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Objectives

The following module was designed to supplement medical students’ learning in the clinic. Please take the time to read through each module by clicking the headings below. Information on epidemiology, screening & testing, classification, signs & symptoms, diagnosis, staging, treatment, and follow-up of breast cancer is provided.

By the end of the tutorial, the following objectives should be addressed:

  1. Identify common risk factors associated with developing breast cancer
  2. Discuss the importance of genetics as a risk factor for breast cancer
  3. Understand which factors confer a higher risk of developing breast cancer
  4. Understand the current recommendations for breast cancer screening in British Columbia.
  5. Understand the broad classification schemes for breast cancer.
  6. Understand the gross and histological features of different types of breast cancers
  7. Understand the importance in determining the presence or absence of molecular markers associated with breast cancers.
  8. Describe the common signs and symptoms of breast cancer
  9. Understand the common areas of metastasis
  10. Understand the general approach to breast cancer diagnosis
  11. Understand the laboratory tests, imaging techniques, and biopsy methods used in the investigation of breast cancer.
  12. Understand the basic anatomy of the breast
  13. Understand the general TNM staging for breast cancer
  14. Understand that breast cancer treatment differs depending on the stage of the tumour.
  15. Understand some factors that influence prognosis
  16. Describe the different modalities used in treating breast cancer.
  17. Describe some indications, contraindications, advantages and disadvantages of the varying treatment modalities.
  18. Understand the purpose of follow-up after treatment of breast cancer
  19. Describe the frequency of follow-up after treatment of breast cancer
  20. Describe the tasks that should be performed at each follow-up visit

Anatomy Review

The breast, which lies on the anterior chest wall superior to deep fascia covering the pectoralis major muscle, is composed of mammary glands with surrounding connective tissue and fat.  Mammary glands consist of secretory lobules and ducts, which converge to form 15-20 lactiferous ducts that are arranged in a spoke-like pattern and drain independently to the nipple.  The largest amount of mammary glandular tissue is found in the upper outer quadrant of the breast, and thus the majority of breast cancers are also found in this region.  [1,2]

‍Image from Gray’s Anatomy for Students [1]

The nipple is surrounded by the areola, which is a darkly pigmented area of skin.  Connective tissue that surrounds the glands is dense and fibrous, and in some regions form suspensory ligaments of Cooper that run from the deep fascia to the dermis of the skin, dividing the breast into lobules [1].  The breast lies on loose connective tissue that is located in the retromammary space between the breast and deep fascia layer [1].

The arterial blood supply to the breast forms a spoke-like pattern and originates from the axillary artery laterally, and internal thoracic artery medially.  Venous drainage runs parallel to the arteries in the opposite direction and drain into the axillary, internal thoracic and intercostal veins [1,2].

Lymphatic drainage occurs predominantly through the axillary nodal route, with 75% of lymph draining into the axillary area.  The remaining 25% of lymph drains through the internal mammary chain [1].

Epidemiology

Breast cancer is the most common cancer in North American women, with one in nine women expected to develop breast cancer over the course of her lifetime.  It is the 2nd leading cause of cancer mortality in women (after lung cancer), and one in 29 women is expected to die from breast cancer.  28% of all newly diagnosed cancers in women are breast cancers, and 15% of all female cancer deaths are due to breast cancer.

Risk Factors

1) Age

The risk of developing breast cancer increases with age. The incidence increases with age until menopause, where the rate then levels off.  This is believed to be due to the effect of estrogen on developing breast cancer.  The peak incidence of breast cancer is between the ages of 50 and 70 years old. [2,3]

2) Reproductive History

Endogenous and exogenous estrogen levels are positively correlated with the development of breast cancer.  It is believed that estrogen is linked to breast cancer development in two ways:  estrogen stimulates breast tissue growth, and breaks down into harmful genotoxic and mutagenic metabolites that affect breast cells. [4]

Factors that influence estrogen levels in women are associated with risks in breast cancer development.  Early menarche, late menopause, nulliparity and later age of parity are associated with a higher risk of breast cancer.  Hormone replacement therapy (both short term and long term use) has been found to increase risk according to a study carried out by the Women’s Health Initiative [2,3,5].  These factors all correlate with the amount and length of time a woman is exposed to estrogen. [2,4]

3) Diet & Lifestyle

Socioeconomic status, alcohol, and obesity play a small role in conferring risk of breast cancer.

Women of a higher socioeconomic status have a greater risk for developing breast cancer.  This is not an independent risk factor and may reflect lifestyle differences such as age of menarche and age of first birth amongst other compounding factors.  [6]

Alcohol intake is associated with an increased risk of developing breast cancer.  The risk in breast cancer increases with an increase in alcohol intake.  It is hypothesized that ethanol may lead to increased levels of estrogen. [2]

Obesity is correlated with an increase in breast cancer amongst post-menopausal women.  A WHI study found that women with BMIs of >31.1 had a 2.5 fold increase in risk compared to women with BMIs of <22.6 [2,3].  This is again related to an increased level of estrogen synthesized by adipose tissue.

4) Genetics

15-20% of all breast cancer patients have a positive family history.  The significance of a positive family history depends on the number of primary relatives diagnosed with breast cancer, as well as their ages of diagnosis. A patient with a strong family history of breast cancer at younger ages confers a higher risk.  [2,6]

About 45% of patients with a positive family history of breast cancer have a known germline mutation.

