I. NATURAL HISTORY, EVALUATION, AND MODES OF TREATMENT
A. Epidemiology and risk factors
Carcinoma of the breast gave way to carcinoma of the lung as the most common cause of cancer deaths among women in the United States in 1986. Despite a decline in incidence since 2003, in 2009, more than 192,000 new cases of breast cancer were diagnosed, and there were about 40,000 women who died from this disease. Currently, more women survive due to earlier diagnosis and better therapy, and the absolute number of deaths per year has been declining since about 1990 with a disease-specific mortality decrease of 2.2% per year since then.
The incidence of breast cancer varies widely among different populations. Women in Western Europe and the United States have a higher incidence than women in most other parts of the world, possibly in part because of the high intake of animal protein, fat, and probably linked to total caloric intake and increased rates of obesity. Caucasian women in the United States are more likely to develop breast cancer compared with African-American women. Mortality from breast cancer, however, is higher in
African-American women than other ethnic or racial groups, although this is confounded by the general increase in cancer-related mortality for lower socioeconomic groups regardless of specific ethnicity. While discrete causes of breast cancer cannot be identified in most individual women, many factors increase a woman’s risk of developing the disease. Among the strongest of the risk factors is family history, particularly if more than one family member has developed breast cancer at an early age. More precisely, genetic linkage analysis led to the discovery of dominant germ-line mutations in two tumor-suppressor genes, BRCA1 and BRCA2, localized to chromosomes 17 and 13, respectively, which are associated with a high risk of female breast cancer as well as ovarian cancer (BRCA1 and BRCA2), male breast cancer (BRCA2), and other cancers. Although these mutations account for less than 10% of all cases of breast cancer, together they may account for over 70% of inherited cases in high-risk populations. It is important to note that most patients with a family history of breast cancer do not have a defined inherited mutation and other, less common, causative mutations are sometimes seen. However, if a woman with breast cancer is under the age of 50 years and has any relative who developed breast cancer before she was 50 years old, her chance of having a mutation in BRCA1 or BRCA2 rises to as much as 25%. Other factors that increase her probability of a mutation include any relative with ovarian cancer or a personal history of bilateral breast cancer or ovarian cancer. Carriers of these mutations have up to a 70% lifetime risk of breast cancer, depending on familial history, perhaps the specific mutation, and other cellular genes that may modify penetrance. The 5-year survival rate of patients with either of the BRCA mutations is not significantly less than for other patients with breast cancer after adjusting for the specific subtypes of breast cancer carriers tend to develop. Additional factors that increase breast cancer risk are early menarche, late age at birth of first child, and prior benign breast disease (particularly if there is a high degree of benign epithelial atypia). Present use of birth control pills appears to have a small effect on the risk of developing breast cancer (relative risk, 1.24); risk from prior use diminishes over time. Although breast cancer may occur among men, such cases represent less than 1% of all breast cancers and are infrequently seen in most hospitals. Male carriers of BRCA2 mutations have a 6% lifetime risk of breast cancer, significantly increasing their risk in comparison to the general population.
Hormone replacement therapy (HRT) can increase the risk of breast cancer. In the Women Health Initiative study, researchers found an increased breast cancer risk of about 10% for every 5 years of HRT use. There was a greater risk with combined estrogen/progesterone products than with estrogen therapy alone; following
the publication of this report, there was a marked decrease in the use of HRT followed in short order by a decline in the incidence of postmenopausal hormone-receptor-positive breast cancer.
B. Prevention
The risk of hormone-receptor-positive breast cancer can be reduced. At least three trials using selective estrogen receptor modulators (SERMs) have demonstrated that 3 to 5 years of preventive treatment with these agents reduces the rate of breast cancer development over the short term. Women at increased risk because of family history, age, and other risk factors, who are treated with the SERM tamoxifen, 20 mg/day, were found to have a 45% reduction in the rate of occurrence of invasive breast cancer compared with women treated with placebo. Noninvasive disease and preneoplastic breast lesions were also decreased. Raloxifene, 60 or 120 mg/day, also appears to reduce the risk of breast cancer in postmenopausal women (who had osteoporosis and a standard or reduced risk of breast cancer), with a relative risk of 0.26. Despite these benefits, SERMs are associated with an increased risk of both venous thromboembolism and endometrial cancer, although the risks with raloxifene appear to be lower than tamoxifen, which has been associated with an increased risk for endometrial cancer of 1.5 to 2 times that of untreated women. In addition, neither of these agents has demonstrated an improvement in survival when used for breast cancer prevention. In the Study of Tamoxifen against Raloxifene trial, these agents were compared and raloxifene was found not to decrease the incidence of preinvasive carcinomas despite a seemingly better outcome than tamoxifen for prevention of invasive cancers. Lasofoxifene, in a trial addressing osteoporosis, similarly reduced the incidence of breast cancer. These agents have similar but not identical toxicity profiles that may guide clinical decisions.
There are several options in the management of women at very high risk because of family history or known gene mutations. Increased surveillance, through the addition of magnetic resonance imaging (MRI) screening on a yearly basis as a supplement to standard mammography, was effective in a high-risk population. In mutation carriers who are at risk for both breast and ovarian cancer, bilateral oophorectomy after childbearing age has been recommended because of the inadequacy of screening tests for ovarian cancer and because it reduces the risk of primary breast cancer. Risk-reducing mastectomy is an effective option with a relative risk reduction of about 90%. Note that despite risk-reducing mastectomy, there is always a small risk of breast cancer in residual breast glandular tissue. SERMs may be useful in patients with BRCA1 and BRCA2 mutations as well. Analysis of blood samples of women who participated in the P-01 (tamoxifen) trial showed that mutation carriers also had a 47% lower risk of breast cancer.
C. Detection, diagnosis, and pretreatment evaluation
1. Screening. Because more lives can be saved if breast cancer is diagnosed at an early stage, many screening programs have been designed to detect small, early cancers. Monthly breast self-examination for all women after puberty and yearly breast examinations by a physician or other trained professional after a woman is 20 years of age is generally recommended, although evidence of effectiveness is limited. Mammography reduces breast cancer mortality by 25% to 30% in women older than 50 years. The benefit for women aged 40 to 50 years has been more difficult to demonstrate because the incidence of breast cancer is lower. Hence, more examinations are needed to find a cancer and save a life. However, additional benefits of early detection via mammography include the option for less disfiguring surgery, reduced utilization of radiation therapy, and decreased need for chemotherapy and other systemic treatments. Therefore, the absolute benefits extend beyond the simple endpoint of survival. As a result, mammography is recommended at age 40 years as a baseline, once every 1 to 2 years between the ages of 40 and 50 years (depending on risk factors and the recommending organization), and yearly after 50 years of age. An upper age of effectiveness is not established. For high-risk women and in family members of mutation-positive patients, annual mammography should be initiated 10 years earlier than the youngest diagnosed relative. Patients with Hodgkin lymphoma (regardless of a history of mantle field irradiation) should have a baseline mammogram by age 25. In BRCA1/BRCA2 mutation carriers, MRI of the breast has recently been approved for screening in addition to annual mammography. Mammography has clearly led to the discovery of many earlier cancers and sharply increased the discovery of preinvasive cancers (ductal carcinoma in situ). These latter are not (yet) invasive and their treatment can be far less complicated than that of invasive breast cancer. Other screening modalities can include ultrasound, but it is more typically used diagnostically to evaluate palpable lesions.
2. Presenting signs and symptoms. Although a large number of nonpalpable cancers are found by mammography, invasive breast cancer is still often discovered by a woman herself as an isolated, painless lump in the breast. If the mass has gone unnoticed, ignored, or neglected for a time (or if it is particularly rapidly growing or aggressive), there may be fixation to the skin or underlying chest wall, ulceration, pain, or inflammation. Some early lesions present with discharge or bleeding from the nipple. Occasionally, the primary lesion is not discovered, and the woman presents with symptoms of metastatic disease, such as pleural effusion,
nodal disease, or bony metastases. About half of all lesions are in the upper outer quadrant of the breast (where most of the glandular tissue of the breast is). About 20% are central masses and 10% are in each of the other quadrants. Up to one-quarter of all women with breast cancer have axillary node metastasis at the time of diagnosis, although this is less common when the primary tumor has been detected by screening.
