Locally advanced breast cancer was once considered a fatal disease. Prior to the routine use of chemotherapy, the vast majority of patients developed distant metastases and died.²^–⁴ In the past, locoregional treatments (i.e., mastectomy alone, radiation therapy alone, or combined surgery and radiation therapy) were attempted to prevent uncontrolled locoregional disease progression. With such strategies, the outcome of patients was poor.²^–⁴ Fortunately, the current outlook for patients with locally advanced breast cancer is much more optimistic. Although distant metastases remain a persistent problem, long-term DFS have significantly improved with systemic treatments.⁵ This improvement in metastatic disease control has also heightened the importance of achieving locoregional control. Arguably, the success of chemotherapy in eradicating micrometastatic disease has allowed the advances achieved in surgery and radiation therapy to also contribute to improved patient survival rates.

It is important to recognize that the term “locally advanced breast cancer” represents a heterogeneous category of biologically diverse diseases. The term itself most commonly refers to patients with stage III breast cancer, but this definition is not universally accepted. In addition to the ambiguity associated with the term “locally advanced breast cancer,” the disease within this category is itself heterogeneous. At the biologically most-aggressive-disease end of the spectrum, stage III breast cancer includes aggressive and rapidly proliferating inflammatory breast cancer. At the less-aggressive-disease end of the spectrum, stage III breast cancer can also represent estrogen receptor-positive indolent disease that has over many years grown to a considerable size but failed to metastasize. These diverse disease characteristics should be considered when making treatment decisions and predicting outcomes.

Epidemiology

The incidence of locally advanced breast cancer is decreasing in the United States, despite the fact that the overall incidence of breast cancer has remained relatively stable. In the most recent estimates of cancer staging provided by the American Cancer Society, the percentage of patients with lymph node involvement at the time of original diagnosis has decreased at a rate of 2.8% per year since 2001. Tumors have also become smaller over time. The incidence rates of tumors 3 cm or larger decreased 27% between 1980 and 1987, and between 1997 and 2000. they continued to decline 1.9% annually.^6,⁷ In the year 2000, it was estimated that only 6% of breast cancers were larger than 5 cm at the time of diagnosis. Given this trend, it is reasonable to estimate that 12,000 patients will be diagnosed with T3 or T4 breast cancer in the coming year. The use of mammography screening has decreased during the last decade, however, and, accordingly, the most recent data have shown a slight increase in the percentage of tumors over 5 cm.⁸ Still, stage III breast cancer represents a small percentage of the total breast cancers diagnosed in the Unites States each year. In developing countries and in countries with a lack of screening programs and public education about the disease, the percentage of patients diagnosed with stage III disease is much higher.

There are still subgroups of patients in the United States for whom locally advanced breast cancer remains an epidemiologic problem. For example, black women are more often diagnosed with locally advanced disease than white women.^6,⁷ This finding was first noted during the 1980s and continues to be true today. There are many possible reasons for the higher incidence of locally advanced breast cancer in blacks, including decreased access to medical care, less use of screening mammography, and biologic differences in the cancer. Specifically, breast cancers in black women tend to be of higher grade and more often lack estrogen receptors compared with those in white women.^9,¹⁰

Biologic Characteristics And Molecular Biology

Locally advanced breast cancer can result either from rapid disease growth with early spread to the lymphatics or from a delay in diagnosis. A thorough patient history and physical examination combined with an assessment of the tumor’s biologic features can help to distinguish these two categories. Typically, rapid disease growth occurs in the setting of high-grade tumors that have high proliferative indices, high rates of estrogen receptor-negative disease, and higher rates of HER2/neu overexpression (basal or HER2 phenotypes; see Part G, Breast Cancer Overview). These tumors may develop during the interval between screening mammograms. In contrast, a high percentage of locally advanced breast cancers are of low or intermediate grade and are hormone receptor-positive (luminal phenotypes; see Part G, Breast Cancer Overview). Oftentimes, such patients have not undergone screening and may present months after first appreciating a breast abnormality.