  • Hereditary breast ovarian cancer syndrome (HBOC): BRCA1 and BRCA2 are the two most commonly identified germline mutations associated with a 50-85% lifetime risk in developing breast cancer.  BRCA1 is also associated with a 45% risk of developing ovarian cancer by 70 years of age, as well as prostate, colon, liver, and bone cancer [2].  BRCA2 mutations are associated with a 23% lifetime risk of ovarian cancer, as well as male breast cancer, pancreas, gall bladder, stomach, melanoma, and prostate cancer [2].  There are many mutations of the BRCA1 and BRCA2 genes which have a varying but high penetrance, and are inherited in an autosomal dominant manner. [2,6]
  • Li-Fraumeni syndrome: A rare mutation of the p53 tumour suppressor gene on chromosome 17 confers a high penetrance for breast cancer.  Li-Fraumeni is also associated with an increase in male breast cancer, prostate cancer, and colorectal cancer.
  • Cowden syndrome: A rare mutation of the PTEN tumour suppressor gene confers a high penetrance for breast cancer.  Cowden syndrome is also associated with hamartoma, thyroid, endometrial and brain tumors.
  • Other rare genetic mutations found to be associated with familial breast cancer include the CHEK2 mutation and the STK11 mutation.

5) Personal Breast History

Benign breast disease:

Nonproliferative lesions, such as fibrocystic changes, solitary papillomas, and simple fibroadenomas do not confer an increased risk in developing breast cancer.

Proliferative lesions without atypia such as complex fibroadenomas and intraductal papillomas do increase risk slightly.  Proliferative lesions with atypia, including atypical lobular hyperplasia and atypical ductal hyperplasia, are associated with an even greater risk of breast cancer. [2,6]

A woman’s personal history of breast cancer (whether invasive or in-situ) increases her risk of developing contralateral breast cancer.

Breast density on mammogram is also an identified independent risk factor.  The ease in detection of breast cancer in a dense breast is more difficult than that of a hypodense breast.  In addition, women with >75% breast density have been found to have a 4-5 fold increase in breast cancer risk. [2,6]

‍Table modified from [2,7]

Summary

Breast cancer is the most common female cancer in North America. There are many risk factors associated with breast cancer including: age, reproductive history, diet and lifestyle, genetic, and personal breast history.

Screening

In Canada, breast cancer remains the most common female cancer, with a one in 9 risk of developing breast cancer over a woman’s lifetime.  Similar to many cancers, the earlier a breast cancer is detected and treated, the better the prognosis for the patient.  Effective screening can help detect breast cancer before clinical signs and symptoms appear.

Self Breast Examination (SBE)

In the past, monthly self-breast examinations were recommended to patients.  Recently, this recommendation has fallen out of favor as it was found in a meta-analysis that there is no proven decrease in mortality with conducting monthly SBEs [1].  Furthermore, SBEs lead to an increase cost in health care by increasing mammograms and biopsies of benign lesions, and an increase in stress in women who believe they may have a positive finding [2].   Currently, the Canadian Task Force on Preventive Health Care does not recommend conducting SBEs [2], though the BCCA still encourages women to do so [3].

Clinical Breast Examination (CBE)

Though performing CBEs show no established benefit independent of mammography, many cancer agencies recommend physicians to carry out clinical breast examinations.  The BCCA recommends physicians to carry out annual clinical breast exams as part of a general physical examination for women over age 20 [3].  Many agencies agree that performing a CBE in conjunction with a mammogram is beneficial as a CBE may detect breast abnormalities that are not seen on mammogram. [2]

Mammography

Mammograms are x-ray images of breasts.  Mammography is currently the gold standard of screening used to detect breast cancer.  In BC, the Screening Mammography Program allows women age 40-79 to book for screening mammograms.  Women of age 40-79 with moderate risks of developing breast cancer should be screened annually.  For healthy low-risk women age 50-79, they recommend regular mammograms every two years [4,5,6].  Healthy low-risk women age 40-49 are able to get annual mammograms as well, though there is controversy over the benefit of screening. [5]  Mammograms have been shown to reduce breast cancer mortality by 20-30%, and can detect smaller breast cancers (on average 1.4 cm in diameter) that are otherwise difficult to palpate [5].

Though mammography is presently the most effective screening tool, false negatives can result in false reassurance for patients.  A mammogram can be negative if the cancer is the same density as breast tissue or if the cancer is on the outer border of the breast, and therefore not captured on a mammogram.  About 25% of breast cancers in women age 40-49, 15% in women age 50-59, and 10% in women greater than 60 years old, are missed on mammography.  Conversely, false positives can lead to costly follow-up tests and an increase in stress in patients.  Of all abnormal mammograms, 75% will be benign in nature.  The false positive rate drops from 15% to 7% between initial and subsequent mammograms as the radiologist has a reference mammogram for comparison [5].

Ultrasound

Ultrasound is not recommended as a screening tool for the general population as it has a lower sensitivity and specificity than mammography.  Ultrasound is used in conjunction with mammography when an abnormal finding is detected, as ultrasound is able to differentiate the composition of the mass as solid or cystic.  [2]

Magnetic Resonance Imaging (MRI)

MRI is not recommended as a screening tool for the general population.  A breast MRI has a very high sensitivity rate of 95-100% but a variable specificity rate of 37-97% which makes it an unfavourable screening modality as there are many false positives [2].  Currently, some studies have shown that MRI is superior to mammography screening for high-risk patients only.  No survival benefit has been demonstrated.  The American Cancer Society for MRI screening recommends only individuals with a lifetime risk of 20-25% and individuals with a known or suspected genetic mutation (eg. BRCA1/2, p53, PTEN) to be screened by MRI annually [2,7].