3. Staging. Carcinoma of the breast is staged according to the size and characteristics of the primary tumor (T), the involvement of regional lymph nodes (N), and the presence of metastatic disease (M). An abridged version of the commonly used TNM classification of breast cancer is shown in Table 9.1, and the stage grouping is outlined in Table 9.2. In 2010, the revised American Joint Commission on Cancer staging system for breast cancer was published. Although preliminary staging is commonly done before surgery, definitive staging that can be used for prognostic and further treatment planning purposes usually must await postsurgical pathologic evaluation when the primary tumor size and the histologic involvement of the lymph nodes are established. In up to 30% of patients with palpable breast masses (not found by mammography) but without clinical evidence of axillary lymph node involvement, the histologic evaluation of the nodes reveals cancer. In patients with negative nodes by routine histologic evaluation, serial sectioning may reveal microscopic cancer deposits in additional patients. The principal changes in the new staging system take into consideration the widespread use of immunohistochemical (IHC) and molecular biologic techniques that afford pathologists the ability to detect microscopic metastatic lesions down to the level of isolated tumor cells. It is not clear that there is prognostic value if cancer cells in nodes are detected by enhanced examination, and the current staging system designates nodes as pathologically negative if cells are identified by IHC alone and are in clusters of less than 0.2 mm. The identifier “(i)” is used to indicate isolated tumor cells such that pN0(i+) indicates node-negative disease but the presence of such cells in the node. Similarly, “(mol +)” indicates that a molecular examination such as polymerase chain reaction has found evidence of malignant cells. These changes are included in Table 9.1.
D. Diagnostic evaluation
1. Before biopsy the woman should have a careful history, during which attention should be paid to risk factors, and a physical examination, with a focus not only on the involved breast but also on the opposite breast, all regional lymph node areas, the lungs, bone, and liver. This examination should be followed by bilateral mammography to help assess the extent of involvement and to look for additional ipsilateral or contralateral disease.
TABLE 9.1 TNM Classification of Breast Cancer
Primary Tumor (T)
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
Tis (DCIS)
Ductal carcinoma in situ
Tis (LCIS)
Lobular carcinoma in situ
Tis (Paget)
Paget disease of the nipple with no tumor (Paget disease associated with a tumor is classified according to the size of the tumor)
T1
Tumor ≤2 cm in greatest dimension
T1
mic Microinvasion <0.1 cm in greatest dimension
T1a
Tumor >0.1 cm but not >0.5 cm in greatest dimension
T1b
Tumor >0.5 cm but not >1 cm in greatest dimension
T1c
Tumor >1 cm but not >2 cm in greatest dimension
T2
Tumor >2 cm but not >5 cm in greatest dimension
T3
Tumor >5 cm in greatest dimension
T4
Tumor of any size with direct extension to chest wall or skin, only as described subsequently
T4a
Extension to chest wall, not including pectoralis muscle
T4b
Edema (including peau d’orange) or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast
T4c
Both T4a and T4b
T4d
Inflammatory carcinoma
Regional Lymph Nodes (N): Clinical Classification
NX
Regional lymph nodes cannot be assessed (e.g., previously removed)
N0
No regional lymph node metastasis
N1
Metastasis in movable ipsilateral axillary lymph node(s)
N2
Metastases in ipsilateral axillary lymph nodes fixed or matted, or in clinically apparent ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis
N2a
Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures
N2b
Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastasis
N3
Metastasis in ipsilateral infraclavicular lymph node(s), or in clinically apparent ipsilateral internal mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis; or metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement
N3a
Metastasis in ipsilateral infraclavicular lymph node(s) and axillary lymph node(s)
N3b
Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
N3c
Metastasis in ipsilateral supraclavicular lymph node(s)
Regional Lymph Nodes (pN) Pathologic Classification
pNX
Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study)
pN0
No regional lymph node metastasis histologically, no additional examination for isolated tumor cells
pN0(i-)
No regional lymph node metastasis histologically, negative IHC staining
pN0(i+)
Isolated tumor cells identified histologically or by positive IHC staining, no cluster >0.2 mm
pN0(mol-)
No regional lymph node metastasis histologically, negative molecular findings (RT-PCR)
pN0(mol +)
No regional lymph node metastasis histologically, positive molecular findings (RT-PCR)
pN1
Metastasis in one to three axillary lymph nodes and/or in internal mammary nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent
pN1mi
Micrometastasis (>0.2 mm, none >2.0 mm)
pN1a
Metastasis in one to three axillary lymph nodes
pN1b
Metastasis in internal mammary nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent
pN1c
Metastasis in one to three axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent
pN2
Metastasis in fourto nine axillary lymph nodes or in clinically apparent internal mammary lymph nodes in the absence of axillary lymph node metastasis
pN2a
Metastasis in four to nine axillary lymph nodes (at least one tumor deposit >2.0 mm)
pN2b
Metastasis in clinically apparent internal mammary lymph nodes in the absence of axillary lymph node metastasis
pN3
Metastasis in 10 or more axillary lymph nodes, in infraclavicular lymph nodes, or in clinically apparent ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes with clinically negative microscopic metastasis in internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes
pN3a
Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit >2.0 mm) or metastasis to the infraclavicular lymph nodes
pN3b
Metastasis in clinically apparent ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent
pN3c
Metastasis in ipsilateral supraclavicular lymph nodes
Distant Metastasis (M)
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
RT-PCR, reverse transcriptase-polymerase chain reaction.
