Carcinoma of the breast is the most common cancer in women in the United States (32%) and is second only to lung cancer as a cause of cancer death in women (15%).
Estimated new cases and deaths from breast cancer (women only) in the United States in 2017 :
- New cases: 255,180.
- Deaths: 41,070.
The lifetime risk for women of being diagnosed with breast cancer is currently about 1 in 8.
Breast cancer is relatively uncommon in men; the female-to-male ratio is approximately 100:1.
The risk of developing breast cancer increases with age. Only about 0.8% of breast cancers occur in women < 30 years old and approximately 6.5% develop in women between 30 and 40 years old. Most cases occur in patients over 40 years of age.
Race and ethnicity
White women have a higher overall rate of breast cancer than African-American women; however, this difference is not apparent until after menopause. American Asian and Hispanic women have approximately half the incidence of American Caucasian women. Native-American women extremely low risk of developing breast cancer.
The incidence of breast cancer is significantly higher in the United States and European countries such as the United Kingdom, Denmark, the Netherlands, New Zealand and Switzerland than in India, Japan, Thailand, Nigeria. It has been suggested that these trends in breast cancer incidence may be related to dietary fat consumption.
Causes and risk factors
1. Family history
The degree of relativity
- The relative risk of patients with an affected first-degree relative (mother, daughter, or sister) is 1.7 times higher when compared to controls without affected family members.
- Having two first-degree relatives affected (female or male) increases relative risk by more than 4-6 times when compared to patients without this risk factor.
Age of affected relative at time of diagnosis
- A patient with a mother diagnosed when younger than 60 years is at 2 times increased risk.
- Premenopausal onset of the disease in a first-degree relative is associated with a 3 times increase in breast cancer risk.
Bilateral breast cancer in a relative
- Bilateral cancer in a first-degree relative may increase risk by more than 6 times.
- The relative risk for a woman whose first-degree relative developed bilateral breast cancer prior to menopause is nearly 9 times.
2. Menstrual and reproductive factors
- Early menarche (before the age of 12) has been associated with a two-fold increase in risk.
- Late menopause (after the age of 55) also have a two-fold increase in the risk of developing breast cancer.
- A first full term pregnancy after the age of 30 is associated with a two-fold increase in risk when compared to those with an early first full term pregnancy.
3. Contraceptive pills and Hormone replacement therapy
Epidemiologic data provide strong evidence for an association between plasma estrogens and breast cancer risk.
Oral contraceptive pills
- In 1996 a large meta-analysis showed that a history of recent oral contraceptive use, rather than the duration of use, was a predictor of breast cancer risk.
- This data was based on older high-dose and moderate-dose oral contraceptive pills and not the recently used low-dose pills.
Hormone replacement therapy
In regard to hormone replacement therapy (HRT) or postmenopausal hormone use, results from the Women's Health Initiative (WHI) showed that the overall risks of a combined estrogen and progestin outweigh the benefits.
- In the arm taking estrogen plus progestin there was a 26% increase in risk of invasive breast cancer, compared with the arm taking a placebo. In addition, in women taking these hormones, there were increased risks of heart disease, stroke, and blood clots.
- In the estrogen-alone arm there was no increase in breast cancer risk reported. The? trial also concluded that estrogen alone does not appear to increase or decrease a woman's risk of heart disease, although it does appear to increase her risk of stroke and decrease her risk of hip fracture.
4. Genetic factors
Genetic risk factors account for less than 10% of breast cancers.
Autosomal dominant inheritance is seen in:
- Li-Fraumeni syndrome
- Muir-Torre syndrome
- Cowden disease
- Peutz-Jeghers syndrome
- BRCA1 and BRCA2 mutations
BRCA1, although rare, accounts for 45% of high-risk familial inheritances of breast cancer. The risk of developing invasive carcinoma is close to 50% when younger than 50 years and exceeds 80% prior to 65 years.
Autosomal recessive inheritance is seen in:
5. Proliferative breast diseases
This category comprises the following conditions moderate or florid epithelial hyperplasia, with or without atypica, sclerosing adenosis, and small duct papillomas.
Other benign conditions (mild ductal hyperplasia, adenosis, cystic changes, apocrine metaplasia) are not associated with increased risk.
- Epithelial hyperplasia: Involves proliferation of epithelial layers usually three or more layers in thickness.
- Sclerosing adenosis: Involves increased numbers of benign ducts distorted by sclerosis.
- Papillomas: Papillomas are composed of bland epithelial cells with a well defined fibrovascular core, a basal myoepithelial layer, and intact basement membrane.
- Atypical ductal hyperplasia: Is associated with proliferation of ductal epithelial cells sharing some but not all the features of ductal carcinoma in situ (DCIS).
- Atypical lobular hyperplasia: Is the proliferation of lobular cells sharing features of lobular carcinoma in situ (LCIS) but filling or distending less than 50% of the acini within the lobule.
Risk associated with each type
- Moderate or florid ductal hyperplasia and sclerosing adenosis, papillomas (proliferative breast disease without atypia) pose only a slightly increased risk of breast cancer (1.5-2.0 times).
- Benign proliferative changes with atypical hyperplasia, such as atypical ductal or lobular hyperplasia. These may increase relative risk by 4 times. Patients who have a family history of breast cancer along with a personal history of atypical epithelial hyperplasia have an 8-fold increase in breast cancer risk when compared with patients with a positive family history alone and an 11-fold increase in breast cancer risk when compared with patients who do not have atypical hyperplasia and have a negative family history.
- Noninvasive carcinoma (ductal carcinoma in situ or lobular carcinoma in situ) on previous biopsy: Lobular carcinoma in situ, markedly increases risk (8-11 times).