Summary

Screening guidelines [8]

Classification

Breast cancer is commonly classified histopathologically in accordance with the 2003 WHO classification scheme.  Histopathological classification helps to determine the course of treatment as well as general prognosis.  Other classification schemes involve determining the presence or absence of estrogen receptors, the expression level of the HER2 gene, and the grade of the cancer. [3,4]

Histopathological Classification

‍Modified from [1, 2, 3]

1) Carcinoma-In-Situ

In-situ carcinomas are composed of malignant epithelial cells that are limited to their site of origin and have not spread or invaded past the basement membrane.  These carcinomas, if left untreated, can progress into invasive carcinomas.

  • Ductal Carcinoma in-situ (DCIS)
  • Ductal carcinoma in-situ implies that malignant epithelial cells are found localized within the duct with no spread through the basement membrane.  DCIS makes up 85% of all in-situ findings, and 20% of all abnormal mammogram findings. [2]
  • DCIS can be further subtyped as comedo or noncomedo.
  • Codemo DCIS grows and spreads more rapidly than noncomedo DCIS.  Because of this aggressive growth, malignant cells outstrip their nutrient and oxygen availability, and as a result, areas of necrosis can be found within the duct which calcify overtime and can be picked up on mammogram. [1,2]
  • Noncomedo DCIS is slower growing and can be classified as papillary, cribiform, or solid. [1,2]
  • Lobular Carcinoma in-situ (LCIS)
  • LCIS is the presence of abnormal cells within milk glands (lobules).  LCIS is usually an incidental finding as it does not present clinically and is rarely detected on mammogram.  There is controversy as to whether LCIS is truly a pre-cancerous lesion, as many women who have this condition do not go on to develop invasive breast cancer.  However, women with LCIS have an 8-10 fold increase in risk of developing invasive breast cancer.  LCIS is more commonly found in premenopausal women.  [1,2]

2) Invasive Breast Cancers

Over 95% of all invasive breast cancers are adenocarcinomas derived from epithelial tissue.  Unlike carcinoma in-situ, invasive carcinomas extend through the basement membrane into surrounding breast parenchyma, lymph tissue or beyond.  Other more rare forms of invasive breast cancer include stromal-derived connective tissue cancers including Phyllodes tumors and sarcomas, as well as lymphomas and metastasis of other cancers to the breast [1,2].

Invasive Ductal Carcinoma (IDC)

IDCs make up 65-80% of all invasive breast cancers.  Within IDCs there are further subtypes defined by characteristic histopathological features that influence prognosis.

  • IDC not otherwise specified (NOS)/IDC of no special type (NST) – IDC NOS is a diagnosis of exclusion.  It is the most common diagnosis with an occurrence of 65-80%.  Histopathological characteristics of IDC NOS vary widely.  These carcinomas on gross pathology are gray-white tumors that are usually hard and gritty with a distinct irregular border. [1,2]
  • Medullary carcinoma – medullary carcinomas account for 5-10% of all invasive breast cancers.  They are usually well circumscribed and on gross pathology have a soft fleshy consistency.  Microscopically, they are composed of poorly differentiated cells that grow in a syncytial, or sheet-like, pattern.  Prominent lymphoplasmacytic infiltrates without lymphvascular invasion can be seen.  They are associated with a better prognosis than IDC-NOS.[1]
  • Tubular carcinoma – tubular carcinomas account for 2-3% of invasive breast cancers.  They are usually small with a firm consistency and irregular border.  Microscopically they are similar to benign lesions as they are well-differentiated and do not show extensive chromosomal damage.  They are associated with a good prognosis. [1]
  • Mucinous carcinoma – mucinous carcinomas have a 2% occurrence rate and are found more frequently in women between 60-70 years old.  As the name suggests, they are composed of large pools of mucin, and are usually soft and gelatinous in texture.  On gross specimen they are pale and gray-blue in colour.  They are associated with a good prognosis. [1]
  • Papillary carcinoma – papillary carcinomas are rare with an occurrence rate of 1-2% and are found more frequently in postmenopausal women.  Grossly, they are well-circumscribed masses.  Histologically, they contain papillae and can be surrounded by a fibrous pseudocapsule.  They generally have a favourable prognosis. [1]
Invasive lobular carcinoma (ILC)

Invasive lobular carcinomas are the second most common after IDC and make up 10-15% of all invasive breast cancers.  They are characterized by a single-file of infiltrating cells (called an Indian file pattern) that invade into breast stromal tissue.  On gross specimen, they have a rubbery hard consistency with irregular borders.  ILC metastasizes to atypical sites including the peritoneum, GI tract, ovaries and uterus, and rarely metastasizes to the lungs and pleural cavity. [1]

Inflammatory breast carcinoma

Inflammatory breast carcinoma is a rare but highly aggressive form of breast cancer.  It is usually defined clinically rather than histologically; however, a finding of malignant cells in dermal lymphatic tissue is a hallmark feature of inflammatory breast carcinoma.  Because of its aggressive nature, by the time it is detected, the cancer cells have usually already invaded nearby axillary lymph nodes. [1,2]

‍An example of Paget’s disease of the nipple
Paget’s disease

Paget’s disease is another rare form of invasive breast cancer derived from epithelium.  It presents with clinical signs and symptoms in 70% of patients.  Histologically, it is characterized by large dendritic neoplastic cells (Paget cells) that are located within the epidermis.  There is usually an underlying DCIS or IDC component present as well. [1,2]

Other

Phyllodes tumors, sarcomas, and lymphomas of the breast are extremely rare.  Metastases from other sites of the body are also rare and make up less than 1% of breast malignancies.

Molecular Classification

A newer classification scheme has been proposed as an adjunct to the histopathological classification model.  This scheme divides cancers based on the expression of certain receptors and genes that can guide treatment and better predict prognosis.

1) Hormone Receptor Status

A malignancy can be classified according to the presence or absence of estrogen and progesterone receptors.  About 75% of breast cancers are hormone receptor positive meaning that the cancer will grow in the presence of estrogen and progesterone.  Estrogen receptors are more commonly found than progesterone receptors.  The importance of determining receptor status of a cancer is that it will determine the efficacy of using hormonal therapy as treatment.  The receptor status of a cancer can change over time.

  • Estrogen receptor positive:  ER positive cancers are associated with higher disease-free and survival rates.  ER positive cancers can be treated using anti-estrogen therapy [4].  It is more commonly found in post-menopausal patients [3].
  • Estrogen receptor negative: ER negative cancers are more common in premenopausal patients [3].  They are associated with a poorer prognosis than ER positive cancers, and about 30% of ER-negative cancers will have recurrent tumors that are ER-positive [3].

2) HER2/neu Status

HER2/neu is a proto-oncogene that encodes for a transmembrane growth factor receptor.  Though it is present in normal breast epithelial cells, it is overexpressed in 20-25% of all breast cancers.  HER2/neu overexpression is associated with more aggressive, higher grade tumours [1,4].

Summary:

Breast cancer is most commonly classified by its histopathological appearance.  Recently, molecular classification has also been used as it offers additional information about the tumour Using the two classification systems can help to guide treatment plans and predict prognosis.

Signs & Symptoms

Breast cancer can present in 3 ways:

1) Asymptomatically

Especially with the use of screening mammograms, breast cancer may not present with any signs or symptoms and instead be identified by a mammographic abnormality.  The benefit of mammography screening is that it can lead to the detection and treatment of breast cancer before the patient develops symptoms.[1]

2) Changes in Breast Tissue

Breast Mass

The most common presentation of breast cancer is a breast mass or lump.  A cancerous breast mass is usually firm, hard, irregular and nontender; however, a tender or sore lump does not rule out breast cancer [1].  Breast thickening, ridges, and pain are more associated with benign breast conditions.  The breast mass should not change in size with menstruation.  A mass that is fixed to the skin or chest wall is more suspicious of a breast cancer [2].

Nipple Changes

Spontaneous nipple discharge that is unilateral, blood stained, or associated with a mass is suspicious of a breast cancer.  A nipple that becomes inverted should also be further investigated.

Paget’s disease of the breast: Paget’s disease is an in-situ cancer that invades the skin of the nipple.  It is often associated with an underlying invasive cancer and must be treated aggressively with surgery [1].  Paget’s disease presents with unilateral red, pruritic, and scaling (eczema) of the nipple and areola areas [1,3].

Skin Changes

Paget’s disease of the breast: Paget’s disease is an in-situ cancer that invades the skin of the nipple.  It is often associated with an underlying invasive cancer and must be treated aggressively with surgery [1].  Paget’s disease presents with unilateral red, pruritic, and scaling (eczema) of the nipple and areola areas [1,3].

Inflammatory breast cancer: Inflammatory breast cancer is an aggressive form of breast cancer that presents similarly to mastitis.  Skin on the breast may become erythematous, pruritic, and warm to touch.  The breast itself may become edematous and tender as cancer cells invade and block lymph channels.  “Peau d’orange” is often the term used to describe physical breast changes associated with inflammatory breast cancer. [1,3]

‍Left breast showing peau d’orange

3) Metastatic Changes (Late Signs & Symptoms)

Symptoms of metastasis usually suggest that breast cancer has spread beyond the breast and into other areas of the body.  Because 75% of the lymph drainage is through the axillary lymph nodes, masses felt in the axilla area may be a sign of breast cancer spread.  These masses are usually small, hard, and painless. [1, 2]

Breast cancer most commonly metastasizes to the lungs, liver, bone and brain. Generalized metastatic symptoms can include weight loss, decrease in appetite, and nausea [2].

Summary

Breast cancer can occur asymptomatically or symptomatically.  The most common presentation of breast cancer is the detection of a breast mass.  Other breast changes that should be further investigated include nipple changes and change in breast skin.  Late presentations of breast cancer can manifest as metastatic symptoms, which often result in a poorer prognosis for patients.

Diagnostic Approach

History

Taking a good history is an important initial step in the diagnosis process of breast cancer.  If patients come in with a concern about a breast lump, information elicited should be the duration, growth, size, change in size, and change in physical appearance.  In addition, it is important to know if the patient has had a past history of breast cancer.  Information about past mammograms and last mammogram should also be elicited.

Taking a general history is crucial and will offer additional information.  Patients should be asked about their general well being presently, their past medical history, and their family history.  Because of the increased risk associated with family history of breast cancer, a detailed family history of breast cancer should be noted.  Patients should also be asked questions relevant to risk factors for development of breast cancer including their menstrual status, parity, use of hormone therapy and history of breast feeding.

Physical Exam

A local exam of both breasts should be conducted annually for women over age 20.  The breasts should be examined both sitting and lying down.  On observation, any visible masses or obvious asymmetry should be noted, as well as any skin changes.  Upon palpation of the breast, any abnormal lumps should be noted and details should include location, size, depth, mobility or fixation, consistency, contours, and any overlying skin changes.

Signs of distant disease should also be investigated.  This includes palpation of lymph nodes, especially the axillary and supraclavicular nodes.  Examination of the lungs, liver, and skeleton should be completed to assess for distant metastasis.

Lab Investigations

Though there are no specific blood tests that are diagnostic for breast cancer, a panel of lab investigations is part of the work-up.  Lab investigations can help determine whether breast cancer has metastasized to other organs, and can help evaluate the state of other organs for treatment purposes.

Imaging

1) Bilateral Mammogram

If a screening mammogram detects an abnormality, or if a new lump is discovered on CBE, a diagnostic mammogram of both breasts should be carried out.  A diagnostic mammogram allows for the abnormal finding to be further investigated, and allows for a more thorough inspection of both breasts. [3]

2) Ultrasound

Ultrasound may be indicated to further evaluate an abnormal mass found in mammography, or for women with dense breasts.  Ultrasound imaging is able to differentiate a solid mass from a cystic tumor. [1,2]

3) MRI

MRI may also be used to follow up on an abnormal finding found on mammography.  It may be a useful tool to determine the extent of breast cancer spread after an abnormality has been located.  If axillary lymph nodes are found to be positive for breast cancer, MRI can help to find the primary tumor that may not be detected on mammography. [1,2]

4) Chest X-Ray (CXR)

A CXR may be used to assess if breast cancer has metastasized to the lungs.[1]

5) Liver Imaging (CT or US)

Liver imaging via CT or ultrasound may be indicated if lab tests or physical findings suggest metastasis to the liver. [1]

6) Bone Scan

A bone scan may be carried out if there is indication that the cancer may have spread to the bones.  If alkaline phosphatase levels are increased, axillary lymph nodes are positive, or the patient complains of bone pain, then a bone scan may be useful to assess metastasis. [1]

Biopsy

If an abnormal breast mass is suspicious of being a cancer, a biopsy is the most definitive method of diagnosis.  The type of biopsy depends on the degree of suspicion, size, and location of the lesion. [1,2].

Low to moderate suspicion

For lesions that are low to moderately suspicious, the following methods of obtaining tissue samples include:

1) Fine-Needle Aspiration (FNA)

FNA is most often used for breast lumps that resemble cysts.  A thin needle is inserted into the lump, and fluid and cells are aspirated.  The sample is then sent to pathology to rule out the presence of malignant cells. [1,2]

2) Core Needle Biopsy

Core needle biopsies yield a larger sample of cells to analyze, and is the method of choice for breast lumps that are palpable.  A large gauge hollow needle is inserted into the lump to obtain core samples of cells. [1,2]

3) Stereotactic Biopsy

Stereotactic core biopsies are similar to core needle biopsies except that this is performed with the aid of radiological imaging.  Stereotactic biopsies are useful when the breast abnormality is seen only on mammography but cannot be palpated. [1,2]

4) Ultrasound-Guided Biopsy

Ultrasound guided biopsy is another method of obtaining core samples of abnormal breast tissue that cannot be palpated. [1,2]

High suspicion

For lesions that are highly suspicious and well-demarcated, excisional biopsies are performed:

1) Excisional Biopsy

If the highly suspicious breast mass is palpable and has a high probability of being malignant, an excisional biopsy will be performed.  A surgeon will attempt to excise the entire abnormal mass with a margin of normal tissue.  The excised mass is then sent to pathology. [1,2]

2) Wire-Localized Biopsy

If the breast mass in question is not easily palpated, a wire-localized biopsy can be used to demarcate the suspicious area.  Under X-ray guidance, a radiologist inserts a thin wire that demarcates the mass.  The surgeon is then able to use the wire guide as well as the x-ray films to excise the demarcated area.  After the procedure, the patient is imaged again to ensure that the entire lesion was excised. The excised mass is then sent to pathology. [1,2]

Summary

The diagnosis of breast cancer involves history taking, physical examination, and laboratory investigation as initial steps.  Follow-up after an abnormal clinical breast examination or mammogram includes imaging and possibly performing a breast biopsy to definitively rule in or rule out breast cancer.  Further imaging of other organ systems may be indicated if metastasis is suspected.

Staging

‍TNM Staging

TNM staging, as outlined by the American Joint Committee on Cancer (AJCC), is the most widely used and accepted system.  Breast cancers are based on T (Tumour), N (Nodal involvement) and M (metastasis) [2,3,4].

See the AJCC cancer staging system here: [link]

Using the TNM system, breast cancer can then be staged from 0 – IV, which will guide treatment modality as well as provide an average 5 –yr survival rate.

TABLE 2: STAGING OF BREAST CANCER BASED ON TNM SYSTEM

Summary

Breast cancer staging is an important step used to determine the extent of breast cancer disease in a patient and the prognosis.  In addition, staging provides details that are important when deciding upon a treatment plan.  Breast cancer is currently staged using the TNM classification established by the American Joint Committee on Cancer.

Management

Breast cancer treatment varies widely depending on the stage of the cancer.  Surgery, radiation treatment, chemotherapy and hormone therapy are the main treatment modalities that are considered.  Whenever possible, breast cancer is treated by surgery, and is supplemented with radiotherapy, chemotherapy and/or hormone therapy.

Some factors that determine prognosis are also useful in guiding treatment decisions.  General prognostic factors include:

  • Stage – the higher the stage the poorer the prognosis.
  • Lymph node status – the extent of lymph node involvement remains the most important factor in determining prognosis [1].
  • Primary tumor size – this is related to staging of the cancer
  • Grade of tumor – low grade, well differentiated tumors are associated with better survival statistics. The Nottingham combined histologic grading system is recommended by the AJCC.  Pathologists assign values of 1-3 (1 being favourable and 3 being unfavourable) for each of the 3 morphologic categories: tubule formation, nuclear pleomorphism, and mitotic count.  Based on the cumulative score between 3-9, a grade can be assigned [2]:
  • Estrogen & progesterone receptor status – As previously mentioned, ER/PR positive tumours are associated with a better prognosis.
  • HER2/neu status – overexpression of HER2/neu are associated with a poorer prognosis, but is a predictor of efficacy to chemotherapy drugs.

The treatment modalities for the different stages of breast cancer vary based on operability of the cancer and the extent of spread to other organs.  The goals of treatment will also vary from curative to palliative depending on tumour, patient, and treatment factors (see general cancer management principles).