Inflammatory breast cancer, a subcategory of locally advanced disease, has unique clinical presentations and biologic traits. The diagnosis of inflammatory carcinoma is made on the basis of the clinical history and physical examination findings. The clinical history of a patient with inflammatory breast cancer should include a description of breast erythema, warmth, and heaviness of relatively rapid onset and progression (typically progressing over a period of ≤3 months). On physical examination, brawny edema of the breast is present, which may or may not be associated with a breast mass. Inflammatory breast cancers should be differentiated from neglected breast primary tumors that slowly progress over many months to up to a year. Neglected locally advanced cancers always are associated with a large breast mass or advanced adenopathy that has caused secondary inflammatory changes in the breast that mimic those of inflammatory breast cancer.

Histopathologic findings of inflammatory breast cancer are most commonly characterized by a high histologic grade, a high percentage of cells in the S phase, aneuploidy, absent estrogen receptor expression, and high expression of TP53 and epidermal growth factor.¹¹ Some authors have found that HER2/neu is not more commonly overexpressed in inflammatory breast cancer than in noninflammatory advanced disease,^11,¹² although more recent studies have reported higher rates of HER2/neu overexpression.¹³ The potential higher rate of both HER2/neu and epidermal growth factor receptor (EGFR) has permitted new opportunities for clinical trials investigating the targeting of these tyrosine kinase receptors.

Recent work has also suggested that many of these tumors overexpress RHOC guanosine triphosphatase (GTPase) and have loss of expression of the WIPS3 tumor suppressor gene. If confirmed and validated, these markers may prove to be useful for diagnosis and may be future therapeutic targets.14,15 Another biomarker with a unique expression pattern in inflammatory breast cancer is E-cadherin. E-cadherin is thought to play an important role in cellular adhesion and has been noted to be overexpressed in a high percentage of cases of inflammatory breast cancer and may contribute to the tumor emboli formation within the dermal lymphatic channels.^16,¹⁷

One of the pathologic hallmarks of inflammatory breast cancer is invasion into the dermal lymphatics and erythema of the skin, which may in part be representative of tumor angiogenesis. Shirakawa and colleagues ¹⁸ found inflammatory breast cancer xenografts to have a particular pattern of neovascular growth in which blood vessels within cancer tissue did not have a lining of endothelial cells. In addition, human inflammatory breast cancer specimens have been noted to have a higher microvessel density pattern compared with noninflammatory breast cancer.^16,19 These data suggest that the angiogenesis pathway may be a therapeutic target for treatments in inflammatory breast cancer.

Pathology And Pathways Of Spread

As in early-stage disease, most locally advanced breast cancers are infiltrating ductal carcinomas, although because of the greater difficulty in detecting lobular cancers with mammography, this histologic type can also present as locally advanced disease. It is unusual for locally advanced disease to have favorable breast cancer histologic findings such as tubular, medullary, and mucinous characteristics, unless a patient neglects a slowly growing primary tumor.

The pathways of spread of locally advanced breast cancer are most commonly through the regional lymphatics. Involvement of the axillary level I to II nodes is common in patients presenting with a T3 or T4 primary tumor. In addition, such patients are at risk for disease in the level III axillary, supraclavicular, and internal mammary lymph nodes. Figure 62-1 shows an axial CT image of a patient with a locally advanced breast cancer that has involved the internal mammary and axillary lymph nodes. Patients with locally advanced disease are also at risk of hematogenous spread, most commonly to the lung, liver, bone, and brain.

Figure 62-1 Axial chest CT image of a patient with locally advanced cancer of the left breast that involves multiple low axillary lymph nodes as well as lymph nodes in the internal mammary chain (highlighted by arrows).

Clinical Manifestations, Patient Evaluations, And Staging

Patients with locally advanced breast cancer commonly present after detecting a breast mass on self-examination. Not infrequently, there is a significant interval from the period of first noticing the breast abnormality to the time of presentation for medical care. During this interval, the breast mass usually increases in size. After a long delay before seeking treatment, patients can present with a bleeding or ulcerative mass that occupies most of the breast. Over time, some breast cancers can cause involution of the breast, giving the appearance of an autoamputation.

