CANCER OF THE BREAST
Breast Cancer
Breast cancer today is not what it was 20 years ago. Survival rates are climbing, thanks to greater awareness, more early detection, and advances in treatment. For roughly 200,000 Americans who are diagnosed with breast cancer each year, there are plenty of reasons to be hopeful.
Breast Cancer Symptoms
There are ofteo symptoms of breast cancer, but sometimes women may discover a breast problem on their own.
Signs and symptoms to be aware of may include:
- A painless lump in the breast.
- Changes in breast size or shape.
- Swelling in the armpit.
- Nipple changes or discharge.
Breast pain can also be a symptom of cancer, but this is not common.
Signs of Inflammatory Breast Cancer
Inflammatory breast cancer is a rare, fast-growing type of cancer that often causes no distinct lump. Instead, breast skin may become thick, red, and may look pitted — like an orange peel. The area may also feel warm or tender and have small bumps that look like a rash.
Breast Cancer & Mammograms
The earlier breast cancer is found, the easier it is to treat. And mammograms, X-rays of the breast, can detect tumors before they are large enough to feel. The American Cancer Society recommends yearly mammograms beginning at age 40 for women at average risk. While the U.S. Preventive Services Task Force recommends a screening mammogram every two years from age 50 to 74. It also notes that before age 50, each woman should check with a doctor to find out what screening schedule is right for her, considering the potential benefits and harms from screening.
Breast Ultrasound and MRI
Besides a mammogram, your doctor may order additional imaging with breast ultrasound. An ultrasound can help determine the presence of cysts, fluid-filled sacs that are not cancer. An MRI may be recommended along with a mammogram for routine screening in certain women who have a higher risk of breast cancer.
Breast Self-Exams
It was once widely recommended that women check their own breasts once a month. But studies suggest these breast self-exams play a very small role in finding cancer. The current thinking is that it’s more important to know your breasts and be aware of any changes, rather than checking them on a regular schedule. If you want to do breast self-exams, be sure to go over the technique with your doctor.
What If You Find a Lump?
First, don’t panic. Eighty percent of breast lumps are not cancerous. Lumps often turn out to be harmless cysts or tissue changes related to your menstrual cycle. But you should let your doctor know right away if you find anything unusual in your breast. If it is cancer, the earlier it’s found the better. And if it’s not, testing can give you peace of mind.
Breast Biopsy
The only sure way to determine whether a lump is cancer is to do a biopsy. This involves taking a tissue sample for further examination in the lab, sometimes through a small needle. Sometimes surgery is done to take part of or the entire lump for testing. The results will show whether the lump is cancer, and if so, what type. There are several forms of breast cancer, and treatments are carefully matched to the type of cancer.
Hormone-Sensitive Breast Cancer
Some types of breast cancer are fueled by the hormones estrogen or progesterone. A biopsy can reveal whether a tumor has receptors for estrogen (ER-positive) and/or progesterone (PR-positive). About two out of three breast cancers are hormone sensitive. There are several medications that keep the hormones from promoting further cancer growth.
The image shows a molecular model of an estrogen receptor.
HER2-Positive Breast Cancer
In about 20% of patients, breast cancer cells have too many receptors for a protein called HER2. This type of cancer is known as HER2-positive, and it tends to spread faster than other forms of breast cancer. It’s important to determine whether a tumor is HER2-positive, because there are special treatments for this form of cancer.
Breast Cancer Stages
Once breast cancer has been diagnosed, the next step is to determine how big the tumor is and how far the cancer has spread. This process is called staging. Doctors use Stages 0-4 to describe whether cancer is localized to the breast, has invaded nearby lymph nodes, or has spread to other organs, such as the lungs. Knowing the stage and type of breast cancer will help your health care team formulate a treatment strategy.
Breast Cancer Survival Rates
The odds of surviving breast cancer are strongly tied to how early it is found. According to the American Cancer Society, 100% of women with Stage 1 breast cancer live at least five years, compared to women without cancer – and many women in this group remain cancer-free for good. The more advanced the cancer, the lower this figure becomes. By Stage 4, the five-year relative survival rate declines to 20%. But these rates can improve as more effective treatments are found.
Breast Cancer Surgery
There are many types of breast cancer surgery, from taking out the area around the lump (lumpectomy or breast-conservation surgery) to removing the entire breast (mastectomy.) It’s best to discuss the pros and cons of each of these procedures with your doctor before deciding what’s right for you.
Radiation Therapy for Breast Cancer
Radiation therapy uses high-energy rays to kill cancer cells. It may be used after breast cancer surgery to wipe out any cancer cells that remain. It can also be used along with chemotherapy for treatment of cancer that has spread to other parts of the body. Side effects can include fatigue and swelling or a sunburn-like feeling in the treated area.
Chemotherapy for Breast Cancer
Chemotherapy uses drugs to kill cancer cells anywhere in the body. The drugs are often given by IV, but are sometimes taken by mouth or shot. Chemotherapy may be done after surgery to lower the odds of the cancer coming back. In women with advanced breast cancer, chemotherapy can help control the cancer’s growth. Side effects may include hair loss, nausea, fatigue, and a higher risk of infection.
Hormone Therapy for Breast Cancer
Hormone therapy is an effective treatment for women with ER-positive or PR-positive breast cancer. These are cancers that grow more rapidly in response to the hormones estrogen or progesterone. Hormone therapy can block this effect. It is most often used after breast cancer surgery to help keep the cancer from coming back. It may also be used to reduce the chance of breast cancer developing in women who are at high risk.
Targeted Drugs for Breast Cancer
Targeted therapies are newer drugs that target specific properties within cancer cells. For example, women with HER2-positive breast cancer have too much of a protein called HER2. Targeted therapies can stop this protein from promoting the growth of cancer cells. These drugs are often used in combination with chemotherapy. They tend to have milder side effects compared to chemotherapy.
Life After Diagnosis
There’s no doubt that cancer is a life-changing experience. The treatments can wear you out. You may have trouble managing daily chores, work, or social outings. This can lead to feelings of isolation. It’s crucial to reach out to friends and family for support. They may be able to go with you to treatments, help out with chores, or just remind you that you are not alone. Many people choose to join a support group — either locally or online.
Breast Reconstruction
Many women who have a breast removed choose to undergo reconstructive surgery. This replaces the skin, nipple, and breast tissue that are lost during a mastectomy. Reconstruction can be done with a breast implant or with tissue from somewhere else in your body, such as the tummy. Some women opt to begin reconstruction at the same time as their mastectomy. But it’s also possible to have reconstructive surgery months or years later.
Breast Forms
An alternative to breast reconstruction is to be fitted for a breast form. This is a breast-shaped prosthesis that fits inside your bra. Wearing a breast form allows you to have a balanced look when you are dressed — without undergoing additional surgery. Like reconstructive surgery, breast forms are often covered by insurance.
Breast Cancer: Why Me?
The most obvious risk factor for breast cancer is being a woman. Men get the disease, too, but it is about 100 times more common in women. Other top risk factors include being over age 55 or having a close relative who has had the disease. But keep in mind that up to 80% of women with breast cancer have no family history of the illness.
Breast Cancer Genes
Some women have a very high risk of breast cancer because they inherited changes in certain genes. The genes most commonly involved in breast cancer are known as BRCA1 and BRCA2. Women with mutations in these genes have up to an 80 percent chance of getting breast cancer at some point in life. Other genes may be linked to breast cancer risk as well.
Risk Factors in Your Control
Being overweight, getting too little exercise, and drinking more than one alcoholic beverage per day can raise the risk of developing breast cancer. Birth control pills and some forms of postmenopausal hormone therapy can also boost your risk. But the risk goes back to normal after these medications are stopped. Among survivors, good lifestyle choices may be helpful. Recent studies suggest that physical activity may help lower the risk of a recurrence and it’s a proven mood-booster.
Breast Cancer Research
Doctors continue to search for more effective and tolerable treatments for breast cancer. The funding for this research comes from many sources, including advocacy groups throughout the country. Many of the 2.5 million breast cancer survivors and their families choose to participate in walk-a-thons and other fundraising events. This links each individual fight against cancer into a common effort for progress.
CYTOGENETIC STUDIES
Breast cancers, like other forms of malignancy, are thought to progress by accumulation of a series of genetic and resulting phenotypic changes in the pathways regulating growth, tissue compartmentalization, and responses to therapy. Although several specific mutations (oncogenes and suppressor genes, discussed below) have been identified with high frequency and proven relevance in breast cancer, there are certainly many more important genetic changes remaining to be fully elucidated. Using classic cytogenetic methodology and studies of loss of heterozygosity (LOH), genetic regions identified as commonly rearranged, amplified, or otherwise altered have been commonly detected on chromosomes 1, 3, 6, 7, 8, 9, 11, 13, 15, 16, 17, 18, and 20. More recently, the powerful technique of comparative genomic hybridization (CGH) has allowed additional implication of chromosomes 10, 12, and 22. Although it has only begun to be used in this type of study, the technique of CGH allows rapid analysis of genomic imbalances, even in a very small region. Using this technique, an initial study has shown that fibroadenomas are devoid of genetic imbalances and that aneuploid breast tumors contain far more chromosomal aberrations than diploid breast tumors.
The most common genetic abnormalities in breast cancers (as in most tumors) appear to be LOH at multiple loci. A LOH allows the function of a recessive mutation in an allele of a tumor-suppressor gene by removal of the dominant, normal allele. At the present time, in addition to the two BRCA loci noted earlier, LOH on 13q and 17p are known to specifically involve the tumor-suppressor genes Rb-1 and p53, respectively, during the progression of breast cancer. Other suspected tumor-suppressor genes have been proposed on 7q, 9p, 11p, 11q, 17q, and 18q. For example, the cell cycle inhibitor p16 (or MTS-1 or CDKN2) is localized on 9p and is currently under study for mutational frequency and function. [ref: 16] Another example is the proposed metastasis suppressor nm23 on 17q, whose expression is commonly down-modulated but not commonly mutated in breast cancer despite its localization in a chromosomal region of generally elevated frequency of LOH.
The second most common type of cytogenetic alteration in breast cancer appears to be gene amplification. The initial step in gene amplification is thought to be the formation of extrachromosomal, self-replicating units termed double-minute chromosomes. These genetic elements then later become permanently incorporated into chromosomal regions and are termed homogeneous staining regions. An amplified genetic unit (amplicon) is initially much larger than the actual size of the principal gene of biologic importance to tumorigenesis. Thus, silent or irrelevant genes may be detected coamplified with one or more expressed genes on an amplicon. The principal, best-established amplified and functional genes for tumorigenesis (also called dominant oncogenes) detected to date in breast cancer are the growth factor receptor c-erbB2, and the nuclear transcription factor c-myc. The genes encoding cell cycle kinase regulatory proteins termed cyclin D(1) and cyclin E are also considered likely candidate oncogenes; the former is commonly amplified in breast cancer, while the latter is functionally dysregulated. A significant amount of work remains to be done to identify other potentially important genes in breast cancer. For example, chromosomes 6 and 11 can suppress breast cancer in chromosome transfer experiments. [ref: 18] In addition, DNA gains are common on 1q, 6p, 13q, and 16p, and DNA losses are common on 20 and 22. However, in each of these cases the specific genes involved have not been identified.
STEROID AND GROWTH FACTOR PATHWAYS OF CELLULAR REGULATION
MUTATION AND REGULATION OF STEROID RECEPTORS
The estrogen and progesterone receptors are dimeric, gene-regulatory proteins. In mammary tissue, a single gene encodes an estrogen receptor subunit, and these subunits homodimerize and complex with additional proteins, such as heat shock proteins, to form the complete estrogen receptor (ER) assembly. [ref: 19] Recent studies have complicated the picture with the identification of alternate spliced and mutated forms of the ER in breast cancer and some normal tissues such as brain and uterus. [ref: 19,20] A single gene encodes three different isoforms of the progesterone receptor subunit in mammary tissue; both homodimeric and heterodimeric forms of the progesterone receptor (PR) result. [ref: 21-23] The multiplicity of progesterone and estrogen receptor isoforms in breast cancer may allow for significant variations in patterns of dimerization and in resultant variations in specificity of ligand recognition with respect to agonist versus antagonist and differential regulation of target genes. [ref: 19,24] On top of this complexity, each receptor is able to adopt multiple conformations, depending upon the characteristics of interaction of the steroid (or nonsteroid ligand) with the receptor binding pocket. For example, the estrogen receptor can adopt at least three distinct conformations, depending on the antiestrogen bound.