Treatment: In-Situ Carcinoma

With screening mammography a large number of breast abnormalities are caught early.  The management of in situ disease is thus important.Diagnosis of an in-situ carcinoma is generally associated with a good prognosis.

Treatment of DCIS (Ductal Carcinoma In Situ)

DCIS can turn into a more serious invasive breast cancer if left untreated.  Due to its limited spread, surgery is the primary treatment modality for DCIS.  There are several treatment options that patients can choose from depending on the severity of DCIS and other risk factors present.

Total Mastectomy:

In the past, patients with DCIS would have a total (or simple) mastectomy, which consisted of removing the entire breast while leaving the underlying muscles intact [1].

Breast Conserving Surgery (Lumpectomy):

More recently, breast conserving surgery followed by external beam radiation has been another option for patients with a small, low-grade DCIS.  Breast conserving surgery gives the added benefit of preserving some of the breast [1].

Hormonal therapy has been shown in some research to be beneficial in preventing ipsilateral and contralateral invasive breast cancer occurrence after DCIS surgery [2].  The use of hormonal therapy tamoxifen after surgery is discussed with patients to evaluate the benefits and risks of side effects and to determine if tamoxifen is a suitable treatment modality [1].

Treatment of LCIS (Lobular Carcinoma In Situ)

Unlike DCIS, LCIS is not known to be a premalignant lesion and instead may be used as a risk marker for developing invasive breast cancer [1,2].  The treatment of LCIS will depend on the patient and additional identified risks:

Observation:

Women with few additional risk factors may want to be closely monitored instead of pursuing treatment.  Observation includes regular breast examinations and bilateral mammography [2].

Hormonal Therapy: Tamoxifen

Similar to patients diagnosed with DCIS, tamoxifen has been shown in some research to decrease the incidence of developing invasive breast cancer.  Again, the pros and cons of hormonal therapy should be discussed with the patient [2].

Prophylactic Total Bilateral Mastectomy:

Though considered to be an aggressive treatment, patients who are at high risk of developing invasive breast cancer may opt to go through with prophylactic bilateral mastectomy [1,2].

Treatment: Stage I, II, IIIA (operable disease)

The treatment plan for patients with operable breast cancers involves surgery as the primary treatment modality.  Depending on the extent of spread of the cancer and the nodal status, adjuvant therapy in the form of regional radiation, hormonal therapy, chemotherapy and/or biological therapy will be included [1].  The goal of adjuvant systemic therapy is to decrease cancer recurrence by eliminating micrometastic lesions that may have spread from the original primary tumour [3].

Surgery

As with surgical DCIS treatment, patients may undergo either breast-conserving therapy  (BCT) with external beam radiation, or modified radical mastectomy [1,2].  Many studies have evaluated the efficacy between the two surgical methods, and it was found that survival rates were equal for patients who qualified for both surgical modalities [3].

Breast-Conserving Therapy (Lumpectomy) With Radiation

BCT is appropriate for smaller breast cancers that can be removed with good margins while still preserving breast cosmetics.  BCT is followed with external beam radiation to minimize the chance of spread from possible residual tumour.  Lumpectomy may also involve lymph node dissection as well if positive lymph nodes are identified by sentinel node biopsy or palpable disease [2].  Operable stage IIIA cancers often do not qualify for BCT due to the size of the tumour [2].

Modified Radical Mastectomy

A modified radical mastectomy involves removing the entire breast including a series of axillary lymph nodes [1].

Sentinel Node Biopsy

The sentinel nodes are the first nodes that receive lymphatic drainage form the breast.  Because cancer cells often metastasize via lymph channels, the sentinel nodes are usually the first nodes that will contain malignant cells in invasive breast cancers.  The American Society of Clinical Oncology (ASCO) recommends sentinel node dissection for invasive breast cancers greater than 2mm [4].

Radiation

External beam radiation is performed in women who qualify for and choose BCT as their surgery procedure.  Studies have shown that performing radiotherapy after BCT decreases the local rate of recurrence of breast cancer by 66% [3].  External beam radiation may also be given to the lymph nodes if they are found to be positive.  After a mastectomy, if a tumour is larger than 5 cm, if there is evidence of lymph node involvement, or if malignant cells are in close proximity to the surgical margins (and no re-excision is possible), then radiation to the chest wall may be indicated [2].

Hormonal Therapy

Hormonal therapy is given post-operatively with the goal of minimizing breast cancer recurrence or spread.  Hormonal Therapy includes tamoxifen and aromatase inhibitors. It is used for breast cancers that are estrogen and progesterone receptor positive.  Hormonal therapy is not effective for treating ER/PR negative breast cancers [1,2].

Chemotherapy

Chemotherapy is generally the adjuvant treatment of choice for high-risk cancers or cancers that are ER and PR negative.  Because invasive breast cancers tend to be more aggressive in premenopausal women, chemotherapy is recommended as an adjuvant treatment after surgical removal of the primary breast tumour regardless of tumour status [2].  For post-menopausal women, chemotherapy is indicated if the tumour is ER/PR negative or if the patient is at high risk for a reoccurrence [1].  For women over age 70, the benefits of chemotherapy are weighed against the negative side effects, and the health of the patient is also considered before starting adjuvant treatment [1].

For patients wanting BCT who have primary tumors that are larger (eg. some stage II and operable stage IIIA cancers), neoadjuvant chemotherapy may be given prior to surgery in an attempt to shrink the mass [2,3].

