TREATMENT Breast Cancer
One of the most exciting aspects of breast cancer biology has been its subdivision into at least five subtypes based on gene expression profiling.
PRIMARY BREAST CANCER
Luminal A: The luminal tumors express cytokeratins 8 and 18, have the highest levels of estrogen receptor expression, tend to be low grade, are most likely to respond to endocrine therapy, and have a favorable prognosis. They tend to be less responsive to chemotherapy.
Luminal B: Tumor cells are also of luminal epithelial origin, but with a gene expression pattern distinct from luminal A. Prognosis is somewhat worse that luminal A.
Normal breast–like: These tumors have a gene expression profile reminiscent of nonmalignant “normal” breast epithelium. Prognosis is similar to the luminal B group. This subtype is somewhat controversial and may represent contamination of the sample by normal mammary epithelium.
HER2 amplified: These tumors have amplification of the HER2 gene on chromosome 17q and frequently exhibit coamplification and overexpression of other genes adjacent to HER2. Historically the clinical prognosis of such tumors was poor. However, with the advent of trastuzumab and other targeted therapies, the clinical outcome of HER2-positive patients is markedly improving.
Basal: These estrogen receptor/progesterone receptor–negative and HER2-negative tumors (so-called triple negative) are characterized by markers of basal/myoepithelial cells. They tend to be high grade, and express cytokeratins 5/6 and 17 as well as vimentin, p63, CD10, α-smooth muscle actin, and epidermal growth factor receptor (EGFR). Patients with BRCA mutations also fall within this molecular subtype. They also have stem cell characteristics.
Breast-conserving treatments, consisting of the removal of the primary tumor by some form of lumpectomy with or without irradiating the breast, result in a survival that is as good as (or slightly superior to) that after extensive surgical procedures, such as mastectomy or modified radical mastectomy, with or without further irradiation. Postlumpectomy breast irradiation greatly reduces the risk of recurrence in the breast. While breast conservation is associated with a possibility of recurrence in the breast, 10-year survival is at least as good as that after more extensive surgery. Postoperative radiation to regional nodes following mastectomy is also associated with an improvement in survival. Because radiation therapy can also reduce the rate of local or regional recurrence, it should be strongly considered following mastectomy for women with high-risk primary tumors (i.e., T2 in size, positive margins, positive nodes). At present, nearly one-third of women in the United States are managed by lumpectomy. Breast-conserving surgery is not suitable for all patients: it is not generally suitable for tumors >5 cm (or for smaller tumors if the breast is small), for tumors involving the nipple-areola complex, for tumors with extensive intraductal disease involving multiple quadrants of the breast, for women with a history of collagen-vascular disease, and for women who either do not have the motivation for breast conservation or do not have convenient access to radiation therapy. However, these groups probably do not account for more than one-third of patients who are treated with mastectomy. Thus, a great many women still undergo mastectomy who could safely avoid this procedure and probably would if appropriately counseled.
Sentinel lymph node biopsy (SLNB) is generally the standard of care for women with localized breast cancer and clinically negative axilla. If SLNB is negative, more extensive axillary surgery is not required, avoiding much of the risk of lymphedema following more extensive axillary dissections. In the presence of minimal involvement of a sentinel lymph node, further axillary surgery is not required.