In most cases, regional adenopathy is evident at the time of diagnosis of T3 or T4 primary breast cancers. Pain, limited range of motion, edema, and weakness or numbness of the arm is possible in patients with advanced axillary and supraclavicular adenopathy.

Patients with inflammatory breast cancers most frequently describe a rapid onset of breast erythema and increasing breast size and/or heaviness. Often, these changes progress over days or weeks and are frequently initially misdiagnosed as breast cellulitis. Figure 62-2 shows a photograph of the presenting appearance of the breast in a patient with inflammatory breast cancer. The history of presenting signs and symptoms is the critical determinant in classifying a breast cancer as inflammatory.

Figure 62-2 Photograph of a patient who presented with T4d inflammatory breast cancer of the left breast. The breast has central erythema and edema in the nipple-areola region.

All patients presenting with locally advanced disease require a comprehensive initial history and physical examination. As mentioned, during the history, it is critical to establish the time course of presenting signs and symptoms because these elements are necessary to distinguish inflammatory breast cancer from other T4 tumors. In addition to breast symptoms, the history should include questions concerning changes in general health and questions specifically relating to symptoms possibly due to metastases (e.g., bone pain and change in neurologic status).

The initial physical examination is of critical importance in patients with locally advanced breast cancer. Unlike patients with early-stage disease, the majority of patients with T3 or T4 tumors are treated with neoadjuvant chemotherapy. This treatment significantly shrinks the tumor in most patients, and careful documentation of the pretreatment extent of disease is very important for determination of subsequent locoregional therapies. The breast examination should document breast asymmetry, mass size and whether the mass is freely mobile, skin erythema or edema, and skin or nipple retraction. Mobility of the primary mass should be tested with the pectoralis major muscle contracted and relaxed to distinguish chest wall invasion from invasion into the pectoralis muscle. Skin edema is best assessed with the patient in the supine position. Edema of the skin causes thickening, which makes the hair follicle more prominent, resulting in the classic “peau d’orange” appearance. This can best be appreciated by gently pinching the affected skin between the thumb and first finger. Figure 62-3 shows a patient who presented with T4 primary disease and was found to have peau d’orange dimpling on initial examination. The axilla and supraclavicular fossa should be examined with the patient upright, and regional adenopathy should be described and include the size, consistency, and mobility of axillary, infraclavicular, and supraclavicular lymph nodes. The internal mammary lymph nodes are infrequently palpable, even when involved with disease. Despite this, the parasternal area should be examined for asymmetric prominence with the patient supine.

Figure 62-3 Photograph of a patient with a T4 breast cancer who presented with the classic “peau d’orange” condition due to edema of the skin.

After completion of an examination, the primary tumor and nodal basin should be assigned a clinical T and N stage. The American Joint Commission 2009 clinical and pathologic staging system is provided in Part G, Breast Cancer Overview.

All patients with advanced disease should be staged using bilateral diagnostic mammography, basic serum chemistry tests and blood counts, a chest radiograph, a computed tomography (CT) scan of the upper abdomen, and a bone scan. Patients with T4 disease should have pretreatment photographs taken of the sites of dermal involvement. In addition, at the author’s institution we routinely use ultrasonography to assess the extent of disease in the regional lymph nodes. This is particularly useful in patients treated with neoadjuvant chemotherapy. Ultrasonography can frequently detect unsuspected regional disease in the infraclavicular and supraclavicular fossae. Involved lymph nodes can appear to be enlarged or have abnormal hilar architecture on ultrasonography. We routinely perform fine-needle aspiration to assess the presence of disease in lymphatic locations in which it was not detected by clinical examination.