- Personal history of breast cancer: This also is a recognized risk factor. This factor depends on patient age at time of diagnosis. Risk is increased for younger women. The risk is about 1% per year from the time of diagnosis of an initial sporadic breast cancer. The risk for development of a second primary breast cancer is significantly higher for women with hereditary breast cancer, approximately 5% per year (50%-60% lifetime risk). Also in cases with history of endometrial, ovarian, or colon cancer.
6. Radiation exposure
- Atomic bomb survivors: An increased rate of breast cancer has been observed in survivors of the atomic bomb explosions in Japan, with a peak latency period of 15-20 years.
- Radiation therapy: Patients with Hodgkin's disease who are treated with mantle irradiation, particularly women who are younger than age 20 at the time of radiation therapy were found to have an increased incidence of breast cancer.
7. High-fat diet
Diets that are high in fat have been associated with an increased risk for breast cancer. It has been suggested that differences in dietary fat content may account for the variations in breast cancer incidence observed among different countries.
Alterations in endogenous estrogen levels secondary to obesity may enhance breast cancer risk (aromatization of testosterone to estradiol occurs in the adipose tissue).
Moderate alcohol intake (two or more drinks per day) appears to modestly increase breast cancer risk.
10. Socioeconomic status
The incidence of breast cancer is greater in women of higher socioeconomic background. This relationship is most likely related to lifestyle differences, such as age at first birth.
Symptoms and signs
The left breast is involved more frequently than the right, and the most common locations of the disease are the upper outer quadrant and retroareolar region.
- Asymptomatic: Increasing numbers of breast malignancies are being discovered in asymptomatic patients through the use of screening mammography.
- Breast lumps are detectable in 80% of patients with breast cancer and constitute the most common sign on history and physical examination. The typical breast cancer mass has a dominant character and tends to be:
- Breast pain is the presenting symptom in approximately 5% of patients.
- Skin or nipple retraction in 5% of patients.
- Spontaneous nipple discharge through a mammary duct is the presenting symptom in approximately 2% of patients.
- Breast enlargement is seen in 1% of cases.
- Nipple crusting or erosion: This can occur in Paget's disease and is the presenting symptom in 1% of the cases.
Memory aid: asymptomatic + 3 signs related to the nipple and 3 related to the whole breast.
Lymph node metasasis
The most common regions that breast cancer may spread to in order of frequency are:
- Bone (80%)
- Lung (25%)
- Liver (20%)
- Brain (15%)
- Other organs which include the bone marrow, brain, ovaries, spinal cord, eye (20%).
Breast self examination
The American Cancer Society (ACS) recommends that:
- Beginning in their 20s, women should be told about the benefits and limitations of breast self-examination (BSE).
- There is no data to suggest that breast self examination reduces the risk of mortality from cancer.
- Women who performed breast self-examination were found to be more likely to have smaller tumors and less likely to have axillary node metastases than those who did not.
A major problem with breast self-examination as a screening technique is that it is rarely performed well.
Clinical breast examination
The ACS recommends clinical breast examination for women:
- Between ages 20 and 39 - every 3 years
- Beginning at age 40 - every year
The clinical examination should include inspection and palpation of the breast and regional lymph nodes. If the clinician detects an abnormality, the patient should then undergo diagnostic imaging rather than screening.
- There is no data to suggest that clinical breast examination reduces the risk of mortality from cancer.
- Approximately 20% of breast cancers are detected by clinical breast examination.
Screening mammography is performed in the asymptomatic patient to detect an occult breast cancer. Currently, the American Cancer Society recommends:
- Beginning at age 40 years - annual mammography and examination by a physician
- Mammography has a sensitivity and specificity of 90% if there is a palpable mass.
- In impalpable cases the sensitivity and specificity are reduced to 50%.
- It detects the majority of cases an average of 2 years prior to any perceptible clinical signs or symptoms.
- Multiple prospective randomized controlled trials have demonstrated that mammography can reduce the mortality from breast cancer by 24% in women aged 50-74.
This, however, does not apply to younger women, particularly those aged younger than 40 years. In addition, the sensitivity of mammography is decreased significantly in young patients with dense breast tissue and possibly with augmentation prosthesis. Mammography seldom is recommended in patients younger than 30 years. Exceptions to this rule would be young women with extensive family histories for breast cancer.
Mammographic findings & suggestive lesions
- Breast masses: Stellate shape, irregular or spiculated margins suggest cancer.
- Evaluating the breast for calcifications: Pleomorphic calcifications less than 0.5 mm (microcalcifications).
- Architectural distortion and asymmetry suggest cancer.
- Skin thickening
- Nipple changes
- Axillary adenopathy
The American College of Radiology established the standard for classification of radiographic abnormalities, known as the Breast Imaging Reporting and Data System
(BI-RADS), as follows:
|0||Incomplete examination||Usually requiring further imaging or evaluation|
|I||Normal||Follow-up study in 1 year|
|II||Benign||Follow-up study in 1 year|
|III||Likely to be benign||Follow-up mammogram in 6 months|
|V||Highly suspicious for malignancy||Biopsy recommended|
As an adjunct to mammography, ultrasonography (US) can be particularly useful in younger patients or women with fibrocystic change and should be the initial investigation for palpable lesions in women younger than 35 years. Its main use remains in distinguishing solid from cystic lesions. In the workup of nonpalpable lesions, US can be used to guide a needle biopsy or to place a localizing wire to direct an excisional biopsy.
- In palpable masses it sensitivity and specificity are about 95%.
Magnetic Resonance Imaging (MRI)
MRI is a particularly useful modality for detailing architectural abnormalities in the breast and can help detect lesions as small as 2-3 mm. MRI should be used in scarred breasts, implants, multifocal lesions, and for borderline lesions planned for breast conservation.
- Has a sensitivity approaching 100% but its specificity is only 50%.
The label typically used is technetium Tc 99m Sestamibi, a compound that concentrates in mitochondria and whose efflux is related to expression of the multidrug resistance protein. Therefore, the size of the signal distinguishes the high metabolic rate of a malignant tumor and may help predict resistance to chemotherapy.
