Mark D. Pegram, Cristiane Takita, and Dennis A. Casciato
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence
1. The American Cancer Society (ACS) estimated that breast cancer was diagnosed in 207,090 women and 1,970 men in the United States during 2010. Another 54,010 women were diagnosed with in situ breast carcinoma. Breast cancer was estimated to be the cause of death in 40,640 women and 450 men during that year.
The death rate from breast cancer in North America has been declining, with a 1.7% annual reduction in mortality since 1992. This decline has occurred despite an increased incidence of the disease over the same time period. Over the last 10 years, mortality caused by breast cancer in the European Union has fallen by 9.8%. These reductions are most likely owing to increased early detection and improved efficacy of adjuvant therapies.
2. Although breast cancer is the most common neoplasm in women, accounting for 26% of all cancers diagnosed annually, it is overall the second leading cause of cancer death (following lung cancer). Breast cancer, however, is the leading cause of cancer death in women aged 65 years.
3. The incidence of breast cancer is highest among women of higher socioeconomic background. Although the incidence of breast cancer is higher in whites, black women are more likely to die from the disease. This disparity may be related both to delay in diagnosis because of restricted access to health care and to differing biology of the disease (e.g., higher frequency of HER2-negative, estrogen receptor [ER]-negative, and progesterone receptor [PR]-negative disease in these populations).
B. Genetic predisposition. Most breast cancers diagnosed are sporadic and not associated with any clear familial genetic predisposition. Approximately 10% of breast cancer patients, however, have tumors that can be attributed to inherited germline mutations in genes that control DNA repair, cell growth regulation, or cell cycle control.
1. Germline genetic defects associated with an increased risk of breast cancer include the following:
a. BRCA-1. First identified in 1990, the BRCA-1 gene is assigned to chromosome 17q21. The gene product is a 1,863 amino acid nuclear protein with pleiotropic activities including sensing or signaling DNA damage, transcriptional regulation, transcription-coupled DNA repair, and ubiquitin ligase activity. Several hundred different mutations have been identified by DNA sequence analysis. Particular BRCA-1 mutations are prevalent in specific populations (e.g., del 185 mutation among patients of Ashkenazi Jewish ancestry). Mutation of BRCA-1 accounts for about 20% of all familial breast cancers.
(1) BRCA-1 mutations are inherited in an autosomal-dominant fashion with variable penetrance and are associated with an increased risk of breast, ovarian, prostate, and possibly colorectal cancers, though two studies published in the Journal of the National Cancer Institute in 2004 failed to demonstrate association between germline BRCA gene mutation and colon cancer risk.
(2) Breast tumors harboring BRCA-1 mutations frequently lack expression of both ER and PR and lack amplification of the HER2 gene. These tumors very frequently also have somatic mutations in the P53tumor suppressor gene.
(3) Molecular classification of BRCA-1 mutant tumors by gene expression profiling frequently demonstrates a “basal” breast cancer phenotype (see Section II.B.).
(4) Patients with inherited mutation of BRCA-1 can expect a 50% to 85% lifetime risk for breast cancer and a 15% to 45% risk for ovarian cancer.
b. BRCA-2. First sequenced in 1995, the BRCA-2 gene is assigned to chromosome 13q12. The gene encodes a 3,418 amino acid protein involved in DNA repair. As with BRCA-1, many different mutations have been described in the BRCA-2 gene in affected individuals.
Germline mutations in BRCA-2 are associated with an increased risk of a unique spectrum of human neoplasms, including melanoma, breast cancer (in both men and women), ovarian cancer, and pancreatic cancer. Breast cancers associated with BRCA-2 mutation are frequently ER positive and tend to occur at an older age than with BRCA-1.
c. Li–Fraumeni syndrome is caused by germline mutations in the P53 tumor suppressor gene found on chromosome 17p13. In addition to breast cancer, there is an increased risk of other tumor types (sarcomas, brain tumors, leukemia, and adrenal tumors). The lifetime risk of breast cancer associated with this syndrome is about 50%.
d. The PTEN gene is assigned to chromosome 10q22–23 and encodes a tumor suppressor. Cowden syndrome is the clinical phenotype resulting from mutations in PTEN. The syndrome is a rare autosomal-dominant disorder characterized by multiple benign hamartomas and malignant tumors (breast and thyroid cancers). The syndrome is recognized by the pathognomonic presentation of facial trichilemmomas and fibromas of the oral mucosa that cause cobblestone appearance of the tongue and acral palmoplantar keratoses. The risk of breast cancer is increased by approximately 50% in subjects with mutation of the gene.
e. CHEK-2. This cell cycle checkpoint kinase gene is an important component of the cellular DNA repair pathway. Mutation of the gene increases the risk of breast cancer in women by twofold and in men by tenfold.
f. RAD-51. RAD51C is essential for homologous recombination repair; a biallelic missense mutation can cause a Fanconi anemia–like phenotype. Six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer were found (exclusively) within 480 pedigrees with the occurrence of both breast and ovarian tumors.
g. Mutations in other genes have been associated with an increased risk of breast cancer (e.g., ATM and STK11—Puetz–Jeghers syndrome). In approximately half of subjects with an apparent familial association with breast cancer based on analysis of the pedigree, no specific gene mutation can be found.
2. Genetic testing for BRCA-1 and BRCA-2 is commercially available but should be interpreted in consultation with a genetic counselor. Factors that indicate an increased likelihood of having germline BRCAmutations include
a. Multiple cases of early onset breast cancer
b. Ovarian cancer with a family history of breast or ovarian cancer
c. Breast and ovarian cancer in the same individual
d. Bilateral breast cancer
e. Male breast cancer
f. Ashkenazi Jewish ancestry
3. American Society of Clinical Oncology (ASCO) guidelines recommend that cancer predisposition genetic testing should be offered when (1) there is a personal or family history suggestive of a genetic cancer susceptibility condition, (2) the test can be adequately interpreted, and (3) the test result will influence medical management. Once a proband has been identified as a carrier for a heritable cancer predisposition condition, it is important that patients and their family members be counseled regarding additional screening and prevention strategies and be alerted to the risk of other primary neoplasms.
4. Prophylactic surgery. Prophylactic bilateral mastectomy reduces the risk of breast cancer among BRCA mutation carriers by more than 90%. Prophylactic bilateral salpingo-oophorectomy reduces the risk of ovarian cancer (although not primary peritoneal carcinoma) by 90% and also reduces the risk of breast cancer by approximately 65% in premenopausal women with BRCA abnormalities.
5. Insurance issues. The United States Health Insurance Portability and Accountability Act (HIPAA) of 1996 states that genetic information may not be treated as a pre-existing medical condition for the purposes of denying insurance coverage or basing the cost of insurance. In addition to federal policy, many states have additional laws to prevent discrimination owing to genetic information. Consequently, most insurance companies will pay for genetic testing and any subsequent treatment that is indicated.
C. Etiologic factors
1. Endogenous estrogen exposure. The following factors affecting endogenous estrogen exposure have been associated with an increased risk of breast cancer in epidemiologic studies.
a. Nulliparity
b. Late first full-term pregnancy (women who completed their first full-term pregnancy after age 30 are two to five times more likely to develop breast cancer compared with those who had had term pregnancies <18 years of age).
c. Early menarche (<12 years of age)
d. Late menopause (>55 years of age)
e. Lactation may reduce the risk of breast cancer
2. Hormone replacement therapy (HRT) following menopause. A preponderance of the evidence from previous historical cohort studies suggested that the risk of breast cancer was increased modestly by long-term estrogen use alone and that women on estrogen plus progestin were more likely to have tumors with more favorable biologic characteristics (hormone receptor positive disease) and lower tumor stage. The Women’s Health Initiative (WHI) studywas begun in 1993 with the following results and effects:
a. The WHI was a placebo-controlled study that enrolled 10,739 patients with a history of prior hysterectomy and 16,608 patients with an intact uterus. The former were randomized to receive conjugated equine estrogen (CEE, 0.625 mg/d) versus placebo, and the latter to CEE (0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) versus placebo. The hypothesis being tested in this trial was that long-term CEE + MPA would have more benefit than risk on chronic diseases, such as coronary heart disease.
b. Published in 2003, the study demonstrated a 24% increase in the risk of breast cancer among the women with an intact uterus randomized to receive CEE + MPA (P = 0.003). Moreover, tumors detected in the CEE + MPA group had a larger mean tumor size (1.7 vs. 1.5 cm, P = 0.038) and were more likely to have lymph node metastasis (25.9% vs. 15.8%, P = 0.033). In addition, more women in the CEE + MPA group had abnormal mammograms at 1 year (9.4% vs. 5.4%, P <0.0001). The study further demonstrated that the risk both of ER/PR positive as well as ER/PR negative disease was increased similarly, contrary to previous reports from non–placebo-controlled cohort studies. With longer follow-up (median = 11 years), breast cancer mortality also appears to be increased with combined use of estrogen plus progestin. Finally, the use of CEE + MPA was found to decrease the risk of colorectal cancer, although the colorectal cancers that were diagnosed were of more advanced stage.
c. The WHI study concluded that combined CEE + MPA increases the number of abnormal mammograms and the risk of invasive breast cancer, and that breast cancers are diagnosed at a later stage. This increased risk of invasive breast cancer was not seen in the women with prior hysterectomy who were randomized to receive CEE alone. The use of CEE alone increased the risk of stroke, decreased the risk of hip fracture, and did not affect the risk of coronary heart disease.
d. It is important to note that patients with prior hysterectomy in this study were more likely to report past or current hormone use, had a higher body mass index, and that 41% had prior bilateral oophorectomy.
e. Together, these data led to a revised view of postmenopausal HRT because use of CEE + MPA potentially leads to delay in diagnosis of two of the three most common cancers in postmenopausal women:
(1) HRT with CEE + MPA should be used at the lowest possible dose and shortest duration sufficient to control vasomotor or vaginal symptoms.
(2) Women with prior hysterectomy treated with CEE for a short-term have no significant increase in breast cancer risk, although the risk of stroke is increased.
f. Subsequent to publication of findings from the WHI study, there was a sharp decline in the number of new prescriptions for HRT in the United States from 22.8 million in the first quarter of 2001 to 15.2 in the first quarter of 2003. Coincident with this practice was a sharp (7%) decrease in the breast cancer incidence, especially among older women with hormone receptor positive disease, suggesting a possible link between decreased incidence and decreased exogenous estrogen and progestin exposure in the form of HRT.
3. Age. The incidence of breast cancer increases steadily with age. Approximately 75% of all cases are diagnosed in postmenopausal women. The risk of developing breast cancer at age 25 years is 1 of 19,608, whereas the lifetime risk is 1 of 8 for women living into their 80s.
4. Benign breast disease. Most forms of benign breast disease, such as fibrocystic disease, are not associated with increased risk. Hyperplasia with atypia, papillomas, sclerosing adenosis, and lobular carcinoma in situhave been reported to be associated with an increased risk. Hyperplasia with atypia is felt to be a proliferative disease that is associated with an 8% risk of developing invasive breast cancer in patients with a negative family history and a 20% risk in patients with a positive family history of breast cancer.
5. Physical activity. Most cohort studies suggest an inverse association between physical activity and breast cancer risk, regardless of the age at which the physical activity occurred.
6. Ionizing radiation. Exposure to radiation increases the risk of breast cancer. Medical radiation therapy (RT) to the chest, for example to a mantle field for Hodgkin lymphoma, can increase subsequent risk of breast cancer. Exposure to fallout from nuclear weapons also appears to increase risk. Recent epidemiologic data following the Chernobyl nuclear power plant disaster suggest higher incidence of breast cancer in the years following the disaster. Breast cancers following radiation exposure typically have long latency, often a decade or more following the exposure.
7. Ethanol. Studies have shown a positive linear relationship between incremental alcoholic beverage intake and increasing breast cancer risk.
II. PATHOLOGY, MOLECULAR CLASSIFICATION, AND NATURAL HISTORY.Breast cancer is a highly heterogeneous disease. Classification based on clinical and pathologic features have historically been used to guide in the treatment of patients. Although classic histopathologic classification of breast cancer remains important, molecular characterization of the disease is rapidly emerging as a vital tool for understanding clinical prognosis, as well as predicting response to systemic therapies.
A. Classic histopathologic classification. Based on cellular morphology, breast tumors can be broadly categorized as tumors composed of cells of ductal origin (ductal adenocarcinomas) or of lobular origin (lobular carcinomas). Breast malignancies are further classified into invasive (infiltrating) carcinomas capable of metastasizing, and noninvasive disease that can invade beyond the basement membrane (ductal carcinoma in situ, [DCIS], also known as intraductal carcinoma).
1. Ductal adenocarcinoma (70% to 80%) is the most common invasive histology. The clinical prognosis is highly variable, ranging from indolent to rapidly progressive. Prognosis may be estimated by evaluation of cellular morphologic characteristics and molecular markers, such as expression of ER, PR, Ki67 (a marker of cell proliferation, see Section V.B.5), and HER2.
2. Lobular carcinoma (10% to 15%). Invasive lobular carcinoma is capable of metastasis and has a stage-adjusted prognosis similar to infiltrating ductal carcinoma. Invasive lobular carcinomas may be especially difficult to diagnose because of their unique single cell radial pattern of tissue invasion (the so-called Indian-filing on light microscopy) rendering them frequently non-palpable or mammographically silent. Invasive lobular carcinomas are somewhat more likely to be bilateral compared with infiltrating ductal carcinomas. Metastases from lobular breast carcinomas have a predilection for pleuropericardial surfaces.
To be distinguished from invasive lobular carcinoma, lobular carcinoma in situ (LCIS) is a benign lesion associated with an increase risk of developing subsequent invasive disease, either ductal or lobular. LCIS, in and of itself, is of no clinical consequence, however.
3. Special subtypes with a favorable prognosis (<10%) include papillary, tubular, mucinous, and pure medullary carcinomas.
4. Inflammatory breast cancer (approximately 1%) is a particularly aggressive subtype that can be recognized microscopically based on presence of dermolymphatic invasion. Clinically, this is often associated with cutaneous erythema of the breast (which can mimic mastitis) and cutaneous edema (“peau d’orange”).
5. Paget disease of the breast, which is characterized by unilateral eczematous change of the nipple, is frequently seen in association with underlying DCIS.
6. Cystosarcoma phyllodes constitutes <1% of all breast neoplasms. About 90% of phyllodes tumors are benign and about 10% are malignant. Although these tumors rarely metastasize, they can recur locally. Surgical resection with ample margins is necessary to optimize local control.
7. Rare tumors include squamous cell carcinoma, lymphoma, and sarcoma.
B. Molecular classification of breast malignancy. Molecular classification of breast tumors can be based on single gene assays, such as ER, PR, HER2 gene copy numbers, proliferation index, and Ki67; or on multigene expression platforms, which can measure dozens to even thousands of gene transcripts simultaneously. Multigene transcript profiles use either real-time quantitative polymerase chain reaction (RT-PCR) or gene chip expression microarray. An example of the former is the Oncotype DX assay (see Section VIII.A.2.b), and Mammaprint is an example of the latter (see Section VIII.A.2.c).
The classification of breast cancer based on gene expression profiling has not yet been completely reconciled with classic histopathologic classification. Gene expression profiling using DNA microarrays have, however, defined new molecular subtypes of breast cancer associated with the cell-of-origin distinction. Recent reports indicate distinct gene expression profiles for inflammatory breast cancer, lobular breast cancer, HER2-positive breast cancer, and BRCA-mutant breast cancer. Based on these observations, breast cancer has been divided into at least five subgroups with distinct biologic features and clinical outcomes.
1. Luminal A. The luminal tumors express cytokeratins 8 and 18, have the highest levels of ER expression, tend to be low grade, will most likely respond to endocrine therapy, and have a favorable prognosis. They tend to be less responsive to chemotherapy.
2. Luminal B. Tumor cells are also of luminal epithelial origin, but with a gene expression pattern distinct from luminal A. Prognosis is somewhat worse than luminal A.
3. Normal-like breast tumors. These tumors have a gene expression profile reminiscent of nonmalignant “normal” breast epithelium. Prognosis is similar to the luminal B group.
4. HER2-amplified. These tumors have amplification of the HER2 gene on chromosome 17q and frequently exhibit coamplification and overexpression of other genes adjacent to HER2. HER2-positive cases have significantly decreased expression of ER and PR and have upregulation of vascular endothelium growth factor (VEGF). Historically, the clinical prognosis of such tumors was poor. With the advent of trastuzumab therapy, however, the clinical outcome for patients with HER2-positive tumors has markedly improved.
5. Basal. These ER- or PR-negative and HER2-negative tumors (the so-called triple negative) are characterized by markers of basal or myoepithelial cells. They tend to be high grade and express cytokeratins 5/6 and 17 as well as vimentin, p63, CD10, smooth muscle actin, and epidermal growth factor receptor (EGFR). It is likely that the basal group is still somewhat heterogeneous; for example, patients with BRCA-1 mutant tumors also fall within this molecular subtype. Overall, patients with basal breast cancers have a poor prognosis, although they likely benefit to some extent from chemotherapy.
C. Location and mode of spread. The most common anatomic presentation of breast cancer is in the upper outer quadrant. Breast cancers spread by contiguity, lymphatic channels, and blood-borne metastases. The most common organs involved with symptomatic metastases are regional lymph nodes, skin, bone, liver, lung, and brain. Internal mammary nodes have evidence of tumor in 25% of patients with inner quadrant lesions and 15% with outer quadrant lesions. Internal mammary node metastases rarely occur in the absence of axillary node involvement.
D. Clinical course. The clinical course of breast cancer is heterogeneous at best, but, generally, there are trends based on stage. Early breast cancer is curable, but has a chance of distant metastases occurring even 10 to 20 years after treatment. Locally advanced cancer has an increased risk of latent distant metastasis. In some women, the course is quite rapid, particularly in women with aggressive tumors having indicators of a poor prognosis. Metastatic breast cancer (except in rare cases) is not curable but typically has a course of stable or responsive disease on therapy, sometimes for months, and then progression in a stepwise fashion.
III. SCREENING AND EARLY DETECTION
A. Mammography detects about 85% of breast cancers. A distinction should be made between diagnostic mammography and screening mammography. A screening mammogram is an x-ray study of the breast used to detect breast changes in women who have no signs or symptoms of breast cancer. A diagnostic mammogram is an x-ray study of the breast that is used to check for breast cancer after a lump or other sign or symptom of breast cancer has been found. Although 15% of breast cancers cannot be visualized with mammography, 45% of breast cancers can be seen on mammography before they are palpable. A normal mammographic result must not dissuade the physician from obtaining a biopsy of a suspicious mass.
Digital mammography is gradually replacing film mammography. Digital mammography takes an electronic image of the breast and uses less radiation than film mammography. Digital mammography allows improvement in image storage and transmission because images can be stored and sent electronically. Diagnostic software may also be used to help interpret digital mammograms. Digital systems, however, currently cost approximately one and a half to four times more than film systems.
1. The American College of Radiology BI-RADS System for reporting mammographic findings is as follows:
Category 1: Negative
Category 2: Benign finding
Category 3: Probably benign finding. Short interval follow-up is suggested. The findings have a very high probability of being benign, but the radiologist would prefer to establish stability.
Category 4: Suspicious abnormality: biopsy should be considered. These are lesions that do not have characteristic findings of breast cancer, but have a definite probability of being malignant.
Category 5: Highly suggestive of malignancy.
2. Meta-analysis of eight randomized mammogram screening trials has shown a 24% reduction in the mortality rate of breast cancer. Mortality reductions have been observed in trials of women aged 40 to 69 years with mammography performed at intervals of 12 and 24 months.
3. The ACS recommends an annual mammogram for women at average risk beginning at age 40. Breast cancer mammographic screening should continue annually regardless of age as long as the woman is in reasonably good health, has a life expectancy of at least 3 to 5 years, and would be willing to undergo therapy. Chronologic age alone should not be used as a reason to discontinue screening mammography.
B. Breast physical examinations. Despite the lack of data showing a reduction in risk of death from breast cancer owing to clinical breast examination (CBE) or breast self-examination (BSE), the ACS has maintained recommendations related to both of these screening modalities.
1. CBE is recommended for women at average risk of breast cancer beginning in their 20s. CBE should be part of a periodic health examination and should occur at least every 3 years. Women aged 40 years and older should receive CBE, preferably annually, and, ideally, before, or in conjunction with, the annual screening mammogram.
2. Women should be told about the benefits and limitations of BSE in their 20s. Women who choose to do BSE should receive instruction and have their technique reviewed on the occasion of a periodic health examination.
C. High-risk patients. The ACS reported that women at increased risk for breast cancer might benefit from additional screening strategies beyond those offered to women at average risk. These interventions may include initiation of screening at a younger age, shorter screening intervals, or the addition of other radiologic investigations in addition to mammography, including magnetic resonance imaging (MRI) or ultrasound.
1. ACS guidelines recommend MRI screening in addition to mammograms for women who have at least one of the following conditions:
a. A BRCA1 or BRCA2 mutation
b. A first-degree relative (parent, sibling, child) with a BRCA1 or BRCA2 mutation, even if they have yet to be tested themselves
c. A lifetime risk of breast cancer that has been scored at 20% to 25% or greater based on one of several accepted risk assessment tools that evaluate family history and other factors
d. A history of radiation to the chest between the ages of 10 and 30 years
e. Germline p53 mutation (Li–Fraumeni syndrome), or hamartoma syndromes associated with PTEN mutation (Cowden syndrome or Bannayan–Riley–Ruvalcaba syndrome), or one of these syndromes based on a history in a first-degree relative
2. The ACS guideline indicates that sufficient evidence still does not exist to recommend for or against MRI screening in women who have
a. A 15% to 20% lifetime risk of breast cancer, based on one of several accepted risk assessment tools that evaluate family history and other factors
b. LCIS or atypical lobular hyperplasia (ALH)
c. Atypical ductal hyperplasia (ADH)
d. Very dense breasts or unevenly dense breasts (when viewed on a mammogram)
e. Already had breast cancer, including DCIS
3. Contralateral breast cancer. A study published in the New England Journal of Medicine shows that MRI scans can be a useful adjunct for finding contralateral breast tumors in women with newly diagnosed disease. In this report, 969 newly diagnosed breast cancer patients were studied; MRI found 30 early-stage tumors that mammograms and physical examinations could not detect and missed only three tumors (see Lehman et al., 2007).