Because the growth of breast cancer is often regulated by the female sex steroids, determinations of the cellular concentrations of ER and PR in the tumor are currently used to predict which patients are of good prognosis and may also benefit from antihormonal therapy. Although these assays were originally designed as radioligand assays, they are more commonly performed today using radioimmunoassay and immunohistochemical technologies. While extremely useful, it has been repeatedly noted that these assays do not provide perfect prognostic tools for the disease. Although more than 60% of human breast cancers are ER-positive, no more than two-thirds of these ER-positive tumors respond to endocrine therapy. In addition, 5% to 10% of the patients designated ER-negative appear to initially respond to endocrine therapy. To improve the value of determinations of the ER for tumor prognosis, the presence of the estrogen-regulated PR protein is now routinely determined. In many breast tumor cell lines and in normal, ER-containing tissues, such as the endometrium and brain, PR expression also has been shown to be positively regulated by estrogen. It is still not known whether ER regulates PR iormal human mammary epithelium or if ER and PR are coexpressed in the same subpopulation of ductal and lobular luminal cells, although it is likely. It is of interest that the ER and PR appear to be strongly up-regulated in hormone-dependent breast cancer relative to normal mammary epithelium. As noted earlier, it is not clear what relationship exists between ER+ and ER- forms of the disease. Recent studies have shown that ER-negative breast cancer cell lines do not transcribe the ER mRNA due to an extensive methylation of the 5′ promoter of the gene. [ref: 32] Treatment of ER-negative breast cancer cells in vitro with azacytidine, an inhibitor of gene methylation, resulted in expression of a functional ER. [ref: 33] Central questions in breast cancer research focus on mechanisms of desensitization of the disease to antihormonal therapy and design of strategies to maintain antihormonal responses in patients. Recent studies have suggested that tamoxifen resistance of breast cancer may be associated with hypersensitization to the weakly estrogenic effects of the drug, perhaps due to expression of receptor-associated regulatory proteins, receptor mutation, or selection for variant receptor isoforms. [ref: 34-36] Although measurement of PR improves the predictability of hormone dependency of a tumor, this relationship remains imperfect. Retrospective clinical studies have demonstrated that only 70% of PR-positive and 25% to 30% of PR-negative tumors respond to hormone therapy. The reasons for these discrepancies are unclear but may include laboratory error, differential metabolism of tamoxifen, the ability of a mutated ER or PR to regulate gene expression in the absence of ligand, [ref: 19,37-39] the ability of defective or phosphorylated ER or PR to bind ligand but not regulate gene expression, or the ability of either defective or phosphorylated receptor to induce constitutive synthesis of otherwise regulated proteins. Clearly, a challenge for the future is development of more routine, potentially informative ER and PR assays, such as binding of the ER to an estrogen-responsive DNA element (ERE), mutational analysis of ER by the polymerase chain reaction, or other techniques, which may be necessary to further improve the accuracy of prediction of tumor response to endocrine therapy. Another major hope is that study of other genetic changes in breast cancer, including those in growth factors, their receptors, and their signalling will also improve our ability to predict functionality of the steroid receptor pathways relative to therapeutic outcomes.
The ER cannot be clearly classified as an oncoprotein or tumor suppressor protein. Although it clearly mediates onset and progression of the disease, unexpected results were obtained when the ER was expressed endogenously in ER-positive breast cancer lines and compared with its heterotypical expression in formerly ER-negative lines. In striking contrast to its normal function in ER-positive cell lines, ER expressed in ER-negative cell lines functions to suppress cell growth, in spite of its normal action to regulate expression of certain hormonally responsive genes. [ref: 40,41] Thus, the multiple differences between ER+ and ER- breast cancer appear to include incompatible growth-regulatory mechanisms. We also do not understand the molecular basis for a lack of expression of PR in certain ER-positive breast cancers. A recent cell hybridization study with an antiestrogen-resistant, ER-positive but PR-negative subline of MCF-7 has shown that loss of PR expression is a recessive phenotype in this system. [ref: 42] Increased expression and altered isozyme patterns of the cellular enzyme protein kinase C (PKC) family has also been implicated during malignant progression of breast cancer. [ref: 43] As described below, this enzyme family can act to down-modulate ER mRNA, activate ER function, independently induce some estrogen-responsive genes with AP-1 sites in their promoters, and allow more invasive cellular characteristics to be expressed. [ref: 44] The PKC family contains at least nine cytoplasmic-nuclear enzymes, which possess serine-threonine specificity for phosphate addition to other cellular proteins [ref: 45]; different isotypes serve different cellular functions. The activity of PKC is known to be regulated by hormones and/or growth factors during normal lactational differentiation and to contribute to regulation of casein expression. [ref: 45] PKC activity has been suggested to be elevated in ER-negative and drug-resistant breast cancer relative to ER-positive breast cancer. Treatment of ER-positive breast cancer with an activator of PKC, such as the phorbol ester 12-O-tetradeconyl phorbol-13-acetic; (abbreviated TPA or PMA) leads to rapid down-regulation of ER, destabilization of its mRNA, and phosphorylation of the ER protein, coincident with modulation of its function. [ref: 46-49] Phosphorylation of ER and PR, induced by estrogen itself, growth factor pathways (such as insulin-like growth factor-1 (IGF-1)), heregulin, cAMP, dopamine agonists, and other hormones may also constitutively activate the steroid receptors. [ref: 50-53] Other current studies have suggested that receptors for other steroids (potential cancer prevention agents, retinoids and vitamin D) may modulate ER/PR function by forming heterodimers with ER or PR or by modulating chromatin interactions of ER and PR.
Malignant Tumors of the Breast
Breast cancer is the most frequently diagnosed cancer in American women, and the second most frequent cause of cancer death. [ref: 1] Over the past several decades, there has been a fairly steady and large increase in the incidence of the disease. Data collected between 1988 and 1990 indicate that the lifetime risk of developing breast cancer is 12.2%, or
In this chapter, we describe the salient features of the disease, stressing practical information of importance to clinicians and findings that are new since the last edition of this book. For more detail, the interested reader is referred to a related textbook in this series devoted to diseases of the breast.
RISK FACTORS FOR BREAST CANCER
Multiple factors that are associated with an increase in breast cancer risk have been identified. These can be grouped under the general headings of genetic and familial factors, hormonal factors, dietary factors, benign breast disease, and environmental factors. However, despite the recognition of these risk factors, approximately 50% of women who develop breast cancer have no identifiable risk factors beyond being female and aging.
GENETIC AND FAMILIAL FACTORS
A family history of breast cancer has long been recognized as a risk factor for the disease. The identification of the BRCA1 gene, [ref: 6] which, when mutated, is associated with an extremely high risk of breast cancer development, has provided new insights into breast cancer risk. At present, it appears that there are two types of breast cancer risk associated with a family history of breast cancer. True inherited breast cancer, due to the inheritance of a specific germline mutation of a tumor-suppressor gene from either maternal or paternal relatives, is uncommon, and is estimated to account for 5% to 10% of breast cancer cases in the
Breast cancer susceptibility genes appear to be transmitted in an autosomal dominant manner. [ref: 7,9] At present, mutations of BRCA1, BRCA2, and the p53 tumor-suppressor gene have been found to carry a markedly increased risk of breast cancer, and the identification of other cancer-susceptibility genes in the future is likely. Germ-line mutations of the BRCA1 gene, located on chromosome 17q21, are associated with a 50% risk of breast cancer by about age 45 and an 85% lifetime risk. [ref: 12,13] In addition, the risk of a second primary breast cancer is 65% for mutated BRCA1 gene carriers who live to age 70. [ref: 13] Males with a mutation do not appear to have an increased risk of breast cancer, but may have an increased risk for prostate cancer. [ref: 14] Over 80 distinct mutations in BRCA1 have been characterized in high-risk families. [ref: 15] Ashkenazi (Eastern European) Jews appear to have a high rate of a specific mutation in BRCA1 called 185delAG. Retrospective screening for BRCA1 mutations in a population of Ashkenazi Jews who underwent screening for Tay-Sachs disease identified a specific mutation (185 delAG) in 1% of samples. [ref: 16] Preliminary data from 98 patients thought to have BRCA1 mutations suggest that prognosis in these patients may be slightly better than in women with sporadic tumors, [ref: 17] but this remains to be confirmed.
At this time, there is inadequate information to answer a number of important questions about mutations in BRCA1. BRCA1 is a large gene and it is not yet certain that all mutations carry the same risk. The implication of mutations that occur in the absence of a strong family history of the disease is also uncertain. However, a recent report indicates that the BRCA1 gene product has an aberrant subcellular location in many breast cancers that do not carry germ-line BRCA1 mutations, [ref: 18] suggesting a larger role for this gene in the pathogenesis of breast cancer than was initially anticipated. A second gene, BRCA2, has been identified on chromosome 13 and is associated with early-onset breast cancer, but not ovarian cancer. [ref: 19] The level of breast cancer risk with mutations of BRCA2 is similar to that seen with BRCA1. Mutations of BRCA2 also confer an increased risk of male breast cancer. Breast cancer is also observed as part of other familial syndromes including the Li-Fraumeni syndrome, [ref: 20] Cowden’s syndrome, [ref: 21] Muir syndrome, [ref: 22] and ataxia telangiectasia. [ref: 23]
HORMONAL FACTORS
Breast cancer is clearly related to hormones, and numerous studies have linked breast cancer incidence to the age of menarche, menopause, and first pregnancy. The age-specific incidence of breast cancer rises at a steep rate with age up to the time of menopause and then the rate of rise slows to one sixth of that seen in the premenopausal period. Although the absolute age-specific incidence is higher in postmenopausal women than in premenopausal women, the dramatic slowing of the rate of rise in the age-specific incidence curve suggests that ovarian activity plays a major role in causing breast cancer. [ref: 24] Intrauterine exposure to high concentrations of estrogen may even increase breast cancer risk. [ref: 25] Age at menarche and the establishment of regular ovulatory cycles seem to be strongly associated with breast cancer risk. [ref: 26,27] There appears to be a 20% decrease in breast cancer risk for each year that menarche is delayed. [ref: 26] The late onset of menarche is associated with a delay in the establishment of regular ovulatory cycles, which is thought to have an additional protective effect by some investigators, although there is dispute on this point. [ref: 28-30] A woman’s level of physical activity, even if moderate, can have an impact on the likelihood of ovulatory cycles and perhaps for this reason may alter breast cancer risk. [ref: 31] Age at menopause is another factor in breast cancer risk. The relative risk of developing breast cancer for a woman with natural menopause before age 45 is half that of a woman whose menopause occurs after 55. [ref: 32] Oophorectomy before age 50 decreases breast cancer risk, with an increasing magnitude of risk reduction as the age at oophorectomy decreases. From these data, it seems likely that the total duration of menstrual life is an important factor in breast cancer risk.