Scintimammography is less sensitive than MRI for lesions smaller than 1 cm, is more specific for palpable lesions and is useful for detecting axillary involvement. It can also be useful in cases with impalpable masses due to its high specificity in this setting.
- Has a sensitivity and specificity of 90% in detection of impalpable masses.
Positron emission tomography (PET)
PET is the most sensitive and specific of all the imaging modalities for breast disease. However, it is also one of the most expensive and least widely available. PET is useful in axillary assessment, scarred breasts, and multifocal lesions.
- Has a sensitivity of 95% and specificity of 100%.
FNAC (Fine needle aspiration cytology)
- FNAC (Fine needle aspiration cytology) from breast mass: sensitivity 95% & specificity 98%.
However, it should not be used for diagnosing lymph node metastasis (only excisional biopsy). One drawback of FNAC is that it cannot differentiate between invasive and insitu cancers as only cells are seen and the architecture cannot be evaluated as in biopsies. Aspiration of a simple benign breast cyst should yield non-bloody fluid and result in complete resolution of the lesion.
Ultrasound /? stereotactic core biopsy
This technique is helpful in cases where there are findings in the mammography. A wire or needle guided lumpectomy can follow this procedure.
- Wide-bore needle biopsy is less sensitive but more specific when compared to FNAC (specificity 100%)
An excisional biopsy, in which the entire breast mass is removed, definitively establishes the diagnosis. When the mass is extremely large, an incisional biopsy (which entails removal of only a portion of the mass) may be more appropriate.
- Specificity of 100%.
Ductal lavage is currently being developed and analyzed as a minimally invasive tool to identify cellular atypia within breast ducts in women who are already at high risk for developing breast cancer. Preliminary results indicate that this method has a low sensitivity and specificity (Journal of the National Cancer Institute 2004;96:1488-1489,1510-1517).
Doubling times for primary breast cancer ranged from 44 to more than 1,800 days, with a mean of 212 days. Metastatic lesions may have a slightly faster average rate of growth than primary tumors.
The World Health Organization classification of breast tumors organizes both benign and malignant lesions by histologic pattern. Epithelial tumors comprise the largest group, including intraductal papilloma, adenomas, intraductal and lobular carcinoma in situ, invasive (ductal and lobular) carcinoma, and Paget disease of the nipple. Invasive ductal carcinoma is by far the most common type.
The relative frequency of malignant breast cancers are:
- Ductal carcinoma:78%
- Lobular carcinoma: 9%
Alveolar & mixed types are bilateral. Solid & signet ring have worse prognosis than IDC with high tendency to metastasize.
- Comedocarcinoma: 5%
- Medullary: 4%.
- Inflammatory: worst prognosis
- Paget's: unilateral eczema of the nipple.
The pathological classification of breast cancer is based on on the anatomic or structural units
present in the female breast. These units consist of large, medium, and small ducts from which a variety of tumor types arise.
1. Large ducts
Tumors arising from duct epithelium may be found only within the lumen of the ducts of origin;
that is, the carcinomas are intraductal and do not penetrate the basement membrane or invade surrounding stroma. Most frequently, such tumors arise from large ducts and may present as several types.
Ductal carcinoma in situ (DCIS)
The noninvasive variety of ductal carcinoma, referred to as intraductal carcinoma or ductal
carcinoma in situ (DCIS), is a proliferation of a subgroup of epithelial cells confined to the mammary ducts without light microscopic evidence of invasion through the basement membrane into the stroma.
DCIS, like invasive ductal carcinoma, occurs more frequently in women, although it accounts for approximately 5% of all male breast cancers. The average age at diagnosis of DCIS is 54-56 years, which is approximately a decade later than the age at presentation for LCIS.
The clinical signs of DCIS include a mass, breast pain, or bloody nipple discharge. On mammography, the disease most often appears as microcalcifications.
The risk of developing an invasive carcinoma following a biopsy-proven diagnosis of DCIS is between 25% and 50%. Virtually all invasive cancers that follow DCIS are ductal and ipsilateral and generally present in the same quadrant within 10 years of the diagnosis of DCIS. DCIS is less likely than LCIS to be bilateral and has approximately a 30% incidence of multicentricity. DCIS is considered a more ominous lesion than LCIS and appears to be a more direct precursor of invasive cancer.
A variety of histologic patterns of DCIS have been recognized. The most frequently encountered are:
The different histologic patterns have been associated with differences in biologic behavior. Some researchers have divided DCIS into two subgroups: comedo and noncomedo types. As compared with the noncomedo subtypes, the comedo variant has a higher proliferative rate, overexpression of HER-2/neu, and a higher incidence of local recurrence and microinvasion.The role of assays for estrogen and progesterone receptors (ER and PR) in DCIS has not been established.
Comedocarcinoma: is characterized by ducts that are dilated and filled with carcinoma cells. These are necrotic and can be expressed as semisolid necrotic plugs. Such cancers are not usually regarded as a separate cell type but rather represent a descriptive variant of intraductal carcinoma. Patients whose DCIS exhibits comedo features have been shown to have increased rates of local recurrence and may progress more rapidly to invasive breast cancer compared to other types.
Papillary carcinoma: If they grow into the ducts with a papillary configuration, they are recognized as papillary carcinomas. Such lesions are rare, accounting for about 1% of breast cancers. Histologically, pleomorphic duct epithelial cells with disturbed polarity can be demonstrated, as can their "heaping up" into papillae. Difficulty may be encountered in differentiating a papillary carcinoma from a benign atypical papilloma.
Papillary carcinomas rarely invade the surrounding stroma. A survival rate approaching
100% may be anticipated upon complete excision of such tumors. When these tumors do invade surrounding tissue, they grow rather slowly and attain considerable bulk. Skin and fascial attachments are unusual, and axillary node involvement is a late feature. Clinically, noninvasive tumors are found to be movable, circumscribed lesions that have a soft consistency not unlike that of fibroadenomas.
