Thomas A. Buchholz, David E. Wazer, and Bruce G. Haffty
Patients who present with locally advanced breast cancer require care from a multidisciplinary team that incorporates diagnostic imaging, chemotherapy, surgery, and careful pathology assessment, including molecular-based studies, radiation, and, if indicated, biologic and hormonal therapies. The treatment outcome for an individual patient may depend on the degree to which this multidisciplinary approach is integrated and the expertise of the treatment team. The input and coordination from each multidisciplinary discipline is especially important in the management of patients with locally advanced disease because such patients have the highest risk of disease recurrence without optimal treatment and require the most complex decision making.
Fortunately, the outcome for patients with locally advanced breast cancer has improved dramatically. Before the routine use of chemotherapy, patients treated with mastectomy, radiation, or a combination of the two had high rates of distant metastases and death.1–2,3 The introduction of adjuvant and neoadjuvant chemotherapy and hormone therapy regimens has significantly improved the prognosis. Furthermore, new systemic regimens and introduction of biologic therapies have offered additional improvements and further increased the importance of local-regional disease eradication.
This chapter focuses on the management of locally advanced breast cancer, with a focus on local-regional control and radiation therapy. There is no consensus on the definition of “locally advanced breast cancer,” but most commonly this term refers to stage III disease, meaning advanced primary or nodal disease without clinically evident systemic metastases. In addition to reviewing management strategies for stage III breast cancer, this chapter also reviews the role of postmastectomy radiation and systemic treatments for patients with all stages of invasive breast cancer. Management and outcome of locally recurrent breast cancer and selected unusual presentations of breast cancers are also discussed.
TABLE 57.1 ESTIMATES OF BREAST CANCER EXTENT OF DISEASE AT DIAGNOSIS FOR 2005–2006
EPIDEMIOLOGY OF LOCALLY ADVANCED BREAST CANCER
Between 1980 and 1987, the incidence of breast cancer increased by approximately 4% each year, in part because of the increase in use of screening mammography. Between 1987 and 1994 the incidence was constant and then increased again at a 1.6% rate up until 1999, after which time breast cancer incidence has decreased by 2% per year.4 Between 1988 and 2000 there was a steady increase in tumors diagnosed at a size of 2.0 cm or less, but since 2000 this incidence rate has decreased by 3.3% per year, and the rate of tumors of >5.0 cm has increased by 2% per year since 1992.4 A few reasons undoubtedly contributed to the decline in the percentage of cases of locally advanced disease at diagnosis during the late 1980s. First, mammographic screening resulted in a larger proportion of patients being diagnosed with earlier disease stages. A second important contribution was women’s health initiatives and public education efforts that prompted women to seek medical care at the first sign of a breast mass. Finally, the medical community has become better educated about appropriate standards for evaluating a breast mass.
Table 57.1 gives estimates of the percentage of breast cancers diagnosed as T3 disease or with lymph node involvement according to data from the Surveillance, Epidemiology and End Results (SEER) Program, as reported by the American Cancer Society. Estimates indicate that 230,480 new cases of invasive breast cancer will be diagnosed in 2011.5 Using the percentages in Table 57.1 would yield an estimated 16,134 new cases with primary tumors of >5.0 cm and 69,144 new cases with lymph node–positive disease at diagnosis.
Table 57.1 also includes data concerning the distribution of disease in Whites and in African Americans. African-American women with breast cancer more commonly present with advanced primary disease and lymph node–positive disease than do White women with breast cancer.4 This has been explained on the basis of both socioeconomic factors and biology. Specifically, African-American women with breast cancer reportedly have less access to medical care and undergo screening mammography less often than do White women. African-American women also more often have breast cancers that are of higher nuclear grade and more frequently have estrogen receptor (ER)-negative disease compared with white women.6,7
Inflammatory breast cancer is an important subcategory of locally advanced breast cancer that has a unique epidemiology, presentation, and biology. Inflammatory breast cancers are rare, accounting for only 2% of all breast cancers in the United States.8 Estimates indicate that approximately 4,000 cases of inflammatory breast cancer would be diagnosed in the United States in 2010. During the 1990 s, the incidence of inflammatory breast cancer increased slightly. No known risk factors have been identified that are unique for the development of this form of breast cancer. However, the disease tends to occur in a younger population than does noninflammatory breast cancer. The proportion of African-American women with breast cancer diagnosed with inflammatory breast cancer is higher than the proportion of White women with breast cancer. Lymph node involvement at the time of diagnosis is much more common in patients with inflammatory breast cancer than in those with noninflammatory breast cancer, and it is more common for patients with inflammatory breast cancer to have distant metastases at diagnosis.8
NATURAL HISTORY
Natural History of Locally Advanced Breast Cancer
The outcomes of patients who present with locally advanced breast cancer were once poor, but improvements in treatments have changed the prognosis considerably. Currently, many patients with locally advanced disease can be cured. As the disease grows within the breast, the tumor may infiltrate or invade the dermis or the chest wall. Skin retraction may occur because of tumor invasion of Cooper’s ligaments, although this process can also be present in early-stage disease. Tumor growth can also lead to infiltration or obstruction of the lymphatic drainage of the breast and breast skin, causing edema of the breast, known as peau d’orange. In addition, primary tumor growth increases the risk of spread through the lymphatics to involve regional lymph nodes and/or spread hematogenously to involve distant sites such as the liver, lung, bone, and brain.
Most advanced primary tumors are associated with axillary lymph node involvement at the time of diagnosis. The axillary lymph node region is divided into three levels, defined according to their relationship to the pectoralis minor muscle: level I lymph nodes are inferolateral to the muscle, level II are beneath the muscle, and level III are superomedial to the pectoralis muscle (these lymph nodes are also called infraclavicular lymph nodes). Additional lymph nodes that may be involved in locally advanced breast cancer include Rotter’s nodes, which are located between the pectoralis minor and pectoralis major muscles, and the supraclavicular and internal mammary lymph nodes. Figure 57.1 shows computed tomography (CT) scans from patients with locally advanced breast cancer presenting with involvement of the level II axilla (Fig. 57.1A), an infraclavicular lymph node (Fig. 57.1B), a Rotter’s lymph node (Fig. 57.1C), and an internal mammary lymph node (Fig. 57.1D).
The clinical course of locally advanced breast cancer depends on several factors, including the specific disease characteristics at presentation, the biologic features of the disease, and the treatment given. Without treatment, almost all locally advanced breast cancers eventually metastasize to visceral organs and become life-threatening.1,2 Local disease progression can lead to ulceration of the breast skin, pain, bleeding, and infection. Progression of untreated regional lymphatic disease can cause pain, brachial plexopathy, arm edema, obstruction and thrombosis of the brachial vasculature, and skin ulceration.
Treatment advances have improved survival rates for women with locally advanced breast cancer. Before the use of systemic treatment became routine, patients with advanced disease treated with mastectomy, radiation therapy, or both had 5-year survival rates of only 25% to 45%.1–2,3 After the introduction of combined-modality treatments including surgery, radiation therapy, and chemotherapy, the 5-year survival rates approach 80% for patients with stage IIIA disease and 45% for patients with stage IIIB disease.9 More recent data suggest continued improvement with the addition of more-effective systemic regimens. For example, a recent SEER study examining patients with IIIB/C disease reported a 2-year breast cancer death rate of only 10%.10 The subset of patients with inflammatory breast cancer had a worse outcome than those with noninflammatory IIIB/C disease. In addition to stage, survival of locally advanced disease is dependent on other factors. For example, an elderly woman with a neglected ER-positive, hormonally responsive, stage III breast cancer that did not metastasize over a 1- to 2-year period of growth will have a much more favorable prognosis compared to a young woman with an ER-negative T4 tumor that presented with a history of rapidly progressive disease.
When considering improvements in the outcome of patients with stage III disease over time, it is important to recognize the effect of stage migration. Improvements in diagnostic imaging over time increase the likelihood of detecting metastatic disease, which results in some cases of stage III disease being reclassified as stage IV, which can have the effect of improving the outcome statistics for both stage III and stage IV disease. A similar effect was introduced by the 2003 change in the American Joint Commission of Cancer (AJCC) breast cancer staging system, which incorporated the number of positive lymph nodes in the pathologic disease stage. Specifically, many patients with four or more positive lymph nodes in the past would have had stage II disease but are classified as having stage III disease in the 2003 staging system. Indeed, a study that compared the stage-specific survival of 1,350 patients staged according to the 1988 AJCC staging system to the stage-specific survival of the same patients restaged according to the 2003 AJCC system found that the 10-year overall survival rates were significantly higher when the 2003 system was used, both for patients with stage II disease (76% [2003] vs. 65% [1988], p < .0001) and for those with stage IIIA disease (59% [2003] vs. 45% [1988], p < .0001).11 The reason for the better stage-specific outcome was that restaging into the 2003 system led to most of the patients with four or more positive lymph nodes being moved from the stage II to the stage III category.
FIGURE 57.1. Computed tomography images of patients with lymph node involvement at the time of diagnosis. A: Image from a patient with involvement of axillary lymph nodes in the level II axilla. The white arrows show the involved lymph nodes, which are just beneath the pectoralis minor muscle. B:An involved level III axillary lymph node (white arrow) that extents superomedially to the pectoralis minor muscle. C: An involved Rotter’s lymph node (white arrow), which is anterior to the pectoralis minor and beneath the pectoralis major muscle. D: Image from a patient with an involved internal mammary lymph node (white arrow).
FIGURE 57.2. Photograph of a patient with a locally advanced noninflammatory right breast cancer at the time of diagnosis.
Natural History of Inflammatory Breast Cancer
Inflammatory breast cancer is a clinically defined subcategory of locally advanced breast cancer. The hallmarks of inflammatory breast cancer are rapid disease onset and the clinical findings of skin erythema, edema (peau d’orange), brawny breast induration, warmth, and asymmetric enlargement. Typically, extensive lymphovascular invasion by tumor emboli is present that involves the superficial dermal plexus of vessels in the papillary and high reticular dermis.12 It is critical to distinguish inflammatory breast cancers from locally advanced breast cancer with secondary lymphatic congestion. Neglected primary tumors can also lead to breast erythema, edema, warmth, and asymmetric enlargement, particularly when bulky axillary adenopathy impedes the normal lymphatic flow from the breast. However, the former has a history of rapid onset, whereas the latter tends to have a long interval between the first symptom and the presentation for medical treatment.