An extensive intraductal component is a predictor of recurrence in the breast, and so are several clinical variables. Both axillary lymph node involvement and involvement of vascular or lymphatic channels by metastatic tumor in the breast are associated with a higher risk of relapse in the breast but are not contraindications to breast-conserving treatment. When these patients are excluded, and when lumpectomy with negative tumor margins is achieved, breast conservation is associated with a recurrence rate in the breast of 5% or less. The survival of patients who have recurrence in the breast is somewhat worse than that of women who do not. Thus, recurrence in the breast is a negative prognostic variable for long-term survival. However, recurrence in the breast is not the cause of distant metastasis. If recurrence in the breast caused metastatic disease, then women treated with lumpectomy, who have a higher rate of recurrence in the breast, should have poorer survival than women treated with mastectomy, and they do not. Most patients should consult with a radiation oncologist before making a final decision concerning local therapy. However, a multimodality clinic in which the surgeon, radiation oncologist, medical oncologist, and other caregivers cooperate to evaluate the patient and develop a treatment plan is usually considered a major advantage by patients. Adjuvant Therapy
The use of systemic therapy after local management of breast cancer substantially improves survival. More than half of the women who would otherwise die of metastatic breast cancer remain disease-free when treated with the appropriate systemic regimen. These data have grown more and more impressive with longer follow-up and more effective regimens. PROGNOSTIC VARIABLES
The most important prognostic variables are provided by tumor staging. The size of the tumor and the status of the axillary lymph nodes provide reasonably accurate information on the likelihood of tumor relapse. The relation of pathologic stage to 5-year survival is shown in Table 108-2. For most women, the need for adjuvant therapy can be readily defined on this basis alone. In the absence of lymph node involvement, involvement of microvessels (either capillaries or lymphatic channels) in tumors is nearly equivalent to lymph node involvement. The greatest controversy concerns women with intermediate prognoses. There is rarely justification for adjuvant chemotherapy in most women with tumors <1 cm in size whose axillary lymph nodes are negative. HER2-positive tumors are a potential exception. Detection of breast cancer cells either in the circulation or bone marrow is associated with an increased relapse rate. The most exciting development in this area is the use of gene expression arrays to analyze patterns of tumor gene expression. Several groups have independently defined gene sets that reliably predict disease-free and overall survival far more accurately than any single prognostic variable including the Oncotype DX¯ analysis of 21 genes. Also, the use of such standardized risk assessment tools such as Adjuvant! Online (www.adjuvantonline.com) is very helpful. These tools are highly recommended in otherwise ambiguous circumstances.
Estrogen receptor status and progesterone receptor status are of prognostic significance. Tumors that lack either or both of these receptors are more likely to recur than tumors that have them.
Several measures of tumor growth rate correlate with early relapse. S-phase analysis using flow cytometry is the most accurate measure. Indirect S-phase assessments using antigens associated with the cell cycle, such as PCNA (Ki67), are also valuable. Tumors with a high proportion (more than the median) of cells in S-phase pose a greater risk of relapse; chemotherapy offers the greatest survival benefit for these tumors. Assessment of DNA content in the form of ploidy is of modest value, with nondiploid tumors having a somewhat worse prognosis.
Histologic classification of the tumor has also been used as a prognostic factor. Tumors with a poor nuclear grade have a higher risk of recurrence than tumors with a good nuclear grade. Semiquantitative measures such as the Elston score improve the reproducibility of this measurement.
Molecular changes in the tumor are also useful. Tumors that overexpress erbB2 (HER2/neu) or have a mutated p53 gene have a worse prognosis. Particular interest has centered on erbB2 overexpression as measured by immunohistochemistry or fluorescence in situ hybridization. Tumors that overexpress erbB2 are more likely to respond to doxorubicin-containing regimens; erbB2 overexpression also predicts those tumors that will respond to HER2/neu antibodies (trastuzumab) (Herceptin) and HER2/neu kinase inhibitors.
Other variables that have also been used to evaluate prognosis include proteins associated with invasiveness, such as type IV collagenase, cathepsin D, plasminogen activator, plasminogen activator receptor, and the metastasis-suppressor gene nm23. None of these has been widely accepted as a prognostic variable for therapeutic decision-making. One problem in interpreting these prognostic variables is that most of them have not been examined in a study using a large cohort of patients. ADJUVANT REGIMENS
Adjuvant therapy is the use of systemic therapies in patients whose known disease has received local therapy but who are at risk of relapse. Selection of appropriate adjuvant chemotherapy or hormone therapy is highly controversial in some situations. Meta-analyses have helped to define broad limits for therapy but do not help in choosing optimal regimens or in choosing a regimen for certain subgroups of patients. A summary of recommendations is shown in Table 108-3. In general, premenopausal women for whom any form of adjuvant systemic therapy is indicated should receive multidrug chemotherapy. Antihormone therapy improves survival in premenopausal patients who are estrogen receptor positive and should be added following completion of chemotherapy. Prophylactic surgical or medically induced castration may also be associated with a substantial survival benefit (primarily in estrogen receptor–positive patients) but is not widely used in this country.