1. IDC NOS
Infiltrating duct carcinomas in which no special type of histologic structure is recognized are designated "not otherwise specified" (NOS) and are the most common duct tumors, accounting for almost 80% of breast cancers. They are characterized clinically by their stony hardness to palpation. When they are transected, a gritty resistance is encountered, and the tumor retracts below the cut surface. Yellowish, chalky streaks that represent necrotic foci are observed. Histologically, varying degrees of fibrotic response are present. As a rule, they do not become large. They frequently metastasize to axillary lymph nodes, and their prognosis is the poorest of the various tumor types. More than half (52.6%) of breast cancers are pure infiltrating duct lesions (NOS).
Special types of IDC
Medullary carcinoma, composing 5 to 7% of all mammary carcinomas, often attains large dimensions. This tumor is formed by cells of relatively high nuclear grade, and usually exhibits an extensive infiltration of the tumor by small lymphocytes. Medullary carcinomas have a relatively well-circumscribed border, sometimes described as a "pushing" border, in contrast to the NOS tumors in which small nests of cells tend to infiltrate the adjacent stroma more extensively. A study of medullary cancer using 336 typical and 273 atypical medullary breast cancers from 6,404 patients enrolled in various Stage I and Stage II National Surgical Adjuvant Breast Project (NSABP) trials indicated that the survival of patients with typical medullary cancers was better than that for patients with NOS invasive ductal carcinomas. Survival was comparable for those with atypical medullary and NOS types.
Tubular carcinoma is an invasive carcinoma in which tubule formation is highly prominent. This tumor has a low nuclear grade with some cell polarity. Its prognosis is favorable, and, when combined with small size, it is a highly curable tumor.
Mucinous or colloid carcinoma, which composes about 3% of all mammary carcinomas, is characterized on microscopy by its nests and strands of epithelial cells floating in a mucinous matrix. It usually grows slowly and can reach bulky proportions. When the tumor is predominantly mucinous, the prognosis tends to be good. Two entities represent special manifestations of mammary carcinoma.
Papillary carcinoma: See above.
2. Small ducts
Lobular carcinoma in situ
With the increased use of mammography, a much higher proportion of noninvasive cancers is being detected. Lobular CIS consists of a neoplastic proliferation of cells in the terminal breast ducts and acini. It is characterized by small and round cells of low nuclear grade that fill and expand lobules without penetration of the basement membrane. Though these lesions are low grade, there is a 15-30% risk for development of invasive carcinoma in the same or the opposite breast. This risk is greatest within 10-15 years after the diagnosis is established. Whereas DCIS often accompanies invasive ductal carcinoma, and may well be its usual precursor, LCIS may be followed by invasive ductal or invasive lobular carcinomas in either breast. LCIS thus is more a systemic marker than a local precursor. Recent investigations suggest that LCIS is heterogeneous, and there is biologic variability. Therefore, there may be certain subtypes of LCIS that are more likely to progress to invasion.
There is no mass lesion or mammographic abnormality associated with this disease. The pathologist is the only physician who makes this diagnosis. LCIS is found in 0.5-3.8% of otherwise benign breast biopsies. The true incidence of lobular carcinomas is uncertain. It has been emphasized that noninvasive mammary carcinomas make up almost 5% of all neoplastic lesions of the female breast and that LCIS accounts for about 50% of these, or 2.5 to 2.8% of all tumors. The incidence of LCIS has doubled over the past 25 years and is now 2.8 per 100,000 women. In the past, the peak incidence of LCIS was in women in their 40s. Over the past 3 decades, the peak incidence has increased to the 50s. The incidence of LCIS decreases in women who are in their 60s-80s. This may be related to the use of hormone replacement therapy (HRT).
Pathology: Most commonly in both breasts in multifocal and multicentric. If LCIS is found in a breast, >50% will have residual LCIS in the ipsilateral breast and >1/3 will have LCIS in the contralateral breast. Classically, involved acini are filled and distended by a uniform population of cells. At least half of the acini are involved within the lobular unit (this distinguishes it from atypical lobular hyperplasia in which fewer than half of the acini are expanded or distorted by a uniform population of lobular cells.
Lobular carcinoma arises from the small end ducts of the breast.
Invasive lobular carcinoma is similar to LCIS but the lesion extends beyond the boundary of the lobule or terminal duct from which it arises. Often the small cells interdigitate between collagen bundles in a single line, so-called "Indian file". At other times, lobular carcinoma may be nearly indistinguishable from the conventional infiltrating duct carcinoma.?The increase in invasive lobular carcinoma peaks in women in their 70s. It is associated with both synchronous and metachronous contralateral primary tumors in 30% of the cases.
Inflammatory breast cancer
Inflammatory breast cancer, or "dermal lymphatic carcinomatosis", is an uncommon form of rapidly advancing breast cancer that usually accounts for approximately 1% to 3% of all breast cancer diagnoses. Inflammatory breast cancer causes the breast to appear swollen and inflamed. This appearance is often caused when cancer cells block the lymphatic vessels in the skin of the breast, preventing the normal flow of lymph fluid and leading to reddened, swollen and infected-looking breast skin; hence the designation "inflammatory" breast cancer. It can easily be confused with mastitis an infection of the breast ducts. To increase the confusion with infection, resulting in treatment with antibiotics, and sometimes, but not always, the antiobiotic treatment changes the appearance of clinical symptoms.? The reason for an apparent response to antibiotics when IBC is present is not known, and may delay the diagnosis of IBC.
With inflammatory breast cancer, the breast skin has a thick, pitted appearance that is classically described as peau d'orange (resembling an orange peel). Sometimes the skin develops ridges and small bumps that resemble hives. These features may be present at the time of primary diagnosis or as part of the clinical picture of recurrent breast cancer.