Despite the natural history of inflammatory breast cancer being one of rapid disease progression and early distant dissemination,12,13 in the United States, approximately 70% of patients with inflammatory breast cancer have only evidence of local-regional disease at the time of diagnosis.14 Patients with inflammatory breast cancer typically have a worse clinical outcome than do other patients with T4 disease, suggesting that inflammatory breast cancer is a distinct biologic entity.10 However, the prognosis for patients with inflammatory breast cancer has improved. Before the availability of combination chemotherapy, inflammatory breast cancer was almost uniformly fatal. Fewer than 5% of patients treated with surgery, radiation therapy, or both survived past 5 years, and the expected median survival time for such patients was <15 months.13 Local recurrence rates after surgery or radiation therapy were also high at approximately 50%.15,16 The introduction of doxorubicin-based chemotherapy improved outcomes.17,18 An evaluation of the outcome of patients with inflammatory breast cancer registered in the SEER Program found that breast cancer–specific survival rates for patients with inflammatory breast cancer improved continuously throughout the 1990s.19 Currently, local control rates for patients treated with chemotherapy, mastectomy, and postmastectomy radiation approach 70% to 80%, and 5-year survival rates are approximately 40%.17,18
CLINICAL PRESENTATION OF LOCALLY ADVANCED BREAST CANCER
Locally advanced breast cancer most commonly is diagnosed after a palpable mass is detected within the breast. Advanced disease can cause symptoms such as local or regional pain, bleeding, paresthesia, and paresis. As previously indicated, it is critically important to determine the onset of symptoms and the rate of disease progression to reach an accurate diagnosis as to whether an advanced breast cancer represents an inflammatory carcinoma.
Diagnostic Workup
For patients with locally advanced breast cancer, the workup should start with a careful history and physical examination. The breast examination should include note of the breast symmetry, as well as careful inspection for involvement or edema of the skin. Peau d’orange can sometimes be subtle and at times can be best detected through gentle compression of the dermis between two fingers, which can elicit an increased prominence of the hair follicles and skin thickening compared with the skin overlying the contralateral breast. This finding may be missed on a quick visual inspection. Other times, physical examination findings are more obvious. Figure 57.2 shows a photograph of a patient with a neglected locally advanced breast cancer presenting with peau d’orange, inflammatory changes, breast retraction and involution, and effacement of the nipple–areola complex. Medical photographs are helpful to document the extent of visible abnormalities before treatment is begun and can be used to assess disease response to treatments.
The extent of palpable disease should also be measured and documented. Fixation of a breast mass to the pectoralis muscle or chest wall should be determined by assessing the mobility of the mass with the pectoralis muscle relaxed and contracted. Regional lymph nodes should be thoroughly evaluated by careful clinical examination with the patient in both supine and sitting positions. Clinical nodal evaluation may be supplemented with ultrasonographic imaging.
All cases of locally advanced disease require complete staging before initiation of therapy. Laboratory studies should include a complete blood cell count and serum chemistry profile with liver function tests. Radiographic studies should include a chest radiograph, a CT scan of the abdomen, a bone scan, and plain radiographs of symptomatic regions or areas of increased uptake on bone scans. Bone scans are recommended for all patients with locally advanced disease; up to 35% of patients with clinical stage III cancer can show abnormal bone scan results.20 If any neurologic symptoms suggestive of cerebral metastases are present, a contrast-enhanced CT scan or gadolinium-enhanced magnetic resonance imaging (MRI) scan of the brain should be obtained. Gadolinium-enhanced MRI is the preferred imaging technique if leptomeningeal carcinomatosis is suspected.
There is increasing interest in the use of [18F]fluorodeoxyglucose positron emission tomography (PET)/CT for disease staging of patients with locally advanced breast cancer, particularly those with inflammatory breast cancer. In a study of 41 women presenting with inflammatory breast cancer, PET/CT was able to detect distant metastases that were not found with other staging studies in 17% of the patients.21
Staging of Locally Advanced Breast Cancer
A comprehensive discussion of disease staging systems for breast cancer is provided in Chapter 56. Some staging considerations are particularly relevant to patients with stage III disease. Stage III breast cancer can represent either T3 disease (tumors >5.0 cm) with involved lymph nodes, N2 or N3 disease, or T4 disease.22
Specific aspects of both primary tumor and nodal staging in locally advanced breast cancer warrant additional consideration. Specifically, T4 disease may represent invasion into the chest wall (T4a), tumors associated with breast edema or skin ulceration or satellite nodules (T4b), both invasion and T4b characteristics (T4c), or inflammatory breast cancer (T4d). Invasion of disease into the pectoralis major muscle without chest wall invasion and dimpling or fixation of the overlying skin does not qualify as T4 disease. Both clinical and pathologic staging systems have been established for N2 and N3 disease. Clinical N2 disease signifies either involved axillary lymph nodes that are fixed to one another or to surrounding structures (N2a) or involved internal mammary lymph nodes without concurrent disease in the axilla (N2b), as determined by physical examination or imaging studies. Clinical N3 disease is disease that involves the infraclavicular region (N3a), both the axilla and internal mammary lymph nodes (N3b), or the supraclavicular region (N3c). Pathologic N2 disease represents involvement of 4 to 9 axillary lymph nodes with at least one focus measuring >2.0 mm (N2a) or clinical involvement of internal mammary lymph nodes with pathologically negative axillary lymph nodes (N2b). Pathologic N3 disease represents involvement of an infraclavicular lymph node or 10 or more involved lymph nodes with at least one focus measuring >2.0 mm (N3a), clinical involvement of internal mammary lymph nodes with 1 to 9 axillary lymph nodes involved, pathologic involvement of a sentinel internal mammary lymph node with four or more axillary lymph nodes involved (N3b), or a metastasis in the supraclavicular region (N3c).22
Neoadjuvant chemotherapy is recommended for most patients with locally advanced breast cancer. The initial extent of disease is an important factor for later local-regional treatment decisions and will be known only from the initial physical examination and radiographic findings. It is therefore imperative that disease in all patients be carefully assigned a clinical stage before any treatment is begun.
FIGURE 57.3. Five-year survival rates for patients with positive axillary lymph nodes according to tumor size and year of diagnosis. (Data from Elkin et al.30; reprinted from Buchholz TA. Locally advanced breast cancer. In: Haffty BG, Wilson L, eds. Handbook of radiation oncology. Sudbury, MA: Jones and Bartlett, 2008.)
PATHOLOGY AND BIOLOGY OF LOCALLY ADVANCED BREAST CANCER
The histopathology of locally advanced disease is relatively similar to that of early-stage disease. Both infiltrating ductal carcinoma and lobular carcinoma can present as locally advanced disease. However, it is unusual for histologically “favorable” tumor types (e.g., tubular carcinoma, mucinous carcinoma, and medullary carcinoma) to present at advanced clinical stages unless the breast mass has been present for a long time.
The term “locally advanced breast cancer” encompasses a biologic spectrum of diseases. Locally advanced disease that has developed between interval (annual) screening mammograms is most often ER-negative, with high nuclear grade and high proliferative index. In contrast, patients who present with extensive local-regional disease after years of medical neglect more often are found to have ER-positive disease with low nuclear grade and low proliferative index.
Inflammatory breast cancer also has biologic characteristics that differ from those of noninflammatory breast cancer. Specifically, inflammatory cancer more often is of high histologic grade, shows high percentages of cells in S phase and aneuploidy, does not express the ER, and expresses high levels of p53 and epidermal growth factor.23,24 Of interest, most investigators have found that HER2/neu overexpression is no more common in inflammatory breast cancer than in noninflammatory advanced disease.23,25 Other, more recently discovered markers include the propensity of inflammatory tumors to overexpress RhoC GTPase and to not express the tumor suppressor gene WIPS3.26,27Finally, others have described that inflammatory breast cancers with loss of MUC-1 may be associated with poorer survival than tumors that express MUC-1. If these findings are confirmed and validated, markers such as these may prove to be useful for diagnosis and possibly as future therapeutic targets.26,27 More recently, investigators have noted that overexpression of E-cadherin may play an important role in the tumor emboli formation that is typically noted in the dermal lymphatics, and preclinical work suggests that targeting E-cadherin may decrease invasiveness.28,29
GENERAL MANAGEMENT AND TREATMENT RESULTS FOR LOCALLY ADVANCED BREAST CANCER
Locally advanced disease requires multimodality therapy aimed at eradicating all disease in the local-regional area and preventing distant disease recurrence. These goals are best achieved through the use of combined-modality treatments that include chemotherapy, surgery, and radiation. In addition, ER-positive disease should be treated with hormonal therapy, and HER2/neu–positive disease should be treated with trastuzumab. Combined-modality therapy has significantly improved the prognosis for patients with advanced breast cancer. As previously noted, the prognosis of patients with locally advanced disease treated in the era before chemotherapy was available was very poor, with 5-year survival rates of only 25%.1–2,3 In contrast, more recent single-institution studies have reported 5-year survival rates approaching 80% for patients with stage IIIA disease and 45% for patients with stage IIIB disease.9 National database studies also reflect improvements in survival over time. For example, a study evaluating the outcome of patients with lymph node–positive breast cancer demonstrated that 5-year survival rates were significantly better in the group treated in 1995–1999 than in the group treated in 1975–1979 (Fig. 57.3).30 The most recent data from the American Cancer Society estimated an 84% 5-year survival for patients diagnosed between 1999–2005 who had lymph node–positive disease without distant metastases.4 These survival statistics are likely to show continued improvement over time because since 1999 several positive phase III clinical trials have shown that a new systemic treatment strategy may improve outcome among patients with lymph node–positive breast cancer. What is particularly exciting is that some of these advances represent incremental improvements in outcome over previous advances, so that when the benefits are added together the improvements over time become quite significant. As evidence of this improvement, an interesting study recently reported that between 1950 and 1980, the U.S. Food and Drug Administration approved fewer than 5 new systemic treatments for breast cancer during each decade; in contrast, 6 new agents were approved during the 1980s, and 12 new agents were approved during the 1990s.31 The pace of change in available therapeutics has been even greater in the last decade. These new treatments are likely to continue to improve the prognosis for patients with advanced breast cancer during the decades to come, and the rate at which new agents for breast cancer treatment are introduced is expected to accelerate with identification of new therapeutic targets.
Overview of Treatment
Locally advanced breast cancer can present as either operable disease or inoperable disease. The current standard of treatment for all patients with inoperable breast cancer is to proceed with neoadjuvant chemotherapy as the initial therapy. Approximately 80% to 90% of patients with advanced breast cancer will show partial or complete clinical response to neoadjuvant chemotherapy,32,33 and most patients presenting with inoperable breast cancer become candidates for surgery after neoadjuvant treatment.
No criteria have been agreed upon to distinguish inoperable from operable disease. In general, neoadjuvant chemotherapy is preferred if an initial surgical procedure is not likely to completely resect all gross disease with achievement of negative surgical margins. This includes most patients with T4 disease and all patients with inflammatory breast cancer, and for such patients neoadjuvant chemotherapy can allow primary closure of the skin flaps of the mastectomy. For patients with operable stage IIIA disease, initial surgery followed by adjuvant chemotherapy or neoadjuvant chemotherapy are equally good options. The advantages of each are highlighted in the following.