Data on postmenopausal women are also controversial. The impact of adjuvant chemotherapy is quantitatively less clear-cut than in premenopausal patients, particularly in estrogen receptor–positive cases, although survival advantages have been shown. The first decision is whether chemotherapy or endocrine therapy should be used. While adjuvant endocrine therapy (aromatase inhibitors and tamoxifen) improves survival regardless of axillary lymph node status, the improvement in survival is modest for patients in whom multiple lymph nodes are involved. For this reason, it has been usual to give chemotherapy to postmenopausal patients who have no medical contraindications and who have more than one positive lymph node; hormone therapy is commonly given subsequently. For postmenopausal women for whom systemic therapy is warranted but who have a more favorable prognosis (based more commonly on analysis such as the Oncotype DX methodology), hormone therapy may be used alone. Large clinical trials have shown superiority for aromatase inhibitors over tamoxifen alone in the adjuvant setting, although tamoxifen appears essentially equivalent in women who are obese and therefore presumably have higher endogenous concentrations of estrogen. Unfortunately the optimal plan is unclear. Tamoxifen for 5 years followed by an aromatase inhibitor, the reverse strategy, or even switching to an aromatase inhibitor after 2–3 years of tamoxifen has been shown to be better than tamoxifen alone. Continuation of tamoxifen for 10 years yields further benefit and is a reasonable decision for women with less favorable prognoses. Unfortunately, multiple studies have revealed very suboptimal adherence to long-term adjuvant endocrine regimens, and every effort should be made to encourage their continuous use. No valid information currently permits selection among the three clinically approved aromatase inhibitors. Concomitant use of bisphosphonates is almost always warranted; however, it is not finally settled as to whether their prophylactic use increases survival in addition to just decreasing recurrences in bone.
Most comparisons of adjuvant chemotherapy regimens show little difference among them, although small advantages for doxorubicin-containing regimens and “dose-dense” regimens are usually seen.
One approach—so-called neoadjuvant chemotherapy—involves the administration of adjuvant therapy before definitive surgery and radiation therapy. Because the objective response rates of patients with breast cancer to systemic therapy in this setting exceed 75%, many patients will be “downstaged” and may become candidates for breast-conserving therapy. However, overall survival has not been improved using this approach as compared with the same drugs given postoperatively. Patients who achieve a pathologic complete remission after neoadjuvant chemotherapy not unexpectedly have a substantially improved survival. The neoadjuvant setting also provides a wonderful opportunity for the evaluation of new agents. For example, a second HER2 targeting antibody, pertuzumab, has been shown to provide additional benefit when combined with trastuzumab in the neoadjuvant setting.
Other adjuvant treatments under investigation include the use of taxanes, such as paclitaxel and docetaxel, and therapy based on alternative kinetic and biologic models. In such approaches, high doses of single agents are used separately in relatively dose-intensive cycling regimens. Node-positive patients treated with doxorubicin-cyclophosphamide for four cycles followed by four cycles of a taxane have a substantial improvement in survival compared with women receiving doxorubicin-cyclophosphamide alone, particularly in women with estrogen receptor–negative tumors. In addition, administration of the same drug combinations at the same dose but at more frequent intervals (every 2 weeks with cytokine support as compared with the standard every 3 weeks) is even more effective. Among the 25% of women whose tumors overexpress HER2/neu, addition of trastuzumab given concurrently with a taxane and then for a year after chemotherapy produces significant improvement in survival. Although longer follow-up will be important, this is now the standard care for most women with HER2/neu-positive breast cancers. Cardiotoxicity, immediate and long-term, remains a concern, and further efforts to exploit non-anthracycline-containing regimens are being pursued. Very-high-dose therapy with stem cell transplantation in the adjuvant setting has not proved superior to standard-dose therapy and should not be routinely used.
