The following module was designed to supplement medical students’ learning in the clinic. Content was developed in accordance with the ‘Oncology Goals and Objectives for Medical Students’ established by the Canadian Oncology Education Group (1).
Upon completion of this module, students should be able to:
The breast lies on the anterior chest wall superior to deep fascia covering the pectoralis major muscle. Breast tissue may extend as far medially as the sternal edge, and as far laterally as the mid-axillary line. It also projects superiorly into the axilla in a structure called the axillary tail. In the vertical axis, breast tissue typically extends from the level of the second rib to that of the sixth rib (1).
The breast is composed of three major components: glandular tissue, connective tissue, and fat.
Mammary glands are composed of secretory lobules and ducts. Each breast contains 15-20 lobes of glandular tissue, which are in turn are made up of numerous smaller lobules. These lobules secrete milk, which then drains into a branching system of ducts. These ducts converge to form 15-20 larger lactiferous ducts, each of which drains independently to the nipple (1,2).
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 region1.
Dense, fibrous connective tissue surrounds the secretory lobules of the breast. Additional structural support is provided by the suspensory ligaments of breast. These fibrous bands connect the superficial and deep fascial layers that surround the breast, and are continuous with the dermis of the skin (1).
The remainder of the breast is composed of adipose tissue. The proportion of adipose and connective tissue can vary considerably among different women and at different times. In non-lactating women, fat tissue predominates, while in lactating women, glandular tissue is more abundant.
Additional structures are present on the surface of the breast. The nipple is a richly innervated projection of skin that contains the outlets for the breasts’ lactiferous ducts. Surrounding the nipple is the areola, a circular area of pigmented skin. The colour of a normal areola can range from pink to dark brown. The periphery of the areola contains the glands of Montgomery. These modified sweat glands secrete an oily substance that lubricates and protects the nipple, particularly during breastfeeding (1,2).
The internal thoracic artery provides the principal blood supply of the breast. However, the upper outer quadrant of the breast is supplied by branches of the axillary artery, including the lateral thoracic, superior thoracic and subscapular arteries. Venous drainage runs parallel to the arteries arterial supply, in the opposite direction and drains 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).
Breast cancer is the most common cancer in North American women, with one in eight women expected to develop breast cancer over the course of her lifetime (1). It is the second leading cause of cancer mortality in women (after lung cancer), and one in 31 women are expected to die from breast cancer (1). In 2017, breast cancer accounted for 25% of all new cancer diagnoses, and 13% of all cancer deaths in women (1).
It is clear that breast cancer continues to pose a significant health threat to Canadian women. However, there is hope: with the implementation of improved screening and management programs, breast cancer mortality has decreased by 30% over the last decade in British Columbia (2).
Numerous risk factors have been proven to be associated with the development of breast cancer. The impact of each of these factors ranges considerably, with some factors exerting a small increase in risk (RR<2) and others a much larger increase (RR>4).
Table developed from information provided by the BC Cancer Agency2 and the British Columbia Breast Cancer Guidelines (3).
Given that breast cancer is the most common malignancy in women, it’s unsurprising that 15-20% of all breast cancer patients have a family history of breast cancer (4).
The extent to which a family history of breast cancer increases risk depends on the particular features of the patient’s family history. A family history of pre-menopausal breast cancer in a first-degree relative approximately doubles a woman’s risk of developing breast cancer5. Other high-risk features on family history may be associated with an even greater increase in risk, including a history of bilateral breast cancer in a pre-menopausal relative, breast cancer in three or more relatives, or breast cancer in a male relative (5).
Several genetic mutations have been identified that confer a higher risk of developing breast cancer. Approximately 5-10% of breast cancers are believed to be caused by inherited gene mutations (5).
BRCA1 and BRCA2 are the two most commonly identified germline mutations in breast cancer. They are inherited in an autosomal dominant manner (4). The presence of one of these mutations is associated with a 50-85% lifetime risk of developing breast cancer. BRCA1 is also associated with a 45% risk of developing ovarian cancer by 70 years of age (4). These mutations are more common in the Ashkenazi Jewish population, among whom 1/40 women are carriers (5).
A loss-of-function mutation in the p53 tumour suppressor gene results in Li-Fraumeni Syndrome. This syndrome is associated with an increased risk of breast, prostate, and colorectal cancer (4).
A loss-of-function mutation in the PTEN tumour suppressor gene results in Cowden Syndrome. This syndrome is associated with an increased risk of breast, thyroid, endometrial, and brain cancer (4).
Several other germline mutations have been identified that are associated with an increased risk of breast cancer, including the CHEK2, STK11, and PALB2 mutations (2,4).