Parity and age at first birth are other factors that influence breast cancer risk. Nulliparous women are at greater risk for the development of breast cancer than parous women, with a relative risk of about 1.4. [ref: 33] The effect of term pregnancy on breast cancer risk varies with the age at first birth, with women whose first full-term pregnancy occurs after age 30 having a twofold to fivefold increase in breast cancer risk compared with women having a first full-term pregnancy before age 18 or 19. [ref: 27,33,34] Abortion, whether spontaneous or induced, before full-term pregnancy seems to ablate the protective effect, and in several studies, it appears to increase risk. [ref: 35-37] Other studies show no increase in risk after termination of pregnancy [ref: 38-40]; however, all studies attempting to link abortion and risk are limited by recall bias. These apparently contradictory effects of pregnancy on risk have been explained in a variety of ways. Breast tissue may undergo differentiation as a result of the hormonal changes of a full-term pregnancy and these differentiated cells are less likely to undergo malignant transformation, or the persisting changes in hormone levels after a full-term pregnancy may alter the proliferative rate of the breast epithelium. In incomplete pregnancy, the breast is exposed only to the high estrogen levels of early pregnancy, and this may be responsible for the increased risk seen in these women. [ref: 41,42]
Studies of the effect of lactation on breast cancer risk have had inconsistent results, but recent studies [ref: 43,44] have suggested that a long duration of lactation reduces breast cancer risk in premenopausal women. The effect of exogenous hormones, in the form of hormone replacement therapy and oral contraceptives, on breast cancer risk has been extensively studied, but has not been clearly established. Two recent metaanalyses of the effect of estrogen replacement therapy demonstrate small but statistically significant increases in risk (relative risks, 1.3 and 1.06) for users. [ref: 45,46] In these studies, risk appeared to increase with duration of estrogen use. Overall, there is no convincing evidence of an increased risk of breast cancer in women who have ever used oral contraceptives. [ref: 47-49] Some studies suggest that an increased risk of premenopausal breast cancer is seen in young (less than age 35) women using oral contraceptives [ref: 47,48,50] and that this risk may be related to duration of use. [ref: 49] Studies of other subsets of women (i.e., those with a family history of breast cancer or a history of benign breast disease) have not produced consistent findings.
DIETARY FACTORS
A possible relation between breast cancer and diet has been suggested by the large variation internationally in breast cancer incidence rates. National per capita fat consumption correlates with incidence and mortality from breast cancer. That these differences are not solely due to genetics is suggested by studies of migrants. [ref: 51,52] Japanese women immigrating to the
Epidemiologic studies of fat consumption and breast cancer risk have produced inconclusive results. Kinlen compared breast cancer rates betweeuns who were vegetarians or ate only small amounts of meat and single British women who ate regular diets and observed no differences. [ref: 53] Breast cancer mortality among Seventh-Day Adventists, a group that eats a diet low in animal fats, is not significantly lower than expected compared with the general population. [ref: 54] In the largest prospective study of dietary fat, 89,538 nurses between the ages of 34 and 59 were studied. No relation between breast cancer risk and total fat, saturated fat, linoleic acid, or cholesterol intake was found. [ref: 55] A recent pooled analysis of seven cohort studies involving 337,819 women demonstrated no difference in breast cancer risk between women in the highest and lowest quintile of fat intake. [ref: 56] Thus, over the range of fat intake seen in Western societies, there is no apparent association between breast cancer risk and fat intake in adults. However, this does not rule out an effect of fat intake during childhood or adolescence. Multiple studies suggest an association between alcohol intake and breast cancer risk. A metaanalysis of 12 case-control studies demonstrated a relative risk of 1.4 for each
MANAGEMENT OF THE HIGH-RISK PATIENT
Although a number of epidemiologic factors that influence a woman’s risk of breast cancer have been identified, there is no consensus as to what constitutes “high risk” with the exception of those women with a family history consistent with genetically transmitted breast cancer. The designation of a woman as “high risk” causes considerable anxiety for the woman, her family, and her physicians, and this concern may result in unnecessary physician visits, more frequent mammography, and an excessive number of breast biopsies.
A formal evaluation of the patient’s risk of breast cancer begins with a careful history to evaluate the presence of known risk factors. A breast examination should be done to exclude the presence of breast pathology and assess the difficulty of the examination. The optimal time to obtain a first mammogram is controversial, but in women with a substantial risk based on history, it is reasonable to obtain the initial mammogram at age 35. On mammography, the presence of any suspicious lesions and the density of the normal parenchyma should be noted. In women whose risk status is based on a diagnosis of atypical hyperplasia or lobular carcinoma in situ, an opinion from a pathologist experienced in the diagnosis of breast disease should be sought. The criteria used to classify a lesion as atypical hyperplasia or even low grade in situ carcinoma have not been agreed upon, even by experts in the field. [ref: 72]
In women with multiple relatives with breast or ovarian cancer (usually more than 3) from the same side of the family, particularly at a young age, referral for genetic counseling and testing should be considered. [ref: 73] Genetic testing may provide critical information for risk estimation. As discussed above, women found to have a mutation in p53 or BRCA1 have a lifetime risk of breast cancer of 85%. [ref: 12,74] Although such testing is a powerful tool, it is important to remember that few studies on the accuracy of tests for BRCA1 are currently available, and quality control standards have not been established. In addition, women without cancer who belong to a high-risk family will obtain more information from testing if a specific mutation has been identified in a family member who has cancer. A negative test for BRCA1 in a cancer-free woman could mean that she does not share the family risk of breast cancer development if BRCA1 is involved, or it could mean that a different gene is responsible for breast cancer in this family. [ref: 75] Beyond concerns about the accuracy of the test are possibly profound problems related to anxiety, guilt, employment discrimination, and insurance coverage. For these reasons, genetic testing should only be undertaken in a center capable of providing skilled pretest and posttest counseling.
After determining the presence of risk factors and assessing the difficulty of breast examination and imaging, an attempt should be made to provide the patient with a quantitative estimate of her absolute risk of breast cancer development over a defined time interval. (Estimates of relative risk are considerably less useful.) It is well known that women tend to overestimate their risk of developing the disease, often to a large degree. It is also important to emphasize that only one third of women who develop breast cancer will die of the disease, [ref: 3] and an estimate of the risk of death due to breast cancer should also be provided.
A major problem in risk estimation has been the lack of knowledge of the interactions among risk factor because most studies have addressed only a single risk factor. Gail and colleagues [ref: 76] have developed a model that incorporates age at menarche, age at first live birth, number of first-degree relatives with breast cancer, and number of previous breast biopsies to provide an individualized risk estimate for breast cancer development at different ages over various time intervals. This model has been tested in the Texas Breast Screening Project [ref: 77] and the Nurses Health Study [ref: 78] populations and has been found to be generally accurate in women undergoing regular mammographic screening. However, the model is not useful in estimating risk in women with a strong family history of breast cancer because it includes only first-degree relatives.
The currently available approaches to the management of the high-risk woman are prophylactic mastectomy or careful surveillance. [ref: 79] There are no absolute indications for prophylactic mastectomy. The degree of breast cancer risk that is acceptable will vary between individuals. Prophylactic surgery is never an emergency and should not be undertaken because of anxiety over a breast cancer diagnosis or death in a friend or relative. For the woman whose fear of breast cancer is out of proportion to her level of risk, psychologic counseling should be obtained. Many women who are appropriate candidates for prophylactic surgery will also benefit from psychologic counseling. Consultation with a reconstructive surgeon to obtain detailed information about breast reconstruction is often helpful to women considering prophylactic surgery. However, it is important to emphasize to every woman considering prophylactic mastectomy that even when the operation is properly performed, it does not guarantee freedom from subsequent breast cancer. [ref: 80] Prophylactic mastectomy is knowot to remove all breast tissue and the long-term subsequent risk, although substantially decreased, is not known with certainty.
At present, the alternative to prophylactic mastectomy is close surveillance. This approach entails monthly breast self-examination (BSE), annual diagnostic mammography, and a physician breast examination every 4 to 6 months. Data on the efficacy of this approach in a high-risk population are limited. Baines and To [ref: 81] examined the BSE practices of 89,835 women participating in the Canadian National Breast Screening Study and found that women with a first-degree relative with breast cancer scored significantly higher on tests of BSE proficiency than women with a negative family history. A retrospective study of breast cancer screening in 24 high-risk families found more node-negative, favorable cancers in the screened group, [ref: 82] and Singletary and coworkers [ref: 83] reported that in a group of 87 women with metachronous bilateral breast cancer, a higher percentage of the second cancers found during followup were node-negative or noninvasive than the presenting carcinomas. Awareness of personal breast cancer risk [ref: 84] and a physician recommendation for a screening procedure [ref: 85,86] are associated with increased compliance. This emphasizes the importance of a careful assessment of risk and an effective communication of this risk and of a follow-up surveillance program in women who elect this approach. Participation in clinical prevention trials is an excellent adjunct to a close surveillance program and this is discussed later.
PREVENTION OF BREAST CANCER
Despite advances in the diagnosis and treatment of breast cancer, one third of the women who develop breast cancer will die of the disease. Recognition of this limitation of currently available therapies has resulted in a new focus on breast cancer prevention. At present, the only method of prevention that is available in routine clinical practice is prophylactic mastectomy. However, little agreement exists on the efficacy of this procedure or the appropriate indications for its use. Both subcutaneous and simple (total) mastectomy have been employed for prophylaxis. In a subcutaneous mastectomy, the breast parenchyma is removed through an incision in the inframammary crease, preserving the nipple-areolar complex. With this approach, breast tissue must be left behind under the nipple and areola to prevent their devascularization, and access to the periphery of the breast (axillary tail, subclavicular area) is often difficult. One study of 12 subcutaneous mastectomies done on cadavers demonstrated retained breast tissue in 83% of cases. [ref: 87] There are multiple reports of breast cancer occurring in women following subcutaneous mastectomy, [ref: 88-90] and laboratory studies support the clinical concern that a reduction in the volume of breast tissue may not be associated with a proportionate reduction in breast cancer risk. [ref: 91,92] Pennisi and Capozzi [ref: 93] reported a 0.4% incidence of breast cancer in 1500 women who underwent subcutaneous mastectomy. Unfortunately, these data provide little information relevant to high-risk women because many of these women had subcutaneous mastectomy for conditions such as nonproliferative fibrocystic disease that are now knowot to increase the risk of breast cancer development. In addition, systematic follow-up was not carried out, and 30% of the patients had no follow-up at all.
The alternative to subcutaneous mastectomy is total or simple mastectomy, in which an ellipse of skin including the nipple-areola complex is removed to allow removal of the breast tissue. Although it is likely that 100% of the breast tissue is not removed with this procedure, removal of the nipple-areola complex clearly decreases the amount of residual breast tissue. Unfortunately, there are no large clinical studies of the risk of breast cancer after prophylactic simple mastectomy. Holleb and coworkers [ref: 94] have reported two cases of breast cancer occurring 10 to 15 years after prophylactic simple mastectomy, indicating that this potential exists. When prophylactic simple mastectomy is undertaken, meticulous attention to the removal of all possible breast tissue is important. The procedure should be similar to a therapeutic mastectomy and should include the use of thin skin flaps. [ref: 80] The drawbacks to the widespread use of prophylactic mastectomy as a prevention strategy are readily apparent, and have focused attention on the development and testing of chemopreventive agents. Three large clinical trials are ongoing to test the antiestrogen tamoxifen as a breast cancer preventive agent. Much of the impetus for the use of tamoxifen as a chemopreventive agent comes from trials of its use as an adjuvant therapy, which demonstrated a reduction of approximately 40% in the rate of contralateral breast cancers in tamoxifen-treated women compared with controls. Prevention studies with tamoxifen are ongoing in the
SCREENING
One potentially important strategy in reducing breast cancer mortality is the use of screening to achieve earlier detection of cancer. Earlier diagnosis is hypothesized to result in treatment before metastasis in some patients and, thereby, avert death due to the disease. The main methods for earlier detection of breast cancer have been mammography and physical examination performed by a trained health professional. Other potential methods of screening, such as BSE, have not yet been demonstrated to be of value, and some methods, such as thermography and computed tomographic (CT) scanning, have been showot to be of value. A variety of newer breast imaging techniques are currently being developed, but none have reached the point of being tested as a screening method. The usefulness of mammography in recent years has been enhanced by technical advances that provide increased visualization of the breast parenchyma and less exposure to radiation. It is important to distinguish between the use of mammography in the evaluation of symptomatic patients (discussed below) and its use in asymptomatic women as a screening method.
The ability of mammography to detect cancers well before they are apparent on physical examination has been indisputably established. However, this does not ensure that breast cancer mortality will be reduced. To eliminate a variety of important biases, randomized trials are necessary to assess accurately the effect of screening on breast cancer mortality. A number of such trials have been performed and have clearly shown that screening reduces breast cancer mortality in women aged 50 to 74 by approximately 26%.
The finding that screening reduces breast cancer mortality has important implications regarding the natural history of the disease. Some evidence suggests that metastases occur very early in the course of the disease and that breast cancer should be considered a systemic disease from its onset. [ref: 96] However, the reduction in breast cancer mortality by screening provides compelling evidence that early diagnosis and treatment of breast cancer can avert the onset of metastasis. Thus, breast cancer can metastasize during its clinical evolution and should not be considered a systemic disease in all patients.