TABLE 57.2 CONSIDERATIONS REGARDING THE SEQUENCING OF SURGERY AND CHEMOTHERAPY FOR PATIENTS WITH OPERABLE LOCALLY ADVANCED BREAST CANCER
Neoadjuvant Chemotherapy—Advantages and Disadvantages
Neoadjuvant chemotherapy has become an increasingly popular treatment strategy for patients with stage II or III breast cancer. The use of neoadjuvant chemotherapy has several potential advantages over the traditional sequence of surgery followed by adjuvant chemotherapy, but it also carries some disadvantages (Table 57.2). Several trials have clearly shown that neoadjuvant chemotherapy substantially reduces the size of the primary tumor and nodal metastases in >80% of cases. Accordingly, for patients with large primary tumors, the approach of using chemotherapy as the initial treatment has been shown to increase the probability that breast-conserving surgery can be performed.32,34–36 A second advantage of using chemotherapy first is that this sequence allows the response of the disease to a particular chemotherapy regimen to be assessed, which in turn could provide an opportunity to “cross over” to a different treatment regimen if disease in an individual patient shows little or no response to the first regimen. By doing so, a potentially effective second-line agent can be given rapidly, and the toxicity of an ineffective first regimen can be avoided.
Neoadjuvant chemotherapy has also been proven to be extremely valuable for clinical research. After several studies showed a strong correlation between the achievement of a pathologic complete response (pCR; defined as no residual cancer being found in the postchemotherapy surgical specimen) and survival,32–34 investigators began using pCR rates as a short-term surrogate of the success of a chemotherapy regimen. Phase III randomized trials in which pCR rates were used as the primary endpoint have allowed the activity of two chemotherapy regimens to be compared with relatively small study populations and very short follow-up times relative to studies comparing two chemotherapy regimens used in an adjuvant setting. Neoadjuvant chemotherapy can also facilitate translational research to investigate the mechanisms of chemotherapy-induced cell death and chemotherapy resistance. For example, it has proven feasible to study changes in tumor genomes in response to treatment and how such changes correlate with chemotherapy response through the use of cDNA microarrays from serial biopsy specimens.37 Such studies are likely to provide significant insights into the heterogeneity of tumor response and to identify new targets for therapies.
Some have asserted that treatment with neoadjuvant chemotherapy also provides additional prognostic information. Clearly the prognosis for patients with a pCR (defined as complete eradication of invasive disease and negative axillary lymph nodes at the time of surgical treatment) is better than the prognosis would have been before treatment. However, an equal percentage of patients will be found to have residual disease after chemotherapy, which confers a worse prognosis than originally anticipated. Therefore, the true value of the additional prognostic information from the use of neoadjuvant chemotherapy will come only when additional treatments become available that can positively influence prognosis for those with a high residual disease burden. Currently, there are a number of clinical protocols to evaluate new therapeutics specifically in patients who exhibit a poor response to neoadjuvant treatment.
One theoretical advantage of neoadjuvant chemotherapy that has not been borne out in practice was the hope that earlier delivery of chemotherapy might improve survival for patients with locally advanced breast cancer. Clearly most of the patients who present with advanced disease and subsequently die of that disease do so as a consequence of the progression of metastatic disease that was present at a microscopic level at the time of diagnosis. Therefore, the suggestion that initiating chemotherapy at diagnosis (when the micrometastatic tumor burden would be lowest) would improve outcome relative to delaying chemotherapy until after surgical resection was a rational one. This was further supported by preclinical animal studies showing that removal of the primary tumor could increase the growth rate of existing micrometastases and that treating animals with either chemotherapy or tamoxifen before resection of the primary tumor abrogated this adverse effect.38
Two large randomized trials have been conducted to test the hypothesis that neoadjuvant chemotherapy could improve survival in patients with operable breast cancer. The first of these trials was the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 study, in which 1,523 patients with operable breast cancer were randomly assigned to receive four cycles of doxorubicin and cyclophosphamide (AC) either before or after surgical treatment.32,34 After 16 years, the overall survival rates and disease-free survival rates were nearly identical between the two groups (p = .99 and p = .93, respectively).39 However, in an unplanned subgroup analysis the authors found an interaction between age and sequencing of chemotherapy. Patients younger than 50 years of age had a 16-year overall survival of 61% with neoadjuvant chemotherapy versus 55% with adjuvant chemotherapy. An opposite trend noting an improvement with adjuvant chemotherapy was noted in the patients 50 years old and older.39 A second randomized prospective trial, conducted by the European Organization for Research and Treatment of Cancer (EORTC), confirmed these results and again found equivalent rates of 10-year survival and distant metastases between the neoadjuvant chemotherapy and adjuvant chemotherapy treatment groups.40 A meta-analysis of data from 3,946 patients treated in nine randomized trials comparing neoadjuvant with adjuvant chemotherapy in breast cancer found no statistical difference in the risk of death (risk ratio, 1.00), disease progression (risk ratio, 0.99), or distant disease recurrence (risk ratio, 0.94).41
The increasing use of neoadjuvant chemotherapy in patients with clinically negative lymph nodes has also created a controversy with respect to the sequencing of chemotherapy and sentinel lymph node surgery. It is clear from the B-18 trial and other institutional studies that neoadjuvant chemotherapy leads to complete eradication of disease within lymph nodes in roughly 20% to 40% of patients.32,42 If this eradication occurs selectively within the sentinel lymph node but not in other involved axillary lymph nodes, there is the potential that the false-negative rate of sentinel lymph node surgery after chemotherapy may be higher than sentinel lymph node surgery performed prior to chemotherapy. In addition, the original extent of axillary disease is unknown when sentinel lymph node surgery is performed after chemotherapy. This can have implications with respect to radiation treatment field design or recommendations concerning whether to use postmastectomy radiation. In some instance, this can also have implications with respect to adjuvant chemotherapy treatment decisions.
There are some advantages to performing the sentinel lymph node surgery after rather than before neoadjuvant chemotherapy. Of importance, with this strategy, most commonly patients only have to go one surgery rather than two. Second, if a component of disease is removed prior to surgery, then the prognostic value of achieving a pCR is less certain. Finally, performing surgery prior to chemotherapy delays the administration of systemic treatments, particularly if an axillary metastasis is found and the patient then undergoes an axillary dissection. Finally, because patients will more commonly have pathologically lymph node–negative disease after neoadjuvant chemotherapy, they more commonly will not require a completion axillary dissection.43
A number of groups have studied the identification rates and false-negative rates associated with sentinel lymph node surgery. The largest experience has been from the NSABP B-27 trial, which randomized 2,411 patients to one of three neoadjuvant chemotherapy regimens. A total of 428 of these patients had lymphatic mapping attempted. Successful identification of a sentinel lymph node was made in 85%, and the false-negative rate was 11% (defined as the number of patients with positive nonsentinel lymph nodes with a negative sentinel lymph node divided by the total number of patients with positive axillary lymph nodes).44
A meta-analysis investigated 1,273 patients (21 published studies) treated with a sentinel lymph node biopsy with subsequent axillary dissection following neoadjuvant chemotherapy.45 These authors reported a pooled identification rate of 90% and false-negative rate of 12%. Because these outcomes are similar to those reported in multicenter studies in which sentinel lymph node surgery was performed prior to systemic therapy, delaying sentinel lymph node surgery until after chemotherapy appears acceptable.
Neoadjuvant Hormonal Therapy
There are fewer data concerning the long-term outcome of patients treated with hormone therapy prior to surgery. In part this is because most patients treated with neoadjuvant systemic treatments for an ER-positive breast cancer have disease extent that necessitates both chemotherapy and hormonal treatments. However, interest in neoadjuvant hormonal therapy increased after reports from studies that found that patients with ER-positive disease have a lower probability of achieving a pCR compared to those with ER-negative disease.46 For example, patients with lobular breast cancer, in whom >90% of tumors are ER-positive, have particularly low rates of pCR.47 In addition, some patients with ER-positive breast cancer that is locally advanced and/or lymph node–positive at presentation are not candidates for neoadjuvant chemotherapy due to comorbid medical conditions. For such patients, treatment with neoadjuvant hormonal therapy is a reasonable option.48
Responses to neoadjuvant hormonal therapy occur over a slower period of time than those to neoadjuvant chemotherapy, and the rates of pCR with hormonal therapy are lower than those achievable with neoadjuvant chemotherapy. After aromatase inhibitors became available for postmenopausal patients with ER-positive disease, neoadjuvant hormone therapy trials were developed to directly compare the activities of various agents. A 330-patient randomized trial run in the United Kingdom compared 3 months of anastrozole, tamoxifen, or combined anastrozole/tamoxifen and found response rates of 36% to 39%, with only 1% to 3% achieving a clinical complete response.49 In the subgroup of 124 patients who were not candidates for breast conservation at diagnosis, the rates of breast conservation after 3 months of neoadjuvant hormone treatment were highest in the anastrozole-alone arm. An Italian trial randomized patients to 3 months of anastrozole versus tamoxifen and also noted a higher rate of breast conservation after treatment with anastrozole alone versus tamoxifen alone.50 The overall response rates were similar to those in the United Kingdom study.
Breast Conservation Therapy After Neoadjuvant Chemotherapy
As noted, one of the potential benefits of neoadjuvant chemotherapy is that a large primary tumor will respond favorably to neoadjuvant chemotherapy, thereby rendering the disease amenable to a breast conservation surgical approach. One important consideration for performing breast-conserving surgery after neoadjuvant chemotherapy concerns the volume of surgical resection. This is less of a problem for patients with small initial primary tumors that shrink still further after neoadjuvant chemotherapy. However, for patients with T3 disease for whom initial breast-conserving surgery would be deforming, the volume of resection after neoadjuvant chemotherapy must be directed at the residual nidus rather than the original extent of disease. In some instances, neoadjuvant chemotherapy successfully shrinks large primary tumors to smaller residual niduses that can easily be resected in small volumes of tissue with good or excellent aesthetic outcomes. However, breast cancers can respond to neoadjuvant chemotherapy in a variety of ways, as shown in Figure 57.4. For tumors that shrink to a residual nidus, limited surgery would successfully resect the volume of residual disease, and the outcome, particularly for those with a pCR, would be expected to be excellent. However, in other cases, tumors respond favorably to neoadjuvant chemotherapy, but the residual disease is diffuse, multifocal, and scattered throughout the original tumor volume. In such cases, a small surgical resection carries the risk of leaving a residual disease burden within the breast. Careful selection of cases for breast conservation is therefore critical.
One of the first studies to provide findings regarding appropriate selection criteria for breast conservation after neoadjuvant chemotherapy examined 143 mastectomy specimens from patients given neoadjuvant chemotherapy to determine patterns of residual disease and their relationships to clinical factors.51 Only 23% of tumors had clinical and pathologic features that would have predicted success with breast conservation. Important selection criteria included resolution of skin edema, favorable clinical response to neoadjuvant treatment, lack of multicentricity, and lack of extensive lymphovascular space invasion.
FIGURE 57.4. Three potential pathologic outcomes of a primary tumor that responds to neoadjuvant chemotherapy. (From Buchholz TA, Hunt KK, Whitman GJ, et al. Neoadjuvant chemotherapy for breast carcinoma: multidisciplinary considerations of benefits and risks. Cancer 2003;98:1150–1160.)