Biopsies of the erythematous areas and adjacent normal-appearing skin reveal poorly differentiated cancer cells filling and obstructing the subdermal lymphatics. Inflammatory cells are rarely present. Patients typically have signs of advanced cancer, including palpable axillary nodes, supraclavicular nodes, and/or distant metastases.
Paget's disease of the nipple
This disease presents as a persistent dermatitis of the nipple. Clinically, the patient presents with a relatively long history of eczematoid changes in the nipple, with itching, burning, oozing, and/or bleeding which is often unresponsive to topical steroid and antibiotics. The nipple changes are associated with an underlying carcinoma in the breast that can be palpated in about two-thirds of the patients. The alert physician may biopsy the nipple revealing the characteristic changes. Clinically impalpable and radiologically undetectable disease is present in about 40% of the patients. Most commonly, this is an infiltrating ductal carcinoma but occasionally a ductal carcinoma in situ (DCIS) may be present. Overall, this cancer is rare, comprising 1-4% of all patients with breast carcinoma.
Under the microscope, there is a proliferation of malignant epithelial cells scattered throughout the epidermis. The cells have abundant pale staining cytoplasm surrounding a hyperchromatic nucleus with prominent nucleoli.
Other histological types
Several other histologic types of mammary carcinomas have been described but are rarely encountered. Adenocystic carcinoma, carcinosarcomas, pure squamous cell carcinoma, metaplastic carcinomas (carcinoma with osseous or cartilaginous stroma), basal cell carcinomas, and so-called lipid-rich carcinomas have been observed. Because of their rarity, clinical correlates are practically nonexistent.
Staging and prognostic factors
Staging techniques -
1. Bone scan
The bone scan can detect an abnormality prior to the radiograph becoming abnormal. Abnormal areas of accumulation are seen related to osteoblastic activity. Purely lytic lesions such as multiple myeloma may be missed on the bone scan.
- Bone scans are quite sensitive (70%) for the detection of metastatic disease, but the specificity is lower than the sensitivity (60%), hence the need for correlation with plain radiographs and CT.
The poor specificity is because any process involving bone will result in increased bone turnover and an abnormality on the bone scan. Thus, inflammatory, traumatic, and metabolic abnormalities will result in increased areas of localization on the bone scan.
2. Bone X-ray
Compared with other imaging techniques, radiography is relatively insensitive in detecting bone metastases, especially subtle lesions.
- Can detect lesions that are 2 cm or larger. Metastases to bone become apparent on radiographs only after the loss of more than 50% of the bone mineral content at the site of disease.
- Useful in confirmation of lesions that are detected by bone scan.
3. CT scan of bone lesion
CT scans of the bone is useful in detection of metastasis or confirmation of bone lesions detected by bone scan.
- More sensitive than radiography in the detection of metastatic lesions and is useful for confirmation of the results obtained by scintigraphy (bone scans), especially in sacral lesions - specificity 90%.
4. MRI of the bone
- Whole body MRI has been reported to be superior to bone scans in detection of bone metastasis. Sensitivity is 80% and specificity is >90%.
5. PET scan for bone lesions
- FDG PET has the highest sensitivity in detecting bone metastasis: 90%. Its specificity approaches 100%.
Pulmonary metastasis (25%)
1. Chest x-ray
A chest radiograph in two planes is indicated on a regular basis to screen for metastatic disease in the follow-up of patients with primary tumors that preferentially spread to the lungs.
- Sensitivity and specificity for chest radiography were 50 and 90%, respectively for nodules >5mm.
- It more accurately detects a 1-cm nodules 1cm or greater.
2. Chest CT
When metastatic nodules are identified, helical computed tomography (CT) of the chest? should be performed to assess their number and characteristics.?
- A high-resolution CT scan can identify nodules 3 mm in diameter.
- CT has an overall sensitivity 62% in detecting pulmonary nodules (all sizes). However it underestimated the extent of the disease in 25%, and overestimated the extent of the disease in 14%.
- Sensitivity is increased to 95% for intrapulmonary nodules more than or equal to 6 mm and 100% for intrapulmonary nodules > 10 mm.
The limitations of CT scan in this study were mainly associated with pleural-based nodules and intrapulmonary nodules < 6 mm.
Liver metastasis (20%)
1. Ultrasonography of the liver
Ultrasonography is inexpensive and readily available, but its value compared to single-slice helical CT (SSCT), MSCT, and MRI is limited as a consequence of reduced sensitivity and specificity. In general, the US appearance of liver metastases is nonspecific.
- Sensitivity is operator dependent. It is valuable, inexpensive, quick, and portable, and it can depict lesions as small as 1 cm with a sensitivity approaching 80%.
- The specificity of US in detecting liver metastases is poor, and its overall false-negative rate is 50%. However, the presence of multiple hepatic nodules of different sizes within the liver is nearly always due to metastases.
2. Abdominal CT
CT is the most sensitive technique for the detection of liver metastases.
- Contrast-enhanced scans offer a high degree of sensitivity, as high as 80-90%. The specificity is 99%.
Brain metastasis (15%)
Screening for brain metastasis is not routinely done in breast cancer and is only done for those with symptoms suggestive of brain involvement.
1. CT scan of the brain
CT scan of the brain is currently the method of choice in screening for brain metastasis. Patients with multiple lesions are even more likely to have metastatic disease. Prior to definitive therapy, patients with a single metastasis by contrast-enhanced CT should undergo a contrasted MRI examination, if available.
- 92% sensitivity, 99% specificity
2. MRI of the brain
Gadolinium-enhanced MRI is superior to contrast-enhanced CT in the diagnosis of brain metastases. It is particularly useful in patients shown to have a single metastasis by contrast-enhanced CT prior to definitive therapy.
3. FDG-PET for brain lesions
FDG-PET is not considered superior to CT or MRI in the initial evaluation of suspected brain metastases.
