Breast Cancer

Disease/Disorder

Definition

Breast cancer is an abnormal growth or proliferation of cells within the breast tissue. It usually involves the ducts (tubes that carry milk to the nipple, ductal cancers) and lobules (glands that make milk, lobular cancers).¹ It occurs in both men and women but is rare in men.²

Etiology

Cancer arises from a complex series of steps involving mutated genes that enhance the ability of the cells to grow. This in turn leads to the development of a tumor. The majority of cancers arise as the result of acquired gene mutations, while a small percentage occur from inherited mutations. The cancer can then spread via lymphatic vessels and lymph nodes from the breast tissue to other parts of the body.¹

Epidemiology including risk factors and primary prevention

The American Cancer Society (ACS) projects 310,720 new cases of breast cancer in women for 2024 with 42,250 women dying from their disease.² While the incidence rate has increased by 0.6% per year, the death rate has decreased by 1% per year. The median age at diagnosis is 62 years.³ Males account for less than one percent of breast cancer cases.⁴ Breast cancer has traditionally been less common in non-industrialized nations and associated with higher mortality rates in these areas. Industrialization in developing countries is associated with rapid increases in breast cancer risk, likely related to increased detection due to improved breast cancer screening.⁵

Risk factors: age, family history of breast cancer, mutations in breast cancer susceptibility genes BRCA1 and BRCA2, increased exposure to endogenous estrogens (early menarche, late menopause, delayed childbearing, lower parity), a diet high in animal fat, alcohol use, smoking obesity, physical inactivity, high breast density, and exposure to ionizing radiation.^2,6

Screening with mammography may decrease breast cancer mortality.⁷  The literature demonstrates that routine self-breast exams or routine physician-performed breast exams for patients who are already receiving recommended screening mammography or other imaging does not improve early detection of cancers.⁸ This does not negate the importance of monitoring one’s breast for changes and reporting unexplained changes to one’s physician. For patients with high breast cancer risk, breast MRI can improve detection by supplementing mammography.⁹

Patho-anatomy/physiology

The main stages in progression of breast cancer from normal cells are usually¹

• Hyperplasia: increased cell growth;
• Atypical hyperplasia: alteration of cell adhesion and polarity;
• Carcinoma in situ: appearance of increased histologic and biologic diversity in cells;
• Carcinoma: invasion into surrounding stroma.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Cancer staging by the American Joint Committee on Cancer TNM system is based on these five factors: location, size (extent of the tumor), number, lymph node involvement (the spread to nearby sites), and metastasis (spread to distant sites).¹⁰

Primary tumor (T) categories

TX: Primary tumor cannot be assessed.
T0: No evidence of primary tumor.
Tis: Carcinoma in situ (DCIS, LCIS, or Paget disease of the nipple with no associated tumor mass)
T1: (includes T1a, T1b, and T1c): Tumor is 2 cm (3/4 of an inch) or less across.
T2: Tumor is more than 2 cm but not more than 5 cm (2 inches) across.
T3: Tumor is more than 5 cm across.
T4: (includes T4a, T4b, T4c, and T4d): Tumor of any size growing into the chest wall or skin. This includes inflammatory breast cancer.

Nearby lymph nodes

NX: Nearby lymph nodes cannot be assessed (for example, if they were removed previously).
N0: Cancer has not spread to nearby lymph nodes.

• N0(i+): Tiny amounts of cancer are found in underarm lymph nodes by using either routine or special stains. The area of cancer spread contains less than 200 cells and is smaller than 0.2 mm.
• N0(mol+): Cancer cells cannot be seen in underarm lymph nodes (even using special stains), but traces of cancer cells were detected using RT-PCR.

N1: Cancer has spread to 1 to 3 axillary (underarm) lymph node(s), and/or tiny amounts of cancer are found in internal mammary lymph nodes (those near the breastbone) on sentinel lymph node biopsy.

• N1mi: Micrometastases (tiny areas of cancer spread) in lymph nodes under the arm. The areas of cancer spread in the lymph nodes are at least 0.2 mm across but not larger than 2mm.
• N1a: Cancer has spread to 1 to 3 lymph nodes under the arm with at least one area of cancer spread greater than 2 mm across.
• N1b: Cancer has spread to ipsilateral internal mammary lymph nodes, but this spread could only be found on sentinel lymph node biopsy (it did not cause the lymph nodes to become enlarged).
• N1c: Both N1a and N1b apply.

N2: Cancer has spread to 4 to 9 lymph nodes under the arm, or cancer has enlarged the internal mammary lymph nodes (either N2a or N2b, but not both).