Biological Therapy

Biological therapy involves using the body’s immune system to slow down the progression of cancer cells.  For breast cancer, Trastuzumab (trade name: Herceptin) is the biologic of choice that is used in conjunction with chemotherapy for patients with breast tumours that over express the HER2/neu gene.  Trastuzumab is a monoclonal antibody that will bind to the HER2/neu receptor thereby blocking its downstream effect [2,3].

‍Treatment: Stage IIIB, IIIC, IV (inoperable disease)

‍The goals of treatment for advanced stage invasive breast cancers can be divided into curative or palliative.  Inoperable tumours are those that are attached to the chest wall or skin, or those that have spread to lymph nodes that are attached to other structures.  Surgery as the primary treatment is also not appropriate for breast cancers that have extensively spread to supraclavicular lymph nodes or to other organs [1].

Curative Treatment

Generally, multimodal treatment with the intent to cure applies to otherwise healthy patients with inoperable stage IIIB and IIIC disease [2,3].  Apart from biopsy to determine the receptor status and HER2/neu status of the tumour, no other surgery is initially performed.  The receptor status and HER2/neu status determines if endocrine and biologic therapy use will be beneficial to the patient [2,3].

Primary treatment for advanced stage IIIB and IIIC cancer involves aggressive combination chemotherapy.  Anthracycline and taxane chemotherapy drugs are typically used and studies show that the majority of patients show favourable responses to this treatment [2,3].  For tumours with ER/PR positive status, endocrine treatment may be given as an additional treatment.  For tumours with over expression of the HER2/neu gene, trastuzumab may be given as an additional treatment [1,2,3].

The degree of tumour response to chemotherapy will determine subsequent treatment options.  For tumours that decrease in size, surgery in the form of a modified radical mastectomy may now become an option followed by radiation therapy.  Studies have shown that 80-90% of previously inoperable cancers that undergo chemotherapy treatment will become operable breast cancers [3].  For tumours that do not respond well, regional radiation to the chest wall, axillary, and supraclavicular areas may be performed [1].

Palliative Treatment

Palliative treatment goals for women with metastatic stage IV disease include prolonging life, controlling symptoms, improving QOL (quality of life) and controlling tumour burden.  The median survival time for patients diagnosed with stage IV disease is 18-24 months [3].  The main treatment modality involves systemic treatment in the form of chemotherapy, hormone therapy or biologic therapy depending on the receptor status and HER2/neu status.  The goal of systemic therapy is to decrease the progression rate of disease and/or to control symptoms of metastasis [2,3].

External beam radiation treatment may be considered to control localized symptomatic metastases, such as painful bone metastases, spinal cord metastases, bronchial obstruction and large painful chest wall masses [1,2].

Surgery may be considered for palliative intent.  Mastectomies may be considered for patients with large painful fungating breast lesions.  Surgery for isolated brain or spinal cord metastases, isolated lung metastases, and/or isolated liver metastases may help control pain and other symptoms of metastatic disease [1,2].

‍Example of a fungating breast

Follow-up

Purpose of Follow-up Treatment

Following up with patients after the end of treatment is essential as it provides support, addresses any concerns or questions the patient may have, and allows the health care team to assess and monitor any side effects of the treatment.  In addition, follow-up care is critical in early detection of recurrent breast disease [1].

Frequency of Follow-up

Because breast cancer is different for every individual, a follow-up schedule will also vary from patient to patient.  Generally, the first follow-up appointment should be made at 6 weeks post treatment [1].  The patient should discuss the follow-up schedule with her GP and/or oncologist.  Follow-up appointments are recommended every 3-6 months for the first 3 years, every 6-12 months for the next 2 years, and then annually after that [1,2].

Tasks at Each Follow-up Appointment

The patient should be asked about any persistent or new-onset of symptoms, including new aches and pains, shortness in breath, nausea, weight loss, appetite, and any noticeable masses.  A thorough evaluation of the patient’s well-being is important as metastatic cancer or recurrent local cancer can present symptomatically [1,2].

A physical exam involving a clinical breast exam, axillary node palpation, and chest and abdomen examination should be carried out at each appointment.  At 6 months time, a mammogram should be taken as a baseline for subsequent mammograms.  After that, mammograms are recommended every 6-12 months.  Blood tests, chest x-rays, liver and bone scans are not indicated unless there is suspicion of metastasis or new onset of symptoms suggesting recurrence [1,2].

Virtual Patient Case

This case study was designed to supplement your knowledge on the workup of breast cancer and test what you have learned after going through module. Use your mouse to click through the slides and answer each question in the text box provided.

Note: This case can be completed on an iPad. To do this download the (free) Articulate Mobile Player for the iPad by clicking here.

References

Anatomy Review

  1. Drake RL, Vogl W, Michell AW. Gray’s Anatomy for Students. Elsevier Inc.; 2005.
  2. DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles & Practice of Oncology 8th Edition Vol 2. Lippincott Williams & Wilkins, Philadelphia; 2008.

Epidemiology

  1. Canadian Cancer Society, Cancer statistics 2011. Available at: http://www.cancer.ca/Canada-wide/About%20cancer/Cancer%20statistics/stats%20at%20a%20glance/Breast%20cancer.aspx?sc_lang=en. Accessed July 4th, 2011.
  2. DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles & Practice of Oncology 8th Edition Vol 2. Lippincott Williams & Wilkins, Philadelphia; 2008.
  3. Canadian Cancer Encyclopedia from the Canadian Cancer Society. Available at: http://info.cancer.ca/cce-ecc/SearchDetails.aspx?lf=breast&cceid=185. Accessed July 4th, 2011.
  4. Yager JD, Davidson NE. Estrogen Carcinogenesis in Breast Cancer. N Engl J Med 2006; 354:270-282.
  5. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A; WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in health postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 2003; 289(24):3243-53.
  6. Costanza ME, Chen WY. UpToDate: Epidemiology and risk factors for breast cancer. 2011. Available at: http://www.uptodate.com. Accessed July 4th 2011.
  7. Kim-Sing C, Weir L, Kuusk U. Breast cancer risk management for moderate-risk and high-risk women. BCMJ 2004; 46 (8):397-40

Screening

  1. Hackshaw AK, Paul EA. Breast self-examination and death from breast cancer: a meta-analysis. Br J Cancer 2003; 88 (7):1047-53.
  2. Chapman DD. Breast Cancer: Chapter 3: Prevention and Detection of Breast Cancer. Oncology Nursing Society, Pittsburgh; 2007.
  3. BC Cancer Agency. Available at: http://www.bccancer.bc.ca/PPI/TypesofCancer/Breast/default.htm#Screening. Accessed July 5th 2011.
  4. Screening Mammography Program (SMP) of BC. Available at: http://www.bccancer.bc.ca/PPI/Screening/Breast/default.htm. Accessed July 5th 2011.
  5. Olivotto I, Gelmon K, McCready D, Pritchard K, Kuusk U. The intelligent patient guide to breast cancer 4th edition. Intelligent Patient Guid Ltd; 2006.
  6. Poole B, Gelmon K, Borugian MJ, Kan L, Stilwell M. Cancer screening and diagnosis in British Columbia. BCMJ 2008; 50 (4):198-205.
  7. DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles & Practice of Oncology 8th Edition Vol 2. Lippincott Williams & Wilkins, Philadelphia; 2008.
  8. Kim-Sing C, Weir L, Kuusk U. Breast cancer risk management for moderate-risk and high-risk women. BCMJ 2004; 46 (8):397-40

Classification

  1. Yackzan SG. Breast Cancer: Chapter 4: Pathophysiology and Staging of Breast Cancer. Oncology Nursing Society, Pittsburgh; 2007.
  2. Canadian Cancer Encyclopedia from the Canadian Cancer Society. Available at: http://info.cancer.ca/cce%2Decc/default.aspx?toc=10. Accessed July 7th, 2011.
  3. Sabatine MS [editor]. Pocket Medicine 4th edition. Lippincott Williams and Wilkins; 2011.
  4. Olivotto I, Gelmon K, McCready D, Pritchard K, Kuusk U. The intelligent patient guide to breast cancer 4th edition. Intelligent Patient Guid Ltd; 2006.

Signs & Symptoms

  1. Olivotto I, Gelmon K, McCready D, Pritchard K, Kuusk U. The intelligent patient guide to breast cancer 4th edition. Intelligent Patient Guid Ltd; 2006.
  2. Canadian Cancer Encyclopedia from the Canadian Cancer Society. Available at: http://info.cancer.ca/cce%2Decc/default.aspx?toc=10. Accessed July 6th, 2011.
  3. Sabatine MS [editor]. Pocket Medicine 4th edition. Lippincott Williams and Wilkins; 2011

Diagnostic Approach

  1. Canadian Cancer Encyclopedia from the Canadian Cancer Society. Available at: http://info.cancer.ca/cce%2Decc/default.aspx?toc=10. Accessed July 8th, 2011.
  2. Chapman DD. Breast Cancer: Chapter 3: Prevention and Detection of Breast Cancer. Oncology Nursing Society, Pittsburgh; 2007.
  3. Olivotto I, Gelmon K, McCready D, Pritchard K, Kuusk U. The intelligent patient guide to breast cancer 4th edition. Intelligent Patient Guid Ltd; 2006.

Management

[1] Yackzan SG. Breast Cancer: Chapter 4: Pathophysiology and Staging of Breast Cancer. Oncology Nursing Society, Pittsburgh; 2007.

[2] Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010.

Treatment: In-Situ Carcinoma

[1] Canadian Cancer Encyclopedia from the Canadian Cancer Society. Available at: http://info.cancer.ca/cce%2Decc/default.aspx?toc=10. Accessed July 13th, 2011.

[2] National Cancer Institute at the National Institutes of Health. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page4. Accessed July 13th, 2011.

Treatment: Stage I, II, IIIA (operable disease)

[1] National Cancer Institute at the National Institutes of Health. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page6. Accessed July 14th, 2011.

[2] Canadian Cancer Encyclopedia from the Canadian Cancer Society. Available at: http://info.cancer.ca/cce%2Decc/default.aspx?toc=10. Accessed July 14th, 2011.

[3] DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles & Practice of Oncology 8th Edition Vol 2. Lippincott Williams & Wilkins, Philadelphia; 2008.

[4] Chapman DD. Breast Cancer: Chapter 5: Local and Regional Control. Oncology Nursing Society, Pittsburgh; 2007.

Treatment: Stage IIIB, IIIC, IV (inoperable disease)

[1] Canadian Cancer Encyclopedia from the Canadian Cancer Society. Available at: http://info.cancer.ca/cce%2Decc/default.aspx?toc=10#Treatment. Accessed July 15th, 2011.

[2] National Cancer Institute at the National Institutes of Health. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page7. Accessed July 15th, 2011.

[3] DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles & Practice of Oncology 8th Edition Vol 2. Lippincott Williams & Wilkins, Philadelphia; 2008.

Follow-up

[1] Olivotto I, Gelmon K, McCready D, Pritchard K, Kuusk U. The intelligent patient guide to breast cancer 4th edition. Intelligent Patient Guid Ltd; 2006.

[2] Canadian Cancer Encyclopedia from the Canadian Cancer Society. Available at: http://info.cancer.ca/cce%2Decc/default.aspx?toc=10. Accessed July 15th, 2011.

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