- Sensitivity of 90% but low specificity. Neoplasm, inflammation, vascularity, or trauma may cause the abnormal uptake.
Staging of breast cancer
- The TNM staging system for breast cancer
Prognosis (Risk factors for recurrence)
The challenge for the clinician is to determine which patients have the highest risk of recurrence and, thus, are most likely to benefit from adjuvant therapy. In this chapter, we will detail the prognostic factors that affect whether adjuvant therapy is indicated and then describe the various adjuvant treatments that are available.
Higher risk features include hormone receptor negativity, higher histologic grade, age below 35 years, Tumor size >2cm.
HER-2/neu oncogene: Overexpression of the HER-2/neu oncogene reflects an increase in the proliferative activity of a tumor. Overexpression has been demonstrated in 15% to 30% of patients with breast cancer and has been found by most investigators to be associated with shorter survival.
Ploidy and S-phase fraction: The degree of cellular proliferation in breast cancer specimens has shown a strong correlation with outcome. DNA ploidy is the DNA content and number. S-phase fraction is the fraction of cells actively cycling or synthesizing DNA. Aneuploid (those with abnormal DNA content and number) tumors with a high percentage of cells in S-phase are more likely to recur than are tumors with a low S-phase fraction.
Prognostic factors currently under investigation
- Angiogenesis markers
- Histologic subtype
- Lymphatic invasion
- Epidermal growth factor receptor
- Stress response proteins
- Type IV collagenases
- Plasminogen activators
1. Lobular carcinoma in situ (LCIS)
Lobular carcinoma in situ. Presently, treatment options include close follow-up, participation in a chemoprevention trial, tamoxifen (Nolvadex), or bilateral total mastectomy with or without reconstruction. At present, the decision for a given treatment will depend upon the patient's individual risk profile after careful counseling.
2. Ductal carcinoma in situ (DCIS)
Ductal carcinoma in situ (DCIS). Breast-conservation surgery, followed by radiation therapy to the intact breast, is now considered the standard treatment for patients with DCIS.
Axillary lymph nodes
Routine axillary lymph node evacuation is not indicated in the treatment of DCIS since the incidence of positive lymph nodes after axillary lymph node dissection for DCIS is 1%-2%.
?Factors associated with an increased risk of axillary metastasis with a diagnosis of DCIS are
- Extensive DCIS requiring mastectomy
- Suspicion of microinvasion
- DCIS associated with a palpable mass
- Evidence of lymphovascular permeation or invasion seen on review of the slides.
These factors likely are associated with unknown (nondiagnosed) invasive disease and may benefit from sentinel lymph node dissection.
A surgical margin of 1 mm has been associated with a 43% chance of having residual disease at the time of re-excision. When a surgical margin of 10 mm (which may not be practical due to cosmetic reasons) can be obtained, there is an extremely low rate of recurrence (4%), and radiotherapy to the breast may not be necessary.
Adjuvant tamoxifen therapy
Adjuvant tamoxifen therapy was shown to benefit women with DCIS in a recent NSABP trial (NSABP-24) in which the tamoxifen group had fewer breast cancer events than those in the placebo group.
Stage I & II
1. Conservative surgery
Breast-conserving surgery followed by radiation therapy to the intact breast is now considered a standard treatment for the majority of patients with stage I or II invasive breast cancer.
The extent of breast conservation is debatable. Techniques for breast conservation include: lumpectomy, segmental mastectomy, quadrantectomy & others all of which have a similar in outcome. Quadrantectomy is used by some as it has good safety margin (the radical form of conservative surgery).
A consensus statement on breast-conserving therapy issued by the National Cancer Institute (NCI) recommended that the breast cancer be completely excised with negative surgical margins and that a level I-II axillary lymph node dissection be performed. The patient should subsequently be treated with adjuvant breast irradiation. This should be followed by radiation as part of the 1ry therapy.
- Multiple studies have demonstrated that patients with stage I breast cancer who are treated with either breast-conservation therapy (lumpectomy and radiation therapy) or modified radical mastectomy have similar disease-free and overall survival rates.
Contraindications to conservative surgery:
- Tumor is more than 5cm in size.
- Diffuse malignant or indeterminate appearing microcalcifications on mammogram.
- Contraindication to proper cosmesis.
- Prior breast irradiation or contraindication to radiation.
- Persistantly positive surgical margins.
- 1st or 2nd trimester pregnancy.
- Intraduct & retroareolar tumors are relative contraindications.
- History of collagen vascular disease (interfering with healing).
Axillary lymph node surgery following breast conservation
The role of axillary lymph node surgery is controversial when breast conservation is the aim of therapy. Currently, axillary evaluation is recommended in this setting. In these cases sentinel node dissection is recommended when feasible.
The ability to identify the sentinel node can reach as high as 97% when both blue dye and Tc-99m sulfur colloid are used together.
Adjuvant radiation therapy following breast conservation
Breast conservation should be followed by radiation as part of the 1ry therapy.
For patients who undergo axillary dissection and are found to have negative nodes, regional nodal irradiation is no longer routinely employed. For patients with positive nodes, radiation therapy to the supraclavicular fossa and/or internal mammary chain may be considered on an individualized basis.
Patients who are not candidates for breast conservation or are not interested in breast conservation are offered mastectomy.
Adjuvant radiotherapy after mastectomy
Available data suggest that in patients with the following criteria the risk of locoregional failure remains significantly high enough to consider postmastectomy radiation therapy.
- Positive postmastectomy margins
- Primary tumors > 5 cm
- Involvement of 4 or more lymph nodes at the time of mastectomy
Even with the use of high-dose chemotherapy, locoregional failure is a significant problem in these patients without the use of postmastectomy irradiation.
3. Adjuvant chemotherapy
Systemic therapy is indicated only for invasive (infiltrating) breast cancers larger than 1cm in size (in smaller tumors there is a very low risk of recurrence <10%).