Since those findings were published, several groups have studied the clinical outcome of patients treated with breast conservation after neoadjuvant chemotherapy. In general, the outcome results have varied considerably across series, for several possible reasons. First, the selection criteria vary considerably across studies, and not surprisingly studies that include patients with positive surgical margins or inflammatory breast cancer tended to report higher rates of local recurrence.52,53 Similarly, some studies in which patients who achieved complete clinical resolution of disease could elect to forgo surgery showed higher recurrence rates.54 Other studies, however—predominantly from institutions with well-coordinated multidisciplinary teams and careful pathologic analysis of the surgical specimen—reported excellent outcomes.55,56
Two of the most influential publications that addressed breast conservation after neoadjuvant chemotherapy were from the two largest randomized trials (NSABP B-18 and EORTC) comparing neoadjuvant chemotherapy with adjuvant chemotherapy for patients with stage II or stage III breast cancer. The conclusion in both studies was that neoadjuvant chemotherapy offered an advantage because breast conservation rates were higher in the neoadjuvant chemotherapy groups.32,34,36 However, it is important to recognize that approximately 60% of the patients enrolled in these studies were considered candidates for breast conservation at the time of diagnosis. Therefore in the B-18 study, the improvement in breast conservation rates from 60% to 68% for patients treated with neoadjuvant chemotherapy essentially showed that 20% of initial mastectomy candidates (8 of 40 patients) could undergo breast conservation surgery instead after neoadjuvant chemotherapy. Not surprisingly, this increase was directly due to a higher percentage of patients with T3 disease being offered breast conservation after first responding to chemotherapy. Both studies reported that the overall breast recurrence risk in patients treated with neoadjuvant chemotherapy was not statistically different from that in patients treated with surgery first.32,34,36 However, in the B-18 study, the breast recurrence rate in a subset of patients who initially would have required a mastectomy but were treated with breast conservation after a favorable response to neoadjuvant chemotherapy was twice that of the patients with smaller tumors who were treated with surgery first (15.7% vs. 7.6%, respectively).34
A meta-analysis of the nine randomized studies comparing neoadjuvant and adjuvant chemotherapy reported that the use of neoadjuvant chemotherapy was associated with an increase in the relative risk of local-regional recurrence relative to adjuvant chemotherapy (relative risk, 1.22; 95% confidence interval [CI], 1.04 to 1.43).41 This difference was largely influenced by the trials in which surgery was not performed and breast conservation after neoadjuvant chemotherapy was achieved with the use of radiation therapy alone (in those trials the relative risk was 1.53 and the 95% CI was 1.11 to 2.10).41 These findings indicate that patients who achieve a complete clinical response would still benefit from a surgical procedure in addition to radiation.
Two of the largest studies showing acceptable outcomes for breast conservation after neoadjuvant chemotherapy have been from the Istituto Nazionale Tumori in Milan, Italy, and the University of Texas MD Anderson Cancer Center.55,56 The Milan experience consisted of 536 patients treated with neoadjuvant chemotherapy for a primary tumor 2.5 cm in diameter or larger. Eighty-five percent of these patients subsequently had breast-conserving surgery. However, it is important to note that the initial tumor size in more than half of these women was <4 cm, and thus these women may have been candidates for breast conservation at diagnosis. The 8-year rate of breast recurrence as a first site of failure in those treated with breast conservation was 6.8%.55 In the MD Anderson series, 340 carefully selected patients were treated with breast conservation therapy after showing a favorable response to chemotherapy.56Patient selection criteria for the breast-conserving approach included having no residual T4 breast skin abnormalities, negative surgical margins, no multicentric disease, no residual malignant calcifications on postoperative mammogram, and the willingness and ability to undergo both surgery and radiation therapy. With these 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. Four factors were found to be independently associated with breast cancer recurrence and local-regional recurrence: clinical N2 or N3 disease, lymphovascular space invasion, a multifocal pattern of residual disease, and residual disease >2 cm in diameter.56 Eighty-four percent of patients had none or just one of these factors, and the recurrence rate at 10 years in this group was only 4%.57 In contrast, the 4% of patients with three of these factors had a recurrence rate of 45%. Women with primary clinical T3 or T4 disease were at very low risk of recurrence if the tumor shrank to a solitary nidus or showed a pCR, but among patients with T3/T4 tumors that broke up and left a multifocal pattern of residual disease the breast cancer recurrence rate was 20%.56 More recently this same group validated this prognostic index in a more recent cohort of patients. The patients had respective 5-year locoregional recurrence–free survival rates of 92% (score, 0; n = 91), 92% (score, 1; n = 82), 84% (score, 2; n = 38), and 69% (score, 3 to 4; n = 13) (p = .01).58
The investigators from MD Anderson recently updated their experience and compared how treatment with neoadjuvant versus adjuvant chemotherapy affected rates of local-regional failures in 2,984 patients treated with breast conservation therapy between 1987 and 2005. After adjusting for differences in clinical stage, their multivariate analysis demonstrated no differences in local-regional recurrence between surgery-first and chemotherapy-first patients.59
When considering the outcome of breast conservation therapy for patients with locally advanced breast cancer, it is important to consider that patients with stage III breast cancer are at risk for local-regional recurrence even when mastectomy is performed. In addition, patients with advanced disease are at significant risk for distant metastases, which is an additional incentive to avoid removing the entire breast when breast-conserving surgery can be done with acceptably low recurrence rates. The investigators from MD Anderson applied the four prognostic criteria associated with breast recurrence in patients treated with neoadjuvant chemotherapy and breast conservation to a cohort of patients treated with neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation.60 These investigators found that for patients who had none or one of these factors, the results with either local-regional treatment approach were excellent and equivalent. Among patients with two factors, a nonsignificant trend was evident toward fewer local-regional recurrences with mastectomy, and for the small cohort of patients with three or four factors, mastectomy provided a statistically significant benefit. This trend was also noted in their updated validation paper.58
Mastectomy
In the United States, mastectomy continues to be the most common local-regional treatment for breast cancer, particularly for patients with locally advanced disease. Several alternative mastectomy approaches are available for women with breast cancer (Table 57.3). A simple or total mastectomy resects the breast but not the axillary contents. For patients with clinical stage T1/T2 N0 disease who are not interested in breast conservation, a total mastectomy with a sentinel lymph node dissection may be the treatment of choice. A modified radical mastectomy (removal of the breast plus a level I/II axillary dissection) remains the standard of care for patients with clinically positive lymph nodes or locally advanced disease.
TABLE 57.3 TYPES OF MASTECTOMIES USED AS TREATMENTS FOR BREAST CANCER
Postmastectomy Radiation Therapy
Meta-Analyses of Postmastectomy Radiation Therapy Trials
Adjuvant radiation has been used after mastectomy for many decades. Indeed, some of the first randomized, prospective trials in medicine were done to investigate the efficacy of postmastectomy radiation. Despite this, significant controversy remains over the indications for its use. It is clear that mastectomy without radiation offers excellent local-regional control rates for most patients with noninvasive or early-stage, lymph node–negative disease. In contrast, patients with stage III breast cancer (four or more positive lymph nodes or T3/T4 primary tumors) have a clinically relevant risk of local-regional recurrence after mastectomy and thus would benefit from adjuvant radiation. What is less clear is whether radiation provides a survival advantage for patients with stage II breast cancer and one to three positive lymph nodes.
In 1987, Cuzick et al.61 published the first meta-analysis of data from postmastectomy radiation therapy trials and reported that radiation use was associated with a poorer overall survival rate. In a subsequent analysis, the same group reported that postmastectomy radiation therapy decreased the breast cancer death rate but increased the non–breast cancer death rate,62 which resulted in equivalent overall survival rates in the radiation and no-radiation groups. These analyses are mostly of historical interest because of the considerable heterogeneity in the surgical and radiation therapy treatments used in these trials as compared with modern treatment approaches. Moreover, these early trials often enrolled patients with early-stage disease, who would not be predicted to derive any benefit from radiation therapy. Finally, the early studies of postmastectomy radiation predated the use of systemic therapy.
After the Cuzick meta-analyses, the Early Breast Cancer Trialists’ Collaborative Group obtained the raw data from every randomized trial that investigated the role of radiation in breast cancer. Through the years, this group has published a series of meta-analyses that have provided important insights into the risks and benefits of postmastectomy radiation therapy.63 In the most recently published analysis, based on data from 9,933 patients, postmastectomy radiation therapy reduced the 15-year isolated local-regional recurrence rates for patients with lymph node–positive disease from 29% to 8%.64 Of importance, this reduction led to a 5% decrease in the 15-year breast cancer mortality rate (60% vs. 55%). In 2005, the group reanalyzed updated data, with the resulting publication expected in 2012. This updated further subdivided patients according to pathologic lymph node status, and the provisional findings have been presented.65 In this update postmastectomy radiation reduced 15-year rates of isolated local recurrences in pN0 patients from 5.8% to 2.4% (n = 1,277), in patients with one to three positive lymph nodes by 24.7% versus 5.3% (n = 3,316), and in patients with four or more positive lymph nodes by 40.6% versus 12.9% (n = 2,813). The improvement in local-regional recurrence with postmastectomy radiation was associated with a statistically significant improvement in death from breast cancer and overall survival for the patients with one to three positive lymph nodes and those with four or more positive lymph nodes but not for the patients with lymph node–negative disease.65
It is important to recognize the limitations of meta-analyses when considering the relevance of these reports to modern treatments for breast cancer. One problem with including trials dating back to the 1950s is that the radiation doses, fractionation patterns, treatment units, and field designs differ significantly from current standards. To minimize these confounding effects, Van de Steene et al.66 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 in standard practice. When these studies were excluded, use of postmastectomy radiation therapy was associated with an even greater overall survival advantage. Moreover, adjuvant radiation probably can improve survival even further if the risk of dying from micrometastatic disease is minimized through the use of systemic therapy. To investigate this question, Whelan et al.67 performed a meta-analysis of postmastectomy radiation trials that included systemic therapy for both treatment groups. In this analysis, the addition of radiation after mastectomy led to an even greater reduction in the risk of any recurrence (odds ratio, 0.69) and the risk of death (odds ratio, 0.83). Finally, another meta-analysis attempted to account for the quality of radiation delivery in these trials.68 In this study, the authors defined optimal dose as a between 40 and 60 Gy delivered in 2-Gy fractions and optimal treatment field arrangements as ones that included both the chest wall and the regional lymphatics. They then reanalyzed the data from the Early Breast Cancer Trialists’ Collaborative Group according to the quality of radiation treatments and demonstrated that proportional reduction in local-regional recurrence was 80% for trials with optimal dose and treatment fields, compared to 70% and 64% for trials that were suboptimal with respect to dose or field arrangements, respectively. In addition, there was a statistically significant improvement in breast cancer mortality in the trials that used optimal radiation dose and treatment fields but not in the other trials (Fig. 57.5).
In summary, these meta-analyses conclusively demonstrated that radiation has an important role in the management of locally advanced breast cancer. By reducing the risk of recurrence after mastectomy, radiation offers an incremental improvement in overall survival. Radiation seems to offer the greatest benefit when given using modern treatment techniques that minimize the risk of normal-tissue injury and maximize the probability of tumor control and when given to patients who also receive systemic treatments.