• N2a: Cancer has spread to 4 to 9 lymph nodes under the arm, with at least one area of cancer spread larger than 2 mm.
• N2b: Cancer has spread to one or more internal mammary lymph nodes, causing them to become enlarged.

N3: Any of the following

• N3a: either
  • Cancer has spread to 10 or more axillary lymph nodes, with at least one area of cancer spread greater than 2 mm, OR
  • Cancer has spread to the lymph nodes under the clavicle (collar bone), with at least one area of cancer spread greater than 2 mm.
• N3b: either
  • Cancer is found in at least one axillary lymph node (with at least one area of cancer spread greater than 2 mm) and has enlarged the internal mammary lymph nodes, OR
  • Cancer has spread to 4 or more axillary lymph nodes (with at least one area of cancer spread greater than 2 mm), and tiny amounts of cancer are found in internal mammary lymph nodes on sentinel lymph node biopsy.

N3c: Cancer has spread to the lymph nodes above the clavicle with at least one area of cancer spread greater than 2mm.

Metastasis

M0: No distant spread is found on x-rays (or other imaging procedures) or by physical exam.

• cM0(i+): Small numbers of cancer cells are found in blood or bone marrow (found only by special tests), or tiny areas of cancer spread (no larger than 0.2 mm) are found in lymph nodes away from the breast.

M1: Cancer has spread to distant organs.¹⁰

Breast cancer stage grouping (0-IV) is then determined from this information with stage 0 being ductal carcinoma in situ, and stage IV being spread to distant organs or lymph nodes far from the breast. The most common sites of metastasis are the bone, brain, liver, and lung.¹¹

Specific secondary or associated conditions and complications

Currently, there are more than 4.0 million breast cancer survivors in the United States.² Many disorders of the upper limb are associated with ipsilateral breast cancer treatment. Cancer survivors are more likely to take sick leave and less likely to be employed than those without a cancer history.¹² Some of the conditions amenable to rehabilitation listed below are thought to be barriers to return to work^.13 Although the specific incidence of these conditions is not known, rotator cuff disorders are the most common cause of shoulder pain in the general population. So, it is not surprising that this problem complicates rehabilitation in breast cancer survivors.¹⁴ Of note, multiple conditions listed below can coexist in the same patient.

Conditions requiring rehabilitation in the survivorship period include¹⁰

Musculoskeletal disorders

• Postsurgical pain
• Rotator cuff disease
• Adhesive capsulitis (frozen shoulder)
• Arthritis due to osteoarthritis or other degenerative joint disease
• Arthralgias (generalized or focal, associated with aromatase inhibitors, estrogen receptor modulators, and other hormonal treatments)¹⁵

Neuromuscular disorders

• Cervical radiculopathy
• Brachial plexopathy
• Polyneuropathy (due to chemotherapy/immunotherapy or other generalized condition like diabetes or hypothyroidism)
• Mononeuropathy (intercostobrachial neuralgia, carpal tunnel syndrome, or other nerve injury)
• Postmastectomy pain syndrome
• Deconditioning

Lymphovascular/cardiovascular disorders

• Lymphedema (upper extremity, truncal, breast)
• Axillary web syndrome (cording)
• Thromboembolic disease
• Cardiomyopathy (chemotherapy toxicity)
• Deconditioning

Integumentary disorders

• Cellulitis
• Radiation dermatitis
• Radiation fibrosis
• Seroma¹⁶

Metabolic disorders

• Fatigue¹⁷
• Osteopenia/Osteoporosis
• Thyroid dysfunction
• Adrenal insufficiency

Neuropsychiatric disorders

• Cognitive dysfunction (“chemobrain”)¹⁸
• Depression
• Anxiety

Essentials of Assessment

History

Age, menopausal status, family history of breast cancer, BRCA status (if known), associated pain, weakness, numbness, tingling, bladder and bowel dysfunction, cognitive changes, mood/adjustment, sleep, history of prior cancers, cancer of the contralateral breast, treatment history, current activity level, assistance required at home.

Physical examination

• Manual examination of symptomatic and contralateral breast.
• Evaluation of lymph nodes of the neck, torso, axilla and upper extremity.
• Baseline arm circumference measurements.
• Neuromuscular examination (for pre-existing neuropathy, strength impairment, evidence of spinal metastasis).
• Inspection, palpation, and range of motion of joints (for pre-existing arthralgias and shoulder function).

Functional assessment

Ability to do overhead activities, complete activities of daily living, transfers, and gait analysis. Cognitive evaluation should be done if the patient has known brain metastases, or if by history there are any concerns raised. Current exercise practices of the individual patient should be reviewed.