IV. DIAGNOSIS
A. Physical findings and differential diagnosis
1. Breast lumps are detectable in many patients with breast cancer and constitute the most common sign on history and physical examination. The typical malignant breast mass tends to be solitary, unilateral, solid, hard, irregular, and nontender.
2. Spontaneous nipple discharge through a mammary duct is the second most common sign of breast cancer. Nipple discharge develops in about 3% of women and 20% of men with breast cancer, but is a manifestation of benign disease in 90% of patients. Discharge in patients >50 years of age is more likely to represent cancer rather than benign conditions. Milky or purulent discharges are associated with a negligible chance of being cancer.
3. Other presenting manifestations include skin changes, axillary lymphadenopathy, or signs of locally advanced or disseminated disease. A painful breast is a common symptom, but it is usually a result of something other than the cancer. Paget carcinoma appears as unilateral eczema of the nipple. Inflammatory carcinoma appears as skin erythema, edema, and underlying induration in the absence of infection.
B. Evaluation of a breast mass
1. Breast lump or mass in women <30 years of age. Ultrasound is the preferred diagnostic modality for young women with a breast mass. If the mass is solid and suspicious, then mammography followed by tissue diagnosis is recommended. If the mass is thought to be benign ultrasonographically, then the option of tissue diagnosis versus observation with frequent physical and ultrasonographic surveillance is appropriate. If the breast mass appears to be a simple cyst on ultrasound, no intervention is required. If it appears to be a complex cyst, then aspiration is appropriate. If the mass disappears with aspiration and the aspirate is not bloody, then routine screening can again begin.
2. Breast lump or mass in women >30 years of age. Diagnostic mammography should be performed. If the mammographic features are indeterminate, then ultrasonography should be performed. If the mammogram or ultra-sound shows a suspicious lesion, tissue sampling is required.
3. Breast biopsy. When a tissue diagnosis is required, then a choice must be made among the differing techniques.
a. Fine-needle aspiration (FNA) cytology may be performed if both technical and cytopathologic expertise are available. The method is easy, quick, and safe. Seeding tumor cells along the needle track is not a consideration in breast cancer. The sensitivity in diagnosing malignancy has been reported to be 90% to 95%, with 98% specificity. It is, however, impossible to distinguish invasive from in situ carcinoma because only cells are obtained; the architecture of the tissue cannot be assessed with FNA.
b. Ultrasound or stereotactic core biopsy. These techniques are increasingly used as an alternative to excisional biopsy or FNA and are the standard for mammographic changes without accompanying mass; wire- or needle-guided lumpectomies can follow the procedure. In addition, the core biopsy allows sufficient tissue to be removed to appropriately characterize the histology of the specimen. ER, PR, and HER2 testing may be performed if an invasive malignancy is diagnosed.
c. Excisional biopsy is the standard technique for diagnosis of a breast mass if stereotactic or ultrasound-guided core biopsy is unavailable. If excisional biopsy is performed, an adequate amount of normal tissue should be removed around the suspicious lesion so that the biopsy serves as a segmental mastectomy in the event that a malignancy is found. This tactic allows for complete excision with clear margins and full histologic evaluation.
C. Pretreatment staging procedures for invasive breast cancer. Should an invasive breast cancer be found, pretreatment staging may be considered before definitive surgical therapy of the breast and axillary lymph nodes.
1. Complete blood count, liver function tests
2. Chest radiograph, diagnostic bilateral mammography
3. Bone scan and radiologic evaluation of the liver may be considered if the patient is symptomatic or is found to have an elevated alkaline phosphatase.
4. Bone marrow aspiration if there is unexplained cytopenia or a leukoerythroblastic blood smear
5. The role of positron emission tomography (PET), with or without computed tomography, in the initial staging of breast cancer is being evaluated. In general, PET can accurately detect sites of distant disease with a sensitivity of 80% to 97% and specificity of 75% to 94%.
V. STAGING AND PROGNOSIS
A. Staging system. The American Joint Committee on Cancer (AJCC) implemented the current TNM staging system for breast cancer in 2003. The T and M descriptors and prognostic stage groupings are shown in Table 10.1. The N substage descriptors are shown in Table 10.2.
Table 10.1 Postoperative-Pathologic TNM Staging System for Breast Cancer
T1 includes T1mi; T0 and T1 tumors with nodal micrometastases only are classified as stage Ib; MO includes MO(i+).
Adapted from the AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010.
Table 10.2 Posteropative-Pathologic TNM Staging System for Breast Cancer: Regional Lymph Nodes (N)a
aNode classification is based on ALN dissection with or without SLN dissection. Classification based solely on SLN dissection without subsequent ALN dissection is designated (sn) for sentinel node; for example, pN0(sn).
bLymph node involvement identified by IHC only is designated by “i”; for example, pN0(i+)(sn).
c“Clinical detection” of IMLN is defined by clinical examination or by imaging studies (excluding lymphoscintigraphy) or by fine needle aspiration biopsy with cytologic evaluation.
ALN, axillary lymph nodes; IHC, immunohistochemistry; IMLN, internal mammary lymph nodes (in the inter-costal spaces along the edge of the sternum); pN, pathologically evaluated nodes; RLN, regional lymph nodes (axillary, internal mammary, and transpectoral [“Rotter’s”]); SLN, sentinel lymph node.
Adapted from the AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010.
B. Prognostic factors
1. Tumor grade is an important prognostic variable; the higher the grade, the more guarded the prognosis. The Nottingham combined histologic grade (Elston–Ellis modification of the Bloom–Scarff–Richardson grading system) is recommended by the AJCC staging system. A tumor is graded by assessing three morphologic features (tubule formation, nuclear pleomorphism, and count of mitoses). A value of 1 (favorable) to 3 (unfavorable) is assigned to each feature. A combined score of 3 to 5 points is designated grade 1, 6 to 7 points is grade 2, and 8 to 9 points is grade 3.
2. Pathologic stage has a clear impact on expected survival.
a. Tumor size. The risk of recurrence increases linearly with tumor size for patients with fewer than four lymph nodes involved with metastases; thereafter, the prognostic weight of lymph node metastases generally supersedes tumor size. The effect of tumor size on prognosis is reflected by the following SEER 5-year survival data (adapted from Carter et al., 1989).
The 20-year breast cancer–specific, disease-free survival for node-negative patients treated with mastectomy alone is about 92% for pT1a–b tumors and 75% to 80% for pT1c tumors. Tumor grade affects these probabilities.
b. Lymph node involvement is the greatest prognostic indicator for breast cancer recurrence. Because of the changes in staging systems for breast cancer, the potential for confusion exists regarding the long-term prognosis for patients by pathologic stage. The 1988 staging system did not differentiate breast cancer stage by numbers of lymph nodes involved. The 2003 TNM staging system and subsequent revisions as shown in Table 10.2 does address this issue.
c. Distant metastases. Many patients with stage IV disease survive 2 to 4 years, or even longer, depending on sites of metastases, their rate of progression, and response to therapy. Prolonged survival can be achieved, particularly in patients with hormone receptor-positive disease with bone-only metastasis.
3. Hormone receptor status. Patients with tumors that are negative for both ER and PR have a slightly worse prognosis than those patients who have cancers with either ER or PR being positive. These data, however, are based on the National Surgical Adjuvant Breast Project (NSABP) B-06 trial, where ER and PR were measured by biochemical methods. It is felt that ER and PR as measured by current immunohistochemical (IHC) techniques represent very strong predictive factors for response to hormone therapy rather than being strong prognostic factors for survival.
Unfortunately, as many as 20% of current IHC determinations of ER and PR worldwide may be inaccurate (false negative or false positive), mostly because of variation in preanalytic variables, thresholds for positivity, and interpretation criteria. In 2010, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) published recommendations from an international expert panel that conducted a systematic review and critical evaluation of the literature in order to develop recommendations for optimal IHC ER/PR testing performance. The panel recommends that ER and PR assays be considered positive if there are at least 1% positive tumor nuclei in the sample in the presence of expected reactivity of internal (normal epithelial elements) and external controls.
4. HER2 overexpression. All normal cells, including breast epithelial cells, carry two copies of the human epidermal growth factor receptor-2 gene (HER2 or HER2/neu; also known as the c-erbB2 gene). In about 20% of breast cancers, multiple copies of the gene are found owing to gene amplification. HER2 gene amplification results in increased expression of the gene product, a 185-kDa transmembrane receptor tyrosine kinase. Pathologic overexpression of p185HER2 leads to constitutive activation of the HER2 kinase, resulting in increased proliferation, survival, and metastasis of tumor cells.
a. Tumors that overexpress HER2 tend to metastasize earlier and to have a worse prognosis. Tumors that exhibit amplification of the HER2 gene by fluorescent in situ hybridization (FISH) are among the most likely to benefit from systemic humanized monoclonal antibody therapy with trastuzumab (Herceptin).
b. Common methods of identifying HER2 alteration are IHC and FISH. To develop guidelines to improve the accuracy of HER2 testing and its utility as a predictive marker, ASCO and the CAP convened an expert panel, which developed recommendations for optimal HER2 testing performance. The panel recommends that HER2 status should be determined for all invasive breast cancers. Laboratories performing the test must show 95% concordance with another validated test for positive and negative assay results. The recommended algorithm for defining results for both HER2 protein expression and gene amplification is as follows:
(1) A positive HER2 result is IHC staining of 3+ (uniform, intense membrane staining of >30% of invasive tumor cells), a FISH result of >6 HER2 gene copies per nucleus, or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2.
(2) A negative result is an IHC staining of 0 or 1+, a FISH result of <4.0 HER2 gene copies per nucleus, or a FISH ratio of <1.8.
(3) Equivocal results require additional action for final determination.
5. Other biomarkers
a. Ki-67 protein is strictly associated with cell proliferation. Ki-67 protein is present during G1, S, G2, and mitosis phases of the cell cycle, but is absent in resting cells (G0). The fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) has been correlated with the clinical course.
b. DNA flow cytometry can be performed on tumor biopsy material following fluorescent staining with propidum iodide. From this analysis, total DNA content (and thus DNA ploidy) and the percentage of cells undergoing S-phase can be measured.
c. Mutation of the p53 tumor suppressor gene frequently (but not always) leads to aberrant accumulation of dysfunctional p53 protein in the nucleus. Nuclear accumulation of p53 protein can be visualized using IHC staining and has been used as a surrogate marker for p53 gene mutation. Overexpression of normal p53 protein can sometimes be seen in breast cancer cells, even in the absence of p53 gene mutation. Conversely, some tumors harbor p53 mutations that result in protein truncation, which cannot be accurately measured by IHC. Therefore, p53 IHC staining is not an accurate measure of p53 genotype and has limited clinical utility.
VI. MANAGEMENT OF NONINVASIVE BREAST CANCER
A. Ductal carcinoma in situ (DCIS), although noninvasive, is clearly a malignant disease and recurs in about 35% of cases within 10 to 15 years if treated with excisional biopsy alone. The recurrence, if it occurs, is invasive carcinoma in 50% of cases. When axillary node dissection has been performed, metastases have been found in <3% of DCIS cases. When mastectomy has been performed, the disease is often found to be multicentric(additional CIS lesions >2 cm away from the main lesion).
1. Local treatment. Patients often have DCIS found by mammography alone without an accompanying mass. Stereotactic core biopsy is frequently used to make the diagnosis.
a. For women with multicentric DCIS, mastectomy, with or without reconstruction, should be performed. For women with unicentric disease, total mastectomy (without lymph node dissection) or excisional biopsy with adequate negative margins are both acceptable options. Mastectomy cures at least 98% of patients with DCIS.
b. The NSABP B-17 trial randomized 818 women with DCIS treated by lumpectomy to no further therapy or breast RT (see Fisher ER, et al., 1999). The trial demonstrated a reduction in ipsilateral recurrence (invasive plus noninvasive) from 27% to 12% with the use of RT at 8 years of follow-up. Half of the ipsilateral breast tumor recurrences were invasive for those who did not receive radiation. RT reduced the incidence of all noninvasive tumors from 13% to 8% (P = 0.007) and of all invasive tumors from 13% to 3%.
c. The European Cooperative Group Study randomized 1,010 women to receive either 5,000 cGy of RT or observation following surgery (see Julien JP, et al. in Suggested Reading). The relapse rate was 16% without RT and 9% with RT.
d. A select group of women with DCIS might be considered for excision without radiation. These include women with low-grade DCIS with negative surgical margins by at least 1.0 cm in all directions.
2. Adjuvant systemic therapy for DCIS. Data from the NSABP B-24 trial involved 1,804 women who had lumpectomy and RT and were randomized to receive either tamoxifen (20 mg/d for 5 years) or placebo (see Fisher B, et al., 1999). The cumulative incidence of breast cancer events was 8% and 13%, respectively. These data were elaborated in 2002 as follows:
a. The tumors were tested for ER status in 676 of the 1,804 women. The DCIS tumors were ER positive in 75% of those on the placebo arm (344 women) and in 80% of those on the tamoxifen arm (332 women).
b. For the women with ER-negative DCIS, 18% developed an ipsilateral recurrence regardless of the randomization to tamoxifen or placebo. Also, no difference was noted in the incidence of contralateral breast cancer.
c. For women with ER-positive DCIS, 13% of those on placebo and 7% of those on tamoxifen developed an ipsilateral recurrence, and 8% and 3% developed a contralateral breast cancer, respectively. There was no difference in survival.
d. The data support the use of adjuvant tamoxifen for treatment of ER-positive DCIS. The use of adjuvant tamoxifen for ER-positive DCIS, however, must be carefully weighed against the known toxicities of the drug because there was no survival benefit.
B. Lobular carcinoma in situ is also called lobular neoplasia. LCIS is considered by many authorities to be a nonmalignant disease. This tumor tends to be multicentric and is commonly bilateral (approximately 30%). The presence of LCIS is a marker for increased risk of subsequent invasive breast cancer. About 20% of patients with lobular CIS develop invasive breast cancer over 15 years.
1. Surgery is not routinely recommended for LCIS. Annual diagnostic mammography is recommended to follow women who do not undergo mastectomy. In very select circumstances, bilateral mastectomy might be considered for risk reduction.
2. Patients should be counseled regarding the potential benefit of tamoxifen for risk reduction in this circumstance. The NSABP P-1 prevention trial demonstrated a 56% reduction in developing invasive breast cancer among women with a history of a prior LCIS after 5 years of tamoxifen.
3. In the prospective, double-blind, randomized NSABP STAR P-2 clinical trial, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a higher risk of noninvasive breast cancer that was not statistically significant. The risk of other cancers, fractures, ischemic heart disease, and stroke was similar for both drugs.
VII. MANAGEMENT OF EARLY INVASIVE BREAST CANCER: SURGERY AND RT
Management of the primary tumor does not substantially alter the risk of metastases. Variation in local therapies (radical, modified radical, or simple mastectomies, with or without RT) does not alter survival results.
Regional lymph nodes are harbingers of systemic disease and not barriers to tumor spread. Lymph nodes are removed because of the strong prognostic information gained by learning of their involvement. Removal of axillary nodes at surgery does not affect the frequency of recurrence, the development of distant metastases, or survival rates.
A. Surgical management
1. Breast conservation therapy involves the total gross removal of tumor by limited surgery (lumpectomy, segmental mastectomy) followed by RT to eradicate any residual tumor left in the remaining breast tissue. A sentinel nodeprocedure, with or without an axillary nodal dissection, should be done for staging purposes. Contraindications to lumpectomy involve those that make radiation impossible or preclude a cosmetically acceptable result as follows:
a. Absolute contraindications for breast conservation therapy
(1) Prior radiation to the breast or chest wall resulting in excessive exposure of radiation to the chest wall
(2) Radiation to be delivered during pregnancy
(3) Multicentric breast cancer
(4) Diffuse malignant-appearing microcalcifications on mammography
b. Relative contraindications for breast conservation therapy
(1) Multifocal breast cancer requiring two separate incisions
(2) Active connective tissue disease involving the skin, such as scleroderma or lupus erythematosus
(3) T3 disease or a sizable tumor in a smaller breast where the subsequent cosmetic outcome is unacceptable
2. Modified radical mastectomy is the standard surgical procedure for patients who choose surgery as their only local treatment (e.g., to avoid radiation) or for those patients for whom breast conservation therapy is contraindicated. This procedure includes complete removal of the breast as well as axillary lymph node resection. A number of randomized trials have shown survival equivalence for women undergoing modified radical mastectomy versus breast-conserving surgery plus postlumpectomy radiation. The cosmetic deformity that results can be managed by reconstruction or the use of a prosthesis.
3. Axillary lymph node dissection (ALND). Standard pathologic evaluation of the axillary lymph nodes includes a level I and level II (lower and middle) axillary dissection.
a. Lymphedema develops in about 5% of patients (see Section X.B). Nerve damage may occur but is rare.
b. The significance of minimally involved (lesions ≤0.2 mm) axillary nodes is unresolved whether further axillary or systemic treatment is indicated. Such findings should not by themselves be used to upstage the patient or to justify giving local, regional, or systemic therapy.
4. Sentinel lymph nodes (SLN). Most centers have replaced ALND with the SLN technique, which allows a more limited removal of lymph nodes for staging purposes and results in a lower rate of complications (particularly lymphedema). Women with clinically negative axillae are candidates for SLN resection if a surgeon experienced with the technique is available (adequate training and case volume improves the results of SLN biopsy).
a. Completion axillary dissection was offered to most patients with SLN metastases >0.2 mm in diameter, until recently. In 2011, results from a randomized phase III trial of ALND versus no ALND in 891 women with invasive breast cancer and sentinel node metastasis were published by the American College of Surgeons Oncology Group (ACOSOG trial Z0011; see Giuliano AE, et al. in Suggested Reading). Eligibility criteria included women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin (H&E) staining on permanent section. All patients underwent lumpectomy and tangential whole-breast irradiation. At a median follow-up of 6 years, 5-year overall survival was 92% in both groups, suggesting that the use of SLN dissection alone compared with ALND did not result in inferior survival. This study has been criticized for failing to achieve even half the planned accrual goal of 1900 patients.
b. The routine use of cytokeratin IHC for detection of SLN micrometastases should be discouraged. Recently reported results of the ACOSOG Z0010 trial confirmed previous reports that the presence of IHC-detected nodal micrometastases (H&E negative) does not provide useful prognostic information.
5. Breast reconstruction
a. Indications for breast reconstruction include the availability of adequate skin and soft tissue for a reasonable cosmetic result and realistic expectations on the part of the patient.
b. Contraindications to breast reconstruction include inflammatory carcinoma, the presence of extensive radiation damage to the skin from prior treatment, unrealistic expectations on the part of the patient, and the presence of comorbid diseases that render surgery dangerous.
B. RT after breast conserving surgery (BCS). Whole breast irradiation is considered standard of care after BCS in stage I and II breast cancer. The 2005 Early BreastCancer Trialists’ Collaborative Group meta-analysis of the randomized trials showed that the addition of radiation after BCS reduces the risk of local recurrence by 70% at 5 years with a 5% reduction in the 15-year breast cancer mortality (see Clarke et al., 2005).
1. Whole breast RT fractionation
a. Conventional fractionation. The whole breast is usually treated to a dose of 45 to 50 Gy, in 1.8 to 2 Gy per fraction, over a period of 5 weeks.
b. Hypofractionation (shorter treatment length): Whole breast is treated to 42.5 Gy in 16 fractions over 3 weeks. Randomized trials have demonstrated that hypofractionated RT to the whole breast provides similar local control and toxicity compared with conventional fractionation (see Whelan et al, 2010). The American Society for Radiation Oncology (ASTRO) has published guidelines (see Smith et al., 2010) for the use of hypofractionation; patients should
(1) Be at least 50 years old with small or medium-sized breasts
(2) Have tumor stage pT1-T2 pN0
(3) Not require chemotherapy
2. Use of boost of RT after whole breast RT. The benefit in local control with addition of a boost to the tumor bed after whole breast RT has been demonstrated in two randomized trials (see Bartelink et al, 2007; Romestaing et al., 1997). The benefit of the boost is higher in patients who are 40 years of age or younger. The boost dose ranges from 10 to 16 Gy, in 2 Gy fractions, usually using electron beam therapy.
3. Accelerated partial breast irradiation (APBI). Only part of the breast (lumpectomy cavity with margins) receives radiation with APBI. RT is usually delivered over 4 to 5 days. The rationale of APBI is that most of local recurrences after BCS occur close or at the lumpectomy site. Available techniques for APBI are interstitial catheters or balloon brachytherapy, 3D-conformal RT, or intraoperative techniques. APBI is still considered investigational and should be offered only for highly selected patients with low risk of recurrence. ASTRO guidelines (Smith et al., 2009) for suitable patients to receive APBI outside of a protocol are
a. Patient age ≥60 years
b. pT1, pN0 disease
c. ER+
d. Absence of lymphovascular invasion
e. Negative surgical margins (>2 mm)
4. Nodal RT after BCS and axillary surgery (SNL biopsy or ALND)
a. Regional nodal irradiation is not necessary in patients with pathologic node negative disease.
b. In the past, there was no consensus on regional nodal RT in patients with node positive disease after BCS. The NCI Canada recently presented the interim analysis of the MA-20 trial (see Whelan et al., ASCO 2011, abstract 1003) which randomized patients who underwent BCS and axillary dissection to whole breast RT with or without regional nodal irradiation (internal mammary, supraclavicular and high axillary nodes). The stages evaluated were T1-2, N1 and high risk N0 (T3N0 or T2N0 with <10 nodes removed). The tumors also had to manifest one of the following: ER-negative, grade 3, or the presence of lymphovascular invasion.
At median follow-up of 62 months, there was a statistically significant improvement in 5-year locoregional disease-free survival DFS (96.8% vs. 94.5%), distant DFS (92.4% vs. 87%) and DFS (89.7% vs. 84%) with a trend in overall survival (92.3% vs. 90.7%, P = 0.07) in favor of adding nodal irradiation. The results of this trial will probably increase the number of patients who will be offered nodal irradiation.
C. Postmastectomy irradiation (PMRT) for patients with locally advanced breast cancer (LABC)
1. Sites of locoregional recurrence (LRR). At the time of LRR, the chest wall is the most common site, representing about two-thirds of the treatment failures. The second most common site of failure is the supraclavicular/infraclavicular region (43%), followed by axillary recurrences (12%) (see Strom et al., 2005).
2. Rationale for PMRT in patients with LABC
a. Randomized trials from Denmark (Danish 82b) and British Columbia in stage II or III, high risk premenopausal breast cancer patients, treated with modified radical mastectomy and adjuvant chemotherapy showed that the addition of radiation reduced the locoregional failure by 20% with a 10% gain in survival.
b. The Danish 82c trial randomized 1,375 postmenopausal high-risk breast cancer patients after mastectomy with ALND and tamoxifen plus or minus PMRT. The trial showed similar reduction in locoregional recurrence and a survival benefit with addition of radiation.
c. The Early Breast Cancer Trialists’ Collaborative Group published a meta-analysis of the randomized PMRT trials, including about 8,505 women with node positive disease treated with mastectomy and axillary clearance. PMRT reduced the locoregional recurrence by 20% with a 5.4% gain in the 15-year breast cancer mortality (see Clarke et al., 2005).
3. ASCO guidelines for indications of PMRT:
a. Patients with T3N1, or stage III tumors
b. Patients with ≥4 positive axillary nodes
c. Positive or close (<1 mm) surgical margins (a NCCN guideline)
4. Controversial issues with PMRT:
a. Patients with 1 to 3 positive axillary nodes
b. A subset analysis of the Danish 82b & 82c trials, in patients who had at least eight or more axillary nodes removed, showed a reduction of the 15-year locoregional recurrence from 47% to 4% in patients with 1 to 3 positive nodes with the addition of PMRT. There was also a 15-year survival benefit after PMRT in the 1 to 3 positive nodes (57% vs. 48%; see Overgaard et al., 2007).
c. Consider PMRT for patients with 1 to 3 positive axillary nodes if
(1) The patient’s age is ≤35 years
(2) There is involvement of >20% of the axillary nodes, or gross extracapsular extension, or <10 nodes removed
(3) The tumor is grade 3 or demonstrates the presence of lymphovascular invasion
5. PMRT field design:
a. Chest wall irradiation is always given if PMRT is recommended.
b. Supraclavicular and infraclavicular nodal irradiation is recommended for patients with ≥4 positive axillary nodes.
c. Internal mammary nodal irradiation is controversial; consider treating if these lymph nodes are clinically or pathologically involved.
d. Axillary nodal irradiation is not routinely used since the incidence of axillary recurrence after ALND (level I and II nodes) is about 3%. The incidence of arm lymphedema after ALND and axillary irradiation can be up to 30 to 40%, which makes the benefit/risk ratio of axillary irradiation small. Axillary irradiation is suggested if there is
(1) Inadequate or incomplete axillary dissection
(2) Evidence of gross residual disease in the axilla
(3) Extensive extracapsular extension, which suggests a high residual tumor burden and is usually associated with a large number of involved axillary nodes
VIII. MANAGEMENT OF EARLY INVASIVE BREAST CANCER: ADJUVANT CHEMOTHERAPY
A. Principles. An overview of the randomized trials of adjuvant chemotherapy has been reported by the Early Breast Cancer Trialists’ Group. Application of about 6 months of polychemotherapy reduces the annual breast cancer death rate by about 38% for women <50 years of age, and by about 20% for those aged 50 to 69. Table 10.3 shows the approximate reductions for mortality at 10 years by chemotherapy for patients who are 35 or 60 years of age and whose tumors are either negative or positive for hormone receptor activity.
Table 10.3 Approximate Reduction of Mortality at 10 Years with Adjuvant Chemotherapy for Breast Cancers
a“Mortality” is the number of deaths caused by breast cancer among 100 patients; “Reduction” is the fewer number of deaths caused by breast cancer among 100 patients. Data do not account for HER2 positivity or treatment with trastuzumab.
C-H, chemotherapy followed by hormonal therapy for 5 years; H, hormonal therapy alone.
Adapted from Adjuvant Online and Woodward WA, Strom EA, Tucker SL, et al. Changes in the 2003 American Joint Committee on Cancer Staging for breast cancer dramatically affect stage-specific survival. J Clin Oncol 2003;21:3244.
1. Candidates for adjuvant systemic therapy. Women at sufficiently high risk to warrant adjuvant chemotherapy include nearly all women with positive axillary lymph nodes and many with high-risk, node-negative disease as well. Historically, node-negative patients with sufficiently high risk to be considered as candidates for adjuvant chemotherapy tend to be those with tumors that (1) are hormone receptor negative, high grade, or poorly differentiated; (2)overexpress HER2; (3) have markers of increased proliferation (e.g., mitotic index, high Ki-67, or elevated S-phase fraction); (4) have evidence of angiolymphatic invasion; (5) have a high-risk recurrence score based on the Oncotype DX assay; or (6) have high-risk disease based on MammaPrint analysis. The relative benefit of chemotherapy depends on many factors, including the woman’s age at diagnosis, presence of comorbidities, and her hormone receptor status.
2. Patient selection for adjuvant chemotherapy. If a woman’s risk of recurrence is 100%, a relative risk reduction of 30% would reduce her risk to 70%; however, if a woman’s risk is only 10%, a relative risk reduction of 30% will reduce it to a 7% risk of recurrence. Thus, for early breast cancer but with poor prognostic markers, treatment recommendations must be made with a blend of the science and art of medicine. Moreover, patients with favorable prognostic features may be spared the toxicities of chemotherapy and treated appropriately with adjuvant endocrine therapy alone.
a. Adjuvant! Online. Patient selection for appropriate systemic adjuvant therapy has been revolutionized by computerized decision-making tools such as Adjuvant! Online (www.adjuvantonline.com). Breast cancer outcome estimates made by Adjuvant! Online are for patients who have (1) unilateral, unicentric, invasive adenocarcinoma of the breast, (2) undergone definitive primary breast surgery and axillary node staging, and (3) no evidence of metastatic or known residual disease.
In this online algorithm, professionals enter age, comorbidities, ER status, tumor grade, tumor size, and the number of positive lymph nodes. Then that person selects for type of adjuvant endocrine therapy (i.e., tamoxifen, aromatase inhibition) and adjuvant chemotherapy regimen (first, second or third generation). A report is then generated estimating 10-year recurrence risk or 10-year mortality (a) with no systemic adjuvant therapy, (b) with adjuvant endocrine therapy alone, (c) with adjuvant chemotherapy alone, or (d) both endocrine and chemotherapy. Graphic printouts of the results are available for counseling patients on both the risks and the benefits of adjuvant chemotherapy.
Potential shortcomings of Adjuvant! Online include the relative lack of clinical data for patients who have very small lymph node-negative tumors or who are elderly, and the absence of important known risk factors such as HER2(although a new version will include data on HER2 and adjuvant trastuzumab). An important update to Adjuvant!Online will include a genomic version that does include Oncotype DX recurrence scores.
b. Oncotype DX assay quantifies the likelihood of breast cancer recurrence in women with newly diagnosed, early stage, lymph node-negative, ER-positive breast cancer. The assay is performed using formalin-fixed, paraffin-embedded tumor tissue. This multiplex PCR assay measures messenger RNA (mRNA) transcripts of a panel of 16 breast cancer-associated genes that correlate with distant metastases and 5 control genes. The calculation of the Recurrence Score (RS) then combines the gene expression data into a single result (0 to 100).
(1) The Oncotype DX gene panel and RS calculation were validated in a large, independent, multicenter clinical trial of adjuvant tamoxifen treatment (NSABP Study B-14). Patients treated adjuvantly with tamoxifen in this trial could be classified according to recurrence scores into high risk (RS ≥31), intermediate risk (RS = 18 and <31), or low risk (RS <18) based on 10-year distant disease-free survival.
(2) In addition to prognostic information, the Oncotype DX assay may indicate the probability of response to adjuvant therapies. In the B-14 study, patients with low or intermediate risk had a significant benefit from the use of adjuvant tamoxifen, whereas the high risk group did not. Moreover, in a retrospective subset analysis of the NSABP B-20 study (a randomized trial of adjuvant chemotherapy with CMF-like regimens), patients in the high-risk recurrence score strata significantly benefited from adjuvant chemotherapy, whereas the intermediate and low-risk groups did not achieve statistical significance.
(3) An ongoing, randomized clinical trial is prospectively evaluating whether patients with intermediate recurrence scores (defined by RS 11–25) benefit from adjuvant chemotherapy.
(4) Oncotype DX has also been evaluated in a pilot retrospective study in patients with lymph node positive, ER-positive disease. Similar to observations in lymph node-negative disease, the pilot study indicated little (if any) benefit from anthracycline-based (but not containing a taxane) adjuvant chemotherapy for patients with low-risk RS, whereas patients with high-risk RS had a significant impact from adjuvant therapy. Prospective confirmation of these findings using modern adjuvant chemotherapy regimens is necessary for this observation to be practice changing.
c. MammaPrint analyzes a DNA microarray consisting of 70 genes regulating cell cycle, invasion, metastasis, and angiogenesis. This assay requires the use of fresh tumor tissue preserved in a special buffer designed to preserve RNA integrity.
By performing DNA microarray analysis on primary breast tumors of patients, a gene expression signature that was strongly prognostic for development of distant metastasis in lymph node-negative patients was identified. The gene expression profile was validated on a consecutive set of >1,000 patients and has been demonstrated to be superior to commonly used clinical parameters in predicting disease outcome. A potential advantage of the MammaPrint assay is its inclusion of both ER-negative and ER-positive early stage patients.
B. Chemotherapy regimens. The National Comprehensive Cancer Network (NCCN) intermittently reviews the available published clinical trial data regarding benefits from adjuvant systemic treatments for breast cancer. In their 2011 Breast Cancer Practice Guidelines, recommendations were made concerning preferred chemotherapy options to offer women depending on their HER2 status (see www.nccn.org, Breast cancer, v2.2011). Commonly used regimens are shown in Table 10.4. Drug dosing and schedules for these options are shown in Table 10.5.