Modified from the American Joint Committee on Cancer Staging. AJCC cancer staging manual(7th ed.)
New York: Springer; 2010.
TABLE 9.2 Stage Grouping of Breast Cancer*
Stage
Description
0
Tis, N0, M0
I
T1, N0 or Nmi, M0
IIA
T2, N0, Mo
T0-1, N1, M0
IIB
T2, N1, M0
T3, N0, M0
IIIA
T0-2, N2, M0
T3, N1-2, M0
IIIB
T4, any N, M0
IIIC
Any T, N3, M0
IV
Any T, any N, M1
*Patients are staged in the highest group possible for their composite TNM. For example, a patient with T1a, N2, M0 would have stage IIIA disease because of the N2 status.
2. Excisional or core needle biopsy of the primary lesion is performed, and the specimen is given intact (not in formalin) to the pathologist, who can divide the specimen for histologic examination, hormone receptor assays, and HER2 testing (by immunohistochemistry examination or fluorescence in-situ hybridization [FISH]).
3. After confirmation of the histology, the patient is evaluated for possible metastatic disease. It is important to emphasize that history and physical examination are the most critical components of this assessment.
a. Typical studies include a chest radiograph, complete blood count, and blood chemistry profile.
b. Other studies, including radionuclide scan of the bones, skeletal survey (usually obtained only if the radionuclide scan is positive), and computed tomography (CT) scan of the liver (abdomen), are optional unless the history, physical examination, or blood studies suggest a poor prognosis or point to specific organ involvement. There is continued evolution in imaging recommendations, and recent data suggest that integrated positron emission tomography-CT may replace most or all other imaging tests.
c. Histology. About 75% to 90% of all breast cancers are infiltrating ductal carcinomas, and up to 10% are infiltrating lobular carcinomas; these two types have similar overall behavior but the latter tend to be hormone responsive and HER2-negative. In addition, their patterns of metastatic spread can vary even if the overall risks of metastases are similar. The remainder of the histologic types of invasive breast carcinoma may have
a somewhat better prognosis but are usually managed more according to the stage than to the histologic type. Microarray technology has added nuance to the traditional, histology-based categorization of breast cancer and supports the view that this is a disease with distinct subtypes. About 15% of breast cancers are basal-like (basal epithelial subtype) with a relatively high concordance with the conventionally defined “triple negative” (hormone-receptor and HER2-negative) subset. Luminal tumors are generally hormone receptor-positive, but it is the luminal A subtype that is most clearly hormone responsive. Triple negative tumors are seen in association with BRCA1 mutations and in women of lower socioeconomic status. Each of these subtypes (luminal A, B, basal-like, HER2-positive, etc.) is associated with a distinct typical natural history in terms of time to develop distant metastases.
E. Approach to therapy
Many institutions have established multidisciplinary teams or centers to facilitate coordinated treatment planning. It may be useful in some settings to pursue this particular clinical care structure, but there are other reasonable strategies to employ in the development of an optimal care plan for individual patients.
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Carcinoma of the Breast
Carcinoma of the Breast
Patrick Glyn Morris
Clifford A. Hudis