Consideration should be given for referral to the BC Cancer Hereditary Cancer Program for genetic testing if the patient’s history is significant for:
Several risk factors for breast cancer development are thought to be mediated by increased estrogen levels in the body. Estrogen is believed to increase the risk of breast cancer via two mechanisms: estrogen stimulates breast tissue growth, and estrogen breaks down into genotoxic and mutagenic metabolites (6).
The more menstrual cycles a woman experiences, the greater her exposure to estrogen. Therefore, any factor that increases the number of menstrual cycles a woman experiences is associated with an increase in breast cancer risk. This includes early menarche (age < 11 years), late menopause (age > 55 years), nulliparity, and later age of first pregnancy (age > 30 years) (5). Higher parity is thought to be protective against breast cancer due to lessened estrogen exposure (5).
The use of hormone replacement therapy (HRT) has been found to increase risk of breast cancer, according to a study carried out by the Women’s Health Initiative (7). Combined HRT (estrogen and progesterone) is associated with a greater risk than estrogen alone (5). This risk is most significant with a duration of use greater than 5 years, and risk appears to return to baseline a few years after discontinuing HRT (5).
Similarly, long-term use (>10 years) of oral contraceptive pills containing estrogen and progesterone have been shown to increase the risk of breast cancer. Again, this increased risk dissipates after discontinuing use (5).
Obesity is associated with an increased risk of breast cancer, particularly in post-menopausal women. Women with a BMI of 31.1 or higher have a 2.5 times greater risk of developing breast cancer than those with a BMI of 22.6 or lower (5,7). This association is thought to be mediated by higher estrogen levels due to estrogen production in a larger amount of adipose tissue.
Alcohol consumption is associated with an increased risk of breast cancer. Higher levels of alcohol consumption are associated with greater risk. However, even low levels of consumption (>1 drink per day) have been shown to increase risk. This association is thought to be mediated by increased estrogen levels associated with alcohol consumption (5).
The risk of developing breast cancer increases with age. The incidence increases with age until menopause, where the rate then levels off (4). This is believed to be due to the effect of estrogen-exposure on developing breast cancer. The peak incidence of breast cancer is between 50 and 70 years of age (4).
Nonproliferative lesions, such as fibrocystic changes, solitary papillomas, and simple fibroadenomas do not confer an increased risk in developing breast cancer.
Benign proliferative lesions without atypia such as complex fibroadenomas and intraductal papillomas are associated with a slightly increased risk of future breast cancer development.
Proliferative lesions with atypia, including atypical lobular hyperplasia and atypical ductal hyperplasia, are associated with an increased risk of breast cancer (4,5).
A personal history of breast cancer (including both invasive and in-situ pathologies) significantly increases risk of developing new breast cancer (4,5).
Women with dense breast tissue in 75% or more of their breasts (as determined by mammography) are 4-6 times more likely to develop breast cancer than women with minimal dense breast tissue (4,5). Increased breast density also decreases the sensitivity of mammography for detection of breast malignancies (5).
A past history of radiation exposure to the chest, neck and axilla (mantle radiation field) has been associated with an increased risk of breast cancer. This is particularly noted in women who have undergone radiation therapy for Hodgkin lymphoma prior to 30 years of age (5).
Additional risk factors for breast cancer development remain under investigation, and require further elucidation of mechanism.
Individuals with higher socioeconomic status are at increased risk of breast cancer. This may reflect lifestyle differences such as age of menarche and age of first birth amongst other compounding factors. It is not currently thought to act as an independent risk factor for breast cancer development.
Smoking may be a weak risk factor for breast cancer development, but this has yet to be fully characterized (5).
Male breast cancer is rare, accounting for less than 1% of all breast cancers. In Canada, 230 cases are estimated to have been diagnosed in 2017 (5). Risk factors for breast cancer in men include a family history of breast cancer, presence of BRCA mutations, Klinefelter syndrome, and exposure to chest radiation.
Effective screening programs can enable the detection of breast cancer before clinical signs and symptoms appear. As with many cancers, the earlier a breast cancer is detected and treated, the better the prognosis for the patient.
In the past, monthly self-breast examinations (SBEs) were recommended to patients. Since then, this recommendation has fallen out of favour, as a 2003 meta-analysis found that monthly SBEs did not confer any mortality benefit (1). Furthermore, SBEs lead to increased health care costs via increased investigation of benign lesions. They may also result increased emotional distress in women who believe they have a positive finding (2).
Currently, the Canadian Task Force on Preventive Health Care does not recommend conducting SBEs (3). The BC Cancer Agency continues to encourage SBEs, but acknowledges that there is no evidence of improved survival associated with this practice (4). If SBE is performed, it should be conducted in the week following the menstrual period, and should include inspection and palpation of the breast and axilla (4).
Clinical breast examinations (CBEs) have not been shown to independently improve survival in breast cancer (3,4). However, the combination of mammography screening programs and CBEs have been shown to decrease mortality from breast cancer (3,4). On the basis of this combined benefit, some cancer agencies continue to recommend that physicians carry out CBEs. Currently, the BC Cancer Agency neither recommends nor discourages annual CBEs as part of breast cancer screening, but states that physical examination may improve early detection when performed in conjunction with screening mammography (4).
Mammograms are x-ray images of breasts. A standard mammogram consists of a medial-lateral oblique view and a cranio-caudal view of both breasts (5).
Mammography may be performed as either a screening or a diagnostic investigation. It is considered the gold standard screening investigation for breast cancer (5). Screening mammography is undertaken in asymptomatic women to detect the presence of otherwise unsuspected breast cancer.
It is important to note that screening mammography differs from diagnostic mammography, which includes several additional radiographic views. Diagnostic mammography should be performed in patients with breast symptoms or physical exam findings, patients with breast implants, and patients with a personal history of breast cancer (5). As such, these patient populations are not eligible for participation in the screening program.
Mammography can detect breast cancers that are clinically asymptomatic and non-palpable on breast exam, and has been shown to reduce breast cancer mortality by 25% among women who are screened regularly (6).
In 2017, British Columbia’s cancer detection rate was 5.4 cases per 1000 screens, and the positive predictive value of an abnormal mammogram for a final diagnosis of breast cancer was 6.1%. Over the period of 2013-2017, the British Columbian breast cancer screening program has a sensitivity of 94% and specificity of 92% (7).
Mammography is an effective screening tool for breast cancer with a definitive mortality benefit. However, it also presents significant risks that should be considered and discussed with patients.
Mammography does not detect all breast cancers. This is especially significant in younger women, whose denser breast tissue makes mammograms more difficult to interpret. In women ages 40-49, 25% of breast cancers are missed on mammography, while in older women (age > 50 years), 10% of breast cancers are missed (6).
Conversely, false-positive mammograms can result in costly and invasive follow-up tests, as well as distress for patients. On average, 7% of women screened by mammography will be called back for additional testing6. Of these women, more than 95% do not have cancer (6).
Women may express concern about radiation exposure from mammography. However, the amount of radiation associated with a mammogram is quite low, about 0.7 mSv, and is unlikely to be associated with any increased risk of malignancy (5).
The BC Screening Mammography Program (BCSMP) makes recommendations for breast cancer screening based on an assessment of the benefits and risks discussed above. Given that older age is a significant risk factor for breast cancer development, the risk-benefit ratio for screening tends to be more favorable in older women.
The BCSMP recommends that women aged 40-49 years discuss the benefits and risks of screening mammography with their physician and make on individualized decision based on their personal values. If a decision is made to proceed with mammography, the patient will be recalled every two years by the BCSMP (4). The Canadian Task Force on Preventative Health Care (CTFPHC) recommends against screening mammography in this population, but states that it may be considered if consistent with a woman’s values (3).
In women aged 50-74 years, both the BCSMP and the CTFPHC recommend screening mammography every two years (3,4). These patients will be recalled every two years by the BCSMP and no referral is required.
In patients aged 75 years or older, the BCSMP recommends a discussion of risks and benefits with the patient’s physician prior to proceeding with screening (4). If mammography is chosen, it is available every two to three years, and the patient will not be recalled by the BCSMP. The CTFPHC states that there is insufficient evidence to recommend for or against screening in this age group (3). Screening should be discontinued if the patient’s comorbidities suggest a limited life expectancy (4).
Women at particularly high risk for breast cancer, including those positive for BRCA1 or BRCA2 mutations, are recommended to undergo annual screening mammograms beginning at age 40 years, or 10 years earlier than the youngest age at diagnosis of a relative (4). An annual screening breast MRI is also recommended for BRCA1/2 mutation carriers4.
In recent years, breast density has gained increasing recognition as a risk factor for breast cancer development. As such, the BC Cancer Breast Screening Program now includes breast density scores on screening mammogram reports. Density is scored on a 4-point scale ranging from A to D, with D representing the densest breasts. A score of D is associated with a 2.2 times increased risk of breast cancer for women aged 50-74 (8).
Ultrasound is not recommended as a screening tool for the general population as it has lower sensitivity and specificity than mammography. Ultrasound may be used in conjunction with mammography when an abnormal finding is detected and is especially useful for differentiating solid and cystic components of a mass (2). Ultrasound may also be used to guide biopsy of breast lesions.