Laboratory studies

Special laboratory testing done on the breast tissue removed usually consists of:

• Estrogen receptor (ER) and progesterone receptor (PR) status testing.
• Human epidermal growth factor receptor (HER)2/neu receptor status testing.
• Gene profile testing may be done by microarray assay or reverse transcription-polymerase chain reaction (e.g., MammaPrint, Oncotype DX)¹

Patients on active cancer treatment may also need laboratory monitoring for treatment-related side effects and to assist with medication dosing, including:

• Chemistry panel to assess common electrolytes like sodium and potassium and kidney function
• Liver function panel
• Blood count to assess for anemia (low amounts of red blood cells), thrombocytopenia (low platelet count), and neutropenia (low amount of a white blood cell that protects against some infections)

Imaging

• Screening for breast cancer is done using imaging, usually mammography, for patients who have substantial risk (based on sex, age, and the other factors listed above).
• Screening mammography for average-risk women is recommended by ACS guidelines to be offered starting at 40-45 years old based on a risk/benefit discussion, and recommended annually from ages 45-54, and every other year for ages 55-75.¹⁹
• According to the United States Preventive Services Task Force (USPSTF), screening is recommended every other year from ages 40-74.²⁰
• Ultrasound may be used as an adjunct to mammogram. This is typically recommended in node-negative cancer, for women with dense breast tissue to visualize breast changes that are difficult to see on mammogram, and to guide biopsies. Addition of ultrasound to mammogram increases both detection of cancer and false positive rate.²¹
• MRI (Magnetic Resonance Imaging) is recommended for patients with higher risk of developing breast cancer and to determine the extent of the cancer. Although more expensive than ultrasound, MRI may detect cancers missed by mammogram or ultrasound, but also increase false positive rate. The sensitivity of mammogram, ultrasound, and MRI together is very high.⁹
• PET (Positron Emission Tomography) scans are used to assess if cancer has spread to lymph nodes or other parts of body, and also response to treatment in metastatic disease.
• Scintimammography, positron emission mammography (PEM), electrical impedance imaging (EIT), and elastography are all types of breast imaging being studied for use in women.¹

Supplemental assessment tools

• Breast biopsy (fine-needle, core needle, stereotactic, and excisional).
• DEXA (dual-energy X-ray absorptiometry, now called DXA) scans in post-menopausal women to evaluate bone status, which may be affected by breast cancer treatment.
• Cardiac testing should be performed in patients who may be started on anthracycline (doxorubicin) or trastuzumab, which are chemotherapies associated with cardiac toxicity.
• Serum tumor markers (e.g., CEA, CA15.3, CA27.29, HER-2/neu oncogene product) to help with treatment decisions and response to treatment.¹

Early predictions of outcomes

Predictors of poor prognosis are metastatic disease, axillary node involvement, estrogen receptor (ER)- and progesterone receptor (PR)- negative and HER-2 neu negative (triple negative) tumor histology, lymphovascular invasion, and age of 35 years or less at diagnosis. Concurrent pregnancy or use of assistive reproductive technology is no longer thought to significantly change survival, even in patients with estrogen-receptor positive disease.²²

Surgical treatment

Types of surgery for treatment of breast cancer include breast-conserving surgery and mastectomy. Lumpectomy, partial mastectomy, quadrantectomy, and segmental mastectomy are all types of breast-conserving surgery. A sentinel lymph node biopsy is a sampling of the closest lymph node to the tumor; it is the minimum done to determine if there is node involvement, which affects prognosis as above. An axillary node dissection is a more extensive surgery to remove several lymph nodes for patients with known node involvement.²³

Breast reconstruction can be performed immediately at the time of mastectomy or delayed. Delayed reconstruction is typically recommended for patients that need radiation. Timing also depends on individual patient preference.²⁴ Types of surgery for breast reconstruction after treatment include tissue flaps from native muscle tissue, and silicone or saline implants – with or without nipple-areolar preservation.  Implant reconstruction involves initial placement of tissue expanders, gradual capsule expansion, followed by implant placement. Implants may be placed either subpectoral or prepectoral. The most common types of tissue flaps are transverse rectus abdominis muscle flaps, deep inferior epigastric perforator flaps, and latissimus dorsi flaps.²⁵ Since these move muscle tissue that supports the core (either the abdomen or the upper back), muscle function may be affected. Smoking and elevated BMI are thought to be unfavorable factors in predicting satisfaction with reconstruction. Potential complications include capsular fibrosis and implant loss.²⁴

For those that cannot have or do not choose reconstruction, external breast prostheses are an option. They vary in size, shape, and weight are offered commercially at supply stores. Nipple prostheses are also available. Some breast-conserving and even mastectomy may spare the nipple. Nipple loss can be a difficult adjustment for patients, and a tattoo of a nipple may be an option.