One major unresolved issue regarding mammographic screening is its effect in women aged 40 to 49. Given the high quality of mammography currently available, small, nonpalpable breast cancers are now commonly being detected in these women. However, the results from the available randomized trials do not clearly show a benefit after 7 to 9 years. [ref: 95] Because breast cancer is less common in younger women, larger studies are needed to answer this question definitively. It has also been argued that because of technical flaws one of the screening studies (Canadian) should not be included in metaanalysis and that a longer follow-up time is necessary to demonstrate the effectiveness in women aged 40 to 49. [ref: 97] However, mammographic imaging is less sensitive in younger women than in older women, the subclinical phase of the disease is estimated to be shorter, [ref: 98] and recent modeling of the Swedish trials suggests that most of the benefit in women aged 40 to 49 is achieved by screening after these women reach age 50.
The screening trials have helped to determine the resources and expenses necessary for an effective screening program. To achieve maximal mammographic screening, quality control of both the images obtained and the reading of these images must be maintained. This requires the efforts of well-trained and experienced radiology technicians, physicists, and mammographers at many steps along the process. In addition, using guidelines currently accepted in the
BIOPSY TECHNIQUES FOR SUSPICIOUS BREAST LESIONS
In this section, the various techniques to biopsy suspicious palpable and mammographic breast lesions are described. The major techniques used to diagnose palpable breast masses are fine-needle aspiration (FNA), core-cutting needle biopsy and excisional biopsy. (Incisional biopsy is occasionally used to diagnose very large breast masses, but this technique has largely been replaced by the less invasive aspiration or core biopsy.). Both FNA and core biopsy are office procedures. Excisional biopsy, with rare exceptions, is an outpatient procedure that can be done using local anesthesia.
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The main issue surrounding the use of FNA is the risk of false-negative results. Large series of FNA have demonstrated a sensitivity of 87%, an incidence of insufficient specimens ranging from 4% to 13%, and a false-negative rate of 4% to 9.6%. [ref: 103-105] Fibrotic tumors, infiltrating lobular, tubular, and cribriform histologies, and physician inexperience have all been found to be sources of false-negative aspirates. False-positive aspirates are extremely uncommon, and are reported in fewer than 1% of cases in most large series. [ref: 103-107] However, FNA does not reliably distinguish invasive cancer from ductal carcinoma in situ (DCIS), potentially leading to the overtreatment of gross DCIS. Core-cutting needle biopsy has many of the advantages of FNA, but also provides histologic details of the lesion. The accuracy of core biopsy is similar to that reported for FNA, with sensitivities of 79% to 94%. [ref: 108,109] Shabot and colleagues [ref: 110] prospectively compared the diagnostic accuracy of FNA and core-cutting needle biopsy in 81 women. The accuracy of FNA was 96% compared with 79% for the core-needle technique. No false-positive results were observed in any of these reports.
Excisional biopsy has been the standard technique for the diagnosis of breast masses. It has the advantage of allowing a complete evaluation of the tumor size and its histologic characteristics before selecting definitive local therapy. When an excisional biopsy is done, an attempt should be made to remove a small margin of grossly normal tissue around the tumor.
Frozen section is generally reliable in the diagnosis of palpable breast masses, but indications for its use in the evaluation of nonpalpable breast lesions are limited. The abnormalities being sought by needle-localization biopsy are usually small, and are often histologically borderline and difficult to diagnose on frozen section. Sacchini and colleagues [ref: 119] noted a discordance rate of 12% between the frozen-section diagnosis and the final histologic diagnosis in a study of 403 nonpalpable lesions. Errors in distinguishing atypical hyperplasia from DCIS accounted for most of the discrepancies. Tinnemans and colleagues [ref: 120] had 2 false-positive results in a series of 297 nonpalpable lesions diagnosed by frozen section, and a 3% incidence of false-negative results. Because needle-localization biopsy is rarely undertaken with a plan to proceed to definitive therapy at the same operation, a careful examination of the entire lesion with paraffin sections is generally the more prudent course.
Recently, stereotactic core-needle biopsies have been advocated as an alternative to excisional biopsy in the management of nonpalpable breast abnormalities. A technique for stereotactically directed FNA was first described in 1977, but did not gain widespread acceptance because of concerns in the
CARCINOMA IN SITU. DUCTAL CARCINOMA IN SITU
Ductal carcinoma in situ (also referred to as noninfiltrating or intraductal carcinoma) is a proliferation of presumably malignant epithelial cells confined to the mammary ducts and lobules without demonstrable evidence of invasion through the basement membrane into the surrounding stroma. It is an entity distinct in both its clinical presentation and its biologic potential from lobular carcinoma in situ (discussed later). In the past, DCIS was an uncommon lesion that was routinely cured by mastectomy, and little attention was given to defining its natural history or exploring alternative local treatments.
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The widespread use of screening mammography has resulted in a significant increase in the detection rate of DCIS, and the acceptance of breast-conserving therapy for the treatment of invasive carcinoma has raised questions about the routine need for mastectomy in a lesion that is only “precancerous.” This combination of factors has made the management of DCIS one of the most widely debated issues in diseases of the breast today.
DCIS has a variety of clinical presentations. In the past, most DCIS was “gross” or palpable. However, DCIS accounts for only a small percentage of palpable breast cancers. [ref: 129] DCIS may also present as pathologic nipple discharge, with or without a mass, as Paget’s disease of the nipple, or it may be identified as an incidental finding in a breast biopsy done for another abnormality. Today, an abnormal mammogram is the most common presentation of DCIS. DCIS usually appears as clustered microcalcifications, although nonpalpable masses may also be DCIS. [ref: 130] In many reports of mammographically directed biopsies, DCIS accounts for 50% or more of the malignancies identified.
DCIS is heterogeneous in terms of its histopathology, extent, and biologic behavior. Based primarily on the growth pattern, DCIS can be classified into comedo and noncomedo subtypes (cribriform, micropapillary, solid, clinging). In comparison with the noncomedo subtypes, the comedo type appears more malignant cytologically, has a higher proliferative rate as determined by thymidine-labeling studies, is more likely to be associated with areas of microinvasion, and more often exhibits biologic markers such as aneuploidy, overexpression of the HER 2/neu (C-erbB-2), cyclin D1, and p53 oncogenes, absence of bcl-2 expression, and angiogenesis. [ref: 134-141] (It is also possible that with more experience these or other markers might become useful in distinguishing DCIS from benign proliferative breast lesions, such as atypical hyperplasia.) The mammographic presentation of the two types of DCIS is also different. [ref: 142] The comedo subtype is more often associated with the so-called casting (i.e., linear) or coarse granular microcalcifications, whereas the noncomedo type is more often associated with the fine granular microcalcifications. Mammographic estimates of the size of the comedo type closely approximate the histologic size of the tumor, whereas the estimates of size of the noncomedo type based on the extent of microcalcifications may be considerably smaller than the histologic size when two-view mammography is used. [ref: 142] The use of magnification mammography significantly improves size estimation for noncomedo DCIS. [ref: 143] New classification systems using a combination of architecture, nuclear grade, and necrosis have been proposed, [ref: 144-147] but the merits of these systems in predicting the biologic behavior of DCIS remain to be proved.
The uncertainty regarding the natural history of DCIS has resulted in a wide range of treatments, from excision alone to mastectomy. Comparisons among reports are difficult because of differences in patient populations, lack of standardization of surgical and radiotherapeutic techniques, and changes in patient evaluation, selection, and treatment over time. Mastectomy is known to be curative treatment for approximately 98% of patients with DCIS, whether gross or mammographic. Despite this, several factors have contributed to the greater use of breast-conserving therapy. These include the increasingly frequent identification of very small areas of DCIS with mammography, the acceptance of breast-conserving therapy for invasive cancer, and the recognition that true multicentricity is rare in DCIS. [ref: 143,159] A number of investigators have studied the use of excision alone as a treatment for DCIS. In general, patients treated with this approach have been highly selected and it is unclear how many women with DCIS meet these selection criteria. Approximately one half of the local recurrences seen after treatment with excision alone contain invasive carcinoma. The risk of local recurrence, at least for the first 10 years following excision, seems to be considerably greater for the comedo subtype compared with the noncomedo subtype. [ref: 144,160] Long-term studies of the results of salvage treatment in patients with local recurrence are not yet available and the time course to local recurrence may be quite prolonged, especially for low-grade DCIS. All of this emphasizes the need for long-term follow-up before drawing any firm conclusions on the use of excision alone for DCIS. Radiation therapy (RT) has been combined with excision in an attempt to improve local control in patients with DCIS.
Whether RT is necessary for all patients with DCIS treated with a breast-conserving treatment remains uncertain. Retrospective data indicate that highly selected patients (with small, low-grade lesions) have a low rate of local recurrence after excision. The results from NSABP B-17 do not confirm these observations, but questions have been raised about the mammographic and pathologic assessment used in this study. [ref: 166] Additional prospective studies evaluating this important question are needed.
Although it is anticipated that developments in molecular biology will one day allow better prediction of progression to invasive carcinoma, current efforts should be directed toward minimizing local recurrence in patients treated with a breast-conserving approach. Because most patients with DCIS have nonpalpable mammographic lesions, careful mammographic evaluation is critical. As previously discussed, magnification views allow a more accurate estimate of the extent of the lesion. Needle localization should be used to guide the biopsy, and if the calcifications are extensive, bracketing wires are useful to aid in complete excision. Specimen mammography is essential to help confirm the excision of calcifications, and in many cases, a postexcision mammogram should also be obtained to confirm that all of the calcifications have been removed. A detailed pathologic evaluation is also needed and this should include orientation and inking of the specimen before sectioning and a measurement of both the size of the lesion and the specimen. Because accurate measurement of microscopic DCIS is often difficult, reporting the number of blocks in which DCIS is present as well as its maximal extent on a given slide is useful. The correlation of microcalcifications with the DCIS and the margin status should be noted. If margins are involved, the location and extent of involvement should be stated, and wheegative, the proximity of the lesion to the margin should be noted. Mammographic confirmation that all suspicious microcalcifications have been removed and negative margins of resection are considered necessary to assure a low rate of recurrence following breast-conserving treatment. Residual microcalcifications or involved margins are indications for reexcision. The final answers on the risk of breast-conserving therapy for DCIS will be obtained only after longer follow-up of currently available data and studies with greater numbers of patients with more precisely characterized lesions. There are no data available on the role of tamoxifen in patients with DCIS and, at this time, there is no indication for its use outside of a controlled clinical trial, several of which are currently underway.
LOBULAR CARCINOMA IN SITU
Lobular carcinoma in situ (LCIS), unlike DCIS, lacks both clinical and mammographic signs. LCIS is characterized microscopically by a solid proliferation of small cells with small, uniform, round to oval nuclei. The cells have a low proliferative rate, are typically estrogen receptor-positive, and rarely overexpress the HER2/neu oncogene. [ref: 167-169] LCIS is multicentric in 60% to 80% of cases, [ref: 170-173] and is frequently bilateral. The true incidence of LCIS in the general population is unknown, with the reported incidence in biopsy specimens ranging from 0.5% to 3.6%. LCIS is diagnosed more commonly in younger women compared with older women, with the mean age at diagnosis between 44 and 46 years.This age distribution may be due to regression of LCIS following menopause or may simply reflect the fact that benign breast abnormalities that require biopsy are more common in premenopausal women. LCIS is diagnosed about 10 times more frequently in white women than black women in the
CLINICAL EVALUATION AND STAGING
The pretreatment evaluation of the breast cancer patient should determine the clinical stage of the disease and identify contraindications to breast-conserving therapy or immediate breast reconstruction. Clinical evidence of stage III disease is often an indication for systemic therapy before local treatment. A bilateral diagnostic mammogram should be obtained before surgical biopsy. In patients with microcalcifications, additional magnification views of the tumor site are very useful in patients being considered for breast-conserving treatment. Morrow and colleagues found that 97% of 216 women selected for breast-conserving treatment on the basis of clinical examination and magnification mammography were able to undergo the procedure based on histologic findings. In addition, unsuspected contralateral carcinoma is identified in 2.4% of cases. The use of magnetic resonance imaging (MRI) to identify the presence of mammographically occult multifocal carcinoma is under evaluation. Preliminary reports indicate that MRI might be able to identify additional foci of disease in 20% to 35% of patients, [ref: 190,191] suggesting that this may be a useful procedure in patients desiring breast-conserving therapy, but further study is needed to establish the clinical role of the procedure.