FIGURE 57.5. Data from a meta-analysis showing the association between postmastectomy radiation therapy and locoregional recurrence, breast cancer mortality, and mortality from other causes. The trials were analyzed and divided according the appropriateness of the radiation dose (labeled in the figure as “inadequate or excessive”) and design of the radiation treatment fields. This figure shows that the trials with the highest quality of radiation therapy achieved the greatest proportional reduction in locoregional recurrences, were the only trials associated with an improvement in breast cancer mortality, and were the only trials that did not find an association between radiation use and increased mortality from other causes. (From Gebski V, Lagleva M, Keech A, et al. Survival effects of postmastectomy adjuvant radiation therapy using biologically equivalent doses: a clinical perspective. J Natl Cancer Inst2006;98(1):26–38.)
Phase III Randomized Trials Investigating Postmastectomy Radiation Therapy
The three most recently completed randomized trials investigating the efficacy of postmastectomy radiation for patients with stage II or III breast cancer were conducted in the 1980s and have 15- to 20-year outcome data. The largest of these studies was the Danish Breast Cancer Cooperative Group 82b trial, which randomly assigned 1,708 premenopausal women with stage II or III breast cancer to receive mastectomy followed by nine cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy or mastectomy, radiation therapy, and eight cycles of CMF chemotherapy.69 At the same time, this group also conducted the 82c trial, in which >1,300 postmenopausal women were randomly assigned to undergo mastectomy and 1 year of tamoxifen or mastectomy, tamoxifen, and radiation therapy.70 Finally, a smaller trial, conducted in Vancouver, Canada, randomly assigned 318 premenopausal women with lymph node–positive disease to undergo mastectomy and CMF chemotherapy with or without postmastectomy radiation therapy.71 In all three of these studies, patients treated with radiation had a lower long-term risk of isolated local-regional recurrence than did patients randomized to no radiation therapy. Of importance, these improvements led to fewer patients developing metastatic disease and an improvement in overall survival.71,72 The results from these three trials are shown in Table 57.4.
Several important concepts can be ascertained from these studies. First, these studies, together with the Oxford meta-analyses, clearly demonstrate that by reducing local-regional recurrence, postmastectomy radiation therapy could improve overall survival. Second, these trials demonstrated that these patients had a clinically relevant risk of local-regional recurrence despite the use of either CMF chemotherapy or tamoxifen. These findings imply that the benefits of systemic treatments are predominantly to lower the competing risk of distant metastases, which makes the achievement of local-regional control more important.
One controversy that arose after the publication of these studies concerns the most appropriate indications for postmastectomy radiation. Specifically, these trials led to a debate as to whether postmastectomy radiation therapy is indicated for patients with stage II breast cancer with one to three positive lymph nodes. Most of the patients enrolled in the Danish and British Columbia trials had stage II disease with one to three positive lymph nodes.69–71Accordingly, many have argued that these findings suggest that all patients with lymph node–positive disease should receive radiation after mastectomy. This argument is further supported by the recent analysis from the Early Breast Cancer Trialists’ Collaborative Group, which also noted a survival advantage in the patients with one to three positive lymph nodes.65 The difficulty in interpreting these data, however, is that many patients in these trials did not undergo a formal level I/II axillary dissection. In the Danish studies, the median number of axillary lymph nodes resected was only seven,69 which is approximately 50% of the number reported from studies conducted in the United States. In addition, 76% of the patients had <10 lymph nodes removed, and 15% had three or fewer lymph nodes removed.69 In the Vancouver trial, the median number of resected lymph nodes was 11.73 Given the less extensive axillary surgery done in these studies, it is highly probable that some of the patients in these studies reported as having had one to three positive lymph nodes would have had four or more positive lymph nodes if a standard axillary dissection had been performed. Correspondingly, their risk of a chest wall or supraclavicular recurrence would be higher than that usually estimated for patients with one to three positive nodes. Moreover, failure to remove these additional involved axillary lymph nodes would predispose patients to axillary recurrence, which could be avoided by a more complete axillary dissection. Indeed, the most recent update of the Danish studies reported that 43% of all local-regional recurrences included recurrence in the axilla.72 To further investigate this question, the Danish investigators reanalyzed their trial results specifically with regard to the patients who had eight or more lymph nodes resected. For the patients with one to three positive lymph nodes, there continued to be significant improvements in local-regional control (96% vs. 73%) and overall survival (57% vs. 48%) in the patients randomized to receive postmastectomy radiation.74
TABLE 57.4 LOCAL-REGIONAL RECURRENCE, RATES OF DISTANT METASTASIS, AND OVERALL SURVIVAL IN RANDOMIZED TRIALS COMPARING THE USE OF POSTMASTECTOMY RADIATION FOR PATIENTS TREATED WITH MASTECTOMY AND SYSTEMIC THERAPY69–72
TABLE 57.5 LOCAL-REGIONAL RECURRENCE RATES IN PATIENTS NOT TREATED WITH RADIATION AFTER MASTECTOMY IN RANDOMIZED CLINICAL TRIALS75–78
Risks of Local-Regional Recurrence After Modified Radical Mastectomy and Systemic Treatment
Another aspect to consider concerning the data of the patients with one to three positive lymph nodes treated in these trials is that the local-regional recurrence rates appear much higher than for patients treated in the United States with standard modified radical mastectomy and systemic treatments. Specifically, the 18-year rate of isolated local-regional recurrence for the patients in the Danish studies treated with mastectomy and systemic treatment was 41% and the 18-year rate for the subgroup with one to three positive lymph nodes was 37%.72 Even in limiting the analysis to patients with eight or more lymph nodes resected, the local-regional recurrence rate was 27%.74 In the updated Oxford analysis, the 15-year overall rate of local-regional recurrence was 25%, although it is important to note the a majority of patients included in this subset of the meta-analysis were the patients treated in the Danish trials.65
The risks of recurrence in the Danish and Vancouver trials after mastectomy and chemotherapy were high relative to those reported from large series from the United States and from a European cooperative group. To help define the indications for radiation, several groups recently conducted studies to assess which patients are at risk for local-regional recurrence after treatment with a mastectomy that included a level I/II axillary dissection, systemic treatment, and no radiation. The results from the largest of these studies are summarized in Table 57.5.75–78 In general, the findings suggest that the 10-year local-regional recurrence risk for patients with one to three positive lymph nodes was approximately 12% to 15%, which is nearly one-third of the local-regional recurrence rate in the no-radiation group of the Vancouver and Danish trials and one-half that of the Oxford overview. The reasons for these lower risks are not clearly known but probably reflect differences in the surgical procedure performed. In addition, these patterns-of-failure studies reported outcomes at 10 years, whereas the randomized, prospective studies reported outcome data at 18 and 20 years. In the Danish studies, the local-regional recurrence rate rose relatively consistently by 1% per year between the 10th and 25th follow-up years.72 Similarly, in the Vancouver randomized trial, approximately 20% of local-regional recurrences in the group that did not receive postmastectomy radiation developed after 10 years of follow-up.71
Stage II breast cancer with one to three positive lymph nodes is also heterogeneous with respect to other prognostic factors that affect local-regional recurrence risk. Table 57.6 shows various cofactors that have been found to increase the risk of local-regional recurrence within this subgroup. Cheng et al.80 analyzed 110 patients with a minimum follow-up of 25 months who were treated with modified radical mastectomy without radiation and had one to three positive axillary nodes (median number of nodes examined, 17). Sixty-nine patients received adjuvant chemotherapy and 84 received adjuvant hormonal therapy with tamoxifen. These investigators defined four factors (age <40 years, tumor ≥3 cm, ER-negative disease, and lymphovascular invasion) that segregated the patients into a high-risk group (with three or four factors) and a low-risk group (with two or fewer factors). Tumor size was also found to be an important cofactor in work from MD Anderson, but those authors found a size of 4 cm to increase the risk. Finally, findings from the International Breast Cancer Study Group Trials I through VII found that premenopausal women with one to three positive lymph nodes had local-regional recurrence risks ranging from 19% to 27% if they had G2-3 disease with vascular invasion but that risk was <15% if they had G1 disease with no vascular invasion.77Among postmenopausal women with one to three positive lymph nodes, those with G3 disease and tumors >2 cm had a local-regional recurrence risk of 24% as compared with less than 15% for those with G1–2 disease with tumors <2 cm.
Margin status is another important co-risk factor in this cohort. In an analysis of the 34 of patients with close or positive margins whose primary tumor was smaller than 5 cm with zero to three positive axillary nodes and who received no postoperative radiation, Freedman et al.81 reported a relatively high risk of local relapse, but only among younger women. Five chest wall recurrences appeared at a median interval of 26 months (range, 7 to 127 months), resulting in an 8-year cumulative incidence of a chest wall recurrence of 18%. Patient age correlated with the cumulative incidence of chest wall recurrence at 8 years; the rate for women of age ≤50 years was 28% versus 0% for women older than 50 years (p = .04). Katz et al.82 also found close or positive margins to be an independent risk factor for the development of local-regional recurrence after mastectomy, but in that series age did not affect this risk. The 10-year risk for the 29 patients with close or positive margins was 45%; the risk was 33% for those with pectoralis fascia invasion even when negative margins were achieved.
The presence of multicentric disease is strongly associated with other risk factors for local-regional recurrence, such as tumor size and nodal involvement. However, in patients with stage II disease with one to three positive lymph nodes, multicentric disease does not seem to elevate the risk of local-regional recurrence. Fowble et al.83 reported that patients with multicentric disease without other strong risk factors for postmastectomy chest wall relapse had a 5-year actuarial risk of an isolated local-regional recurrence of 8%. By comparison, Katz et al.82 found a 10-year recurrence risk of 37% for patients with multicentric disease, but limiting the analysis to only patients with one to three positive lymph nodes eliminated any association between multicentric or multifocal disease and local-regional recurrence.
TABLE 57.6 COFACTORS ASSOCIATED WITH A >15% LOCAL-REGIONAL RECURRENCE AFTER MASTECTOMY AND CHEMOTHERAPY IN PATIENTS WITH ONE TO THREE POSITIVE LYMPH NODES
The MD Anderson group recently re-evaluated their local-regional recurrence risk in a more contemporary era of patients with zero to three positive lymph nodes treated after publication of the Danish trial results.84 Since that time, the institutional philosophy was to consider postmastectomy radiation for the subgroups of patients with one to three positive lymph nodes: age <40 years, lymphovascular space invasion, tumor size <4 cm, three positive lymph nodes or a positive lymph node ratio of 20% or greater, or extensive extracapsular extension. In general, patients without these features and those with T1,2 N0 disease were not offered postmastectomy treatment. The authors analyzed >1,000 patients treated for a pT1 or pT2 tumor between 1997 and 2002 with mastectomy, a modern chemotherapy regimen, and no radiation. They analyzed the locoregional outcome of 753 patients with negative lymph nodes, 176 with one positive lymph node, 69 with two positive lymph nodes, and only 21 patients with three positive lymph nodes. The 10-year locoregional recurrence rates were low overall, with respective rates of 2.1% (node negative), 3.3% (one positive node), and 7.9% (two positive nodes). The group with three positive lymph nodes was too small to provide meaningful data. These data suggest that the selection criteria used were effective in selecting a cohort of patients with early-stage, lymph node–positive disease who are at very low risk of having a local-regional recurrence.