Environmental

Patients should be counseled on weight reduction, engagement in regular/daily exercise, smoking cessation, and abstention from alcohol.

Social role and social support system

Women with breast cancer should be encouraged to continue as much of their previous personal, professional and social life as possible. They should take advantage of support from friends, family, and community sources, such as www.cancer.org, to ease the psychosocial stress associated with breast cancer and improve treatment effectiveness. Patients should be screened for premorbid psychological disorders and coping skills as these factors can play an important role in quality of life, Treatment should be offered for mood and adjustment disorders. Resources should be made available as soon as possible to all patients, especially those at high risk.²⁶

Professional issues

Applicable issues include informed consent, education of family and friends, language barriers, and the patients’ comfort in discussing their diagnosis, prognosis, and treatment. As the number of unique specialists increases, the time and economic burden of frequent medical appointments may be an issue for some patients, particularly those with limited income or transportation difficulty.²⁷ Access to the most up-to-date care is an issue, especially in socioeconomically disadvantaged populations.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Oncologic management strategies available for risk reduction in high-risk women include intensive surveillance and genetic testing, chemoprevention with Selective Estrogen Receptor Modulators (SERMs) vs aromatase inhibitors, and prophylactic surgery. Surveillance, consisting of monthly breast self-examination, annual screening mammography, and clinical breast examinations once or twice yearly, does not clearly result in early detection in high-risk women.¹⁹

Treatment may be a combination of surgery (lumpectomy/mastectomy, sentinel lymph node biopsy, axillary lymph node dissection, reconstruction), chemotherapy, radiation, hormonal therapy (tamoxifen, aromatase inhibitors), and immunotherapy (immune checkpoint inhibitors).^15,16,28,29 Chemotherapy may occur before or after surgery. Radiation typically occurs after resection, but before reconstruction, if possible and desirable as radiation may alter cosmesis.

Rehabilitation management depends on the impairments present (see appropriate modules.). For breast cancer patients, rehabilitation typically focuses on upper limb neuromuscular and lymphovascular disorders. There are over a dozen unique guidelines from professional societies recommending regular exercise for all cancer survivors. ACS recommends at least 75-150 minutes per week of vigorous exercise or 150-300 minutes of moderate exercise for cancer prevention.³⁰ ACS released 2022 guidelines for patients on active cancer treatment that recommended exercise for patients on active treatment with curative intent³¹. Patients receiving palliative treatment may also benefit from activity within the limits of fatigue and safety to avoid medical complications, depending on life expectancy.  

At different disease stages

Rehabilitation should begin early in order to maximize and maintain function and quality of life. Prehabilitation includes pre-operative measures of physical and psychosocial wellbeing and occurs between cancer diagnosis and beginning of acute treatment.³² Physical impairment from breast cancer and its treatments can arise at any stage of the disease.

Prehabilitation exercises can be prescribed at the time of cancer diagnosis to prevent postoperative shoulder dysfunction.³³ Scapular stabilization exercises are particularly helpful in this population and can be performed both before surgery and after drains have been removed.³⁴ During and after chemotherapy or radiation, aerobic exercise can be helpful to combat fatigue, decreased endurance, and depression.³⁰

During survivorship, patients may have more energy to focus on formal rehabilitation. Rehabilitation and pain control also play a significant role in the palliative care patient. Evidence is increasing for the use of exercise to improve bone density not only in patients with local cancer, but also in patients with active disease metastatic to bone.³⁵ Supportive care should be offered for painful conditions to maximize function.

Lymphedema is a common impairment seen in breast cancer patients after treatment and can be managed with manual decompression therapy and compression garments.³⁶ Lymphedema management is covered in another article in PM&R KnowledgeNOW^®, as are impairments from metastatic disease.

Coordination of care

Effective collaboration and communication should take place between oncologists, surgeons, physiatrists, physical therapists, occupational therapists, case managers, psychologists, and social workers. Regular team and family meetings are helpful in coordinating care through improving communication.

Patient & family education

This should focus on:

• Benefits of exercise for fatigue, strength, range of motion, bone health, and cancer risk reduction and information on appropriate exercise regimens.
  • American Cancer Society guidelines for physical activity: 150-300 minutes of moderate activity or 75-150 minutes of vigorous intensity activity in a week³⁰
• Dietary interventions and lifestyle modifications to optimize Body Mass Index
• Education on known possible side effects of specific chemotherapy agents, hormonal therapy, radiation therapy, immunotherapy agents, and surgical resection. This can help with compliance with treatment and management of side effects.
• Education on lymphedema risk and prevention, and the need to carry out lymphedema management at home (e.g., compression sleeves, pneumatic devices).
• Education on fertility options if treatment will affect fertility.

