene mutations. In contrast, DCIS are consistently positive for E-cadherin and β-catenin and show typical peripheral CK8-18 expression and decreased expression or negativity for HMW keratin, which is normally expressed in the ductal basal cell layer.

Invasive Breast Cancer

Invasive ductal carcinoma

Invasive ductal carcinoma is the most commonly diagnosed breast cancer and tends to metastasize through the lymphatics. It accounts for 75% of breast cancers. The Nottingham Histologic Scoring system is used to grade invasive ductal carcinoma (Table 2). The total score is between 3-9. 3-5 points are graded as grade 1; 6-7 points as grade 2; 8-9 points as grade 3 (16).

 

 

Invasive lobular carcinoma

It accounts for 5% to 15% of invasive breast carcinoma. Tumor cells typically have a growth pattern characterized by round, small, noncohesive and relatively uniform neoplastic cells infiltrating the stroma singly or in a single line. It affects older women than invasive ductal carcinoma and its increased incidence, especially in postmenopausal women, suggests a possible association with hormone replacement therapy. There are classical, solid, alveolar, pleomorphic and mixed types. E-cadherin inactivation by mutation, loss of heterozygosity or methylation are characteristic molecular changes, especially in the pleomorphic invasive lobular carcinoma subtype (17).

Breast Cancer Diagnosis

The need for early detection of breast cancer has led to the emergence of various screening methods aimed at reducing morbidity and mortality associated with the disease. Breast self-examination is an intuitive, inexpensive, non-invasive and universally accessible method of identifying masses in the breast. The only equipment required to complete a comprehensive breast self-examination is a wall-mounted mirror to perform the visual examination. During the tactile part of the procedure, the examination can be performed supine and a pillow can be used to support the back or shoulder. No medical staff or assistance is required. Because of the expected changes in breast anatomy given the relationship of the examination to the menstrual cycle, screening should be performed monthly, ideally at the end of the patient's menstrual period. If the patient is amenorrheic, the examination should continue on the same selected day each month (18).

How is Mammography Performed?

Mammography is the best population-based method for screening, with a low x-ray dose for detailed visualization of the breast. Mammography can be done in two ways: screening and diagnostic. Those with a family or personal history of breast cancer may need additional examinations to the diagnostic/screening mammogram. In young women, mammography is not sensitive due to dense breast structure and is evaluated with breast ultrasonography. Ultrasonography is useful in assessing the consistency and size of breast masses. It also plays a major role in guided needle biopsy. The Breast Imaging Reporting and Data System (BI-RADS) includes levels of classification among radiologists to interpret breast lesions in a standardized format and guide the diagnosis of breast cancer. However, abnormalities requiring biopsy are usually detected in 1-2% of screening mammograms, the majority of which (80%) are benign lesions (19).

How is Cancer Staged?

The American Joint Committee on Cancer Staging System (AJCC) has evolved in response to improved imaging and surgical techniques, enhanced pathological assessment and a better understanding of tumor biology. In the 8th edition of the AJCC, patients are clinically classified using traditional Tumor - Node - Metastasis (TNM) anatomical information modified by estrogen receptor (ER), progesterone receptor (PR), HER2 and Ki67 biomarker expression, and a clinical prognostic stage group is created (22).

T (Primary Tumor):

Tis: Carcinoma in situ, Paget's disease without tumor T1: ≤ 2 cm, T1a: 0.1-0.5 cm, T1b: 0.5-1 cm, T1c: 1-2 cm T2: >2cm, ≤5 cm T3: >5 cm T4: T4a- Chest wall invasion, T4b- Skin involvement, T4c- T4a+T4b, T4dInflammatory breast cancer

N (Regional Lymph Nodes):

N1: Mobile ipsilateral axillary lymph nodes N2: Fixed or conglomerated ipsilateral axillary lymph nodes N3: Involvement of N3a- ipsilateral infraclavicular lymph nodes, N3b- ipsilateral internal mammarian lymph nodes N3c- ipsilateral supraclavicular lymph nodes M (Distant Metastasis): M1: Distant metastasis
 

 

 

How is Breast Cancer Treatment?

Multidisciplinary treatments for patients with operable breast cancer combine local, i.e. surgical and radiation therapies, with systemic therapies including a wide range of drugs. Systemic therapy is crucial to improve disease-free survival, especially based on the control of micrometastases that have the potential to spread throughout the body. Predicting response to treatment and determining the sensitivity of tumors to drugs is essential to select the optimal treatment regimen. Systemic therapy is decided according to a shared decision-making process between patients and researchers based on benefits and risks such as adverse events.

How to Schedule Breast Cancer Treatment?

The timing of systemic treatments for operable breast cancer includes postoperative adjuvant therapy and preoperative neoadjuvant therapy. According to previous studies, if similar drugs and regimens are used, the effectiveness of these treatments in improving disease-free survival is essentially the same. Drugs administered as systemic therapy are classified as hormone therapy, chemotherapy (CT), and molecularly targeted therapy. These drugs can be given alone as a single agent or used in multi-drug regimens.

Breast cancer is divided into subtypes according to the expression of biological markers. These markers are mainly ER, PR, HER2, and Ki67. They are classified as Luminal A (ER-positive and Ki67 <20%), HER2-expressing (HER2-positive), and triple-negative (ER, PR, HER2-negative). This subtype classification is very useful for selecting the most appropriate systemic therapy. Endocrine therapies are effective in ER-positive breast cancers, and anti-HER2 therapies are effective in HER2-positive breast cancers (23).

How Is Treatment Based on Breast Cancer Risk Factors?

For LCIS, surgery is preferred in the presence of familial risk factors or high risk, while chemoprevention is preferred for other patients. In chemoprevention, tamoxifen, raloxifene, or aromatase inhibitors can be used. For the pleomorphic subtype of LCIS, DCIS treatment options should be applied. Today, in DCIS treatment, radiotherapy (RT) after breast-conserving surgery is accepted as a standard approach. A surgical margin greater than 2 mm is considered safe in DCIS cases undergoing breast-conserving surgery (24). In DCIS treatment, mastectomy is the preferred treatment method in the presence of widespread microcalcifications, continued positivity of surgical margins in resections, multicentric tumors, patients with a history of RT, and the presence of collagen tissue disease.

What Is Preventive Treatment in Breast Cancer?

In operable breast cancer of clinical stages 1, 2A, 2B, and 3A, where breast-conserving surgery is planned, and there is macrometastasis in 1-2 sentinel lymph nodes, axillary dissection may not be performed if RT is to be applied. Absolute contraindications for breast-conserving surgery are widespread suspicious microcalcifications, extensive disease, and persistent positivity of surgical margins. Relative contraindications include tumor size > 5 cm, previous RT, active connective tissue disease, focal surgical margin positivity, and a predisposition to breast cancer (25). In patients undergoing mastectomy, if macrometastasis is present in 1-2 sentinel lymph nodes and RT is not planned, full axillary dissection should be performed. In cases where RT is planned, there is no consensus on omitting axillary dissection. Particularly in triple-negative breast cancer, axillary dissection is recommended in cases of sentinel lymph node positivity.

How Is Treatment Determined by Axillary Lymph Nodes in Breast Cancer?

Neoadjuvant CT is recommended for patients with T1-T3 tumors with positive axillary lymph nodes and T2-T3 tumors with negative axillary lymph nodes that are triple-negative or HER2-positive. In other cases, node positivity alone is not sufficient to make a neoadjuvant therapy decision. Chemotherapy may be prioritized in Luminal B tumors. Neoadjuvant hormonotherapy may be considered in patients who are strongly hormone receptor-positive, older in age, have low performance status, and have additional comorbidities to avoid mastectomy.

Breast Cancer Risk Factors

Breast cancer risk can be linked to a person's genetic makeup. However, there is no definitive cause of breast cancer. Factors that increase the risk of breast cancer include:

• Advanced age,
• Having a family history of breast cancer,
• Genetic BRCA1 and BRCA2 mutations,
• Finding precursor cancer cells in a breast biopsy,
• Starting menstruation early (before age 12-14),
• Starting menopause late (after age 55),
• Not having children,
• Having the first child at an older age,
• Not breastfeeding,
• Low physical activity,
• Obesity and hormone replacement therapy

What Are the Types of Breast Cancer?

Breast cancer types are basically divided into two. These are classified as non-invasive (non-spreading) and invasive (spreading) cancers. Invasive cancer types are as follows:

• Invasive ductal carcinoma: The most common type of breast cancer, accounting for 80%. It starts in the cells lining the milk ducts and then spreads to surrounding areas.
• Invasive lobular carcinoma: Starts in the cells lining the lobules of the breast and then spreads to surrounding breast tissue.

How Are Breast Cancer Stages Determined?

Breast cancer stages are used to determine an appropriate treatment plan for the patient and to predict the course of the disease. Staging is categorized as clinical and pathological. For staging, the patient’s imaging and physical examination findings are identified. Pathological staging is performed by examining the tumor and lymph nodes after surgery. Tumor size and lymph node metastasis are crucial in the progression of the disease.

What Are the Stages of Breast Cancer?

Breast cancer stages are divided into four:

• Stage 0: There are precursor cells of breast cancer. The risk of developing breast cancer is significantly increased.
• Stage 1A: The tumor is smaller than 2 cm and has not spread to the axillary lymph nodes.
• 1B: The tumor is smaller than 2 cm, with micrometastases in the axillary lymph nodes.
• Stage 2A: There is no tumor in the breast, but it has spread to the axillary lymph nodes. Alternatively, the tumor in the breast is smaller than 2 cm and has spread to the axillary lymph nodes, or the tumor in the breast is larger than 2 cm but smaller than 5 cm and has not spread to the axillary lymph nodes.
• 2B: The tumor in the breast is larger than 2 cm but smaller than 5 cm and has spread to the axillary lymph nodes, or the tumor in the breast is larger than 5 cm but has not spread to the axillary lymph nodes.

What Happens After Stage 3 Breast Cancer?

After stage 3 breast cancer, the disease begins to spread more extensively. The stages develop as follows:

• Stage 3A: The tumor in the breast is interconnected. It may have spread to axillary lymph nodes or lymph nodes in front of the chest wall. However, there is no tumor in the breast, or the tumor can be of any size in the breast but has not spread to the breast skin or chest wall.
• 3B: The tumor in the breast has not spread to the chest wall or breast skin. It can be of any size. Additionally, the tumor may have spread to interconnected axillary lymph nodes or lymph nodes in front of the chest wall.
• 3C: There may not be a tumor in the breast. If a tumor is present, it can be of any size. The tumor may have spread to the chest wall and breast skin. Additionally, it may have spread to axillary lymph nodes and lymph nodes below or above the collarbone or lymph nodes in front of the chest wall.
• Stage 4: Cancer cells have spread to other organs in the body such as the bones, brain, lungs, and liver.