The extent of the preoperative work-up should be guided by the clinical stage of the disease and the patient’s symptoms. Patients with DCIS do not require screening for metastatic disease. Bone scans are frequently used as a preoperative screening test for patients with invasive cancer, but the incidence of occult bony metastases detected by scanning in patients with stage I and II disease is less than 5%. [ref: 192-197] False-positive scans are frequent, especially in older women. In contrast, bony metastases are identified by scanning in 20% to 25% of asymptomatic women with stage III disease, making this a worthwhile screening procedure in patients with locally advanced breast cancer.
MRI
The yield of screening liver scans is even lower than that seen with bone scanning, and the test is of little benefit in the preoperative evaluation of stage I and II breast cancer. [ref: 198-200] Liver imaging should be reserved for patients with abnormal liver chemistries or signs or symptoms suggesting hepatic metastases. In many centers, CT scans have largely replaced radionucleide scans for this purpose. Even with more specific imaging techniques, false-positive scans are common, so histologic confirmation of metastases should be considered before abandoning definitive primary therapy on the basis of an abnormal imaging study.
Serum tumor markers have not been shown to be of value preoperatively. Although carcinoembryonic antigen (CEA) may be useful in monitoring response to therapy, it is infrequently elevated in primary breast cancer. Lee found that only 3% of patients with stage I breast carcinoma and 6% with stage II disease had CEA levels greater than 5 mg/mL. [ref: 201] Other markers, such as assays to identify sialomucin (e.g., CA 15-3, CA 549), are more commonly elevated in primary breast cancer, with abnormalities seen in 20% to 50% of patients. [ref: 202-204] However, 20% of patients with benign breast disease have elevated CA 15-3 levels, and elevated levels are seen in benign gastrointestinal disease, diminishing the usefulness of this marker as a screening test.
Staging refers to the grouping of patients according to the extent of their disease. It is useful in (1) determining the choice of treatment for individual patients, (2) estimating their prognosis, and (3) comparing the results of different treatment programs. Staging can be based either on clinical or pathologic findings. Currently, staging of cancer is determined by the American Joint Committee on Cancer (AJCC), which is jointly sponsored by the American Cancer Society, the National Cancer Institute, the
Clinical staging (designated cTNM or TNM) according to the 2010 AJCC system, is based on all information available prior to when the first definitive treatment is used and includes the findings on physical examination, imaging studies, operative findings, and pathologic examination of the breast or other tissues. The extent of tissues examined pathologically for clinical staging is less than that required for pathologic staging, which is described below. Operative findings that are appropriate for clinical staging include the size of the primary tumor, the presence of chest wall invasion, and the presence or absence of regional or distant metastases. The clinical stage is useful in selecting and evaluating therapy.
Pathologic staging (designated pTNM) includes all data used for clinical staging and surgical resection as well as pathologic examination of the primary carcinoma and axillary lymph nodes. A tumor is inevaluable for pathologic staging (pTX) if the excision of the primary carcinoma reveals tumor in any margin of resection by gross pathologic examination. Regional nodes are inevaluable for pathologic staging (pNX) if less than the low axillary lymph nodes (level I) have been resected. Metastatic nodules in the fat adjacent to the mammary carcinoma, without evidence of residual lymph node tissue, are considered regional lymph node metastases. The pathologic stage provides the most precise data to estimate prognosis and to calculate end results.
There are several important rules and definitions for the use of the current staging system:
cT size. The clinical measurement used for classifying the primary tumor should be the one judged most accurate (e.g., physical examination or mammography).
pT size. The pathologic tumor size is a measurement of the invasive component. Specifically, if there is a large in situ component and a small invasive component, the tumor is classified by the size of the invasive component.
For multiple simultaneous ipsilateral (infiltrating, grossly measurable) cancers, one should use the largest lesion to classify T stage and specify that this is a case of multiple lesions. Such cases should be analyzed separately.
Simultaneous bilateral breast cancers should each be staged separately.
Paget’s disease of the nipple without an associated tumor mass (clinical) or invasive carcinoma (pathologic) is classified as Tis. Paget’s disease with a demonstrable mass (clinical) or invasive component (pathologic) is classified according to the size of the mass or invasive component.
Dimpling of the skin or nipple retraction or any other skin change except those described under T4b and T4d may occur in T1, T2, or T3 without changing the classification.
Chest wall includes the ribs, intercostal muscles, and serratus anterior muscle, but not the pectoral muscles.
Inflammatory carcinoma is a clinicopathologic entity characterized by diffuse, brawny induration of the skin of the breast with an erysipeloid edge, usually without an underlying palpable mass. This clinical presentation is due to tumor embolization of dermal lymphatics.
If there is doubt concerning the correct T, N, or M category to which a particular case should be allotted, then the lower (less advanced) category should be chosen.
It should be stressed that the current AJCC system differs significantly from prior versions [ref: 206-210] in allowing all information available prior to when the first definitive treatment is used, including the operative findings and pathologic examination of the resected breast specimen with the primary tumor. In prior systems, clinical staging was restricted to findings available before surgery, namely physical examination and imaging studies. The many changes in the AJCC system over time and its complexity have greatly limited its use and usefulness. In addition, the current system does not address present-day issues in clinical decision-making, such as a patient’s suitability for breast-conserving treatment or the risk of distant relapse with and without systemic therapy. In practice, most clinicians simply use the tumor size and histologic findings of axillary dissection, often grouped for convenience into negative, 1 to 3 positive, 4 to 9 positive, and 10 or more positive. Attempts are underway to develop more useful staging systems.
LOCAL TREATMENT OF INVASIVE BREAST CANCER
In this section, we present the theoretical basis and pertinent data relating to the local treatment of invasive breast cancer and address practical issues in management, including guidelines for patient selection for mastectomy and breast-conserving therapy, indications and complications of axillary surgery, indications for postoperative RT, sequencing of RT and systemic therapy, the use of breast-conserving surgery without RT, local recurrence, breast reconstruction, and special therapeutic problems. The local treatment of breast cancer has long been a source of controversy. For many years, local treatment was considered the domain of the surgeon. However, changes in our understanding of the biology of the disease, the detection of smaller tumors over time, an increasing emphasis on systemic therapy, and greater patient participation in the decision-making process have radically changed the approach to the local treatment of breast cancer over the last 20 years. Today, local treatment of breast cancer involves a collaborative effort between surgeons, radiologists, pathologists, radiation oncologists, reconstructive surgeons, and medical oncologists all working with the patient. Modified radical mastectomy is the most common operative treatment for patients with invasive breast cancer in the United States. The term modified radical mastectomy is used to describe a variety of surgical procedures, but all involve complete removal of the breast, the underlying pectoral fascia, and some of the axillary nodes. Although the modified radical mastectomy may not seem to differ significantly from the radical mastectomy, it represented a major departure from Halstedian principles of en bloc cancer surgery. The switch to modified-radical mastectomy occurred as it became recognized that treatment failure after breast cancer surgery is usually due to the systemic dissemination of cancer cells before surgery, rather than an inadequate operative procedure. In addition, by the 1970s, fewer patients with large tumors with fixation to the pectoral muscle were being seen, making modified radical mastectomy feasible for most women. Several retrospective studies [ref: 215,216] demonstrated no difference in survival between patients treated with modified radical and radical mastectomy, and these findings were confirmed in two prospective randomized trials. Further evidence that radical en bloc surgery did not prolong survival came from several randomized trials comparing radical mastectomy with simple mastectomy and RT.
The principles noted above that led to the use of the modified radical mastectomy also contributed to the development of breast-conserving treatment. In addition was the observation that moderate-dose RT was effective in eliminating subclinical foci of breast cancer after mastectomy. This led to the strategy behind breast-conserving treatment; namely, to remove the bulk of the tumor surgically and to use moderate doses of radiation to eradicate any residual cancer. An initial objection to the use of breast-conserving treatment was the reported “multicentricity” of breast carcinoma. The reported incidence of multicentricity ranged from 9% to 75%, depending on the definition employed, extent of tissue sampling, and the techniques of pathologic examination utilized. [ref: 221-223] These studies were used to argue against anything less than complete mastectomy as optimal local treatment for breast cancer. Considerable clarification of this issue has occurred as a result of the work of
The almost universal acceptance of the Halstedian dogma regarding breast cancer required that a relatively large number of randomized clinical trials be conducted to determine whether survival after breast-conserving treatment equaled survival after mastectomy. Since 1970, there have been six prospective randomized trials [ref: 231-238] using modern radiation techniques in which conservative surgery (CS) and RT have been compared with mastectomy. These trials differ somewhat in patients selection, the details of surgery and RT, and the length of follow-up. Nevertheless, all of these trials show equivalent survival between the 2 treatment options and are summarized in Table 36.2-
Since the 1970s, numerous reports from centers in Europe and North America on the use of CS and RT have demonstrated high rates of local tumor control with satisfactory cosmetic results. These reports have provided useful information in determining the optimal approach to CS and RT, providing guidelines for patient selection and providing patients treated with CS and RT with important information on their expected outcome. Retrospective studies have reported 10-year local recurrence rates ranging from 8% to 20%, very similar to the rates seen in the randomized trials. [ref: 242-251] However, the nonrandomized studies with the longest follow-up emphasize the prolonged time course to local recurrence in some patients undergoing breast-conserving treatment. [ref: 248,249,252] These results have been contrasted to those seen after mastectomy, in which most local failures occur in the first 3 years after surgery. It is possible that late recurrences in conserved breasts may sometimes represent a new primary cancer.
A major goal of breast-conserving treatment is the preservation of a cosmetically acceptable breast. Studies of the long-term cosmetic outcome following CS and RT [ref: 253-256] have shown that treatment-related changes in the treated breast tend to stabilize by 3 years following treatment; however, other factors that primarily affect the untreated breast, such as change in size due to weight gain and the normal ptosis seen with aging, continue to affect the symmetry between a patient’s breasts. Although a variety of patient, tumor, and treatment factors have been reported to influence the cosmetic result, the amount of breast tissue resected appears to be the major factor. [ref: 256-258] For patients who elect breast-conserving treatment, optimal technique is necessary to optimize results, and the basic elements of this are provided in Table 36.2-13 (Fig. 36.2-2).
Various studies have attempted to identify “risk” or “prognostic” factors associated with local recurrence principally to identify patients who might benefit from mastectomy or an altered form of breast-conserving treatment (such as more extensive breast resection or more aggressive irradiation). In addition, these studies are useful to obtain a better understanding of the pathophysiology and significance of local recurrence. Young patient age has consistently beeoted to be associated with an increased risk of local recurrence. [ref: 233,248,259-263]Young patient age is associated with an increased frequency of various adverse pathologic features, such as lymphatic vessel invasion, grade 3 histology, absence of estrogen receptors, and the presence of an extensive intraductal component. However, even when the differing incidence of the pathologic features of the primary tumor between the age groups is corrected for, younger age is still associated with a decreased survival rate and an increased likelihood of recurrence in the breast. [ref: 260,264] Young patient age, however, has similarly been described as an important factor associated with a worse outcome following mastectomy. [ref: 262,265,266] The data from the two randomized trials with longest follow-up do not specifically address the issue of patients younger than 35, but do not show an advantage for one form of local treatment for younger patients. In the
Some, but not all, studies have identified lymphatic vessel invasion (LVI) as an important pathologic risk factor for local recurrence following CS and RT. [ref: 248,269] LVI is also known to be an adverse prognostic factor with regard to survival and has been shown to be a risk factor for local recurrence following mastectomy as well. [ref: 270,271] Thus, lymphatic vessel invasion, like node involvement, may be more useful in assessing overall prognosis than in selecting local treatment for patients with this factor. Infiltrating lobular carcinomas account for 5% to 10% of invasive breast cancers and, in most studies, are associated with a local recurrence rate similar to that seen for infiltrating ductal carcinomas. [ref: 272-276] In the JCRT experience, the presence and extent of associated LCIS was not related to the rate of local recurrence. [ref: 272] Given the diffuse and apparently discontinuous infiltration seen with infiltrating lobular carcinomas, however, a wide resection with clearly negative microscopic margins of resection is generally advised.