Emerging/unique interventions

Treatment outcomes can be measured as performance-based indicators (range of motion [ROM], 6-minute walk test, sit to stands, grip strength, ECOG performance status, Functional Independence Measure), and patient-reported indicators (e.g., pain, fatigue, depression, quality of life [QOL]).

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

There is considerable high-level evidence that exercise improves multiple spheres of function and quality of life in breast cancer patients, both during treatment with chemotherapy, surgery, and/or radiation, and after.^31,34 Exercise was considered safe and demonstrated improved aerobic fitness, muscular strength, body size and composition, fatigue, anxiety, and quality of life during breast cancer treatment.³¹ After treatment, positive effects of exercise have been demonstrated to safely improve aerobic fitness, muscular strength, body size and composition, flexibility, fatigue, physical function, depression and anxiety, body image, quality of life, pain, range of motion, and other symptoms in a dose-dependent manner.^31,37 Exercise is a safe and effective modality that should be incorporated where possible into the plan of care for breast cancer patients and survivors.

Accurate assessment of pain and functional disorders are key to ensuring safe and effective rehabilitation at all points along the cancer continuum. For example, accurate diagnosis and treatment of rotator cuff tendinopathy is important for maintaining the ability to perform activities of daily living for both the patient who is at end-of-life, and the patient who newly completed primary cancer treatment. Lymphedema should be treated with manual decompression therapy by a certified rehabilitation professional/skilled lymphedema therapist.³⁸ Despite some common misconceptions, aerobic exercise is safe in patients with lymphedema and may reduce lymphedema risk after breast cancer treatment.³⁹ It is worth noting that most peripheral nerve dysfunctions may not necessarily be attributable to lymphedema, even when both are present in a patient.⁴⁰

Cutting Edge/Emerging and Unique Concepts and Practice

• Increasing knowledge in the field of cancer genomics and cell biology will eventually lead to more effective patient-specific and less toxic treatments for breast cancer.
• Immune checkpoint inhibitors including cyclin-dependent kinase (CDK)-4/6 inhibitors are being tested and used as part of breast cancer treatment.⁴¹
• Different sub-types of breast cancer continue to be identified and classified. Each sub-type has a distinct response to chemotherapy. The future will focus on the individualization of treatment for breast cancer based the genetic sub-type present.
• Prehabilitation studies continue to show improvements in body composition, emotional well-being, and quality of life in breast cancer patients.³²
• The use of tart cherry extract to improve myalgias and arthralgias associated with aromatase inhibitor use.⁴²
• Increasing use of axillary lymph node irradiation and partial breast irradiation in lower-risk cases.⁴³
• The use of liposomes as a vehicle to deliver chemotherapeutic agents directly into cancer cells, thereby sparing normal surrounding cells, is one potential treatment that offers fewer toxic effects.
• At present, a vaccine for triple-negative breast cancer is in clinical trials.⁴⁴
• Artificial intelligence is being used to improve breast cancer diagnosis and develop treatment prediction models. ⁴⁵
• Circulating tumor cells and circulating tumor DNA levels may be used to predict outcomes for women with metastatic breast cancer.⁴⁶

Gaps in the Evidence-Based Knowledge

Further study on accurate and appropriate screening for breast cancer needs to be completed as recommendations for screening continue to vary. Studies on the timing and dose of exercise (including weight bearing, resistance, and range of motion exercises) for treatment of neuromuscular and lymphovascular disorders should also be executed. The role of cytokines and human growth factors in the growth and treatment of breast cancer as well as the healing of musculoskeletal tissues after breast cancer treatment should be explored further. In a similar manner, it is important to elucidate some of the relationship between newer targeted systemic breast cancer therapies, and side effects such as myositis and polyarthritis, to develop a pathophysiologic understanding.

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Original Version of the Topic

Nandita S. Keole, MD, Michael D. Stubblefield, MD, Jonas Sokolof, DO. Breast Cancer. 8/17/2012.

Previous Revision(s) of the Topic

Jennifer Baima, MD. Breast Cancer. 9/14/2016.

Christian M Custodio, MD, Alexandra I Gundersen, MD. Breast Cancer. 10/13/2021.

Author Disclose

Alexandra I Gundersen, MD
Nothing to Disclose

Timothy J Genovese, MD, MPH
Nothing to Disclose