MRI is not recommended as a screening tool for the general population. A breast MRI has very high sensitivity (95-100%) but variable specificity (37-97%), making it a poor screening tool due to an unacceptably high rate of false-positives (2). Only certain subgroups of high-risk individuals may be screened by MRI, including individuals with an estimated lifetime risk of 20-25%, individuals with a history of chest radiation exposure, and individuals with a known or suspected genetic mutation (eg. BRCA1/2, p53, PTEN) (2,4).
Breast cancer is primarily classified histopathologically in accordance with the 2003 WHO classification scheme, as seen in overview in the flowchart below. Breast cancer may also be classified by the expression of hormone receptors and genetic mutations that are impactful for treatment and prognosis (1).
Atypical ductal hyperplasia and atypical lobular hyperplasia are conditions in which there is an increase in number of abnormal cells growing in the breast ducts or lobules. While they are not malignant conditions, they are associated with a significant increased risk of future breast cancer development (2).
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.
Lobular carcinoma in-situ (LCIS) is a pre-malignant condition arising from the cells of the breast lobules. LCIS is characterized by the presence of atypical cells that have not yet invaded nearby breast tissue (2). It often develops in multiple parts of bilateral breasts at the same time, and is an important marker for the development of future invasive breast cancer. Women with LCIS are thought to have a 10-15% risk per breast of developing breast cancer in the ten to fifteen years subsequent to diagnosis (1). As such, women with LCIS should undergo more frequent screening mammography, and may also be offered hormonal therapy to decrease their risk of future breast cancer development (2).
Ductal carcinomas in-situ (DCIS) are composed of malignant epithelial cells that arise in the breast ducts, and have not yet invaded beyond the basement membrane in their site of origin. DCIS is responsible for 20% of all abnormal mammogram findings (2). DCIS can be classified as low, intermediate or high grade on the basis of pathology, and this grading has prognostic value for the likelihood of post-operative recurrence.
Invasive breast cancers are malignant lesions in which atypical cells have spread through the basement membrane to invade surrounding breast parenchyma, lymphatic tissue or beyond. Over 95% of all invasive breast cancers are adenocarcinomas derived from epithelial tissue. Rarer forms of invasive breast cancer include stromal-derived malignancies, lymphomas and metastasis of other cancers to the breast (2,4).
Invasive ductal carcinomas (IDCs) represent 80% of all invasive breast cancers (5). IDC can be further classified into subtypes defined by characteristic histopathological features.
Invasive lobular carcinomas are the second most common form of invasive breast cancer and represent 10-15% of all invasive breast cancers (2,4). They are characterized by a single-file of infiltrating cells that invade into breast stromal tissue. On gross specimen, they have a rubbery hard consistency with irregular borders. ILC has a tendency to metastasize to atypical sites including the peritoneum, GI tract, ovaries, and uterus, as well as rarely to the lungs and pleural cavity (4).
Inflammatory breast carcinoma is a rare but highly aggressive form of breast cancer. It is more common in young women and in women of African ancestry. It usually presents as a red, warm, swollen breast. The overlying skin may appear pitted, which is known as ‘peau d’orange’ due to its resemblance to the texture of an orange peel. On histopathology, a finding of malignant cells in dermal lymphatic tissue is a characteristic feature (4). At the time of diagnosis, the cancer has often already spread to involve the lymph nodes and distant organs. Prognosis is poor, with an estimated five-year survival of 34% (2).
Paget’s disease of breast is another rare form of invasive breast cancer derived from epithelium. It is more common in women over 50 years of age. It commonly presents clinically, with signs and symptoms including crusting and scaling of skin around the nipple, burning, pruritus, nipple bleeding or discharge, and new nipple inversion. A lump may be felt near or under the nipple. Histologically, it is characterized by large dendritic neoplastic cells (Paget cells) within the epidermis. Paget’s disease of breast is often associated with an underlying DCIS or IDC component (2,4).
An example of Paget’s disease of the nipple
Additional rare breast cancers can occur, including stroma-derived malignancies (phylloides tumors and sarcomas), lymphoma, and metastases from other body sites. In combination, these malignancies represent less than 1% of all breast cancers (2).
A additional classification scheme is used an adjunct to the histopathological classification model. This scheme divides cancers based on their expression of certain hormone receptors and genes that have significance for both management and prognosis.
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/or 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 a treatment. It is important to note that the receptor status of a cancer can change over time.
Both estrogen and progesterone receptor positive cancers are associated with a more favorable prognosis, including higher disease-free survival and reduced mortality. Estrogen-receptor positive cancers can be treated using anti-estrogen therapy (2,6). Estrogen-receptor positive cancers are more common in post-menopausal women (6).
Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene for a transmembrane growth factor receptor. HER2 is present in normal breast epithelial cells, but is overexpressed in 20-25% of all breast cancers. Cancers that overexpress HER2 are considered to be HER2 positive, and are associated with a higher grade and more aggressive rate of spread (2).
Targeted therapies are available for HER2 positive cancers, including Herceptin (transtuzumab), a monoclonal antibody against HER2 protein (2).
Breast cancer can present in three manners:
Breast cancer may not present with any signs or symptoms and instead be identified by a screening mammogram. Screening thus enables earlier diagnosis and results in reduced breast cancer mortality.
The most common presentation of breast cancer is a breast mass or lump. Malignant breast masses are usually firm, hard, irregular and nontender; however, a tender or sore lump does not rule out breast cancer (1). Masses that are fixed to the skin or chest wall are more suspicious of malignancy, as are lesions with overlying skin changes (2). Breast thickening, mastalgia (breast pain), and changes in mass size throughout the menstrual cycle are features more typical of benign breast conditions.
Nipple discharge may be seen in both benign and malignant conditions. However, spontaneous nipple discharge that is unilateral, blood stained, or associated with a mass is suspicious for breast cancer. Changes in the nipple’s appearance, such as new inversion of the nipple, are also concerning for possible malignancy (2).
Paget’s disease is a form of in-situ breast cancer localized to 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 often presents with unilateral erythema, pruritis and scaling of the nipple and areola areas (1). These symptoms are sometimes mistaken for eczema in the early stages of the disease.
Inflammatory breast cancer is an aggressive form of breast cancer that presents similarly to infectious mastitis. Skin on the breast may appear erythematous, pruritic, and warm to touch. As cancer cells invade and block lymphatic vessels, the breast and overlying skin can become edematous. This gives rise to a skin condition known as ‘Peau d’orange,’ in which the skin appears dimpled like an orange peel (1).
Left breast with ‘peau d’orange’
As breast cancer becomes more advanced and spreads to other parts of the body, signs and symptoms may arise outside the breast. Masses felt in the axilla may represent lymphadenopathy caused by malignant spread to the lymph nodes. These masses are typically hard and painless (1).
The most common sites of metastasis in breast cancer are the lungs, liver, bone and brain. Symptoms of metastatic spread can therefore include cough, shortness of breath, jaundice, bone pain, confusion and headache. Additionally, metastatic spread can be associated with non-specific ‘B-symptoms’ including weight loss, loss of appetite, and nausea (2).
Any new breast lesions should be investigated using the ‘triple assessment.’ The ‘triple assessment’ is an overarching approach to breast cancer diagnosis, and refers to the combined use of physical exam, imaging, and biopsy to assess breast lesions.
Taking a good history is an important initial step in the diagnosis process of breast cancer, and can provide valuable information to begin distinguishing between breast malignancy and benign forms of breast disease including mastitis, breast cysts, fibroadenomas, and intraductal papillomas.
The history of presenting illness should focus on eliciting characteristics of the breast mass, including duration, current size of the mass, rate of growth and any changes in the appearance of the breast, nipple or skin. Associated features of the breast mass should also be elicited, including breast pain, changes in the mass throughout the menstrual cycle, and the presence of nipple discharge (1).
Additional information to be elicited includes the presence of any signs or symptoms of lymphatic spread or metastatic disease, as outlined under ‘Signs and Symptoms’.
Any prior history of breast disease should be elicited, including any history of breast hyperplasia, LCIS, or breast cancer1. Information about past mammograms should also be elicited.
Other significant past medical history includes any history of alcohol-use disorder, liver cirrhosis or obesity (as risk factors for breast cancer development), and any prior history of other malignancies. A reproductive history, including age at menarche and menopause, should be taken to assess these risk factors for breast cancer development (1).
Family history should include any history of relatives with breast cancer or ovarian cancer (1). If a positive history is present, details should be elicited including the age of the relative at diagnosis and basic characteristics of their disease course.
Any current use of hormone-replacement therapy or oral contraceptive pills should be assessed.
Any breast concern should be investigated with an appropriate physical examination.
The breast exam should begin with the patient seated and appropriately draped. The breasts should be observed for any visible masses, asymmetry or notable skin changes. The patient should be asked to slowly abduct their arms above their head, and then slowly lower them back down, while the clinician observes for any signs of a breast mass tethering to the skin or muscle. The patient should also be asked to place their hands on their hips and press down in order to elicit any tethering of a breast mass to the pectoralis major muscle (1).
The clinician should next examine the axilla and supraclavicular region by palpation for the presence of any lymphadenopathy (1).