Table 10.4 Selected Adjuvant Chemotherapy Options for Breast Cancer
Key: →, followed by, A, Adriamycin (doxorubicin); C, cyclophosphamide; Carbo, carboplatin; D, docetaxel (Taxotere); E, epirubicin; F, 5-fluorouracil; H, Herceptin (trastuzumab); P, paclitaxel (Taxol). Regimen dosages are shown in Table 10.5.
Adapted from the National Comprehensive Cancer Network (NCCN) Guidelines, version 2.2011. All listed regimens are category 1 (Based upon high-level evidence with uniform NCCN consensus that the treatment is appropriate).
Table 10.5 Adjuvant Chemotherapy Regimens for Breast Cancera
Trastuzumab (Herceptin)-containing regimens: See Section VIII.D.4.
aDrug doses are in mg/m2 body surface area (days on which drugs are given in each cycle and frequency of cycles are in parentheses); all drugs are given intravenously except PO where indicated.
bFilgrastim or pegfilgrastim is given during each 2- or 3-wk cycle.
Adr, Adriamycin (doxorubicin); Cyc, cyclophosphamide, Doc, docetaxel (Taxotere); Epi, epirubicin (Ellence); 5-FU, 5-fluorouracil; Mtx, methotrexate; Pac, paclitaxel (Taxol); wks/wkly, weeks/weekly.
C. Role of taxanes in the adjuvant setting
1. Multiple clinical trials strongly suggest an additional benefit to adding a taxane to an anthracycline-based chemotherapy regimen for women with lymph node-positive breast cancer. Examples include
a. Cancer and Acute Leukemia Group B (CALGB 9344) showed a 17% reduction in risk of recurrence and an 18% reduction in risk of death at a median follow-up of 69 months with the addition of paclitaxel given every 3 weeks for four cycles after four cycles of Adriamycin–cyclophosphamide (AC).
b. NSABP B-28 showed a 17% reduction in risk of recurrence at a median of 65 months by adding paclitaxel sequentially to AC in a manner similar to the CALGB 9344.
c. Breast Cancer International Research Group (BCIRG 001) showed that docetaxel/AC (DAC) delivered every 3 weeks for six cycles resulted in a 28% improvement in disease-free survival (DFS) compared with six cycles of CA-fluorouracil (CAF) with a median follow-up of 55 months. In addition, a 30% improvement in overall survival (OS) was noted during this same time period.
d. Four cycles of DC (docetaxel/cyclophosphamide) has been compared to four cycles of AC in patients with early breast cancer (about half of whom were lymph-node negative). At a median of 7 years follow-up, the difference in DFS between DC and AC was significant (81% DC vs. 75% AC; hazard ratio 0.74, P = 0.033) as was OS (87% DC vs. 82% AC; hazard ratio 0.69, P = 0.032). DC was superior in older patients as well as younger patients. There was no interaction of hormone-receptor status or HER2 status and treatment. Older women experienced more febrile neutropenia with DC and more anemias with AC.
2. Because all ER-positive breast cancers respond less well to chemotherapy compared with ER-negative tumors, the additional benefit of adding a taxane for ER-positive patients is not as pronounced compared with ER-negative patients.
3. What these studies do not tell us is which is the best regimen and which taxane or taxane dosing schedule is superior. In an attempt to address this shortcoming, the Eastern Cooperative Oncology Group (ECOG) conducted a randomized, prospective clinical trial (E1199) designed to compare taxanes (docetaxel vs. paclitaxel) and taxane-dosing schedules (weekly vs. every 3 weeks) head to head. In this 2 × 2 factorial study design, patients received four cycles of AC every 3 weeks followed by (1) paclitaxel every 3 weeks for four cycles, (2) docetaxel every 3 weeks for four cycles, (3) paclitaxel weekly for 12 weeks, or (4) docetaxel weekly for 12 weeks.
a. The primary comparisons failed to demonstrate any significant advantage of one taxane over another, or the weekly schedule over every-3-week schedule. This finding was potentially confounded because a significant fraction of patients randomized to the weekly docetaxel regimen could not feasibly complete all planned cycles because of untoward toxicity.
b. In planned secondary comparisons, both the weekly paclitaxel arm and the every-3-week docetaxel arm were significantly superior to the every-3-week paclitaxel arm. The weekly paclitaxel arm had a significant survival advantage compared with the every-3-week paclitaxel control arm. Moreover, considering toxicities, the weekly paclitaxel arm had a superior therapeutic index, although it was associated with a higher risk of neurotoxicity (peripheral neuropathy).
D. Adjuvant trastuzumab (Herceptin). Trastuzumab is a humanized, monoclonal antibody with specificity for the extracellular domain of the human EGFR-2 (HER2; HER2/neu).
1. Randomized trials. Results from several prospective randomized trials testing adjuvant trastuzumab have been reported. Together, the adjuvant trastuzumab trials are remarkably consistent, with most analyses indeed reporting an overall survival benefit with trastuzumab treatment.
a. In NSABP B-31, patients with HER2-positive, node-positive breast cancer were randomly assigned to AC for four cycles every 3 weeks followed by paclitaxel given every 3 weeks for four cycles or the same regimen with 52 weeks of trastuzumab commencing with the paclitaxel. In the North Central Cancer Treatment Group (NCCTG) N9831 intergroup trial, patients who were HER2-positive with early stage cancer were similarly randomized except that paclitaxel was given by a low dose weekly schedule for 12 weeks; a third arm testing sequential chemotherapy followed by trastuzumab was added.
Because of their similarities, the B-31 and NCCTG N9831 trials with 3,351 patients together were analyzed jointly. With a median follow-up of 2 years, trastuzumab resulted in a 52% reduction in the risk of recurrence (P <0.001) and a 33% reduction in the risk of death (P = 0.015). Similar beneficial effects on DFS were observed when results of the NSABP B-31 and NCCTG N9831 trials were analyzed separately.
b. A third trial (HERA) involving 5,081 patients tested trastuzumab for 1 versus 2 years (compared with no further treatment) following all local therapy and a menu of standard chemotherapy regimens. With early follow-up, 1 year of trastuzumab resulted in a 46% reduction in the risk of recurrence (P <0.0001). The data for 2 years of adjuvant trastuzumab are not yet reported.
c. The BCIRG 006 study randomized 3,222 women with HER2-amplified, node-positive or high-risk node-negative breast cancer to AC followed by docetaxel, AC followed by docetaxel plus trastuzumab (DH) for 1 year, or carboplatin plus docetaxel plus trastuzumab. At 36 months of follow-up, patients receiving AC followed by docetaxel with trastuzumab had a hazard ratio for disease-free recurrence of 0.61 (P <0.0001) when compared with the nontrastuzumab control arm. The hazard ratio for DFS was 0.67 (P = 0.0003) for patients in the carboplatin/docetaxel/trastuzumab (CDH) arm. No statistically significant difference in the hazard ratio for DFS was observed between the two trastuzumab-containing arms. A significant survival benefit was observed in both trastuzumab-containing arms. Importantly, the nonanthracycline arm (TCH) had significantly less cardiac toxicity than the AC followed by the TH arm. Dosages and schedules for these regimens are shown in Table 10.5.
d. A fifth trial (FinHer) randomized 1,010 women to either 9 weeks of vinorelbine followed by three cycles of FEC (defined in Table 10.6) versus docetaxel for three cycles followed by three cycles of FEC. Patients (N = 232) with HER2-positive cancers were further randomized to receive trastuzumab or not for 9 weeks during the vinorelbine or docetaxel treatment. With a median follow-up of 3 years, the addition of trastuzumab was associated with a reduction in risk of recurrence (hazard ratio 0.42; P = 0.01).
2. Cardiac adverse events from adjuvant trastuzumab. In the adjuvant trastuzumab trials, the rates of grade III/IV congestive heart failure (CHF) or cardiac-related death for patients receiving treatment regimens containing trastuzumab ranged from 0% (FinHer trial) to 4.1% (NSABP B-31 trial). The risk of cardiac dysfunction appears to be related to age, baseline left ventricular ejection fraction (LVEF), prior anthracycline treatment, and use of concomitant antihypertensive medications. It is worth noting that patients in all of these trials had rigorous monitoring of LVEF every 3 months while on trastuzumab treatment, and strict guidelines for withholding trastuzumab, even for asymptomatic declines in LVEF, were followed. Moreover, the median age of patients enrolled in all of these trials was about 50 years and virtually any significant cardiac history was exclusionary.
Candidates for treatment with trastuzumab should undergo thorough baseline cardiac assessment, including history and physical examination and assessment of LVEF by echocardiogram or radionuclide scan. Monitoring may not identify all patients who will develop cardiac dysfunction. Caution should be exercised in treating patients with pre-existing cardiac dysfunction. Discontinuation of trastuzumab treatment should be strongly considered in patients who develop a clinically significant decrease in LVEF.
3. HER2 status, topoisomerase II, and the role of anthracyclines. Numerous large retrospective studies have linked HER2 status with response to anthracyclines. Transfection and overexpression of HER2 in breast cancer cell lines does not, however, increase sensitivity to doxorubicin in vitro. This observation suggests that some factor other than HER2 confers drug sensitivity to anthracyclines.
The topoisomerase IIα gene is in close physical proximity to the HER2 gene on the long arm of chromosome 17, and in 35% of patients with HER2 gene amplification, the topoisomerase II gene is coamplified. The current hypothesis is that amplification of topoisomerase II confers sensitivity to anthracyclines, and not HER2 gene amplification per se. Of note, topoisomerase II gene amplification is seen rarely (if ever) in the absence of HER2 gene amplification. Thus, it is arguable whether or not anthracyclines are of any benefit in HER2-negative early stage breast cancers.
The U.S. Oncology Network is currently testing docetaxel plus cyclophosphamide for six cycles, versus the DAC regimen for six cycles in HER2-negative early stage patients. Whether or not to utilize anthracycline-containing adjuvant regimens in HER2-positive disease remains controversial. In the BCIRG 006 adjuvant trastuzumab trial, no statistically significant advantage was seen to an anthracycline-based adjuvant trastuzumab regimen above and beyond a non–anthracycline-based trastuzumab regimen (regardless of topoisomerase II status). However, there was a nonsignificant trend favoring the anthracycline-based regimen.
4. Trastuzumab combinations for adjuvant chemotherapy (cardiac monitoring is done at baseline, 3, 6, and 9 months)
a. Docetaxel/carboplatin (H + D-Carbo; TCH)
Docetaxel, 75 mg/m2 IV on day 1
Carboplatin, AUC 6 IV on day 1; cycled every 21 days for six cycles
Trastuzumab, 4 mg/kg on week 1; followed by 2 mg/kg for 17 weeks; followed by 6 mg/kg every 3 weeks to complete 1 year of therapy.
b. Doxorubicin/cyclophosphamide/paclitaxel (AC → P)
Doxorubicin, 60 mg/m2 IV on day 1 and
Cyclophosphamide, 600 mg/m2 IV on day 1; cycled every 21 days for four cycles
Followed by paclitaxel, 175 mg/m2 IV over 3 hours on day 1; cycled every 21 days for four cycles
Trastuzumab, 4 mg/kg with first dose of paclitaxel; followed by 2 mg/kg weekly or 6 mg/kg every 3 weeks (after completion of paclitaxel) to complete 1 year of therapy
c. Doxorubicin/cyclophosphamide/docetaxel (AC → P). Same as Section D.4.b. except that docetaxel (100 mg/m2 IV) is substituted for paclitaxel at the same schedule
E. Dose-dense therapy. Delivering identical doses of chemotherapy on a more frequent basis is described as dose-dense therapy. One large clinical trial (CALBG 9741) showed a 26% improvement in DFS and a 31% improvement in OS for women with lymph node-positive breast cancer receiving chemotherapy on an every-2-week basis with growth factors when compared with the same regimen delivered every 3 weeks without growth factor support. AC (every 2 weeks for four cycles) was followed by paclitaxel (every 2 weeks for four cycles).