Even if the risk of local-regional recurrence for most patients with one to three positive lymph nodes is relatively low after a modified radical mastectomy and chemotherapy, radiation could still provide a benefit. Indeed, Woodward et al.85 found that the risk of local-regional recurrence after mastectomy and anthracycline-based chemotherapy was only 13% for patients with stage II disease and one to three positive lymph nodes. However, at the same institution, patients with similarly staged disease treated with postmastectomy radiation had a local-regional recurrence risk of only 3%.85 Whether this degree of benefit is clinically meaningful with respect to patient survival is unknown. A recent investigation of this question evaluated data from the SEER Program concerning patients with T1 or T2 primary tumors treated with mastectomy. In that study, radiation use led to a 15% to 20% relative reduction in breast cancer mortality, but this reduction only became significant in a multivariate analysis of patients with seven or more positive lymph nodes.86 Because the treating physicians made the decisions concerning the use of radiation for the patients included in that database, unidentified biases could be present that affected these results. Indeed, other investigators, evaluating data from the same program on patients with T1 or T2 primary tumors with one to three positive lymph nodes, compared the outcome of those treated with breast-conserving surgery with radiation versus mastectomy without radiation.87 In that study, multivariate analyses showed that patients treated with breast conservation plus radiation had significantly improved survival compared with those treated with mastectomy without radiation. Again, unaccounted biases probably affected these results to some degree.
It is also important to recognize that the patients at lowest risk for local-regional recurrence may be the cohort who achieve the greatest relative survival advantage from avoidance of a local-regional recurrence. This is because the risk factors for local-regional recurrence overlap with those for the development of distant metastases. For example, extensive lymph node involvement leads to a high risk of local-regional recurrence but also predicts for a high competing risk of distant metastases that may not be avoided through the use of postmastectomy radiation. In an interesting analysis conducted using data from the Danish randomized trials, investigators demonstrated that the greatest proportional survival advantage associated with postmastectomy radiation was found in the subgroups of patients with the most favorable prognostic features (fewer than three positive lymph nodes, small tumor sizes, ER-positive disease).88
Another cohort of patients in whom the use of postmastectomy radiation is controversial are those with pathologic T3 N0 disease. One reason for this controversy is that there are limited data regarding the risk of local-regional recurrence after mastectomy and systemic treatments in such patients. This lack of data is a consequence of the fact that the majority of breast cancers that are 5 cm or greater will have lymph node–positive disease and that a large percentage of patients with clinical T3 N0 disease are currently treated with neoadjuvant chemotherapy. Historically, patients with pathologic T3 N0 disease who were treated with an initial mastectomy were recommended to receive postmastectomy radiation. However, two recent publications indicated that the risk of local-regional recurrence is relatively low. Floyd et al.89 published data concerning a multicenter study of 70 patients treated with mastectomy, systemic therapy, and no radiation for patients with pathologic T3 N0 disease and reported a 5-year local-regional recurrence of only 8%. Those who had lymphovascular space invasion had a 21% local-regional recurrence compared to a rate of only 4% for those without lymphovascular space invasion. Finally, of the patients who experienced a local-regional recurrence, 89% had the chest wall as their only site of recurrence. In addition, Taghian et al.90 analyzed the outcome of 313 patients with pathologic stage T3 N0 disease who were treated with mastectomy, systemic treatments, and no radiation on NSABP clinical trials. The 10-year LRR for this series was only 7%, with 24 of the 28 local-regional recurrences developing only on the chest wall.
Both the American Society for Therapeutic Radiology and Oncology and the American Society of Clinical Oncology have published consensus statements recommending postmastectomy radiation therapy for women with four or more positive lymph nodes or advanced primary disease. Both statements included the recommendation that an additional trial be performed to further clarify the benefit of postmastectomy radiation therapy for women with stage II disease and one to three positive lymph nodes.91,92 Unfortunately, an Intergroup trial designed to determine the benefits of postmastectomy radiation therapy for such patients closed owing to poor accrual. However, the Selective Use of Postoperative Radiotherapy after Mastectomy trial is accruing patients in the United Kingdom, through EORTC, and in Asia and may in the future provide answers to this question.
In summary, it is clear that postmastectomy radiation offers a significant benefit for patients in terms of a 20% to 40% risk of local-regional recurrence, and therefore it should be recommended for all such patients. It is reasonable to discuss the risks and benefits of radiation for patients with intermediate-risk disease, such as those with pathologic stage II breast cancer. It is hoped that ongoing studies will further refine risk stratification within this subset by considering other cofactors, such as margin status, lymphovascular space invasion, patient age, extent of axillary dissection, and presence of extracapsular disease. In the future, this may be a cohort of patients in whom molecular predictive tests may further stratify treatment decisions.
Postmastectomy Radiation Therapy After Neoadjuvant Chemotherapy
Neoadjuvant chemotherapy has now become a standard initial therapy for most patients with locally advanced breast cancer. As the use of neoadjuvant chemotherapy has become more common, new questions regarding the indications for postmastectomy radiation therapy have arisen. This is because historically the decision to administer radiation therapy was made predominantly on the basis of the pathologic extent of disease. However, neoadjuvant chemotherapy changes the extent of pathologic disease in 80% to 90% of cases, and it is unclear whether and how the posttreatment pathologic information should guide decisions regarding radiation treatment. What has been learned is that the correlations between pathologic extent of disease and local-regional recurrence after mastectomy are different for patients treated with chemotherapy first compared with those treated with surgery first.93 Specifically, one study found that the local-regional recurrence rate associated with a particular pathologic extent of disease after surgery was higher among patients treated with chemotherapy first than among patients treated with surgery first. This is not particularly surprising, in that in the neoadjuvant chemotherapy group, the pathologic examination represented residual disease after treatment, whereas in those treated with surgery first, the extent of disease represented untreated cancer. However, these findings imply that the risk of local-regional recurrence for patients given neoadjuvant chemotherapy is determined by both the pretreatment clinical stage and the extent of pathologically residual disease after chemotherapy.
Information on the efficacy of postmastectomy radiation therapy for patients treated with neoadjuvant chemotherapy is limited. One of the first published studies investigating this issue compared the outcomes of 579 patients who received neoadjuvant chemotherapy, mastectomy, and radiation therapy with those of 136 patients who were treated with neoadjuvant chemotherapy and mastectomy.94 Patients in this study had been treated in prospective chemotherapy trials in which radiation therapy was given on the basis of physician recommendations and patient preferences. Therefore, the patients with worse disease characteristics were more often treated with radiation therapy. Despite this, the local-regional recurrence rate was found to be significantly lower in the group treated with postmastectomy radiation therapy than in the group treated with neoadjuvant chemotherapy and mastectomy (10-year local-regional recurrence rates were 8% and 22%, respectively; p = .001). For patients with clinical stage III disease or extensive disease after chemotherapy, radiation led to significant improvements in local-regional recurrence and overall and cause-specific survival rates. Multivariate analyses indicated that radiation was independently associated with a lower risk of local-regional recurrence (hazard ratio for not receiving radiation therapy, 7.0; p < .0001) and a lower risk of breast cancer death (hazard ratio for not receiving radiation therapy, 2.03; p < .0001).94
The same group of investigators has also shown that among patients with stage III disease who achieved a pCR, the local-regional recurrence rate for those treated with radiation therapy was 7% versus 33% for those who did not receive radiation therapy (p = .040). Radiation use in these patients was also associated with an improvement in survival. Finally, this group also tried to address which patients given neoadjuvant chemotherapy for clinical stage II breast cancer should receive radiation therapy. In a recent publication, they examined patients with clinical T3 N0 disease and reported a 4% 5-year local-regional recurrence rate in 119 patients who received postmastectomy radiation compared to a 24% rate in the 43 patients who did not (p < .001).95
There remains significant controversy as to which patients with clinical stage T1 2N1 disease treated with neoadjuvant chemotherapy and mastectomy benefit from radiation. It may be that response to the chemotherapy may help to guide such treatment decisions. Retrospective analyses from the MD Anderson Cancer Center and the NSABP suggested that patients with clinical stage IIA/IIB disease who have lymph node–negative disease after neoadjuvant chemotherapy and who do not receive radiation have a <10% risk of local-regional recurrence.96,97 This cohort is estimated to represent 40% of the original population. In contrast, for the remaining 60% of the patients who have residual lymph node–positive disease after neoadjuvant chemotherapy, the risk of local-regional recurrence is >15%.96,97 Therefore, the use of neoadjuvant chemotherapy for patients with stage II disease may further risk-stratify patients and permit avoidance of postmastectomy radiation in 30% to 40% of this population. This would permit avoidance of the toxicities and costs in this cohort.
In summary, the use of postmastectomy radiation therapy is reasonable for all patients with clinical T3 or T4 tumors or clinical stage III disease regardless of their response to the chemotherapy regimen. In terms of clinical stage I or II breast cancer, postmastectomy radiation therapy should be recommended for patients with four or more positive lymph nodes after chemotherapy and for the unusual patient in whom the disease progresses and the primary tumor exceeds 5 cm in diameter. Clearly, however, additional studies are needed to quantify the local-regional recurrence risk for patients who present with T1 or T2 N1 disease and have zero to three positive lymph nodes after neoadjuvant chemotherapy.
TABLE 57.7 BENEFITS OF POLYCHEMOTHERAPY VERSUS NO CHEMOTHERAPY IN REDUCING THE 5-YEAR RISK OF BREAST CANCER RECURRENCE
Systemic Therapy
Systemic treatments play a critical role in the multidisciplinary management of both early-stage and locally advanced breast cancer. After tamoxifen and anthracyclines were established as important components of adjuvant treatments in the late 1980s, there were few significant advances for nearly two decades. However, in the recent past the landscape of breast cancer adjuvant and neoadjuvant systemic treatments has rapidly changed. These recent advances in the systemic management of breast have contributed to the decreasing breast cancer death rates recently noted. A full description of the vast array of systemic chemotherapy, hormone therapy, and molecular therapies is beyond the scope of this chapter. However, we will review the current state of these therapeutics.