The available data suggest that an assessment of the microscopic margins of resection (or “margins”) is of great use in predicting the risk of local recurrence. The NSABP has demonstrated that use of its definition of “negative margins” (defined as the absence of cancer cells directly at an inked surface) results in an acceptably low rate of local recurrence and a survival rate comparable with that achieved with the use of mastectomy.
The results of a recent study from the JCRT are consistent with these findings. The study population consisted of 340 patients with an infiltrating ductal carcinoma who received a radiation dose to the surgical site of 60 Gy or greater, whose final microscopic margins of resection were evaluable, and who had at least 5 years of follow-up. A “positive” margin was defined as tumor present at the inked margin of resection, a “close” margin as tumor within 1 mm of the inked margin, and a “negative” margin as no tumor within 1 mm of the inked margin. A “focally positive” margin was defined as tumor at the margin in 3 or fewer low-power fields. These results (shown in Table 36.2-14) indicated low rates of local recurrence for patients with negative margins, whether close or not and whether an EIC is present or not. Taken together with the results from the NSABP and from Duke, the presence of an EIC per se should not be a contraindication to breast-conserving therapy. Patients with an EIC-positive cancer and uninvolved margins of resection are adequately treated with breast-conserving therapy and patients with a EIC-positive cancer and positive margins on an initial resection can be considered for a reexcision of the primary tumor site in an attempt to obtaiegative margins.
The use of breast-conserving therapy in patients with positive margins is controversial. The results in the JCRT series suggest that when patients with an EIC-negative cancer are treated with breast irradiation, including a boost to the primary tumor site, focal involvement of the margins is associated with an acceptably low rate of a local recurrence. This is consistent with the prior observation that EIC-negative cancers are rarely associated with prominent residual cancer in the breast following a limited breast resection. [ref: 225,267] These results suggest that it is reasonable to offer patients with an EIC-negative cancer and only focal margin involvement the option of breast-conserving therapy if a reexcision is not considered feasible.
Microinvasive carcinoma is a poorly defined pathologic entity which is characterized by the presence of DCIS with microscopic or limited invasion. (Microinvasive breast cancer corresponds to one of the definitions of an invasive breast cancer with an EIC described in detail earlier.) Similar to DCIS, it is being diagnosed more frequently because of the increased use of screening mammography. The behavior of microinvasive carcinoma is difficult to determine at this time because there are varying definitions of microinvasive carcinoma used, including “DCIS with only a few cells penetrating the basement membrane,” [ref: 281] “DCIS with one or two foci of invasion measuring not more than
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A final, and critical, factor in the selection of local therapy is patient desire. Several studies indicate that currently more than 50% of patients in the
Of the 337 medically eligible patients who were offered a choice between breast-conserving treatment, mastectomy, or mastectomy with immediate reconstruction, 81% chose breast-conserving treatment. These data suggest that medical contraindications and patient bias are not the primary reasons for the low national rates of breast-conserving treatment. This and other studies suggest that physician bias or their misunderstanding of the contraindications to breast-conserving treatment may be a major factor accounting for high rates of mastectomy. [ref: 298,299] For patients who elect or require mastectomy, breast reconstruction is an important option to discuss. The option of reconstruction should be discussed routinely with the patient before definitive surgery, and reconstruction should be offered to all women who are not candidates for or do not desire breast-conserving therapy. Reconstruction can be done at the time of mastectomy (immediate) or as a secondary procedure. Immediate reconstruction allows for all major surgery to be performed under one anesthesia and for patients to avoid any time without reconstruction. Concerns about immediate reconstruction have included the potential for an increased incidence of local failure, a delay in the diagnosis of local failure, and complications that delay the initiation of systemic drug therapy. There have beeo prospective randomized trials comparing patients undergoing immediate reconstruction to patients undergoing mastectomy alone. A number of retrospective studies have assessed the incidence of local failure in patients undergoing breast reconstruction in comparison with patients treated by mastectomy alone and have not found an increased risk. [ref: 300-302] Concerns that a breast reconstruction may prevent the detection of local recurrence or increase the incidence of complications have also not been confirmed by the available data. [ref: 303-305] In skillful hands, the complication rate should be low, and clinical trials have established that adjuvant chemotherapy does not need to initiated immediately after definitive surgery to be effective. [ref: 306] The various options for reconstruction are discussed in a separate section below.
Of concern in the use of CS and RT is possible long-term carcinogenesis from RT. One possible complication is the induction of a second breast cancer. Breast tissue is known to be sensitive to radiation carcinogenesis with a latency period between exposure and the detection of induced cancers of about 10 years. [ref: 307] Two important factors, radiation dose and age at exposure, influence the likelihood of radiation carcinogenesis in breast tissue. The risk of carcinogenesis increases linearly with doses up to 10 Gy. With doses above 10 Gy, there appears to be a bending of the curve and a decrease, or at least a levelling off, in the risk of carcinogenesis. When doses in the therapeutic range are used (greater than 45 Gy), the risk of carcinogenesis appears to be small. [ref: 308,309] Because the dose to the opposite breast from a course of RT is in the range of 1 to 3 Gy, [ref: 310] tumor induction in the contralateral breast is of greater potential concern than in the ipsilateral breast. Age at exposure to radiation is the other important risk factor for carcinogenesis in human breast tissue. [ref: 307,311] The highest risk occurs in female patients exposed at the youngest age. With increasing age, the risk of carcinogenesis declines. The risk for women over the age of 40 years appears to be negligible, but not zero.
AXILLARY TREATMENT
Axillary treatment in the form of a complete dissection was, for many years, standard management in patients with invasive breast cancer. As dictated by the Halstedian concept of breast cancer spread, axillary dissection was considered a critical component of the surgical cure of the disease. The axillary nodes were considered the “filter” before spread of cancer cells to distant sites could occur. In addition to its potential survival benefit, axillary dissection is also known useful in assessing prognosis and in assuring local tumor control in the axilla. By the 1970s, there was increasing evidence that axillary dissection had a limited impact of on survival. This was most convincingly demonstrated in the NSABP trial B-
With the general recognition that axillary dissection was principally a prognostic rather than therapeutic procedure, a number of studies were undertaken to determine the extent of axillary surgery needed to determine whether nodes were positive or negative. Many of these studies examined the likelihood of “skip metastases,” that is, involvement of nodes in the upper axilla (level III) in the absence of involvement in the lower (level I or II) nodes. Involvement of level III is clearly rare when both level I and II are negative. There is considerable variability in the available literature on the risk of skip metastases to level II. Much of this variability may be due to variations in the definition of which nodal tissue constitutes levels I and II. These disparate observations have led some authors to conclude that a level I dissection provides accurate staging information, [ref: 331] whereas most have concluded that removal of both levels I and II is required. [ref: 332,333] A level I-II dissection is effective at providing local control in the axilla. Among patients treated with a level I-II dissection as part of breast-conserving treatment, axillary recurrence rates of less than 3% have been reported. [ref: 334-337] When patients undergo more limited axillary sampling procedures, the likelihood of local recurrence is related to the number of lymph nodes removed. The 5-year probability of an axillary recurrence is about 20% in patients with no lymph nodes examined and about 10% when only one to two negative nodes are removed. At least 6 to 10 nodes need to be removed to avoid misclassification and optimize local control in the axilla. [ref: 323,337-340] Although a level I-II dissection is generally well tolerated, there are occasional complications. Major complications, including injury or thrombosis of the axillary vein and injury to the motor nerves of the axilla, are infrequent. Minor complications are more common and include seroma formation, shoulder dysfunction, loss of sensation in the distribution of the intercostobrachial nerve, and edema of the arm and breast. A number of recent developments have led to a reexamination of the need for axillary dissection in all patients, including the routine use of adjuvant systemic therapy in many patients with node-negative breast cancer, the increasing use of breast-conserving treatment, and the increasing numbers of patients with small, mammographically detected cancers. One approach to avoiding axillary dissection is to identify cancers with a very low risk of nodal metastases. The incidence of axillary nodal involvement is known to be related principally to tumor size. However, axillary node metastases are still seen in 12% to 37% of cancers measuring
Axillary dissection is also still of value in obtaining local control in the axilla and in providing patients with important prognostic information. The number of involved axillary nodes remains the single most reliable indicator of prognosis. Entry onto most clinical trials still requires the results of surgical staging. It may, however, be possible to identify node-positive patients by the removal of a “sentinel node,” as is done in patients with melanoma. [ref: 352,353] This technique has the potential to allow axillary dissection to be limited to patients with nodal involvement who require axillary dissection for local control and for quantification of the number of involved nodes.
An alternate method of maintaining local control in the axilla is the use of axillary irradiation. Axillary recurrence rates of 3% or less have been reported in clinically node-negative patients undergoing CS and RT without axillary dissection. [ref: 335,354-356] The incidence of lymphedema of the arm and breast after axillary radiation alone appears to be similar to that after surgical dissection, [ref: 253,356,357] but there are other uncommon complications from axillary irradiation that must be considered, particularly when RT is given in conjunction with adjuvant chemotherapy. It may be reasonable in many patients to treat only the lower axillary nodes as part of tangential breast irradiation.
In summary, the role of axillary dissection is in evolution. Axillary dissection can be eliminated for patients with DCIS or with DCIS and small areas of microinvasion and for those with pure tubular carcinoma less than
INDICATIONS FOR POSTOPERATIVE RADIATION THERAPY
Post-operative radiation therapy refers to irradiation of the chest wall and draining lymph node regions used as an adjuvant treatment following definitive surgery (mastectomy). There are two possible rationales for its use. The first is to reduce the rate of local or regional tumor recurrence by treating residual microscopic disease that may have spread beyond the margin of surgical resection. In the absence of postoperative RT, the risk of local recurrence after modified radical mastectomy is principally related to the presence and extent of axillary nodal involvement. If axillary nodes are involved, local recurrence is seen in about 25% of patients, whereas if axillary nodes are uninvolved, local recurrence is seen in only about 5% of patients. Once a local recurrence is clinically manifest, it can be effectively controlled in only approximately 50% of patients. In addition, local recurrence is typically very distressing psychologically. Thus, postoperative RT can benefit high-risk patients simply by preventing local recurrence. The second potential rationale for postoperative RT is to improve survival. It is theoretically possible that residual microscopic local disease after mastectomy may be the only site of persistent cancer and a source of subsequent distant metastases.
Postoperative RT has been shown to decrease the risk of local recurrence by about two thirds. [ref: 220,363,364] Assessing the survival value of postoperative RT requires evaluation within prospective randomized clinical trials. A recent overview of randomized trials showed no survival benefit to the use of RT. [ref: 220] However, this overview analysis did not subdivide the trials into those in which adjuvant systemic therapy was and was not used. Moreover, many of the trials used techniques (now considered outmoded) which delivered considerable dose to the heart. There are only five published trials in which patients were randomized after radical or modified radical mastectomy to postoperative RT or no further treatment in the absence of systemic therapy. [ref: 365-368] None of these trials has demonstrated a clear-cut improvement in the survival rate. The most modern of these trials was conducted in
SEQUENCING OF SYSTEMIC THERAPY AND RADIATION THERAPY IN
PATIENTS TREATED WITH BREAST-CONSERVING TREATMENT
There is uncertainty regarding the optimal sequencing of chemotherapy (ChT) and RT after conservative surgery. The chief goal in sequencing is to obtain the highest rate of survival; additional important goals are to maintain a low rate of local recurrence, a low rate of complications, and a high rate of satisfactory cosmetic results. In considering this issue of combining RT and ChT, it would be useful to know the answers to a number of questions, such as whether a delay in either ChT or RT decreases its effect, whether RT and ChT be given simultaneously without an increase in complications or a decrease in the cosmetic outcome, and whether prior RT affects the ability to give maximal doses of ChT. In addressing these questions, it is also important to bear in mind that there are differences in the implementation of breast-conserving surgery, RT, and ChT from institution to institution and the optimal combination may differ accordingly. It seems intuitively logical that delays in the initiation of ChT will decrease its effectiveness; however, firm data demonstrating this are not available. One effort to address this has focused on the possible benefit of perioperative ChT in patients treated with mastectomy. In a trial performed by the International Breast Cancer Study Group, [ref: 306] node-positive patients were randomized to one cycle of perioperative CMF (within 36 hours of surgery), the same treatment followed by 6 cycles of conventionally timed ChT, or 6 cycles of conventionally timed ChT alone. Disease-free survival was equivalent for patients treated with conventionally timed ChT with or without one cycle of perioperative ChT, and both of these groups had better disease-free survival than patients treated with one cycle of perioperative ChT alone. Similar results have been reported elsewhere. [ref: 394,395] These results suggest that short delays in the initiation of ChT are not harmful.