Although this trial’s data are compelling, they do not differentiate the benefit of dose-dense chemotherapy employing AC versus paclitaxel, either of which could be responsible for the improvement in DFS and OS. One possible explanation is the more frequent dosing of the paclitaxel, which has been shown to be superior to every 3 weeks of paclitaxel in the metastatic setting. The NSABP has recently completed accrual to a large randomized trial (NSABP B-38) comparing two-dose dense adjuvant therapy regimens (one including gemcitabine) versus DAC.
F. Adjuvant chemotherapy is not indicated in the following circumstances:
1. In women with a good prognosis without such treatment, including those with the following conditions:
a. Noninvasive CIS of any size in women of any age
b. Very small primary tumors (<0.5 cm; T1a) and negative axillary lymph nodes, irrespective of the status of hormone receptors
c. Lymph node negative, ER-positive cases with low-risk recurrence score based on Oncotype DX
d. Comorbid medical conditions that make survival beyond 5 years unlikely or that make the potential adverse effects of therapy unacceptable
2. Controversy exists regarding the use of adjuvant systemic chemotherapy for women whose tumors are 0.6 to 1.0 cm with negative hormone receptors or with a grade interpreted as moderately or poorly differentiated.
G. Radiation and chemotherapy. For women who are prescribed both chemotherapy and RT, it is recommended that these modalities be used sequentially with chemotherapy delivered first. RT may be used concurrently with CMF chemotherapy, but not with other published regimens.
H. Adjuvant endocrine therapy
1. Selective ER modifiers. Tamoxifen has been considered the standard of care for all women with an invasive breast cancer that expresses either ER or PR. The benefit of tamoxifen is seen regardless of the patient’s age, the number of involved lymph nodes, and whether or not chemotherapy is used. Trials have demonstrated that patients did the best when taking 20 mg of tamoxifen daily for 5 years. One large trial in women with ER-positive, lymph node-negative breast cancer comparing 5 versus 10 years of tamoxifen in the adjuvant setting has demonstrated a detrimental effect on DFS for those women taking tamoxifen for 10 years. However, preliminary data from the ATLAS study (involving over 15,000 patients randomized to discontinue tamoxifen after 5 years vs. continuation for 10 years) indicate a small but significant reduction in relapse risk with greater benefit amongst women receiving 10 years of tamoxifen.
2. Aromatase inhibitors (AIs) block the peripheral conversion of the adrenal androgens (androstenedione and testosterone) into estradiol and estrone in postmenopausal women. Aromatase inhibitors should not be considered in those women who have any ovarian function because blockage of peripheral aromatization will not block the ovarian production of estrogen and progesterone.
a. The ATAC trial randomized 9,366 postmenopausal women with early invasive breast cancer to one of three arms: anastrozole (Arimidex) 1 mg daily for 5 years, tamoxifen 20 mg daily for 5 years, and the combination of both drugs daily for 5 years (see ATAC Trialists’ Group, 2002). The outcome of those women taking the combination of anastrozole and tamoxifen was the same as that of the women taking tamoxifen alone. At a median follow-up of 48 months, however, findings were an 18% improvement in DFS and a 22% improvement in time to recurrence for those patients with ER-positive tumors who were randomized to anastrozole compared with tamoxifen. In addition, an additional 44% reduction was noted in new contralateral breast tumors for women receiving 5 years of anastrozole.
b. The BIG 1-98 trial is a randomized, phase 3, double-blind study of tamoxifen versus letrozole (Femara) in 6,182 postmenopausal women with steroid receptor-positive early breast cancer (see BIG 1-98 Collaborative Group et al. 2009). Two years of treatment with one agent was followed by 3 years of the other agent. With a median follow-up of 71 months, DFS was not significantly improved with either of the sequential treatments compared to letrozole alone. Moreover, in the 4,922 patients randomized to tamoxifen or letrozole monotherapy, with a median follow-up of 76 months, DFS was superior in the letrozole arm (hazard ratio = 0.88, P < 0.05) with a nonsignificant trend toward improved OS (hazard ratio = 0.87, P = 0.08).
Taken together, results from the ATAC and BIG 1-98 trials support the use of adjuvant AIs for postmenopausal women with hormone receptor-positive invasive early breast cancer.
c. The MA-17 trial randomized 5,187 postmenopausal women with ER-positive and ER-negative invasive breast cancer who had received from 4.5 to 5.5 years of tamoxifen in the adjuvant setting (see Muss et al. 2008). These women were randomized to 5 years of further therapy with either placebo or letrozole. At 30-months median follow-up, letrozole significantly improved DFS in all patients and OS in node-positive patients. Additionally, letrozole decreased the incidence of contralateral breast cancer by 46%. Thus, for postmenopausal women, the addition of letrozole after 5 years of tamoxifen may be considered.
d. Additionally, a double-blind, randomized trial to test whether, after 2 to 3 years of tamoxifen therapy, switching to exemestane (Aromasin) was more effective than continuing tamoxifen therapy for the remainder of the 5 years of treatment has been conducted. Exemestane therapy after 2 to 3 years of tamoxifen therapy significantly improved DFS and reduced the occurrence of contralateral breast cancer as compared with the standard 5 years of tamoxifen treatment.
e. In summary, aromatase inhibition is superior to tamoxifen in postmenopausal ER-positive patients whether used first line in place of tamoxifen, following 2 to 3 years of tamoxifen, or following 5 years of tamoxifen. Comparison of one AI versus another has been tested in the MA 27 trial (exemestane vs. anastrozole), which failed to show any difference in efficacy between steroidal versus nonsteroidal AIs. The optimal duration of AI therapy remains unknown. Ongoing trials will address this issue.
3. Ovarian ablation. Ovarian ablation via surgical oophorectomy or suppression with agonists of luteinizing hormone-releasing hormone (LHRH) is effective therapy for premenopausal ER-positive early stage breast cancer. Available data suggest similar benefit from surgical ovarian ablation as there is with the use of CMF chemotherapy in such patients. Trials currently underway will address whether ovarian ablation plus an aromatase inhibitor will be superior to adjuvant tamoxifen in premenopausal women who are ER positive.
4. Combination chemohormonal therapy. When chemotherapy and tamoxifen are both used in the adjuvant setting, they should ideally be used sequentially, rather than in combination, because of a detrimental outcome when comparing concurrent versus sequential chemohormonal therapy. Whether this observation will also hold true for aromatase inhibitors is unknown.
I. Preoperative (neoadjuvant) chemotherapy
1. The use of preoperative cytoreductive chemotherapy for those who desire breast conservation therapy may be considered. No published survival advantage exists to the delivery of the chemotherapy preoperatively compared with its postoperative use (although in long-term follow-up of the NSABP B-18 study, in subgroup analysis, there appeared to be an advantage for a neoadjuvant approach amongst patients under age 50). No randomized clinical trials have been performed to evaluate the benefit of adjuvant chemotherapy in women who have received both anthracyclines and taxanes in the preoperative setting.
2. For patients with inoperable locally advanced disease at presentation, the initial use of preoperative chemotherapy with an anthracycline and a taxane is standard treatment. Following neoadjuvant therapy, measures aimed at local control usually consist of total mastectomy with axillary lymph node dissection, with or without delayed breast reconstruction, or lumpectomy and axillary dissection. Both local treatment measures are considered to have sufficient risk of local recurrence to warrant the use of chest wall (or breast) and supraclavicular node irradiation. Involved internal mammary lymph nodes should also be irradiated. Tamoxifen (or an AI if postmenopausal) should be added for those with hormone receptor positive tumors.
3. In selected ER-positive patients, neoadjuvant endocrine therapy may be used; for example in elderly or frail patients, or patients with a contraindication to neoadjuvant chemotherapy.
4. For HER2-positive patients, neoadjuvant chemotherapy regimens incorporating trastuzumab have been shown to have impressive pathologic complete response rates. Thus, trastuzumab-based regimens are considered the standard of care for HER2-positive locally advanced disease.
IX. MANAGEMENT: DISSEMINATED DISEASE (STAGE IV). Except in rare cases, stage IV breast cancer is considered incurable. Thus, the focus of treatment for advanced disease should be on palliation of disease-related symptoms.
A. Hormone receptor–positive metastatic breast cancer. For women who have non–life-threatening, ER-positive or PR-positive metastatic breast cancer, single-agent hormone therapy is recommended. Chemotherapy is reserved for hormone-resistant disease, or patients with symptomatic or life-threatening metastases, such as lymphangitic pulmonary metastases or progressive liver metastases.
1. For postmenopausal women, the following agents can be used in a sequential manner:
a. Aromatase inhibitors
(1) Anastrozole (Arimidex), 1 mg PO daily, or
(2) Exemestane (Aromasin), 25 mg PO daily, or
(3) Letrozole (Femara), 2.5 mg PO daily
b. Tamoxifen (20 mg PO daily) or toremifene (Fareston, 60 mg PO daily)
c. Fulvestrant (Faslodex), 500 mg IM monthly
d. Megestrol acetate (Megace), 40 mg PO q.i.d.
e. Fluoxymesterone (Halotestin), 10 mg PO b.i.d. or t.i.d
f. Diethylstilbestrol, 5 mg PO t.i.d.
2. For premenopausal women, options include the following:
a. Tamoxifen
b. LHRH agonist or surgical or radiotherapeutic oophorectomy
c. Megestrol acetate
d. Fluoxymesterone
e. Diethylstilbesterol
B. Chemotherapy. No gold standard chemotherapy regimen exists for metastatic breast cancer. Chemotherapy combinations are shown in Table 10.6; although somewhat more active than single agents, the combinations are associated with more treatment-related side effects. Consequently, sequential single agent chemotherapy (except in cases where rapid response is required) is most commonly used to manage advanced ER-negative (or hormone-refractory ER-positive) disease.