The use of magnetic resonance imaging (MRI) and positron emission tomography (PET) continues to be investigated, and these techniques are not currently considered to be the standard of care. As refinements of these modalities improve their positive predictive value, however, they will likely play important roles in the staging evaluation. Preliminary data from our institution suggest that both PET/CT and breast MRI techniques provide additional clinically useful staging information for patients with inflammatory breast cancer.²⁰ Finally, serum tumor markers such as carcinoembryonic antigen (CEA), CA 15.3, and CA 27-29 are used by some practitioners but are currently not recommended as the standard of care.²¹

Treatment Overview

Patients with stage III disease are optimally treated with a combined-modality approach. The incorporation of systemic treatments into the management of locally advanced disease, along with improvements in surgical and radiation therapies, has significantly improved the outcomes of patients with advanced disease. For example, early studies in which patients with advanced disease were treated with mastectomy and/or radiation therapy reported 5-year survival rates of only 25% to 45%.²^–⁴ In contrast, more recent data have shown that patients with advanced-stage disease, when treated with a combination of surgery, radiation therapy, and chemotherapy, have 5-year survival rates approaching 80% for stage IIIA disease and 45% for stage IIIB disease.⁵

Combined-modality treatments are best administered with input from a coordinated multidisciplinary team of surgeons, medical oncologists, and radiation oncologists. For patients with advanced operable breast cancer, mastectomy followed by adjuvant chemotherapy and radiation therapy is an appropriate therapeutic approach. It is equally appropriate to use chemotherapy as the first therapeutic intervention (called neoadjuvant chemotherapy). For patients who are not optimal surgical candidates at the time of diagnosis because of T4 primary tumors or advanced lymph node disease, neoadjuvant chemotherapy is the standard of care.

Treating patients with advanced primary tumors with chemotherapy prior to surgery has several potential advantages. One advantage is that it gives selected patients with T3 or T4 tumors the option of being treated with breast-preservation surgery. Indeed, numerous studies have indicated that neoadjuvant chemotherapy achieves a substantial reduction in the size of the primary tumor and nodal metastases in more than 80% of cases, which often permits a breast-conserving operation that achieves an acceptable aesthetic outcome.²²^–²⁵ A second advantage is that neoadjuvant chemotherapy allows physicians to assess the primary tumor’s response to a particular chemotherapy regimen. For the minority of patients whose disease does not respond or even progresses, this assessment allows for the change to a different regimen so that the most effective chemotherapy can be given as early as possible and unnecessary toxicity from an ineffective therapy can be avoided. A final advantage of neoadjuvant chemotherapy is that its use permits clinical trials that test new systemic treatments to be conducted and reported in a much more expeditious fashion.

Data from multiple clinical trials indicate that pathologic complete remission (pCR) (i.e., no residual cancer is found in the breast or lymph nodes after neoadjuvant chemotherapy) is associated with an excellent long-term prognosis.22,26 Data from our institution show a 5-year survival rate of 89% for patients with relatively advanced breast cancer in whom a pCR was achieved, versus 64% for patients in whom a pCR was not achieved (p <.01).²⁶ Because higher pCR rates correlate with excellent long-term survival rates, phase III clinical trials have been designed using pCR as the primary endpoint.

One desired advantage of neoadjuvant chemotherapy that has not been realized is the hope that earlier administration of chemotherapy would increase the probability of eradicating preexisting micrometastatic disease. Unfortunately, the two largest trials that compared neoadjuvant and adjuvant chemotherapy found that sequencing chemotherapy before surgery provided no overall survival advantage. Specifically, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 randomized 1523 patients with early-stage, operable breast cancer to receive four cycles of doxorubicin/cyclophosphamide (AC) either before or after surgical treatment. After a long follow-up, the overall survival (OS) and disease-free survival (DFS) rates were nearly identical between the two groups.²⁷ Interestingly, there appeared to be an advantage for neoadjuvant chemotherapy for younger patients and an advantage for adjuvant chemotherapy in older patients. A second large, randomized, prospective trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) also demonstrated equivalent rates of survival and distant metastases between preoperative and postoperative chemotherapy with four cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC).^24,28

The increasing use of neoadjuvant chemotherapy has raised many questions concerning the surgical and radiotherapeutic management of patients with locally advanced breast cancer. Accordingly, it is best to have surgeons, radiation oncologists, and medical oncologists participate in decisions regarding treatment sequencing and provide the necessary multidisciplinary coordination to address the added complexity that neoadjuvant chemotherapy brings to the treatment of patients with locally advanced breast cancer.