Sequencing was evaluated in a randomized clinical trial in which patients treated with mastectomy were randomized to RT followed by ChT (6 cycles of CMF), ChT followed by RT, or a sandwich approach using 3 cycles of ChT initially, RT, then completion of the ChT. With a relatively small number of patients in each arm (about 80), the best results were observed in patients treated with the sandwich approach. [ref: 396] Retrospective reviews of patients treated either with mastectomy or breast-conserving treatment examining the influence of the delay of ChT on outcome have demonstrated conflicting results. [ref: 397-401]
It is also possible that a delay in the initiation of RT to give ChT first may decrease its effectiveness. The information available on this issue is also not definitive. The JCRT previously reported on a retrospective analysis of 295 node-positive patients treated with RT and ChT using a variety of sequences that were not randomly assigned.
The 5-year actuarial total failure and overall survival rates were not statistically different between the arms, but the 5-year actuarial (uncensored) risk of developing distant metastasis was significantly greater in the RT –> ChT arm. This may reflect both the longer interval to initiating ChT and lower drug doses given in patients received RT first. The proportions of patients receiving at least 85% of the planned drug doses were lower in the RT –> ChT arm than in the ChT –> RT arm. The risk of local recurrence was higher in the ChT –> RT arm, consistent with prior studies suggesting that the interval from surgery to RT may have an impact on the effectiveness of RT. These results indicate that for patients at moderate or high risk of developing systemic metastases, it is preferable to give a 12-week course of ChT followed by RT, rather than RT followed by ChT. However, alternative ways of combining RT and ChT that maximize both local and systemic control need to be explored. This trial also does not address whether RT can be delayed for periods of longer than 12 weeks or what is the optimal sequencing in more favorable node-negative patients. Additional information on sequencing is provided in a trial from the International Breast Cancer Study Group designed to evaluate the timing and length of adjuvant systemic therapy. [ref: 409] As part of this protocol, 434 premenopausal patients undergoing breast- conserving therapy were randomized to CMF x 6, CMF x 6 plus late CMF, CMF x 3, or CMF x 3 plus late CMF with all patients receiving breast RT at the conclusion of initial chemotherapy. The 4-year local recurrence rate was 9% for patients receiving CMF x 6 –> RT and was 8% for patients receiving CMF x 3 –> RT, suggesting that RT can be delayed until completion of 6 months of chemotherapy.
Another important question regarding sequencing is whether RT and ChT can be given simultaneously without an increase in complications or a decrease in the cosmetic outcome. The use of simultaneous RT and ChT has the advantage of eliminating the necessity for delaying one of the modalities and also might provide an additive or synergistic interaction between the RT and ChT. The available information on the effects of simultaneous treatment is conflicting and this is likely due to differences in the details of the RT and ChT protocols used. In some studies, patients treated with simultaneous treatment have had greater skin reactions compared with patients treated sequentially, [ref: 410-414] but this has not been seen in other studies. [ref: 415-419] In the experience at the JCRT, acute skin reactions were more pronounced with simultaneous treatment compared with sequential treatment, particularly in patients who received full doses of RT and 4 injections of methotrexate during RT. [ref: 410] It was also found that patients given simultaneous treatment had an increased rate of radiation pneumonitis (particularly when a third field was used to treat the axillary or supraclavicular nodal areas) [ref: 420] and a decrease in the long-term cosmetic result. [ref: 255] In contrast, neither an increase in radiation pneumonitis nor a decrease in the cosmetic outcome was seen when patients were treated with simultaneous RT and CMF in which methotrexate was omitted during the RT. [ref: 386,421] An increase in cardiac complications was reported by the Milan group for patients treated with simultaneous RT and doxorubicin-containing ChT, [ref: 416] but this has not been reported by others. Thus, the use of simultaneous RT and ChT has potential advantages, but the precise details of the administration of these two modalities is important to ensure its safety. The Harvard Cooperative Oncology Group has completed a protocol investigating the use of simultaneous full-dose CMF and a modified program of RT in patients with up to 3 positive nodes. The RT is restricted to the breast alone and is given at 180 cGy/d to a total dose of 3960 cGy to the whole breast followed by a boost of 1600 cGy. This treatment was well tolerated acutely; however, about 50% of patients developed moist desquation. All patients received nearly full doses of ChT but long-term results are pending.A final question regarding sequencing is whether prior RT affects the ability to give full doses of ChT. The available information on this question, reviewed above, is also conflicting and, here too, this is likely due to differences in the specifics of the RT and ChT used.
In conclusion, the available information regarding the optimal sequencing of ChT and RT is limited, mostly based on retrospective reviews and often conflicting. Differences in the details of the treatment (surgery, RT, and ChT) may explain some of the conflicting results. There are concerns about delaying the initiation of ChT in patients at high risk for metastases and the possibility that a delay in the initiation of RT may be associated with an increase in the rate of local recurrence. It may be possible to deliver RT and ChT simultaneously in a safe and effective manner, but the precise details for this have not been established. The results from the Upfront-Outback trial indicate that in patients at moderate or high risk for metastases, it is preferable to begin with ChT rather than RT. Additional data from randomized clinical trials addressing this important issue are required. In the meantime, clinicians faced with this issue might modify the sequence in an individual patient based on both the patient’s risk of metastases and the closeness of cancer cells to the margin of resection. In patients with positive nodes and negative margins of resection, the major focus should be on prompt initiation of ChT, whereas in patients with small tumors, negative nodes, and close margins of resection, it may be prudent not to delay greatly the initiation of RT.
BREAST RECONSTRUCTION
As discussed earlier, breast reconstruction is an important option for a breast cancer patient undergoing mastectomy to consider and should routinely be discussed with the patient before definitive surgery. The only contraindications to breast reconstruction are the presence of significant comorbid conditions that would interfere with the patient’s ability to tolerate a longer operative procedure in the case of immediate reconstruction, or additional procedures in the case of delayed reconstruction. In patients who may require postoperative chest-wall irradiation, implant reconstructions should be avoided because the risk of implant loss is high after RT. [ref: 530] Patient age, [ref: 531] the need for adjuvant chemotherapy, [ref: 305] and poor long-term prognosis are not contraindications to reconstruction. The simplest technique for breast reconstruction involves the use of available tissue and placement of an implant. This approach is best for women with small or moderate-size breasts with minimal ptosis, and requires adequate skin to cover an implant of a size similar to the contralateral breast. The use of limited skin excision, with operative exposure gained by incision, usually leaves enough skin to cover an implant. Oncologic surgeons now generally agree that the only skin that it is necessary to excise for reasons of cancer control is the nipple-areola complex and the biopsy scar. If insufficient skin is available to achieve symmetry with the contralateral breast or for larger or ptotic breasts, a tissue expander may be employed. This technique involves placement of a prosthesis that is only partially inflated beneath the pectoral muscle. Using a subcutaneous injection port, the prosthesis is gradually filled with saline over a period of weeks to months until the desired breast size and shape are achieved. Silicone breast implants have been available for over 30 years. In January, 1992, the Food and Drug Administration (FDA) declared that silicone gel-filled implants could not be used until more information was available about their long-term safety. This moratorium, however, did not apply to saline-filled implants and the FDA later recommended that gel-filled implants be allowed in breast cancer patients pending the results of further study. The major recognized complication of implants is the development of capsular contracture, an excessive scar formation around the implant that may lead to deformity and pain of the breast. Other complications of implants include rupture of the implant and leakage of silicone through the intact implant capsule. The incidence of these complications is uncertain. A major concern regarding the use of silicone implants arose after uncontrolled studies suggested an increased incidence of connective-tissue disease in women with implants. [ref: 532-535] However, multiple epidemiologic studies have failed to document a large increase in the incidence of connective tissue disease in women with implants compared with matched control populations, [ref: 536-539] and in 1995 the American Society of Rheumatologists concluded that scientific evidence does not support an association between implants and connective-tissue disease. However, a recent large retrospective cohort study showed a small, but significant increase in risk (RR, 1.24; 95% confidence interval, 1.08 to 1.41). [ref: 540] Given the low incidence of connective-tissue disease in the general population, an increased relative risk of this magnitude translates into a very small absolute risk for women who elect a silicone implant. Another technique of reconstruction is the use of myocutaneous flaps to transfer skin, fat, and muscle from distant parts of the body. The most commonly used flaps are the latissimus dorsi and transverse rectus abdominis (TRAM) myocutaneous flaps. The use of a flap for reconstruction requires a more lengthy and involved operative procedure than the implant method, and postoperative recovery is somewhat longer because there are two separate incision sites. The latissimus flap is often used in conjunction with a prosthesis because in most cases the flap alone provides insufficient bulk to achieve symmetry. With the latissimus flap, there is only a 1% incidence of complete flap loss. [ref: 541] The transverse rectus abdominis myocutaneous flap usually allows an adequate breast mound to be fashioned without the use of a prosthesis, but its blood supply is more tenuous than that of the latissimus flap, with major necrosis reported in 5% of patients and partial necrosis in as many as 31% of patients. [ref: 305,542] For some patients, the removal of extra tissue from their lower abdomen is an advantage to this procedure. Abdominal wall herniation is seen in 2% to 5% of patients following this procedure, but this percent is dependent on the skill and experience of the operator. Long-term cigarette smoking (more than 20 pack-years) has an acute and chronic effect on microcirculation and, in many centers, is a contraindication to the procedure. If these myocutaneous flaps are not available or not suitable for use, it is possible to transfer composite tissues from distant sites and to perform a microvascular anastomosis to nearby vessels. [ref: 543] This technique, known as a free flap, requires a skilled microsurgeon and prolonged operating time and is only occasionally chosen for primary reconstruction. The potential benefits and complications of the various reconstructive procedures are listed in Table 36.2-20. Regardless of the technique of reconstruction chosen, the creation of a breast mound is the chief goal in breast reconstruction. Surgery on the contralateral breast, such as reduction or mastopexy, may be required to achieve symmetry. Reconstruction of a nipple-areola complex is another secondary procedure that some patients elect to improve the cosmetic appearance. The patient’s owipple should not be used for this purpose, because recurrent carcinoma due to persistence of breast tissue on the nipple has been reported. Microscopic involvement of the nipple is seen in 30% of mastectomy specimens, but is frequently not apparent at the time of gross pathologic examination. [ref: 547-549] The nipple can be reconstructed using a variety of local flap techniques or by the use of full-thickness skin grafts. Tattooing of the grafts produces a color match to the patient’s own areola, and allows any site to be used as the donor. [ref: 550] Tissue from the contralateral nipple should not be used for nipple reconstruction because of the concern of transferring breast tissue to the reconstruction site.
SPECIAL THERAPEUTIC PROBLEMS
PAGET’S DISEASE OF THE NIPPLE
Paget’s disease of the nipple is a rare form of breast cancer that is characterized clinically by eczematoid changes of the nipple. Associated symptoms include itching, erythema, and nipple discharge. Paget’s disease is diagnosed histologically by the presence of large cells with pale cytoplasm and prominent nucleoli (known as Paget cells) involving the epidermis of the nipple. In 1874, Sir James Paget reported that this condition was invariably followed by cancer of the breast usually within 1 year of diagnosis. [ref: 554] In approximately 45% of women with Paget’s disease, a breast mass is detected at presentation, and in most of the remainder, infiltrating or intraductal carcinoma is identified in the mastectomy specimen. The average age of women with Paget’s disease does not differ from that of women with other forms of breast cancer, but symptoms are frequently present for 6 months or more before diagnosis.
