Breast cancer

Author(s): Jennifer Baima, MD

Originally published:08/17/2012

Last updated:09/14/2016

1. DISEASE/DISORDER:

Definition

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

Etiology

Cancer arises from a complex series of steps involving mutated genes. Each mutation enhances the ability of the cell 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.

Epidemiology including risk factors and primary prevention

The American Cancer Society (ACS) projects 246,660 cases of new breast cancer for 2016. Of that, about 99% are in female patients, and 40,450 will die from their disease.2 Although breast cancer has traditionally been less common in non-industrialized nations, its incidence in these areas is increasing. Industrialization in developing countries is associated with rapid increases in breast cancer risk.3

Risk factors: family history, mutations in breast cancer susceptibility genes BRCA1 and BRCA2, increased exposure to endogenous estrogens (early menarche, late menopause, not bearing children, first pregnancy over age 30), a diet high in animal fat, obesity, high breast density, and exposure to ionizing radiation.3

Screening with mammography with or without clinical breast exam may decrease breast cancer mortality.4 Breast MRI improves detection in those at risk with negative mammography.5

Patho-anatomy/physiology

The main stages in progression of breast cancer from normal cells are usually:6

  1. Hyperplasia: increased cell growth;
  2. Atypical hyperplasia: alteration of cell adhesion and polarity;
  3. Carcinoma in situ: appearance of increased histologic and biologic diversity in cells;
  4. 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, number, lymph node involvement, and metastasis.7

“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.

  1. 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.
  2. 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 breast bone) on sentinel lymph node biopsy.

  1. N1mi:Micrometastases (tiny areas of cancer spread) in 1 to 3 lymph nodes under the arm. The areas of cancer spread in the lymph nodes are 2 mm or less across (but at least 200 cancer cells or 0.2 mm across).
  2. 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.
  3. N1b: Cancer has spread to 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).
  4. 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).

  1. 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.
  2. N2b: Cancer has spread to one or more internal mammary lymph nodes, causing them to become enlarged.

N3: Any of the following:

N3a: either

  1. Cancer has spread to 10 or more axillary lymph nodes, with at least one area of cancer spread greater than 2 mm, OR
  2. 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:

  1. 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
  2. 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.
  3. N3c: Cancer has spread to the lymph nodes above the clavicle with at least one area of cancer spread greater than 2mm.

Metastasis

MX: Distant spread (metastasis) cannot be assessed.

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

  1. 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.6

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.7

Specific secondary or associated conditions and complications

Currently, there are more than 2.8 million breast cancer survivors in the United States.7Many 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. Some of the conditions amenable to rehabilitation listed below are thought to be barriers to return to work.8 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.9 Of note, multiple conditions listed below can coexist in the same patient.

Conditions requiring rehabilitation in the survivorship period include:10

Musculoskeletal disorders

  1. Postsurgical pain
  2. Rotator cuff disease
  3. Adhesive capsulitis
  4. Arthralgias

Neuromuscular disorders

  1. Cervical radiculopathy
  2. Brachial plexopathy
  3. Polyneuropathy
  4. Mononeuropathy
  5. Postmastectomy pain syndrome

Lymphovascular disorders

  1. Lymphedema
  2. Axillary web syndrome
  3. Thromboembolic disease

Integumentary disorders

  1. Cellulitis
  2. Radiation dermatitis
  3. Seroma11

Metabolic disorders

  1. Fatigue12

Neuropsychiatric disorders

  1. Cognitive dysfunction= “chemobrain”13
  2. Depression
  3. Anxiety

2. 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, history of prior cancers, and cancer of the contralateral breast.

Physical examination

  1. Manual examination of symptomatic and contralateral breast.
  2. Evaluation of lymph nodes.
  3. Baseline arm circumference measurements.
  4. Neuromuscular examination (pre-existing neuropathy, strength impairment, evidence of spinal metastasis).
  5. Inspection, palpation, and range of motion of joints (pre-existing arthralgias and shoulder function).

Functional assessment

Assess ability to do overhead activities and activities of daily living. Cognitive evaluation should be done if brain metastases are present at time of presentation, 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:

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

Imaging

  1. Screening mammography is recommended by ACS guidelines to be offered to women at average risk at 40 years old and required annually from ages 45-54. Women ages 55 and older can get screening every other year.7
  2. According to the United States Preventive Services Task Force, screening is recommended every other year from ages 50-74. (USPTF)14
  3. Ultrasound may be used as an adjunct to mammogram. This is typically recommended in node-negative cancer and for women with dense breast tissue. Addition of ultrasound to mammogram increases both detection of cancer and false positive rate.15
  4. MRI (Magnetic Resonance Imaging) is recommended for patients with higher risk of developing breast 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.15
  5. 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.
  6. Scintimammography is a type of molecular breast imaging being studied for use in women with dense breasts and subsequently less accurate mammograms. 7

Supplemental assessment tools

  1. Breast biopsy (fine-needle, core cutting, and excisional).
  2. 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.
  3. Cardiac testing should be performed in patients who may be started on anthracycline or trastuzumab.