The sequence of systemic therapy and definitive radiation therapy in women treated with breast-conserving surgery is a subject of continued clinical research. The use of concomitant chemotherapy and irradiation is not recommended due to the radiomimetic effects of chemotherapy and the potential for increased locoregional toxicity.
Delaying chemotherapy up to 8-10 weeks after surgery does not appear to have a negative impact on the development of metastasis or survival.
- CMF (Bonadonna regimen) and its variants (CMF day 21 and CMF day 28).
- CMF-P (In which prednisone 40mg/m2 from day 1 to day 14).
- AC --> TAC
- FEC (CEF)
The role of the taxanes, ie, paclitaxel and docetaxel (Taxotere), in adjuvant therapy is being investigated in clinical trials.
- For all women under 50 years of age at randomization, combination chemotherapy improved 10-year survival from 71% to 78% for those with node-negative disease (an absolute benefit of 7%), and from 42% to 53% for those with node-positive disease (an absolute benefit of 11%).
- For women 50 to 69 years of age at randomization, combination chemotherapy improved 10-year survival from 67% to 69% for those with node-negative disease (an absolute gain of 2%), and from 46% to 49% for those with node-positive disease (an absolute gain of 3%).
4. Adjuvant hormonal therapy
Hormonal therapy with tamoxifen (20 mg PO qd for 5 years) has been shown to be of value in women more than or equal to 50 years of age with estrogen- and/or progesterone-receptor-positive tumors as shown in the (ATAC trial).
The most recent meta-analysis, which included information on 37,000 women in 55 trials of adjuvant tamoxifen, was published in 1998. In this analysis, the benefit of tamoxifen was found to be restricted to women with ER-positive or ER-unknown breast tumors.
- In these women, the 10-year proportional reductions in recurrence and mortality associated with 5 years of use were 47% and 26%, respectively.
- An additional observed benefit was an approximately 50% decrease in the incidence of contralateral breast cancer in patients receiving tamoxifen, regardless of the ER status of the primary tumor.
The benefit of tamoxifen is independent of menstrual status. Long-term follow-up from the NSABP conclusively demonstrates that there is no benefit to continuing tamoxifen therapy beyond 5 years.
Stage III (Locally advanced disease)
The optimal treatment for patients with locally advanced breast cancer has yet to be defined, due to the heterogeneity of this group (stage IIIA and IIIB, M1 supraclavicular nodes).
Neoadjuvant therapy with cytotoxic drugs permits in vivo chemosensitivity testing, can downstage locally advanced disease and render it operable, and may allow breast-conservation surgery to be performed.
Types of neoadjuvant chemotherapy regimens
Preoperative chemotherapy regimens reported to result in high response rates (partial and complete responses) include:
Combination chemotherapy with an anthracycline-based regimen FAC or AC is used most often. Recently published data suggest that the AT regimen of Adriamycin and docetaxel
(Taxotere) given concomitantly may produce equivalently high response rates.
Although not yet definitive, recent data indicate that enhancing dose density may increase the pathologic complete response rate for women with locally advanced disease.
- Neoadjuvant chemotherapy results in complete response rates ranging in about 25% and partial response rates (more than or equal to 50% reduction in bidimensionally measurable disease) in 50% of cases, with total response rates in about 90%.
Patients with large lesions are more likely to have partial responses. Pathologic complete responses do occur and are more likely to be seen in patients with smaller tumors.
Radiation therapy remains an integral component of the management of patients with locally advanced breast cancer.
Operable cases: For patients with operable breast cancer undergoing mastectomy, radiation therapy to the chest wall and/or regional lymph nodes (to a total dose of 5,000-6,000 cGy) is usually employed.
Inoperable cases: For patients whose disease is considered to be inoperable, radiation therapy may be integrated into the management plan prior to surgery.
Multimodality treatment plan
A multimodality approach for locally advanced breast cancer (stage IIIA and IIIB, M1 supraclavicular nodes) consists of
- 4 cycles of neoadjuvant chemotherapy (FAC)
- Followed by surgery for responders / by radiotherapy then surgery for those who do not respond.
- After surgery adjuvant treatment is given in the form of chemotherapy, radiotherapy (unless used in downstaging) and hormonal therapy in those with receptor positive tumors.
Benefit: This approach has been shown to result in the following benefits:
- Stage IIIA disease - 84% 5-year survival rate of
- Stage IIIB disease - 44% 5- year survival rate
- Inflammatory breast cancer - 35%-50% 5-year survival rates
Stage IV (Metastatic disease)
Patients with metastatic cancer can be divided into two groups: those with stage IV disease at presentation and those who develop metastases after primary treatment. They can be divided into low and high risk groups based on the biologic aggressiveness of the disease.
The low-risk group includes
- Patients who develop metastatic disease after a long disease-free interval (i.e. a long disease-free interval from primary breast cancer diagnosis to presentation with metastasis),
- those whose tumors are positive for hormone receptors (estrogen and progesterone),
- those with bone-only disease, and
- those without extensive visceral organ involvement.
Hormone therapy in stage IV
First-line hormonal therapy
These drugs aim at reducing the levels of estrogen hormones in hormone receptor positive cancers. First line hormonal therapy consists of an aromatase inhibitor or tamoxifen, with careful serial assessment of clinical and disease responses. Hormone therapy may be associated with a "flare" response, a temporary worsening of signs and symptoms of disease within the first few weeks of treatment. This response generally means clinical benefit will follow.?
- Overall response rates is 40% for ER positive tumors
- Complete remission occurs in about 13% in ER positive tumors
- Prolonged disease stability (including minor responses) was achieved in an additional 20 to 30% of patients during hormonal therapy. Stable disease for longer than 6 months is associated with survival durations similar to those of patients who achieve a partial or complete response with endocrine therapy.