A variety of exciting approaches are close to adoption, and the literature needs to be followed attentively. Tyrosine kinase inhibitors such as lapatinib and additional HER2-targeting antibodies such as pertuzumab are very promising. Finally, as described in the next section, a novel class of agents targeting DNA repair—the so-called poly–ADP ribose polymerase (PARP) inhibitors—is likely to have a major effect on breast cancers either caused by BRCA1 or BRCA2 mutations or sharing similar defects in DNA repair in their etiology. SYSTEMIC THERAPY OF METASTATIC DISEASE
About one-third of patients treated for apparently localized breast cancer develop metastatic disease. Although a small number of these patients enjoy long remissions when treated with combinations of systemic and local therapy, most eventually succumb to metastatic disease. The median survival for all patients diagnosed with metastatic breast cancer is less than 3 years. Soft tissue, bony, and visceral (lung and liver) metastases each account for approximately one-third of sites of initial relapses. However, by the time of death, most patients will have bony involvement. Recurrences can appear at any time after primary therapy. A very cruel fact about breast cancer recurrences is that at least half of all breast cancer recurrences occur >5 years after initial therapy. It is now clear that a variety of host factors can influence recurrence rates, including depression and central obesity, and these diseases should be managed as aggressively as possible.
Because the diagnosis of metastatic disease alters the outlook for the patient so drastically, it should rarely be made without a confirmatory biopsy. Every oncologist has seen patients with tuberculosis, gallstones, sarcoidosis, or other nonmalignant diseases misdiagnosed and treated as though they had metastatic breast cancer or even second malignancies such as multiple myeloma thought to be recurrent breast cancer. This is a catastrophic mistake and justifies biopsy for virtually every patient at the time of initial suspicion of metastatic disease. Furthermore, there are well-documented changes in hormone receptor status that can occur and substantially alter treatment decisions.
The choice of therapy requires consideration of local therapy needs, the overall medical condition of the patient, and the hormone receptor status of the tumor, as well as clinical judgment. Because therapy of systemic disease is palliative, the potential toxicities of therapies should be balanced against the response rates. Several variables influence the response to systemic therapy. For example, the presence of estrogen and progesterone receptors is a strong indication for endocrine therapy. On the other hand, patients with short disease-free intervals, rapidly progressive visceral disease, lymphangitic pulmonary disease, or intracranial disease are unlikely to respond to endocrine therapy.
In many cases, systemic therapy can be withheld while the patient is managed with appropriate local therapy. Radiation therapy and occasionally surgery are effective at relieving the symptoms of metastatic disease, particularly when bony sites are involved. Many patients with bone-only or bone-dominant disease have a relatively indolent course. Under such circumstances, systemic chemotherapy has a modest effect, whereas radiation therapy may be effective for long periods. Other systemic treatments, such as strontium-89 and/or bisphosphonates, may provide a palliative benefit without inducing objective responses. Most patients with metastatic disease, and certainly all who have bone involvement, should receive concurrent bisphosphonates. Because the goal of therapy is to maintain well-being for as long as possible, emphasis should be placed on avoiding the most hazardous complications of metastatic disease, including pathologic fracture of the axial skeleton and spinal cord compression. New back pain in patients with cancer should be explored aggressively on an emergent basis; to wait for neurologic symptoms is a potentially catastrophic error. Metastatic involvement of endocrine organs can cause profound dysfunction, including adrenal insufficiency and hypopituitarism. Similarly, obstruction of the biliary tree or other impaired organ function may be better managed with a local therapy than with a systemic approach.