The relation between the changes observed in the nipple and the underlying breast cancer remains a matter of controversy. One theory suggests that the nipple involvement represents the migration of malignant cells from the underlying breast tumor, and histologic studies have demonstrated malignant cells extending along ductal structures from the tumor mass to the nipple. [ref: 556,557] Cohen and colleagues [ref: 558] have demonstrated concordant immunostaining with seven antigens between Paget cells and the underlying carcinoma in 18 of 20 patients, and other studies have demonstrated the same staining patterns for C-erbB-2 oncoprotein [ref: 559,560] and carcinoembryonic antigen, [ref: 561,562] suggesting that both the Paget cell and the carcinoma originate from the same cell population. The alternate hypothesis proposes that Paget cells are a separate disease process originating in the epidermis.
Paget’s disease has traditionally been treated with mastectomy. The rationales for this approach are the need to sacrifice the nipple-areola complex, the fact that the subareolar ducts may be diffusely involved with tumor, and the observation that carcinoma may be found at a considerable distance from the nipple. [ref: 551-555] A limited experience with breast-conserving procedures in the management of Paget’s disease has been described. Paone [ref: 553] reported 5 patients who underwent excision of the nipple with a wedge resection of underlying breast tissue who remained free of disease at 10-year follow-up. Lagios and coworkers [ref: 564] reported 5 patients with no palpable breast mass and negative mammograms treated by excision of the nipple-areola complex who remained free of parenchymal recurrence at a mean follow-up of 50 months. One patient, treated with only partial nipple excision, developed recurrent Paget’s disease at 12 months, which was resected. Twenty selected patients with Paget’s disease without clinical or radiologic evidence of parenchymal breast cancer were treated with RT alone or excision plus RT at the Institut Curie from 1960 to 1984. [ref: 565] At a median follow-up of 7.5 years, 3 patients had recurrent disease in the nipple-areolar region and were treated with mastectomy. The 7-year actuarial probability of survival with the breast preserved was 81%. Bulens and coworkers, [ref: 566] using similar selection criteria, reported no local or distant failures in a group of 13 patients treated with breast irradiation alone. Osteen collected a total of 79 patients treated by local excision with or without RT, with 9 local recurrences.
When considering therapeutic options in Paget’s disease, it is helpful to think of the condition as DCIS involving the nipple that usually is associated with additional intraductal or invasive carcinoma in the underlying breast parenchyma. The extent of the underlying involvement will determine the patient’s suitability for breast-conserving therapy. Detailed mammographic evaluation (including magnification views of the subareolar region) and histologic evaluation with margin assessment are essential components of this evaluation. For patients with evidence of diffuse involvement or disease at a distance from the nipple, mastectomy remains the standard therapy. In patients with disease localized to the subareolar area or the nipple-areolar complex, breast-conserving therapy can be considered. This treatment requires removal of the entire nipple-areola complex and some of the underlying ductal region. In carefully selected patients, local failure rates with this approach appear to be similar to those reported for other breast carcinomas. The prognosis in Paget’s disease is related to the stage of the disease and appears to be similar to that of women with other types of breast carcinoma. If invasive breast cancer is found, the need for adjuvant systemic therapy should follow the same guidelines used for other patients with invasive cancer.
Notice:
These study materials were prepared from the book
CANCER: Principles & Practice of Oncology. 5th
HODGKIN’S and non-HODGKIN’S diseases
Objectives:
Students after this lecture should be able to discuss the following in general terms:
1. The difference between a lymphoma and a leukemia and how each typically presents clinically.
2. How the common lymphomas are classified and the differences in clinical presentation and prognosis between Hodgkin’s disease and the non-Hodgkin’s lymphomas.
3. The typical genetic mechanisms involved in the development of lymphomas.
4. What the common signs and symptoms of plasma cell myeloma are and how it is diagnosed.
Definitions:
Lymphomas – these are malignant neoplasms derived from lymphocytes that form “tumors”, usually in lymph nodes but also in other organs or in soft tissue. Unlike the leukemias the tumor cells do not appear in the blood in detectable numbers.
Plasma cell myeloma– these are bone marrow based, monoclonal tumors of plasma cells. Symptoms are related to replacement of normal marrow hematopoietic elements (anemia, etc.) and weakening of the bones resulting in fractures.
TYPES OF LYMPHOMAS:
The lymphomas are broadly grouped into two types:
A. Non-Hodgkin’s lymphomas (60%)
B. Hodgkin’s lymhoma (also known as Hodgkin’s disease) (40%)
Cells of origin: The non- Hodgkin’s lymphomas are derived from either B or T lymphocytes. The cell of origin in Hodgkin’s lymphoma is now known to be of B-cell origin also, but with “crippled” rearrangements of their immunoglobulin genes.
PATHOGENESIS OF LYMPHOMAS
All lymphomas, leukemias and plasma cell myeloma are derived from a single mutated cell and are thus “clonal” or “monoclonal” in origin. The specific mutations involved differ from one type of lymphoma/leukemia to the next but a large number of them involve chromosomal translocations, for example the t(9;22) translocation of chronic granulocytic leukemia or the t(14;18) translocation of follicular lymphomas (see below). Tumor progression, in the form of further mutations, typically occurs during the course of the patient’s disease and results in an increasingly aggressive form of the disease.
SPECIFIC TYPES OF LYMPHOMAS
HODGKIN’S LYMPHOMA (also called HODGKIN’S DISEASE):
Hodgkin’s lymphoma is a form of lymphoma that usually affects young people in their teens, 20’s and early 30’s, with a minor “bimodal” blip at around age 60. It most typically involves the cervical and mediastinal lymph node groups and spreads in a predictable pattern to contiguous lymph node groups (as opposed to “skipping” groups and arising in a more “random” pattern).
The diagnosis of Hodgkin’s lymphoma is made when “Reed-Sternberg cells” are seen in a lymph node along with other characteristic features. These cells are bi- or multi-nucleated tumor cells that have very large nucleoli, resembling viral inclusion bodies. These cells and other less diagnostic mononuclear forms of the tumor cell population appear to produce a number of lymphokines, such as IL-5, that attract other non-neoplastic lymphocytes, histiocytes, fibroblasts and often eosinophils into the affected node. This results in the very characteristic pathologic picture of a lymph node with large amounts of collagenous fibrous tissue (from the fibroblasts), numerous small lymphocytes, histiocytes and eosinophils with relatively few tumor cells. In fact, on occasion a pathologist will have to search through several slides before finding the diagnostic Reed-Sternberg cells.
Hodgkin’s lymphoma has traditionally been divided into 4 histologic sub-types (the Rye Classification):
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4. Lymphocyte depletion (this is very rare and it’s existence is controversial) |
The important thing in Hodgkin’s lymphoma however is not the histologic sub-type but the “stage” of the disease at the time of diagnosis. This will dictate the treatment and the prognosis of the disease.
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Stage I – involving a single node or group of contiguous nodes on the same side of the diaphragm or a single extranodal site (called IE) |
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Stage II – two or more lymph node groups on the same side of the diaphragm or limited contiguous extranodal involvement (IIE) |
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Stage III – lymph node groups on both sides of the diaphragm, may include the spleen (IIIS) or limited extranodal involvement (IIIE) |
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Stage IV – multiple or disseminated foci involving one or more extranodal sites |
Each of these stages can be further divided into A (not affected) or B (affected) subcategories depending on whether the patient also has fever, night sweats or weight loss of >10%.
Practically speaking Stage IV involvement is usually diagnosed when the bone marrow is found to be involved, hence the importance of bilateral iliac crest bone marrow biopsies in staging.
The prognosis of patients with Hodgkin’s disease is now excellent, especially in those with stage I or II disease, who can often be treated with radiotherapy to only the affected areas.
NON-HODGKIN’S LYMPHOMAS:
In contrast to Hodgkin’s disease, the non-Hodgkin’s lymphomas have a range of clinical aggressiveness that depends much more on the specific histologic sub-type than on the stage of the disease. Thus the classification of the specific type of non-Hodgkin’s lymphoma is very important to the correct management of a patient. Non-Hodgkin’s lymphomas are also much more frequently found arising in organ sites other than lymph nodes, such as stomach, lung, salivary glands and even such unlikely sites as brain. Recent studies have shown that a chronic infection of the stomach by a bacteria (Helicobacter pylori) has been associated with lymphomas arising in the stomach.
As mentioned at the beginning of the handout the non-Hodgkin’s lymphomas may be derived from either B- or T-cells. In North America and
The B-cell lymphomas may have either a follicular or a diffuse pattern of growth in the affected lymph node or tissue. In general, follicular lymphomas have a slower rate of growth and a less aggressive clinical course than their diffuse counterparts. The only exception is the “small lymphocytic” lymphoma, which has a very slow growth rate and is the lymph node equivalent of CLL. T cell lymphomas are always diffuse, never follicular.
Classification
The classification of the non-Hodgkin’s lymphomas is currently in a state of flux. The “N.I.H. Working Formulation” was devised in 1979 and is still in many textbooks currently. It is presented below in a somewhat simplified form. More recently a new classification scheme has been devised, based on the cell of origin (B or T) and reflecting specific diseases in terms of characteristic genetic mutations, . This is now referred to has the W.H.O. Classification .
N.I.H. Working Formulation of non-Hodgkin’s Lymphomas: (slightly abridged)
LOW GRADE (clinically slowly growing, but poorly responsive to treatment)
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This lymphoma is slow growing and composed of small round lymphocytes with scant cytoplasm and very few mitoses. They almost all of B-cell origin and express pan B-cell markers, such as CD20, as well as CD5 and CD23. in time they may transform to more aggressive forms of large cell lymphoma. |
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2. Follicular lymphomas– further subdivided on the basis of the relative numbers |
INTERMEDIATE GRADE (more rapidly growing, treated aggressively)
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3. Diffuse lymphomas– again subdivided on the same basis as the follicular |
HIGH GRADE (very rapidly growing, treated very aggressively, often like acute leukemias)
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PLASMA CELL MYELOMA
Plasma cell myelomas are derived from primitive stem cells in the bone marrow that differentiate into mature immunoglobulin secreting plasma cells. The genetic basis of this tumor development is not as consistent as many of the lymphomas and no characteristic translocations are known. The tumor cells gradually replace the bone marrow, especially in the vertebrae, ribs and skull, resulting in bone resorbtion and pathologic fractures (fractures of diseased, rather than normal, bone). Typically affecting older people in their 50’s to 60’s, this disease may present in a number of different ways relating either to (1) bone destruction (fractures), (2) the effects of marrow replacement (anemia, infections) or (3) excessive immunoglobulin production (producing kidney failure). Many students are surprised to learn that a tumor that produces large amounts of immunoglobulin should also be associated with an increased incidence of infections. It should be remembered that the immunoglobulin being produced is monoclonal and hence it is all the same in terms of it’s antigen recognition capacity. In fact the serum concentrations of all other “normal” immunoglobulins is typically decreased and the monoclonal Ig is not an effective substitute in recognizing pathogens, especially bacteria like Strep pneumoniae and Staph aureus.
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A very characteristic feature of myeloma is its tendency to affect the kidneys, either directly from the effects of the immunoglobulin precipitating in the renal tubules (so-called “myeloma kidney”) or more indirectly via hypercalcemia (from bone resorbtion) resulting in kidney stone (calculi) formation. Another form of bad news for the kidney is the development of amyloidosis, with the monoclonal Ig as substrate for the amyloid fibrils. This results in very heavy protein leakage (especially albumin) into the urine, producing the “nephrotic syndrome”.
The prognosis in plasma cell myeloma is related to the extent of disease at the time of diagnosis (i.e., stage of disease). Most patients with extensive bony lesions live less than 1 year and the median survival is only 3 years overall.
Lymphoma lecture slides 184 Kb.
Text was taken from CLINICAL/PATHOLOGIC CORRELATIONS IN MALIGNANT LYMPHOMAS AND PLASMA CELL MYELOMA of Dr. B. F. Burns, Dept of Pathology/Lab Medicine
Prepared by Prof. Igor Y. Galaychuk, MD
2014