Early predictions of outcomes

Adverse prognostic factors are axillary node involvement, ER/PR negative and HER-2 neu negative, lymphovascular invasion, and patients who are 35 yrs or less at diagnosis. Although data is limited, concurrent pregnancy is no longer thought to significantly change survival, even in patients with estrogen-receptor positive disease.16

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.7 A sentinel lymph node biopsy 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 for patients with known node involvement.

Breast reconstruction can be done along with the surgery to remove the cancer or after the tissue has healed. Delayed reconstruction is typically recommended for patients that need radiation. Timing also depends on individual patient preference. Types of surgery for breast reconstruction after treatment include tissue flaps from native muscle tissue and silicone or saline implants. The most common types of tissue flaps are transverse rectus abdominis muscle flaps, deep inferior epigastric perforator flaps, and latissimus dorsi flaps.7 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.17

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 through 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 a more important role in quality of life than cancer-related variables.18 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.

Professional Issues

Applicable issues include: informed consent, education of family and friends, language barriers, and the patients’ comfort in discussing their diagnosis and treatment. Access to the most up-to-date care is an issue, especially in socioeconomically disadvantaged populations.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Oncologic management strategies available for risk reduction in high-risk women include intensive surveillance, chemoprevention with Selective Estrogen Receptor Modulators (SERMs), 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.3

Treatment may be a combination of surgery (lumpectomy/mastectomy, sentinel lymph node biopsy, axillary lymph node dissection, reconstruction), chemotherapy, radiation, and hormonal therapy (tamoxifen, aromatase inhibitors).3 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.). Upper limb neuromuscular and lymphovascular disorders are typically the focus. Although many neuromuscular disorders as listed above are associated with breast cancer, and lymphedema is frequently associated with cancer, not all of these nerve dysfunctions can be attributed to lymphedema. For example, lymphedema is not likely the cause of all carpal tunnel syndrome in breast cancer patients.19

At different disease stages

Rehabilitation should begin early in order to maximize and maintain function and quality of life. Physical impairment from breast cancer and its treatments can arise at any stage of the disease. Accurate assessment of pain and functional disorders are key to ensuring safe and effective rehabilitation, regardless of where along the cancer continuum the patient is at a given time. It is as important for performance of activities of daily living to accurately diagnose and treat a rotator cuff tendonitis in a patient in the final months of life as it is for one who recently finished primary treatment. Lymphedema is a common impairment seen in breast cancer patients after treatment, and can be managed with manual decompression therapy and compression garments. Lymphedema management is covered in another article in Knowledge Now, as are impairments from metastatic disease:

http://me.aapmr.org/kn/article.html?id=85

http://me.aapmr.org/kn/article.html?id=100

At diagnosis, prehabilitation exercises can be offered to prevent postoperative shoulder dysfunction.20 Scapular stabilization exercises are particularly helpful in this population, and can be performed both before surgery and after drains have been removed.21 During chemotherapy or radiation, aerobic exercise can be helpful to combat fatigue and decreased endurance. During survivorship, patients may have more energy to focus on formal rehabilitation. Supportive care should be offered for painful conditions to maximize function. 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 under control, but also in patients with active disease metastatic to bone.22

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 meetings are helpful in coordinating care.

Patient & family education

This should focus on:

  1. Benefits of exercise for fatigue, strength, range of motion, bone health, and cancer risk reduction and information on appropriate exercise regimens.
  2. Dietary interventions and lifestyle modifications to decrease Body Mass Index
  3. Education on lymphedema risk and prevention, and the need to carry out lymphedema management at home (e.g., compression sleeves).
  4. 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, 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. 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. 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.23,24 Exercise is a safe and effective modality that should be incorporated where possible into the plan of care for breast cancer patients and survivors. Lymphedema should be treated with manual decompression therapy by a certified rehabilitation professional.23

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

  1. 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.
  2. Five sub-types of breast cancer have been identified. 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.
  3. 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 less toxic effects.
  4. At present, efficacy of a breast cancer vaccine is under review.25
  5. Mechanical loading improves bone density in bone metastasis from breast cancer in animal models with pathologic fractures..26
  6. Fenretinide, a retinoid, causes apoptosis of breast cancer cells.27
  7. Vitamin D has been inversely associated with risk of breast cancer and further study may unlock beneficial neutraceutical strategies.28

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

Further study on the appropriate timing and dose of exercise for treatment of neuromuscular and lumphovascular disorders should be executed. Human data is needed to determine the effect of exercise on bone density in breast cancer patients with pathologic fracture. 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. For example, increased IGF-1 may be associated with poorer outcome in breast cancer patients, but improved bone density and muscle strength in breast cancer survivors. Since IGF-1 may be the mechanism by which platelet rich plasma is effective in tendinopathy treatment, further exploration of regenerative therapies may prove interesting.