Many patients are inappropriately treated with toxic regimens into their last days of life. Often oncologists are unwilling to have the difficult conversations that are required with patients nearing the end of life, and not uncommonly, patients and families can pressure physicians into treatments with very little survival value. Palliative care consultation and realistic assessment of treatment expectations need to be reviewed with patients and families. We urge consideration of palliative care consultations for patients who have received at least two lines of therapy for metastatic disease. Endocrine Therapy
Normal breast tissue is estrogen dependent. Both primary and metastatic breast cancer may retain this phenotype. The best means of ascertaining whether a breast cancer is hormone dependent is through analysis of estrogen and progesterone receptor levels on the tumor. Tumors that are positive for the estrogen receptor and negative for the progesterone receptor have a response rate of ∼30%. Tumors that are positive for both receptors have a response rate approaching 70%. If neither receptor is present, the objective response rates are <5%. Receptor analyses provide information as to the correct ordering of endocrine therapies as opposed to chemotherapy. Because of their lack of toxicity and because some patients whose receptor analyses are reported as negative respond to endocrine therapy, an endocrine treatment should be attempted in virtually every patient with metastatic breast cancer. Potential endocrine therapies are summarized in Table 108-4. The choice of endocrine therapy is usually determined by toxicity profile and availability. In most postmenopausal patients, the initial endocrine therapy should be an aromatase inhibitor rather than tamoxifen. For the subset of postmenopausal women who are estrogen receptor–positive but also HER2/neu-positive, response rates to aromatase inhibitors are substantially higher than to tamoxifen. Aromatase inhibitors are not used in premenopausal women because their hypothalamus can respond to estrogen deprivation by producing gonadotropins that promote estrogen synthesis. Newer “pure” antiestrogens that are free of agonistic effects are also effective. Cases in which tumors shrink in response to tamoxifen withdrawal (as well as withdrawal of pharmacologic doses of estrogens) have been reported. A series of studies with aromatase inhibitors, tamoxifen, and fulvestrant have all shown that the addition of everolimus to the hormonal treatment can lead to significant benefit after progression on the endocrine agent alone. Everolimus (an mTOR inhibitor) in coordination with endocrine agents is now being explored as front-line therapy and in the adjuvant setting. Endogenous estrogen formation may be blocked by analogues of luteinizing hormone–releasing hormone in premenopausal women. Additive endocrine therapies, including treatment with progestogens, estrogens, and androgens, may also be tried in patients who respond to initial endocrine therapy; the mechanism of action of these latter therapies is unknown. Patients who respond to one endocrine therapy have at least a 50% chance of responding to a second endocrine therapy. It is not uncommon for patients to respond to two or three sequential endocrine therapies; however, combination endocrine therapies do not appear to be superior to individual agents, and combinations of chemotherapy with endocrine therapy are not useful. The median survival of patients with metastatic disease is approximately 2 years, although many patients, particularly older persons and those with hormone-dependent disease, may respond to endocrine therapy for 3–5 years or longer. Chemotherapy
Unlike many other epithelial malignancies, breast cancer responds to multiple chemotherapeutic agents, including anthracyclines, alkylating agents, taxanes, and antimetabolites. Multiple combinations of these agents have been found to improve response rates somewhat, but they have had little effect on duration of response or survival. The choice among multidrug combinations frequently depends on whether adjuvant chemotherapy was administered and, if so, what type. Although patients treated with adjuvant regimens such as cyclophosphamide, methotrexate, and fluorouracil (CMF regimens) may subsequently respond to the same combination in the metastatic disease setting, most oncologists use drugs to which the patients have not been previously exposed. Once patients have progressed after combination drug therapy, it is most common to treat them with single agents. Given the significant toxicity of most drugs, the use of a single effective agent will minimize toxicity by sparing the patient exposure to drugs that would be of little value. No method to select the drugs most efficacious for a given patient has been demonstrated to be useful.
Most oncologists use either an anthracycline or paclitaxel following failure with the initial regimen. However, the choice has to be balanced with individual needs. One randomized study has suggested that docetaxel may be superior to paclitaxel. A nanoparticle formulation of paclitaxel (Abraxane) is also effective.