1. HER2-negative, ER-negative metastatic breast cancer
a. Preferred single agents include the anthracyclines (doxorubicin [Adriamycin], epirubicin [Ellence], or liposomal doxorubicin [Doxil]), the taxanes (paclitaxel [Taxol], docetaxel [Taxotere], or albumin-bound paclitaxel [Abraxane]), capecitabine (Xeloda), or vinorelbine (Navelbine). Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited.
b. Other active agents include gemcitabine, platinoids, vinblastine, irinotecan, mitomycin, ixabepilone, and eribulin. One study showed that ixabepilone plus capecitabine prolonged median progression-free survival (6 vs. 4 months), and increased objective response rate (35% vs. 14%; P < 0.0001) compared with capecitabine alone. In a phase 3 open label study of eribulin versus treatment of physician’s choice (see Cortes et al., 2011) in patients with 2 to 5 previous lines of chemotherapy for advanced disease, OS was significantly improved in women (N = 508) assigned to eribulin compared with TPC (N = 254); hazard ratio = 0.81, P= 0.041).
c. Bevacizumab. A randomized trial of weekly paclitaxel with or without bevacizumab (Avastin) as first-line treatment for patients with metastatic breast cancer has been conducted by ECOG (E2100). A significant improvement in progression-free survival was demonstrated, but no significant benefit seen in terms of OS. In another study, patients with metastatic disease previously treated with anthracyclines and taxanes were randomized to capecitabine alone versus capecitabine plus bevacizumab. The response rate was increased with bevacizumab, but no significant difference was found in time-to-progression or OS. Subsequent results from other follow-on large, prospective, randomized phase III trials of multiple different chemotherapy backbones in the first of second line metastatic setting, with or without bevacizumab, have been far more modest as compared to the initial E2100 results. Consequently, FDA has removed the breast cancer label indication for bevacizumab.
2. HER2-positive metastatic breast cancer
a. Trastuzumab. Data support the use of single-agent trastuzumab or the combination of trastuzumab with chemotherapy drugs. The anthracyclines are to be avoided, however, because of the risk of cardiotoxicity when trastuzumab is combined with these agents. Two randomized trials in women with metastatic breast cancer have shown a survival benefit for women who were placed immediately on trastuzumab therapy with concurrent chemotherapy.
b. Lapatinib is a small molecule, orally bioavailable tyrosine kinase inhibitor of HER2 and EGFR. It is active (in combination with capecitabine) in women with HER2-positive metastatic breast cancer (MBC) that has progressed after trastuzumab-based therapy.
(1) In a randomized pivotal trial of lapatinib, patients with HER2-positive advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1,250 mg/d continuously plus capecitabine at a dose of 2,000 mg/m2 on days 1 through 14 of a 21-day cycle) or capecitabine alone. An interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy arm. The median time to progression of 8 months in the combination-therapy group as compared with 4 months in the capecitabine alone arm. Notable toxicities of lapatinib include rash and diarrhea (similar to other EGFR kinase inhibitors), and only infrequent reports of cardiotoxicity. In combination with capecitabine, an increase in frequency of diarrhea was seen, but other capecitabine-associated toxicities, such as palmar–plantar erythrodysaesthesia, were not significantly increased.
(2) Cross-talk between human EGFRs and hormone receptor pathways may lead to endocrine resistance in breast cancer. In a placebo-controlled, randomized phase 3 study, combination of letrozole (2.5 mg PO daily) plus lapatinib (1,500 mg PO daily) significantly enhanced PFS and clinical benefit rates in patients with MBC that coexpresses hormone receptors and HER2. Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% vs. 1%; rash, 1% vs. 0%, respectively), but were considered manageable.
(3) Preclinical studies in HER2-positive cell lines demonstrate a synergistic interaction between lapatinib and trastuzumab. In one clinical study, patients with HER2-positive MBC who experienced progression on prior trastuzumab-containing regimens were randomly assigned to receive either lapatinib alone (1,500 mg PO daily) or lapatinib (1,000 mg PO daily) in combination with standard dose trastuzumab. The combination resulted in superior PFS and clinical benefit rate compared with single agent lapatinib. In an updated analysis, a significant trend in OS favoring the combination arm was also seen. This regimen offers a chemotherapy-free option with acceptable toxicities for selected patients with HER2-positive MBC.
C. Systemic agents for bone metastases (see also Chapter 33, Section 33.I.E)
1. Bisphosphonates are recommended for women with breast cancer metastatic to bones. Both pamidronate (Aredia, 90 mg IV monthly) and zoledronate (Zometa, 4 mg IV monthly) are effective in reducing bone pain and pathologic fractures. Zoledronate may be superior to pamidronate for reducing (1) bone fractures, (2) spinal cord compression, (3) hypercalcemia of malignancy, and (4) the need for palliative RT in patients with metastatic disease.
2. Denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor kappa B ligand (RANKL, 120 mg SQ) has been compared to zoledronic acid (4 mg IV) every 4 weeks in a randomized, placebo-controlled trial in 1,026 patients with MBC with bone metastasis. The primary endpoint was time to first on-study skeletal-related event (SRE, defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression). Denosumab was superior to zoledronic acid in delaying time to first SRE, (hazard ration 0.82, P = 0.01). Rates of adverse events (including osteonecrosis of the jaw) were similar between the two groups. Denosumab represents a potential SQ treatment option for patients with bone metastasis, without need for renal monitoring.
D. Local therapy for metastatic disease. Metastatic disease is generally treated systemically, but some local problems benefit from local RT.
1. Bone metastases can be followed as markers of disease, but if they are painful or show impending signs of fracture, these usually respond to local RT. If in the axial skeleton, RT should include the vertebrae above and below the involved vertebra. In addition, all patients with bony metastases should receive a bisphosphonate or denosumab (see Section IX.C). Patients with spinal cord compression should be considered for early surgical intervention based on data that demonstrated a higher percentage of ambulatory patients, but no change in OS, if surgical decompression was undertaken before RT.
2. All cervical spine and femoral neck lesions, with or without symptoms, should usually be treated with local RT because of the potential for fracture. Femoral neck lesions may also require surgical fixation.
3. Brain and orbital metastases. Patients who present with headache or nausea and vomiting and metastatic disease should alert the clinician to promptly investigate for brain metastases or meningeal carcinomatosis. Brain MRI, with and without gadolinium, is necessary to diagnose metastatic disease. Solitary lesions may be excised surgically or radiated with new modalities, such as cyberknife or gamma knife. Multiple lesions may be treated with stereotactic radiosurgery with or without whole brain radiation. In general, stereotactic radiosurgery alone for multiple metastasis is a consideration in patients with tumors less than ~4 cm, tumors without significant surrounding edema, a limited number of brain metastasis (four or less), and those with otherwise controlled extracranial systemic metastases with preserved performance status.
4. Chest wall recurrence. These patients are generally treated first with systemic therapy. In some cases, RT may be used, especially when the patient is otherwise without evidence of disease.
X. SPECIAL CLINICAL PROBLEMS
A. Postsurgical edema of the arm without pain was regularly associated with the traditional radical mastectomy but also occurs with less extensive surgery. The incidence is increased in patients who receive postoperative RT. The edema usually develops within 6 months after surgery, but may be delayed much longer. Therapy is not always helpful but includes elevation of the arm, arm compression sleeves, compression pump, lymphomassage, and physical therapy. Physical therapists or occupational therapists trained in lymphatic massage often benefit the patient.
B. Edema of the arm with pain or paresthesias occurring >1 month after surgery may reflect recurrent tumor. The cancer is often not clinically discernible because it resides high in the apex of the axilla or lung and involves the brachial plexus. Patients may complain of tingling or pain in the hands and progressive weakness and atrophy of the hand and arm muscles. If sufficient time passes, a tumor mass becomes palpable in the axilla or supraclavicular fossa, but the patient is usually left with a paralyzed hand unresponsive to therapy. These patients may receive RT to the axilla and supraclavicular fossa, if radiation has not previously been delivered to this region. The recurrence to the brachial plexus may not be easily seen on MRI or CT scanning. PET scanning may be useful in this circumstance. Occasionally, the pain of this nerve involvement is so severe that nerve blocks by a pain management specialist are necessary.
C. Breast implants can create a special challenge in both diagnosis and treatment of breast cancer. No relationship exists between breast implants and the development of breast cancer. In fact, women with breast augmentation with breast implants appear to be less likely to develop breast cancer in their lifetime than women who choose to not have implants placed for cosmetic augmentation. Mammography techniques have been developed to assess the breast tissue in women with implants, and they appear to have the same sensitivity for picking up early breast cancers as in women without implants.
1. When an abnormality is seen on a mammogram in a woman with breast implants, special consideration is given to the type of biopsy techniques that must be used. Stereotactic techniques may be avoided to lessen the likelihood of puncturing the implant. Each case is taken on an individual basis depending on the proximity of the abnormality to the implant.
2. When a woman elects to have a mastectomy as part of her local breast cancer management and subsequently requires chest wall RT, placement of breast implants is frequently avoided. A greater risk exists of scar tissue contracting around the implant with radiation, thus significantly reducing an optimal cosmetic benefit of breast reconstruction. If chest wall radiation is to be considered, most plastic surgeons would prefer to bring a flap of tissue from outside the radiation field to accomplish optimal reconstruction and cosmesis.
D. Breast cancer during pregnancy. In a California registry study, there were 1.3 breast cancers diagnosed per 10,000 live births. Breast cancer during pregnancy is most often associated with larger tumor size and with lymph node metastasis. Histologically, these tumors are often poorly differentiated, more frequently ER-negative and PR-negative, and may be HER2-positive. Delay in diagnosis is typical because tumor masses can be masked by breast engorgement owing to lactation, and inflammatory changes may be mistaken for mastitis.
1. Mammography with shielding can be performed safely, although interpretation can be difficult because of increased breast density. Ultrasonography of the breast and regional lymph nodes is used to assess the extent of disease and also to guide biopsy.
2. Core needle biopsy is preferred for histologic diagnosis and biomarker analysis.
3. Staging assessment of the pregnant patient can be problematic. In addition to complete blood count and serum chemistries, including hepatic function testing, a chest radiograph (with shielding) is feasible. Additionally, in patients who have clinically node-positive or T3 breast lesions, an ultrasound of the liver and directed screening MRI of the thoracic and lumbar spine without contrast can be used. Documentation of metastases may alter the treatment plan and influence the patient’s decision regarding maintenance of the pregnancy.
4. Assessment of the pregnancy should include a maternal fetal medicine consultation.
5. Indications for systemic chemotherapy do not differ for the pregnant patient with breast cancer, although chemotherapy is to be avoided during the first trimester of pregnancy because of the risk of fetal malformation. Fetal malformation risks in the second and third trimester fall to approximately 1.3%, no different than that of unexposed fetuses.
a. The greatest treatment experience in pregnancy has been with anthracycline and alkylating agent chemotherapy. Limited data are found on the use of taxanes during pregnancy, although taxanes have fewer propensities to cross the placental barrier. One popular strategy is to complete cycles of anthracycline plus cyclophosphamide during second or third trimester, followed by a taxane postpartum.
b. Chemotherapy during pregnancy should be avoided following week 35 to avoid hematologic complications at the time of delivery. Ondansetron, lorazepam, and dexamethasone may be used for the antiemetic regimen.
c. There are several case reports of trastuzumab use during pregnancy. Oligohydramnios has been reported in these cases. Trastuzumab should be delayed until the postpartum period.
d. Endocrine therapy and radiation therapy are contraindicated during pregnancy and should not be initiated until the postpartum period.
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