REFERENCES

  1. URL: http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional#Reference1.16. Accessed March 24, 2012.
  2. Siegel RL, Miller KD, and Jemal A. “Cancer statistics, 2015.” CA: a cancer journal for clinicians 2015;65.1: 5-29.
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  7. URL: http://www.cancer.org/cancer/breastcancer. Accessed July 27, 2016.
  8. Silver JK, Baima J, Newman R, Galantino ML, Shockney LD. Cancer rehabilitation may improve function in survivors and decrease the economic burden of cancer to individuals and society. Work. 2013; Jan 1;46(4):455-72.
  9. Ebaugh D, Spinelli B, Schmitz KH. Shoulder impairments and their association with symptomatic rotator cuff disease in breast cancer Med Hypotheses 2011;77:481-487.
  10. Stubblefield MD and Keole N. Upper body pain and functional disorders in patients with breast cancer. PM&R, 2014:6(2); 170-183.
  11. Mukesh MB, Barnett G et al. Association of breast tumor bed seroma with post-operative complications and late normal tissue toxicity: results from the Cambridge Breast IMRT trial. Eur J Surg Oncol 2012:38(10);918–924
  12. van Vulpen, JK, Peeters PHM, Velthuis MJ, van der Wall E, and May AM. Effects of physical exercise during adjuvant breast cancer treatment on physical and psychosocial dimensions of cancer-related fatigue: a meta-analysis. Maturitas
  13. Jung MS, Zhang M, Askren MK, Berman MG, Peltier S, Hayes DF, Therrien B, Reuter-Lorenz PA, and Cimprich B. Cognitive dysfunction and symptom burden in women treated for breast cancer: a prospective behavioral and fMRI analysis. Brain imaging and behavior 2016: 1-12.
  14. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/breast-cancer-screening. Accessed April 9, 2016.
  15. Berg WA, Zhang Z, Lehrer D, Jong RA, Pisano ED, Barr RG, Böhm-Vélez M, Mahoney MC, Evans WP, Larsen LH, Morton MJ. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA 2012; Apr 4;307(13):1394-404.
  16. Theriault RL, Litton JK. Pregnancy during or after breast cancer diagnosis: what do we know and what do we need to know? Journal of Clinical Oncology. 2013 Jul 10;31(20):2521-2.
  17. Kern P, Zarth F, Kimmig R, Rezai M. Impact of age, obesity and smoking on patient satisfaction with breast implant surgery–A unicentric analysis of 318 implant reconstructions after mastectomy. Geburtshilfe und Frauenheilkunde. 2015 Jun;75(06):597-604.
  18. Brunault P, Champagne AL, Huguet G, Suzanne I, Senon JL, Gilles B, Rusch E et al. Major depressive disorder, personality disorders, and coping strategies are independent risk factors for lower quality of life in non‐metastatic breast cancer patients. PsychoOncology
  19. Stubblefield, MD, Kim A, Riedel ER, and Ibanez K. Carpal tunnel syndrome in breast cancer survivors with upper extremity lymphedema. Muscle & nerve 2015:51(6); 864-869.
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  21. Flores AM, Dwyer K. Shoulder impairment before breast cancer surgery. J. Womens Health Phys. Therap. 2014; 38(3):118–124
  22. Rief H, Omlor G, Akbar M, Bruckner T, Rieken S, Förster R, Schlampp I, Welzel T, Bostel T, Roth HJ, Debus J. Biochemical markers of bone turnover in patients with spinal metastases after resistance training under radiotherapy–a randomized trial. BMC cancer. 2016: Mar 17;16(1):1.
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  28. Reimers LL, Crew KD, Bradshaw PT, Santella RM, Steck SE, Sirosh I, Terry MB, Hershman DL, Shane E, Cremers S, Dworakowski E. Vitamin D-related gene polymorphisms, plasma 25-hydroxyvitamin D, and breast cancer risk. Cancer causes & control. 2015: Feb 1;26(2):187-203.

Original Version of the Topic:

Nandita S. Keole, MD, Michael D. Stubblefield, MD, Jonas Sokolof, DO. Breast cancer. Publication Date:2012/08/17.

Author Disclose

Jennifer Baima, MD
Sturdy Memorial Hospital; Honorarium for speaking on cancer rehab

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