The use of a humanized antibody to erbB2 (trastuzumab [Herceptin]) combined with paclitaxel can improve response rate and survival for women whose metastatic tumors overexpress erbB2. A novel antibody conjugate (ADC) that links trastuzumab to a cytotoxic agent has been approved for management of HER2-positive breast cancer. The magnitude of the survival extension is modest in patients with metastatic disease. Similarly, the use of bevacizumab (Avastin) has improved the response rate and response duration to paclitaxel. Objective responses in previously treated patients may also be seen with gemcitabine, vinca alkaloids, capecitabine, vinorelbine, and oral etoposide, as well as a new class of agents, epothilones. There are few comparative trials of one agent versus another in metastatic disease. It is a sad fact that choices are often influenced by aggressive marketing of new very expensive agents that have not been shown to be superior to other generic agents. Platinum-based agents have become far more widely used in both the adjuvant and advanced disease settings for some breast cancers, particularly those of the “triple-negative” subtype. HIGH-DOSE CHEMOTHERAPY INCLUDING AUTOLOGOUS BONE MARROW TRANSPLANTATION
Autologous bone marrow transplantation combined with high doses of single agents can produce objective responses even in heavily pretreated patients. However, such responses are rarely durable and do not alter the clinical course for most patients with advanced metastatic disease. STAGE III BREAST CANCER
Between 10 and 25% of patients present with so-called locally advanced, or stage III, breast cancer at diagnosis. Many of these cancers are technically operable, whereas others, particularly cancers with chest wall involvement, inflammatory breast cancers, or cancers with large matted axillary lymph nodes, cannot be managed with surgery initially. Although no randomized trials have shown any survival benefit for neoadjuvant regimens as compared to adjuvant therapy, this approach has gained widespread use. More than 90% of patients with locally advanced breast cancer show a partial or better response to multidrug chemotherapy regimens that include an anthracycline. Early administration of this treatment reduces the bulk of the disease and frequently makes the patient a suitable candidate for salvage surgery and/or radiation therapy. These patients should be managed in multimodality clinics to coordinate surgery, radiation therapy, and systemic chemotherapy. Such approaches produce long-term disease-free survival in about 30–50% of patients. The neoadjuvant setting is also an ideal time to evaluate the efficacy of novel treatments because the effect on the tumor can be directly assessed. BREAST CANCER PREVENTION
Women who have one breast cancer are at risk of developing a contralateral breast cancer at a rate of approximately 0.5% per year. When adjuvant tamoxifen or an aromatase inhibitor is administered to these patients, the rate of development of contralateral breast cancers is reduced. In other tissues of the body, tamoxifen has estrogen-like effects that are beneficial, including preservation of bone mineral density and long-term lowering of cholesterol. However, tamoxifen has estrogen-like effects on the uterus, leading to an increased risk of uterine cancer (0.75% incidence after 5 years on tamoxifen). Tamoxifen also increases the risk of cataract formation. The Breast Cancer Prevention Trial (BCPT) revealed a >49% reduction in breast cancer among women with a risk of at least 1.66% taking the drug for 5 years. Raloxifene has shown similar breast cancer prevention potency but may have different effects on bone and heart. The two agents have been compared in a prospective randomized prevention trial (the Study of Tamoxifen and Raloxifene [STAR] trial). The agents are approximately equivalent in preventing breast cancer with fewer thromboembolic events and endometrial cancers with raloxifene; however, raloxifene did not reduce noninvasive cancers as effectively as tamoxifen, so no clear winner has emerged. A newer selective estrogen receptor modulator (SERM), lasofoxifene, has been shown to reduce cardiovascular events in addition to breast cancer and fractures, and further studies of this agent should be watched with interest. It should be recalled that prevention of contralateral breast cancers in women diagnosed with one cancer is a reasonable surrogate for breast cancer prevention because these are second primaries not recurrences. In this regard, the aromatase inhibitors are all considerably more effective than tamoxifen; however, they are not approved for primary breast cancer prevention. It remains puzzling that agents with the safety profile of raloxifene, which can reduce breast cancer risk by 50% with additional benefits in preventing osteoporotic fracture, are still so infrequently prescribed. They should be far more commonly offered to women than they are. NONINVASIVE BREAST CANCER
Breast cancer develops as a series of molecular changes in the epithelial cells that lead to ever more malignant behavior. Increased use of mammography has led to more frequent diagnoses of noninvasive breast cancer. These lesions fall into two groups: ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (lobular neoplasia). The management of both entities is controversial. Ductal Carcinoma In Situ
Proliferation of cytologically malignant breast epithelial cells within the ducts is termed DCIS. Atypical hyperplasia may be difficult to differentiate from DCIS. At least one-third of patients with untreated DCIS develop invasive breast cancer within 5 years. However, many low-grade DCIS lesions do not appear to progress over many years; therefore, many patients are overtreated. Unfortunately there is no reliable means of distinguishing patients who require treatment from those who may be safely observed. For many years, the standard treatment for this disease was mastectomy. However, treatment of this condition by lumpectomy and radiation therapy gives survival that is as good as the survival for invasive breast cancer treated by mastectomy. In one randomized trial, the combination of wide excision plus irradiation for DCIS caused a substantial reduction in the local recurrence rate as compared with wide excision alone with negative margins, although survival was identical in the two arms. No studies have compared either of these regimens to mastectomy. Addition of tamoxifen to any DCIS surgical/radiation therapy regimen further improves local control. Data for aromatase inhibitors in this setting are not available.