Meta-Analyses
Similar to their meta-analyses of radiotherapy trials in breast cancer, the Early Breast Cancer Trialists’ Collaborative Group has analyzed overviews of trials investigating chemotherapy and hormonal therapy for breast cancer. Their most recent complete meta-analysis was published in 2005 and evaluated data from almost 150,000 patients treated on 194 randomized trials that investigated chemotherapy or hormonal therapy.98 Only trials that began by 1995 were included, so no data were available concerning the efficacy of taxanes or trastuzumab. More recently, they published an update on the efficacy of adjuvant tamoxifen using data from 21,457 patients treated in 20 randomized trials99and an analysis of trials comparing aromatase inhibitors versus tamoxifen.100
The use of chemotherapy was found to reduce the probability of recurrence and the risk of death both for patients with lymph node–positive disease and those with lymph node–negative disease.98 The proportional reduction in recurrence and breast cancer mortality achieved with chemotherapy was very similar for both groups. However, because patients with positive lymph nodes have a much greater risk of recurrence and death from disease, the absolute percentage who benefit from chemotherapy is greatest in this cohort. Use of multiagent chemotherapy resulted in an improved outcome compared to single-agent chemotherapy. In addition, there was a significant benefit in using anthracycline (fluorouracil, doxorubicin, and cyclophosphamide [FAC] or fluorouracil, epirubicin, and cyclophosphamide [FEC]) chemotherapy compared to CMF chemotherapy. Finally, the benefits of chemotherapy varied according to patient age, with patients younger than 50 years of age achieving a greater proportional reduction in the risk of recurrence (proportional reduction of 36%) than patients 50 to 69 years old (proportional reduction of 29%). The respective proportional reduction in the annual death rates for these cohorts was 38% and 20%. Based on data from this analysis, Table 57.7estimates the 5-year risk of recurrence and the absolute magnitude of benefit polychemotherapy by age and lymph node status.98
Five years of tamoxifen therapy also provide a significant benefit in reducing recurrence (reduced by 47% through 10 years) and improving survival for patients with ER-positive disease (∼33% proportional reduction in breast cancer death rate).99 Tamoxifen provided a benefit for both younger and older patients with ER-positive or ER-unknown disease but did not provide a benefit for patients with ER-negative disease. The data indicate that 5 years of tamoxifen therapy provided better outcomes than 1 to 2 years of treatment. For patients with ER-positive, lymph node–negative disease not treated with chemotherapy, tamoxifen treatment reduced the 10-year risk from 34.8% (no tamoxifen) to 19.1% (tamoxifen). In the lymph node–positive cohort, the 10-year risk of recurrence was 57.0% versus 41.5%, respectively. Tamoxifen continued to provide clinically and significant improvements in similar patients also treated with chemotherapy.99
TABLE 57.8 REVIEW OF ADJUVANT TAXANE CHEMOTHERAPY TRIALS
TABLE 57.9 REVIEW OF ADJUVANT AROMATASE INHIBITOR TRIALS
More Recent Advances: Chemotherapy
There have been important incremental advances beyond the standard of anthracycline chemotherapy in more recent years, most notably the introduction of taxanes. Three of the most important recent trials that have shown a benefit for adjuvant taxanes after anthracycline chemotherapy are the CALGB 9344/Intergroup 0148 trial,101 the NSABP B-28 trial,102 and the BCIRG 001 trial.103 The design and results of these trials are given in Table 57.8. In aggregate, these trials indicated that the addition of taxanes to anthracycline chemotherapy provides an additional reduction in the risk of recurrence in the adjuvant treatment of breast cancer.
These individual trial results have been confirmed in meta-analyses of adjuvant taxane trials in breast cancer. The most recent analysis revealed that incorporating a taxane into anthracycline-based chemotherapy improved disease-free survival (hazard ratio, 0.83) and overall survival (hazard ratio, 0.85). The improvement was not affected by type of taxane, ER expression, number of positive lymph nodes, or menopausal status.104
Once taxanes became established as important components of adjuvant treatment of breast cancer, new trials began investigating the administration schedule of treatments. The CALGB 9741/Intergroup trial randomized patients receiving doxorubicin/ cyclophosphamide (AC) × 4 followed by paclitaxel × 4 or A × 4, paclitaxel × 4, and C × 4 to a schedule that delivered the drugs every 3 weeks versus a “dose-dense” schedule of giving the chemotherapy with growth factor support every 2 weeks.105 The finding from this trial indicated that the dose-dense therapy further improved disease-free survival (4-year disease-free survival rate was 82% [dose dense] vs.75% [every-3-week administration]).
Many oncologists want a less intensive chemotherapy regimen for patients with low-risk disease and for patients with comorbidities. For such patients, a practice changing trial from the US Oncology group compared four cycles of AC to four cycles of docetaxel/cyclophosphamide (TC). With 7-years of follow-up, the TC arm had statistically significant improvements in both disease-free rate (81% vs. 75%; p = .03) and overall survival (87% vs. 82%; p = .03).106
More Recent Advances: Hormonal Therapy
In addition to chemotherapy, hormonal therapy is indicated for all patients with ER- or progesterone receptor (PR)–positive disease. Tamoxifen is the preferred hormonal treatment for all premenopausal women who continue to have ovarian function after chemotherapy. For postmenopausal women, the use of an aromatase inhibitor is equally appropriate. Aromatase inhibitors have proven to be a significant advance in hormonally responsive breast cancer. Unlike tamoxifen, which directly blocks the estrogen receptor on tumor cells, aromatase inhibitors provide beneficial effects by decreasing circulating estrogen by inhibiting the conversion of adrenal testosterone–like hormones into estrogen. Accordingly, aromatase inhibitors do not carry some of the same proestrogenic effects that have been associated with tamoxifen, such as its potentially beneficial effects against osteoporosis and its potentially harmful effects of stimulating the endometrial lining.
After the safety and efficacy of aromatase inhibitors were established in postmenopausal women with ER-positive metastatic disease, these agents were studied in the adjuvant setting and also proved to be of clinical value. Table 57.9 reviews the results of three important recent adjuvant studies in which the use of an aromatase inhibitor was found to be superior to the previously established standard of 5 years of tamoxifen therapy. Based on the results of these trials, there are a number of options for postmenopausal patients, including anastrozole for 5 years, letrozole for 5 years, initial tamoxifen for 2 to 3 years followed by exemestane, or tamoxifen for 5 years followed by 5 years of letrozole.107–110
The Oxford group conducted a meta-analysis of trials comparing aromatase inhibitors versus tamoxifen.100 Aromatase inhibitors provided a 2.9% absolute decrease in the risk of recurrence in a cohort of 9,856 patients treated on trials directly comparing an aromatase inhibitor to tamoxifen. In addition, in trials that tested sequential tamoxifen/aromatase inhibitor versus tamoxifen alone, a 3.1% absolute decrease in recurrence was noted. Based on such data, American Society of Clinical Oncology published a clinical practice guideline recommending that postmenopausal women with hormone receptor–positive tumor receive a treatment that incorporates an aromatase inhibitor.111
More Recent Advances: Trastuzumab
One of the most significant recent advances in breast cancer treatment has been the introduction of trastuzumab into the adjuvant treatment for patients with tumors that have gene amplification of the HER2/neu gene. In 2005, the initial results of a series of randomized, prospective trials designed to evaluate whether the addition of trastuzumab increased the efficacy of adjuvant chemotherapy of patients with HER2/neu overexpression were published. The results of these studies were dramatic and indicated a significant incremental benefit for the use of trastuzumab over chemotherapy alone. Table 57.10 reviews the preliminary results of three of these studies.113–114,115,116 In the United States, the results of two similarly designed trials from the NSABP and the North Central Cancer Treatment Group were combined and after a median follow-up of 3.9 years indicated a 48% reduction in the relative risk of recurrence and a 31% reduction in the risk of death compared to anthracycline and taxane chemotherapy alone.112 In all trials, trastuzumab increased the risk for a decrease in cardiac ejection fraction, and it became more fully appreciated that patients treated with this agent require careful cardiac supervision. For most of these trials, patients who required radiation received trastuzumab concurrently during radiation treatments. No increase in cardiac events or other serious sequelae has been reported as a consequence of the concurrent use of trastuzumab and radiation.117
TABLE 57.10 REVIEW OF TRIALS EVALUATING ADJUVANT TRASTUZUMAB WITH CHEMOTHERAPY FOR PATIENTS WITH HER2/NEU–POSITIVE BREAST CANCER
FIGURE 57.6. Flow diagram of workup and treatment recommendations for patients who present with locally advanced breast cancer.
Treatment Algorithms for Locally Advanced Breast Cancer
Figure 57.6 shows an algorithm for the management of patients with locally advanced operable cancer and patients who present with either operable or inoperable disease. Neoadjuvant chemotherapy is the preferred initial treatment for patients with inoperable disease and for selected patients with advanced but operable disease who are interested in being treated with breast conservation therapy. For such patients, neoadjuvant chemotherapy should consist of a regimen that contains anthracyclines and taxanes, given in either a sequential or concurrent fashion. The rationale of using all agents “up front” rather than splitting the course of treatment is to give the therapy in the most dose-dense fashion. Patients with HER2/neu–positive disease are recommended to receive trastuzumab concurrent with the neoadjuvant taxane.
After neoadjuvant chemotherapy, all patients should undergo surgical resection. Mastectomy remains the standard of care for most patients with locally advanced disease, but breast-conserving surgery can be considered for carefully selected patients. Axillary lymph node dissection should be performed for all patients with involved axillary lymph nodes at the time of presentation, regardless of the clinical response of axillary disease to neoadjuvant treatment. Sentinel lymph node surgery is appropriate for patients who present with a clinical negative axilla prior to neoadjuvant chemotherapy. After surgery, adjuvant radiation to the breast, chest wall, and draining lymphatics should be offered to all patients with clinical stage III disease.
Some cases of advanced disease fail to respond to neoadjuvant chemotherapy, and such patients have a poor outcome. However, a small percentage of patients can achieve long-term survival with aggressive local-regional therapies. A study of 177 patients with advanced disease that was refractory to neoadjuvant chemotherapy reported a 10-year survival rate of 33% after aggressive local-regional treatments.118 Not surprisingly, patients with ER-positive disease had the best outcome, in part because effective systemic therapies were still available to them.
For patients in whom the disease remains inoperable after neoadjuvant chemotherapy, preoperative or definitive radiation remains the treatment of choice. Surgeons and radiation oncologists need to carefully coordinate the care of such patients, and the future operability of the breast needs to be considered early in the treatment course because radiation-induced breast edema and erythema can mimic the clinical findings of advanced breast cancer. A study of 38 patients who underwent radiation therapy with or without mastectomy after the disease remained inoperable after neoadjuvant chemotherapy found that 46% were alive and 33% were free of distant disease at 5 years after treatment.119 Those patients who were able to undergo mastectomy after preoperative radiation had the best local-regional control. Preoperative radiation led to surgical complications in 9% of patients treated with <54 Gy but in 70% of the patients treated to doses of ≥54 Gy.
Some centers have piloted concurrent chemoradiation strategies as neoadjuvant approaches. In one recent study of the use of neoadjuvant paclitaxel followed by concurrent paclitaxel–radiation for patients with operable stage II/III breast cancer, 13 of the 38 patients (34%) experienced pCR and acceptably low treatment toxicity.120 Another group of investigators also completed a phase I/II multi-institutional study of concurrent paclitaxel–radiation for 105 patients with locally advanced breast cancer and also found a pCR rate of 23%.121 Again, acceptable treatment toxicity was noted. However, because other investigators have found significant rates of pulmonary injury when paclitaxel and radiation were given concurrently to women with breast cancer, this approach is best taken within the context of a clinical research protocol.