Second-line hormonal agents
The most commonly used second-line hormonal agents had been progestational drugs, such as megestrol acetate. Recent randomized trials have indicated that the aromatase inhibitors are equally effective for palliation of metastatic disease, have less toxicity, and may provide a survival advantage compared with megestrol acetate. Therefore, they are the drugs of choice for second-line therapy following tamoxifen administration.
- Anastrozole (Arimidex)
- Letrozole (Femara)
- Fulvestrant (Faslodex)
- Exemestane (Aromasin)
Tamoxifen may also be considered as second-line therapy for patients initially treated with an aromatase inhibitor.
Hormonal therapy continues until evidence of disease progression or drug related toxicity precludes further therapy with the same agent. If a partial or complete response to the first hormonal treatment is documented at the time of disease progression, a second hormonal agent may provide further palliation of symptoms and avoid the initiation of systemic chemotherapy. However, subsequent hormonal responses tend to be of shorter duration, and, ultimately, the disease will become refractory to hormonal treatment.
Hormone-refractory disease can be treated with systemic cytotoxic therapy.
- TAC (docetaxel, doxorubicin [Adriamycin], cyclophosphamide), or docetaxel may be used in this situation.
Benefits: see below.
Intermediate- or high-risk patients include
- Patients with rapidly progressive disease
- Patients with visceral involvement
- Disease shown to be refractory to hormonal manipulation by a prior therapeutic trial.
Combination chemotherapy in stage IV
Anthracycline-containing combinations are preferred for these patients.
- Newer combinations of doxorubicin and a taxane are gaining favor for use in patients who have not received > 450 mg/m2 of an anthracycline and whose relapse has occurred more than 12 months after the completion of adjuvant therapy.
- Between 50 and 75% of patients with metastatic breast cancer have responses to first-line chemotherapy.
- Only 15 to 20% of patients will achieve a complete remission, and most of those patients will develop progressive disease within the subsequent 5 years.
- Anthracycline-based combinations appear to be more effective than CMF and CMFVP in several randomized trials, producing not only higher overall and complete remission rates but, in some studies, significant prolongation of survival as well (about 10% of all complete remissions achieved with anthracycline containing regimens last more than 10 years).
Single agents in stage IV
- Vinblastine (Velban)
- Mitomycin (Mutamycin)
- Vinorelbine (Navelbine): Vinorelbine has an objective response rates ranging from 40 to 50% in first-line and 20 to 35% in second-line therapy; however, it has not gained FDA approval, although it is widely used for the treatment of advanced breast cancer.
- Gemcitabine (Gemzar): This agent was approved by the FDA for the treatment of pancreatic cancer, even though its efficacy against breast cancer is substantially higher. Gemcitabine produces responses in about 40% of patients with untreated metastatic breast cancer and in 20 to 30% of those with previous exposure to chemotherapy, including anthracycline-refractory tumors.
- Paclitaxel: One of the most active agents is paclitaxel. Both taxanes have significant antitumor activity in this group of patients with anthracycline-resistant breast cancer, with reported overall response rates of up to 57% and median survival ranging up to 10 months.
- Docetaxel, approved by the FDA for anthracycline-resistant locally advanced or metastatic breast cancer, has demonstrated overall response rates of 41% in doxorubicin-resistant disease. It has been shown to be superior to mitomycin/ vinblastine in patients whose disease progressed after an anthracycline-based chemotherapy regimen. Docetaxel as a single agent produces objective responses in up to 60% of patients with metastatic breast cancer previously unexposed to chemotherapy.
- Capecitabine (Xeloda): has been shown to have substantial antitumor effect in patients whose disease has recurred or progressed after prior anthracycline chemotherapy or after taxane therapy. Prolonged survival, limited toxicity, and response in visceral as well as soft tissue disease add to the benefit of capecitabine.
- 40 to 50% of previously untreated patients with metastatic breast cancer achieve an objective regression after single-agent anthracycline therapy.
- Mitoxantrone and the alkylating agents produce partial or complete responses in 30 to 40% of patients, whereas the other drugs are estimated to have a 20 to 30% response rate.
Trastuzumab is a humanized monoclonal antibody to the HER-2/neu protein, has been approved for use as a single agent in second- and third-line therapy for metastatic breast cancer and in combination with paclitaxel as first-line therapy in this setting.
- The combination of trastuzumab with chemotherapy yields a 45% overall response rate, as compared with a 29% rate with chemotherapy alone. Recent data has shown a superior median overall survival with chemotherapy plus trastuzumab compared with chemotherapy alone (25.4 vs 20.9 months).
- In a multicenter phase II trial of docetaxel, carboplatin / cisplatin, and trastuzumab (TCH) in HER2-positive advanced breast cancer overall responses were observed in 80% of patients receiving cisplatin 60% in those receiving carboplatin. Median times to progression were 10 months for those receiving cisplatin and 13 months in those receiving the carboplatin regimen. Toxicities were mainly hematologic in the carboplatin regimen in the form of grade III and IV thrombocytopenia, neutropenia (with or without fever). In the cisplatin regimen toxicities were mainly non-hematologic and in the form of alopecia, asthenia, GIT toxicities, renal, ototoxicity and neurotoxicity.
During the months subsequent to therapy patient follow up is usually required every 6 months or every year depending on the risk of breast recurrence. A thorough examination is done aiming primarily at the detection of breast cancer in the opposite breast (due to a slightly increased incidence of contralateral breast cancer).
* Examination should include: bilateral breast & axillary exam in addition to supraclavicular lymph node enlargement and liver examination for enlargement and tenderness. A mammogram is requested annually. In cases that have undergone conservative surgery mammographic examination is recommended every 6 months initially then annually.
A chest x-ray, bone scan (sensitive but not specific) and abdominal sonography is requested as dictated by a patients complaints or the results of the examination.
Warning signs that should alert the physician during an examination: