Breast cancer treatment

Cell type

From a histopathological perspective, 15-30% of breast cancers are carcinoma in situ (CIS), while the other 70-85% are invasive carcinoma. Of those breast cancers that are classified as invasive, about 80% are ductal, 10% are lobular, 6% are cribriform, 2% are mucinous, 2% are medullary, 1% are papillary, and <1% are metaplastic.^[1]

Cell grade

In most cases, breast cancers are graded by adding up scores for tubule formation, nuclear pleomorphism, and mitotic count, each of which is given 1 to 3 points. The scores for each of these three criteria are then added together to give an overall score and a corresponding grade as follows:^{[citation needed]}

• 3-5 Grade 1 tumor (well-differentiated).
• 6-7 Grade 2 tumor (moderately differentiated).
• 8-9 Grade 3 tumor (poorly differentiated).

Hormone receptor and HER2 status

For the purpose of predicting the response to treatment, breast cancer can be classified into four major subtypes, based on the presence or absence of certain receptors on the cells of the tumor. In order of prevalence, these are:^[2]

• HR+/HER2-: 70%
• HR-/HER2-: 11%
• HR+/HER2+: 9%
• HR-/HER2+: 4%
• Unknown subtype: 6%

HR refers to hormone receptor (estrogen or progesterone), and +/- indicates its presence or absence. HER2 +/- refers to presence or absence of the HER2 receptor.

HR+/HER2- (also known as luminal A breast cancer) is a slow-growing subtype, while HR+/HER2+ (also known as luminal B breast cancer) is a faster-growing subtype. HR-/HER2- (also known as triple-negative breast cancer) is negative for all three major receptor types.^[3] People with the HR+/HER2- subtype exhibit the highest five-year survival, followed by the HR+/HER2+ subtype and the HR-/HER2+ subtype. The HR-/HER2- subtype has the lowest five-year survival.^[2]

Proliferative index

Determining the proliferative index of cancer cells is an important step in establishing the diagnosis and predicting the prognosis of breast cancers, as well as for the selection of treatment protocols.

One commonly employed method for determining the proliferative index is the mitotic index, which is defined as the percentage of cells undergoing mitosis within a given population of cells.

Measurement of the S-phase fraction (SPF) by flow cytometry is another method of evaluating cell proliferation. An assessment of how many cells are actively synthesizing DNA, the SPF is an important predictor of relapse-free survival in people with breast cancer.

Resection

Surgery is the primary management for breast cancer. A needle-localized biopsy of the tumor is often performed before surgery. Depending on the classification and staging of the tumor, surgery may consist of a radical mastectomy, a modified radical mastectomy, or a lumpectomy (removal of the lump only). If the tissue removed in the operation has resection margins free of cancer, this is an indication that the cancer has been completely excised. If this is not the case, then additional surgery may be necessary.

Mastectomy may be the preferred treatment in certain instances. For example:^[6]

• two or more tumors exist in the breast (a multifocal cancer);
• inflammatory breast cancer;
• previous history of radiation therapy to the chest;
• the tumor is large relative to the size of the breast;
• people who have undergone previous breast-conserving surgery that did not remove all the cancer cells;
• people at high risk of a second breast cancer because of a genetic mutation or strong family history;
• people who are unable or unwilling to undergo radiation therapy.

Removal of axillary lymph nodes is often included as part of breast tumor removal. Treatment with a full axillary lymph node dissection carries an increased risk of lymphedema, pain, reduced arm movement and numbness, while having no axillary lymph nodes removed carries an increased risk of recurrence of cancer. Treatment with less invasive axillary surgery (such as axillary sampling or sentinel lymph node biopsy) appears to be equally efficacious when compared with axillary lymph node dissection.^[7]

Breast reconstruction

Cosmetic deformity causes distress and contributes to postoperative depression in many people after resection of breast cancer. To help alleviate these problems, breast reconstruction surgery with autologous tissue or prosthetic breast implants is often included in holistic approaches to cancer management.^[8] Reconstruction can take place at the same time as cancer-removing surgery, or months to years later. Some women decide not to have reconstruction or opt for a prosthesis instead.

Prophylactic surgery

Some people who have a high risk of developing breast cancer may choose to have risk-reducing surgery before a cancer appears. This may include bilateral mastectomy, removal of the ovaries, or both. Examples of such people include:^[9]

• people who test positive for BRCA1 or BRCA2 mutations;
• people who have pleomorphic lobular carcinoma in situ (PLCIS) plus a strong family history of breast cancer;
• people who have had radiation therapy to the chest (including the breasts) before age 30 years.

Types of radiation therapy

Radiation therapy can be delivered by external beam radiotherapy (EBRT) or by brachytherapy (internal radiotherapy).

In people who have undergone mastectomy, radiation is often delivered by EBRT. In EBRT, X-rays are generated and delivered by a machine called a linear particle accelerator. EBRT treatments for breast cancer are typically given five days a week for five to 10 weeks.

For people with early-stage breast cancer, radiation may be administered to only the breast, and in some cases they may be eligible for brachytherapy. Brachytherapy involves the precise placement of radiation source(s) inside the breast. These approaches may spare healthy tissue from unnecessary radiation.

A newer approach, called accelerated partial breast irradiation (APBI), involves the delivery of radiation to a smaller volume of breast tissue over a shorter period of time. ABPI appears to have fewer side effects, while achieving equivalent treatment results.^[10] APBI reduces the length of treatment to just five days, compared to the typical six or seven weeks for whole breast irradiation. APBI treatments can be given as brachytherapy or EBRT with a linear particle accelerator. These treatments are usually limited to people with well-defined tumors that have not spread.

Chemotherapy

Chemotherapy is a useful modality in the treatment of breast cancer. It usually consists of the administration of some combination of antineoplastic agents according to a specific regimen. The antineoplastic agents destroy or disrupt the growth of cancer cells in order to reduce the risk that breast cancer will recur. Determining the appropriate chemotherapy regimen to use depends on factors such as the stage and classification of the tumor, and the age and health of the patient.^[11]

Hormonal therapy

Patients with estrogen or progesterone receptor-positive tumors are candidates for receiving hormonal therapy to slow the progression of tumors or to reduce the likelihood of recurrence. Hormonal treatments include administration of inhibitors of hormone synthesis (such as aromatase inhibitors and GnRH modulators), hormone receptor antagonists (such as SERMs, SERDs, and antiandrogens), and hormone supplementation.^[12]

Targeted therapy

In patients whose cancer expresses an over-abundance of the HER2 protein, certain monoclonal antibodies may be used to block the activity of the HER2 protein in breast cancer cells. For example, trastuzumab can impair the growth of cancer cells, as well as improve survival in people with breast cancer.^[13] Pertuzumab may work synergistically with trastuzumab on the expanded ErbB family of receptors.^{[citation needed]} Neratinib may be useful in the adjuvant treatment of early stage HER2-positive breast cancer.^[14] PARP inhibitors may be useful in the metastatic setting, and are being investigated for use in the non-metastatic setting. Antibody–drug conjugates include trastuzumab emtansine, trastuzumab deruxtecan, and sacituzumab govitecan.

Immunotherapy

Immunotherapy can also be useful in the treatment of breast cancer. This modality harnesses the body's immune system to help fight cancer, or to treat deleterious side effects caused by antineoplastic agents. For example, granulocyte colony-stimulating factor can be administered to treat chemotherapy-induced loss of neutrophils.

Also, certain monoclonal antibodies can be used in combination with chemotherapy for people with metastatic or locally advanced triple-negative breast cancer. Examples include atezolizumab (a PD-L1 inhibitor) and pembrolizumab (a PD-1 inhibitor).

Cryoablation

Cryoablation is a minimally invasive percutaneous procedure that may be available to some people with breast cancer. This modality uses a cryoprobe to induce freeze and thaw cycles to treat small breast cancers or focal sites of metastatic disease in patients not eligible for surgery.^[15]

Focused ultrasound

High-intensity focused ultrasound (HIFU) is used for thermal ablation of solid tumors, while low-intensity focused ultrasound (LIFU) provides sonodynamic therapy (SDT). Ultrasound-assisted drug delivery systems (US-DDS) improve the delivery of chemotherapeutic agents and help to overcome biological barriers such as the blood–brain barrier.^[16]

Medical imaging

Medical imaging is frequently used to aid in diagnostic decisions in both the screening and treatment of breast cancer. Modalities used include mammography, magnetic resonance imaging, nuclear medicine, and medical ultrasound.^[17][18][19] Mammography is a diagnostic screening tool used to detect tumors in the breast.^[20] It can reveal suspicious masses, abnormal calcifications or other anomalies. Other imaging includes digital breast tomosynthesis (DBT) and contrast-enhanced digital mammography.^[17] Magnetic resonance imaging is a supplemental tool to mammography and ultrasound within the initial screening stages but is typically used in the management of patients with a formal diagnosis of breast cancer, to stage the disease before treatment and to assess the response to treatment.^[21] Medical ultrasound is commonly used for evaluating breast lesions, as well as for guiding biopsy needles to particular regions of interest in the breast. It can also be used to help differentiate cysts from solid tumors based on the size, echogenicity, and vascularity of the mass.^[18]