The next portion of the exam is examination of the breasts by palpation. The patient should be asked to lie in a supine position, as this results in the breast tissue being spread more evenly over the chest. Each breast should be examined separately, and during examination the same-sided arm should be raised behind the patients head to help further distribute the breast tissue. Palpation should be performed in a systematic manner and should include all tissue from the sternal border to the axillary tail. Any abnormal masses should be described in terms of their location, size, depth, mobility or fixation, consistency, contours, tenderness and any overlying skin changes (1).
If suspicious of advanced disease, examination of the lungs, liver, and skeleton should be performed to assess for signs of distant metastasis (2).
There are no blood tests used for the diagnosis of breast cancer. However, lab investigations may be helpful as part of the work-up of suspected breast cancer, particularly to evaluate for the possibility of metastatic disease.
Baseline investigations to be performed prior to chemotherapy typically included a CBC, electrolytes, and renal function (BUN, creatinine). Additional investigations may be performed if there is suspicion of metastatic disease based upon the patient’s clinical presentation. These may include liver function tests (AST, ALT, GGT, bilirubin, albumin), indicators of bony metastasis (alkaline phosphatase, calcium), and imaging investigations such as chest x-ray, CT chest, CT abdomen, or bone scan (3).
Diagnostic mammography is the recommended initial investigation of choice for women over the age of 30 years who present with a breast abnormality on screening mammography or on clinical exam (1).
Bilateral diagnostic mammography should be performed as follow-up to abnormal screening mammography, as it provides additional views to further characterize the abnormality and allows for a more thorough inspection of both breasts (4).
Ultrasound is the initial investigation of choice for women under the age of 30 years who present with a breast abnormality (1). It may also be indicated to further evaluate an abnormality on screening mammography, or to evaluate women with dense breasts. Ultrasound imaging is particularly useful for differentiating solid masses from cystic lesions (2).
MRI is uncommonly used to follow up abnormal findings on mammography. In the case of axillary lymph nodes found to be positive for breast cancer in the absence of a known breast tumor, MRI may be useful to identify the location of the primary tumour (2).
A CXR or Chest CT may be obtained if there is clinical suspicion of metastatic spread of breast cancer to the lungs (3).
Liver US or CT abdomen may be obtained if there is clinical suspicion of metastatic spread of breast cancer to the liver (3).
A bone scan may be conducted if there is clinical suspicion of metastatic spread to the bones, based on the presence of bone pain, elevated alkaline phosphatase levels, positive axillary lymph nodes, or a tumour larger than 5 cm (2).
It is crucial that any breast lesion suspicious for malignancy undergo biopsy, as this represents the only definitive method of diagnosis. The type of biopsy performed depends on the degree of suspicion for malignancy and characteristics of the lesion including size and location (2,5).
For lesions with a low to moderate degree of suspicion for malignancy, the following methods of biopsy may be considered:
FNA is most often used for breast masses 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 (2,5).
Core needle biopsies yield a larger sample of cells and preserve cell architecture. It is therefore the method of choice to assess solid breast masses. A large gauge hollow needle is inserted into the lump to obtain core samples of cells (5).
Stereotactic and ultrasound-guided core biopsies are similar to core needle biopsies except they are performed with the aid of either radiological or ultrasound imaging. These biopsy techniques are useful when a breast abnormality is seen on mammography but cannot be palpated (5).
For lesions that are highly suspicious for malignancy, excisional biopsies are performed:
If a breast mass has a high probability of being malignant based on clinical features, an excisional biopsy may 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 (5).
If a breast mass is highly suspicious for malignancy but not easily palpated, a wire-localized biopsy can be performed. Under X-ray guidance, a radiologist inserts a thin wire to identify the location of the mass. The surgeon is then able to use the wire guide as well as the x-ray films to excise the suspicious 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 (5).
The most widely accepted system for breast cancer staging is TNM staging, as outlined by the American Joint Committee on Cancer (AJCC) (1). This system stages breast cancer according to three primary features. The first feature is the tumor size, represented by ‘T’. The second feature is the extent of spread to regional lymph nodes, represented by ‘N’, which can be determined either clinically (‘cN’) or pathologically (‘pN’). The third feature used to classify breast cancer is the presence of any distal metastasis, represented by ‘M’. On the basis of these features, breast cancer is assigned a TNM status, which correlates to a certain stage of breast cancer according to the table below.
However, in the AJCC’s 2017 update to the TNM staging system, they have recommended that the HER2, estrogen receptor, and progesterone receptor status of the malignancy should be considered in staging. Breast cancer staging has thus become quite complex and is beyond the scope of this module, but the complete AJCC cancer staging system can be reviewed here: [link]
The treatment of breast cancer varies widely depending on the stage of the cancer. Similarly, the goals of treatment also vary from curative to palliative depending on tumour, patient, and treatment factors.