Several prognostic features may help to identify patients at high risk for local recurrence after either lumpectomy alone or lumpectomy with radiation therapy. These include extensive disease; age <40; and cytologic features such as necrosis, poor nuclear grade, and comedo subtype with overexpression of erbB2. Some data suggest that adequate excision with careful determination of pathologically clear margins is associated with a low recurrence rate. When surgery is combined with radiation therapy, recurrence (which is usually in the same quadrant) occurs with a frequency of ≤10%. Given the fact that half of these recurrences will be invasive, about 5% of the initial cohort will eventually develop invasive breast cancer. A reasonable expectation of mortality for these patients is about 1%, a figure that approximates the mortality rate for DCIS managed by mastectomy. Although this train of reasoning has not formally been proved valid, it is reasonable to recommend that patients who desire breast preservation, and in whom DCIS appears to be reasonably localized, be managed by adequate surgery with meticulous pathologic evaluation, followed by breast irradiation and tamoxifen. For patients with localized DCIS, axillary lymph node dissection is unnecessary. More controversial is the question of what management is optimal when there is any degree of invasion. Because of a significant likelihood (10–15%) of axillary lymph node involvement even when the primary lesion shows only microscopic invasion, it is prudent to do at least a sentinel lymph node sampling for all patients with any degree of invasion. Further management is dictated by the presence of nodal spread. Lobular Neoplasia
Proliferation of cytologically malignant cells within the lobules is termed lobular neoplasia. Nearly 30% of patients who have had adequate local excision of the lesion develop breast cancer (usually infiltrating ductal carcinoma) over the next 15–20 years. Ipsilateral and contralateral cancers are equally common. Therefore, lobular neoplasia may be a premalignant lesion that suggests an elevated risk of subsequent breast cancer, rather than a form of malignancy itself, and aggressive local management seems unreasonable. Most patients should be treated with an SERM or an aromatase inhibitor (for postmenopausal women) for 5 years and followed with careful annual mammography and semiannual physical examinations. Additional molecular analysis of these lesions may make it possible to discriminate between patients who are at risk of further progression and require additional therapy and those in whom simple follow-up is adequate. MALE BREAST CANCER
Breast cancer is about 1/150th as frequent in men as in women; 1720 men developed breast cancer in 2006. It usually presents as a unilateral lump in the breast and is frequently not diagnosed promptly. Given the small amount of soft tissue and the unexpected nature of the problem, locally advanced presentations are somewhat more common. When male breast cancer is matched to female breast cancer by age and stage, its overall prognosis is identical. Although gynecomastia may initially be unilateral or asymmetric, any unilateral mass in a man older than age 40 years should receive a careful workup including biopsy. On the other hand, bilateral symmetric breast development rarely represents breast cancer and is almost invariably due to endocrine disease or a drug effect. It should be kept in mind, nevertheless, that the risk of cancer is much greater in men with gynecomastia; in such men, gross asymmetry of the breasts should arouse suspicion of cancer. Male breast cancer is best managed by mastectomy and axillary lymph node dissection or SLNB. Patients with locally advanced disease or positive nodes should also be treated with irradiation. Approximately 90% of male breast cancers contain estrogen receptors, and approximately 60% of cases with metastatic disease respond to endocrine therapy. No randomized studies have evaluated adjuvant therapy for male breast cancer. Two historic experiences suggest that the disease responds well to adjuvant systemic therapy, and, if not medically contraindicated, the same criteria for the use of adjuvant therapy in women should be applied to men.
The sites of relapse and spectrum of response to chemotherapeutic drugs are virtually identical for breast cancers in either sex. FOLLOW-UP OF BREAST CANCER PATIENTS
Despite the availability of sophisticated and expensive imaging techniques and a wide range of serum tumor marker tests, survival is not influenced by early diagnosis of relapse. Surveillance guidelines are given in Table 108-5. Despite pressure from patients and their families, routine computed tomography scans (or other imaging) are not recommended.