Locoregional Treatment Of Patients With Advanced Primary Disease

Breast Conservation after Neoadjuvant Chemotherapy

Historically, all patients with advanced primary breast cancers underwent mastectomy and postmastectomy radiation therapy as the preferred locoregional treatment. However, the high response rates associated with neoadjuvant chemotherapy have allowed for breast conservation in selected patients with advanced disease. The NSABP and EORTC trials comparing neoadjuvant chemotherapy with adjuvant chemotherapy in patients with stage II or III breast cancer found that breast-conservation rates were higher in the neoadjuvant chemotherapy arms.^22,²⁴ This increase was directly due to a greater percentage of patients with T3 disease being offered breast conservation after first responding to chemotherapy. One concern over using chemotherapy before breast-conserving surgery is that many advanced breast cancers do not shrink concentrically to a solitary nidus in response to neoadjuvant chemotherapy. In such cases, surgery directed at the primary core may leave a high burden of microscopic disease around the tumor bed site, which may be associated with higher rates of breast cancer recurrence.

Some clinical data indeed indicate that patients with advanced tumors who have been treated with breast-conservation surgery after neoadjuvant chemotherapy have higher rates of breast cancer recurrence. For example, in the NSABP B-18 trial, the local cancer recurrence rate in patients with large primary tumors in whom a response to neoadjuvant chemotherapy allowed breast-conservation surgery was twice that in patients with smaller tumors who were treated with surgery first (15.7% vs. 7.6%, respectively).²² Other series have also shown relatively high breast cancer recurrence rates in patients who receive neoadjuvant chemotherapy.^29,³⁰ From these data, it is clear that breast-conservation procedures after neoadjuvant chemotherapy are more complex, that multidisciplinary coordination is important, and that proper patient selection for breast-conservation procedures is critical.

With appropriate patient selection and multidisciplinary management, the outcome of breast conservation for selected patients with locally advanced breast cancer can be excellent.³¹ Investigators from the M.D. Anderson Cancer Center reported on 340 carefully selected patients who were treated with breast-conserving therapy after showing a favorable response to chemotherapy. Patient selection criteria for a breast-conserving approach included no postoperative residual malignant calcifications, no residual T4 breast skin abnormalities, negative surgical margins, no multicentric disease, and a willingness and ability to undergo both surgery and radiation therapy. With such criteria, the outcome was favorable, with 5- and 10-year local recurrence rates of 5% and 10%, respectively, despite the fact that 72% of patients in the study had clinical stage IIB or III disease.

Chen and associates ³¹ identified the following four factors associated with breast cancer recurrence and locoregional recurrence: (1) clinical N2 or N3 disease, (2) lymphovascular space invasion, (3) a multifocal pattern of residual disease (defined as noncontiguous foci of disease interspersed among areas of fibrosis or necrosis, granulomas, and giant cells within the resected specimen), and (4) residual disease larger than 2 cm in diameter. Eighty-four percent of patients had either just one of these factors or none of the factors, and this group had only a 4% breast cancer recurrence rate at 10 years.³² In contrast, the 4% of patients with three of these factors had a 45% breast cancer recurrence rate. Having a T3 or T4 tumor did not correlate with breast cancer recurrence in most cases in which the primary tumor shrank to become a solitary nidus or no residual disease was found in the breast after chemotherapy. The breast cancer recurrence rate was 20% in patients with T3 or T4 tumors that broke up and left a multifocal pattern of residual disease, however.³¹ Improvements in breast imagining, such as the use of MRI, may prove to be of value in detecting this pattern of residual disease prior to a surgical intervention.³³

Patients with stage III breast cancer are at risk for locoregional recurrence even when mastectomy is performed. In addition, patients with advanced disease are at significant risk for distant metastases, which is another incentive to avoid removing the entire breast when breast-conserving surgery can be done with acceptable recurrence rates.