Surgery, radiation therapy, chemotherapy and hormone therapy are the main treatment modalities employed in breast cancer management.
As soon as a confirmed tissue diagnosis of breast cancer has been made, the patient should be referred to the appropriate treating physicians as soon as possible. The patient is usually seen first by a surgeon for consideration of resection of the malignancy, unless the disease is identified as metastatic at the time of diagnosis (1). Referral to medical and radiation oncologists is usually done by the surgeon post-operatively, unless the patient wishes to discuss his or her options with the oncologist prior to making a decision about surgery (1).
Other referrals to be considered include genetic counselling if there is suspicion for a hereditary cancer gene, and a fertility program if the patient is pre-menopausal and would like to have children in the future (1).
Surgery is a core component of breast cancer treatment and is offered for all breast malignancies with the exception of stage IV (metastatic) disease (2). For non-metastatic breast cancer, surgery is considered the primary treatment. Adjuvant systemic therapies may then be employed post-operatively to decrease cancer recurrence by eliminating micrometastic lesions that may have spread from the original primary tumour (3).
Several surgical procedures are employed in the management of breast cancer.
Breast conserving surgery (BCS), also known as a ‘lumpectomy’ or partial mastectomy, is a procedure in which the surgeon aims to remove the breast tumour along with a margin of healthy tissue, while sparing the remaining healthy breast tissue (2). When BCS is performed in patients with DCIS or early invasive breast cancer, and followed by external beam radiation therapy, it has been shown to achieve survival rates equal to those of patients treated with complete mastectomy (3). Contraindications to BCS include multicentric tumours, inflammatory breast cancer, persistent positive margins after prior surgical resections, and contraindications to radiation such as pregnancy or history of previous breast irradiation (4). BCS is also not a good option for women with large tumour size relative to breast volume, as a good cosmetic result may not be achieved under these conditions (4).
Mastectomy is a surgical procedure in which the whole breast is removed. In a simple mastectomy, only the breast tissue is removed, with the surrounding musculature and lymph nodes remaining in place. This procedure was historically performed in patients with DCIS and early invasive breast cancer (2). In a modified radical mastectomy, the breast tissue, nipple, axillary lymph nodes and pectoralis fascia are all removed. This procedure continues to be performed in patients for whom BCS is contraindicated or who prefer not to undergo radiation therapy (2).
Some women at high risk of developing further invasive breast cancer may choose to undergo prophylactic total bilateral mastectomy (2). This is not commonly performed as it is considered to be an aggressive treatment.
Surgical management also includes procedures to biopsy lymph nodes for use in cancer staging. A sentinel lymph node biopsy is usually recommended for patients with no clinically palpable lymph nodes (clinically N0) (5). In this procedure, the single axillary lymph node to which cancer is most likely to spread is removed and sent for pathology. If the sentinel lymph node is negative, the cancer is unlikely to have spread to any lymph nodes. If the sentinel lymph node is positive, the patient should undergo complete axillary lymph node dissection to remove the remaining axillary lymph nodes and allow assessment of the extent of the cancer’s lymphatic involvement (5). Patients should proceed immediately to axillary lymph node dissection if they have clinically node positive disease or inflammatory breast cancer (5).
Finally, surgery may be considered for palliative intent. Mastectomies may be considered for patients with large, painful, or fungating breast lesions. Surgery for isolated brain or spinal cord metastases, isolated lung metastases, and/or isolated liver metastases may be considered to help control pain and other symptoms of metastatic disease (2,3).
External beam radiation therapy is an important component of breast cancer management. Radiation therapy is offered to breast cancer patients following breast-conserving surgery in order to reduce the risk of cancer recurrence (5). For early invasive breast cancer, the use of external beam radiation therapy results in a 20% absolute reduction in risk of recurrence at 10 years post-diagnosis, which in turn results in a 5% reduction in breast cancer mortality (5).
Radiation treatment is usually not performed in patients who have undergone modified radical mastectomy for early invasive breast cancer. However, radiation therapy may be offered to these patients if certain high-risk features are present, including lymph-node positive disease (2).
External beam radiation may also target the lymph nodes if they are found to be positive, as well as the chest wall if certain high-risk features are present (2).
The schedule for radiation therapy typically involves treatments being given five days per week for a duration of five to seven weeks (6). Patients may experience side effects from radiation therapy, including (2,5):
External beam radiation may also be considered for palliation. It may be used to control pain and other symptoms arising from localized metastases, such as bone metastases, spinal cord metastases, metastases causing bronchial obstruction, and large or painful chest wall metastases (2).
Hormonal therapies are offered as adjuvant therapies to patients with hormone-receptor positive DCIS or invasive breast cancer of any stage. The duration of recommended use ranges from five years for DCIS to ten years for more advanced breast cancers (2,5). Options for hormonal therapy include selective-estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), ovarian suppression with luteinizing hormone-releasing hormone (LHRH) agonists, and surgical removal of the ovaries.
SERMs are competitive partial agonists for the estrogen-receptor (ER) and have variable agonist and antagonist action on ERs throughout the body. AIs inhibit the enzyme aromatase, which functions to convert androgen precursor molecules to estrogen in the body’s peripheral tissues. AIs are ineffective in pre-menopausal women, as the main source of estrogen in these women is the ovaries (not the peripheral tissues) (2).
In pre-menopausal women, SERMs are the first-line hormonal therapy for estrogen or progesterone-receptor positive breast cancers (2). Tamoxifen is the most commonly used SERM, and has been shown to reduce the risk of breast cancer recurrence by 30-50% in premenopausal women (7). Tamoxifen is also the most commonly used agent in post-menopausal women, in whom it reduces the risk of breast cancer recurrence by 40-50% (7). However, in post-menopausal women with stage 4 breast cancer, AIs are considered first-line due to their greater efficacy in this population (2). The most commonly used AI is letrozole (2).
Tamoxifen is associated with an increased risk of endometrial cancer, DVT/PE and stroke (2,5). It is therefore relatively contraindicated in women with a personal history of venous thromboembolism or endometrial cancer (5). AIs are associated with an increased risk of osteoporosis and dyslipidemia, and caution should be therefore be used when prescribing AIs to women with a history of these conditions (2,5).
Side effects of hormonal therapy may include the following (2):
Chemotherapy is most often used as an adjuvant therapy for breast cancers that are stage II or greater. It is particularly important for breast cancers that are ER and PR negative, as these malignancies do not qualify for hormonal therapy (2). The age, medical comorbidities, and values of the patient should be considered prior to starting any chemotherapy regimen (3).
Chemotherapy may also be used as a neoadjuvant therapy to reduce the size of the tumor prior to surgery. This may render previously non-operable tumors operable or allow breast-conserving surgery in a patient for whom this was not previously feasible goal (2,3).
Multiagent chemotherapy regimens are usually employed due to their greater efficacy (2). Herceptin (trastuzumab) is a monoclonal antibody against the HER2 receptor that is used in the treatment of HER2 positive breast cancers (5).
Information in the table above was derived from the Canadian Cancer Society and the American Cancer Society (2,8,9).
As demonstrated in the table below, the prognosis of breast cancer is determinedly largely by the stage of disease. Stage 0 and Stage 1 disease has a 5-year survival of 98-100%, while Stage 4 disease has a median survival of 18-24 months (2,3,5). Within staging, the presence or absence of spread to lymph nodes is the most important prognostic factor (2). Higher numbers of positive lymph nodes are associated with a worse prognosis (2). The second most important prognostic factor within staging is the size of the tumour, with larger tumours having a worse prognosis (2).
Information in the table above was derived from the Canadian Cancer Society (2).
Additional factors also have an influence on prognosis and may guide treatment decisions. Positive hormone-receptor status is associated with a better prognosis, as these tumours are usually less aggressive and respond well to hormonal therapies (2). HER2 positive status is associated with a worse prognosis, as these tumours are usually more aggressive and more likely to metastasize (2). Younger age at diagnosis (age < 35 years) is also associated with more aggressive, higher-grade tumours, and thus a worse prognosis (2).
Following up with patients after treatment concludes 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 for early detection of recurrent breast disease (1).
Because breast cancer is different for every individual, the appropriate follow-up schedule can also vary considerably. Guidance on this will usually be provided by the patient’s oncologist prior to discharging the patient back to the family physician.
In general, the first follow-up appointment should be made within six weeks after the end of treatment. Follow-up appointments are usually recommended to occur every 3-6 months for the first 5 years, and annually thereafter (2,3).
Each follow-up appointment should include a history, physical examination, and review of any appropriate investigations.
The history is intended to assess the presence of treatment side-effects or disease recurrence. The patient should be asked about any persistent or new-onset symptoms, including pain, shortness of breath, nausea, weight loss, change in appetite, fevers/chills, and any noticeable masses (1).
The physical exam should include a clinical breast exam, axillary node palpation, and an examination of the chest and abdomen.
Diagnostic mammography is the appropriate investigation for follow-up of breast cancer. It should be performed six-months after the end of treatment, and annually thereafter (3). 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).
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.
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