Mastectomy and Postmastectomy Radiation Therapy

A modified radical mastectomy (resection of the breast with level I to II axillary lymph node dissection) remains the most common surgical treatment for patients with locally advanced breast cancer. This treatment is highly effective in achieving excellent rates of long-term locoregional control for many patients with early-stage invasive breast cancer, but patients with locally advanced disease have a high risk of locoregional recurrence after treatment with mastectomy and systemic treatments without irradiation. Postmastectomy radiation therapy benefits this cohort of patients and is effective in reducing locoregional recurrence. Most recent data suggest that by eradicating residual locoregional disease after mastectomy, adjuvant irradiation also improves OS.

Although postmastectomy irradiation has been evaluated in more than 25 trials conducted over 40 years, some significant controversies over its use remain. Historically, it was questioned whether the benefits of postmastectomy irradiation were offset by its associated toxicity. Specifically, in 1987, Cusik and colleagues ³⁴ published the first meta-analysis of data from postmastectomy radiation therapy trials and reported that radiation use was associated with a poorer OS. In a subsequent analysis, Cusik and associates³⁵ reported that postmastectomy radiation therapy decreased the breast cancer death rate but increased the death rate from causes other than breast cancer, a finding that resulted in equivalent OS between the two groups.

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has performed a more recent and comprehensive meta-analysis of trials investigating postmastectomy radiation therapy.³⁶ The 2005 publication of this meta-analysis included data from 9933 patients treated in clinical trials with mastectomy and axillary clearance with or without postmastectomy irradiation. The results of this study clearly demonstrated that postmastectomy radiation therapy reduced the isolated locoregional recurrence rate for patients with lymph node—positive disease treated with mastectomy. Specifically, postmastectomy radiation therapy decreased the 15-year isolated locoregional recurrence rate for patients with lymph node–positive disease from 29% to 8%.³⁶ The more revolutionary finding was that this significant absolute improvement in locoregional control reduced the 15-year breast cancer mortality rate from 60% (no irradiation) to 55% (irradiation). This finding was particularly important in that previous meta-analyses suggested that the benefit of adjuvant irradiation was limited to locoregional control.

The benefits of adjuvant irradiation for patients with locally advanced disease may be greater than those reported in meta-analyses. Many of the trials begun before the 1980s included patients at low risk for locoregional recurrence, and many used unconventional radiation doses, fractionation patterns, and radiation field designs. To minimize these confounding effects, Van de Steene and colleagues ³⁷ conducted a similar meta-analysis but excluded trials that began before 1970, trials with small sample sizes, trials with relatively poor survival rates, and trials that used radiation fractionation schedules that are no longer standard practice. When these less-than-optimal studies were excluded, postmastectomy radiation therapy significantly improved OS, with an odds reduction for death of 12.4%. In addition, Whelan and colleagues³⁸ performed a meta-analysis of the published postmastectomy irradiation trials that included systemic therapy in both treatment arms. In this analysis, the addition of irradiation after mastectomy was also shown to reduce the risk of any recurrence (odds ratio, 0.69) and mortality (odds ratio, 0.83).³⁸

The most recent phase III randomized trials investigating postmastectomy radiation therapy were initiated almost three decades ago but remain relevant in that they used more modern radiation treatment techniques and dose fractionation and included some form of systemic therapy for all patients. Table 62-1 displays the results from these trials. The Danish Breast Cancer Cooperative Group (DBCCG) 82b trial randomized 1708 premenopausal women with stage II or III breast cancer to receive mastectomy followed by nine cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy or mastectomy, radiation therapy, and eight cycles of CMF chemotherapy.³⁹

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