Treatment Results for Locally Advanced Breast Cancer
As noted earlier in this chapter, stage III breast cancer historically has been associated with a very poor prognosis, with high rates of local-regional recurrence, distant metastases, and death. However, advances in all of the disciplines involved in breast cancer treatment have improved the outcome of such patients. With modern treatment strategies that include systemic therapy with taxanes and anthracyclines, appropriate surgical intervention, and local-regional irradiation, outcomes have significantly improved. With respect to local-regional control, a recent study evaluating outcome after mastectomy and radiation for patients with advanced disease that was initially treated with neoadjuvant chemotherapy reported a 10-year local-regional control rate of 89%.94 Patients with ER-negative disease and significant residual disease burden or skin invasion had rates of local-regional recurrence approaching 20%, whereas those without these features had excellent local-regional outcomes. As previously indicated, the risk of distant metastases has also significantly decreased over time. A reasonable estimate of 10-year survival rates for patients given modern treatments for stage III breast cancer is approximately 50%.9
Patients with supraclavicular lymph node disease at diagnosis have a poorer outcome than do other patients with stage III disease. However, because some studies of patients treated with chemotherapy have reported 10-year survival rates of 25%, the AJCC recategorized this stage of disease from stage IV to stage IIIC.122 The local-regional management of such disease should be the same as for stage III disease. A recent study investigating the outcome of 70 patients with supraclavicular disease who were treated with neoadjuvant chemotherapy, surgery, and radiation reported a 5-year local-regional control rate of 77% and a 5-year overall survival rate of 47%.94 Patients in whom the supraclavicular disease showed a CR to neoadjuvant chemotherapy had better outcomes than did those with persistent disease after chemotherapy.
GENERAL MANAGEMENT AND TREATMENT RESULTS FOR INFLAMMATORY BREAST CANCER
Because inflammatory breast cancer is relatively uncommon, no data from randomized studies are available regarding the optimal therapeutic approach for this disease. In general, however, it is clear that management of inflammatory breast cancer requires carefully integrated care by a multidisciplinary team. Ideally, such patients should be evaluated in a multidisciplinary center by all specialists at the time of presentation to confirm the diagnosis of inflammatory disease, document the extent of disease (including photographs of areas of involved skin), and agree on a treatment plan. Inflammatory breast cancer is considered inoperable at presentation and should be treated initially with neoadjuvant chemotherapy (with consideration of trastuzumab if the tumor is HER2/neu–positive). Patients should be carefully monitored for response, and after achievement of the maximal clinical response, patients should be reevaluated for mastectomy. About 80% of patients with inflammatory breast cancer will achieve a clinical response, and their disease will become operable.123 All patients should receive postmastectomy radiation therapy delivered to the chest wall and the draining lymphatics.
The optimal chemotherapy regimen for patients with inflammatory breast cancer includes both anthracyclines and taxanes. The introduction of anthracycline chemotherapy, when combined with local-regional treatments, provided the first evidence of treatment efficacy in this disease. Investigators at MD Anderson conducted a series of single-group prospective trials for patients with inflammatory breast cancer and found that neoadjuvant chemotherapy with FAC followed by local-regional therapy led to a 5-year survival rate of 25%. Subsequently, these investigators introduced sequential FAC or FEC followed by weekly paclitaxel and reported that the addition of taxanes improved the progression-free and overall survival of patients with inflammatory disease.123
Local-regional treatment is an essential component of therapy for inflammatory disease. Before the routine use of chemotherapy, mastectomy, with or without postmastectomy radiation, was associated with a dismal prognosis, and so many physicians abandoned mastectomy in favor of radiation-only treatments. Outcomes after radiation therapy as the sole treatment modality were equally poor. After neoadjuvant chemotherapy became routine, combinations of surgery and radiation have been reevaluated.
De Boer et al.124 published results of a study of 54 patients with inflammatory breast cancer treated after neoadjuvant chemotherapy with either radiation only (n = 35) or mastectomy plus radiation (n = 19). For the patients treated with radiation only, the median progression-free survival time was only 16 months and the local recurrence rate was 34%. However, because these results were not statistically different from those for patients treated with mastectomy, the authors concluded that surgery provided no clinical advantage over chemotherapy and radiation alone. In contrast, Perez et al.125 found that the addition of mastectomy to local treatment significantly improved the outcome of inflammatory breast cancer treatment. Patients given neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation had a local control rate of 79% and a 5-year disease free survival of 40%. These data were also supported by Panades et al.,126 who evaluated 308 patients given chemotherapy as a component of their treatment and found that the 10-year local-recurrence-free survival rates were significantly better for patients who underwent mastectomy than for those who did not (about 60% vs. 34%, respectively; p = .0001), as were the 10-year breast cancer–specific survival rates (about 34% with mastectomy vs. 23% without, p = .005). A multivariate analysis that considered other potential prognostic factors found that the use of mastectomy remained a significant factor for improved local recurrence–free survival (p = .04). Results from an MD Anderson study also confirmed these results, with multivariate analysis revealing that a complete or partial response to neoadjuvant chemotherapy, the use of radiotherapy, and the addition of mastectomy to the therapeutic regimen all significantly improved disease-specificsurvival.127
More recent studies have focused on whether breast conservation can be safely performed for patients who achieved a CR to neoadjuvant chemotherapy.125,128,129,130 Some series reported favorable control rates.130 However, Swain and Lippman131 reported a local recurrence rate of 30% despite their patients having achieved a clinical CR to neoadjuvant chemotherapy and multiple negative biopsies before irradiation. Low and colleagues128 also reported a 40% local recurrence rate in 15 patients with inflammatory breast cancer treated with radiation therapy alone after a biopsy-proven CR. Finally, Brun and colleagues129 reported a 54% local failure rate with attempts at breast conservation, and Chevallier and colleagues132 reported a 61% local failure rate in patients treated with breast conservation after they had achieved a CR to neoadjuvant chemotherapy.
Radiation therapy also has an important role in the management of inflammatory breast cancer. After neoadjuvant chemotherapy and mastectomy, radiation use can be associated with local-regional control rates of >80%.133However, these results have been achieved with high-dose, aggressive treatments. Because inflammatory breast cancer has a rapid doubling time, investigators from MD Anderson investigated an accelerated hyperfractionated radiation delivery schedule in which 51 Gy is delivered to the chest wall and draining lymphatic fields by giving 1.5 Gy twice a day.133 Subsequently, the chest wall is boosted to an additional 15 Gy, given in ten 1.5-Gy fractions twice daily. That approach was found to significantly improve local-regional disease control among patients treated to the 66-Gy total dose compared with a group treated only to 60 Gy on this schedule, with the respective 10-year local-regional control rates being 77% versus 58% (p = .04). Statistically significant improvements were also seen in 5- and 10-year overall survival rates between these two groups (p = .03), and a trend toward improvement in 5- and 10-year disease-free survival rates was noted as well (p = .06). In a more recent update from these investigators in which the outcome of 192 patients treated with neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation was evaluated, the authors reported a 5-year local-regional control rate of 84%.134 Factors associated with higher rates of local-regional control included partial response to chemotherapy, negative margins, three or fewer positive lymph nodes, and the use of taxane chemotherapy.134
Inflammatory breast cancer outcome is also affected by biologic subtype, as determined by ER, PR, and HER2/neu status. An update of the MD Anderson inflammatory breast cancer experience analyzed 316 patients with nonmetastatic inflammatory breast cancer treated with curative intent between 1974 and 2008 who had known ER, PR, and HER2/neu status.135 The 5-year rate of locoregional recurrence in patients with triple-negative disease was much higher than that for other subtypes—39% despite aggressive local-regional treatments—and the 5-year rate of distant metastasis was 57%.135 New therapeutic targets are needed in such patients, and recent research has identified potential biologic roles of NF-κB, Rho C GTPase, WISP3, and E-cadherin.136
In summary, all patients with inflammatory breast cancer require management by a multidisciplinary team. After initial staging and careful documentation of the extent of disease, patients should receive initial chemotherapy. The chemotherapy course should include both an anthracycline and a taxane, which can be given either concurrently or sequentially. Anti-HER2 therapy (trastuzumab) should given with chemotherapy for patients with HER2/neu–positive disease. The majority of patients who exhibit a disease response and become operable should then undergo a modified radical mastectomy. Postmastectomy radiation treatments to the chest wall and draining lymphatics should be given as adjuvant therapy. This approach was recently endorsed by a consensus panel of inflammatory breast cancer experts.137 The dose of radiation to the initial fields should be 50 Gy in 25 fractions given once a day or 51 Gy in 1.5-Gy fractions given twice a day. Subsequently, the chest wall and any areas of gross disease that has not be resected should be boosted to 60 to 66 Gy. Patients with ER-positive disease should also receive hormonal therapy. Some patients will continue to have inoperable disease after neoadjuvant chemotherapy. These patients should receive either preoperative radiation to the breast and draining lymphatics to a dose of 50 to 51 Gy, or, if the disease is unlikely to become resectable, high-dose (72 Gy) definitive radiation is indicated using a reduced-field technique.
Clearly great strides have been made over the last two decades in the management of inflammatory breast cancer, and patients whose disease is managed with trimodality therapy can have local-regional control rates >80% and 5-year survival rates of ≥40% or more. Improvements in systemic therapy will, it is hoped, further augment these results.
GENERAL MANAGEMENT AND TREATMENT RESULTS FOR LOCALLY OR REGIONALLY RECURRENT BREAST CANCER
The development of a local-regional recurrence after primary treatment of an invasive breast cancer, particularly for those treated with an initial mastectomy, often develops into life-threatening condition. Accordingly, all patients should undergo disease restaging at the time of recurrence to rule out metastatic disease. All patients with local-regional recurrence should also have a biopsy for histopathologic confirmation and for re-evaluation of hormone receptor and HER2/neu status.
Local-regional recurrences are relatively uncommon, and patients with local-regional recurrences represent a heterogeneous group. Therefore, treatment strategies must be tailored to individual cases.
Recurrence in the Breast After Breast Conservation Therapy
Mastectomy remains the standard salvage treatment for disease that recurs in the breast after breast-conserving treatment. Most such patients will have been previously treated with breast irradiation and therefore would not be candidates for a breast-conserving approach. However, some single-institutional studies investigated additional breast-conserving surgery with or without radiation. Salvadori et al.138 compared the outcome of 134 patients treated with mastectomy for a localized breast recurrence to 54 highly selected patients treated with a second breast-conserving surgery alone. They found that a second breast recurrence was more common at 5 years in the re-excision group (19% vs. 4%). Komoike et al.139 also reported a relatively high rate (30%) of a second breast relapse after local surgery only for recurrent disease. Experience with giving a second course of radiation therapy following local resection of a breast recurrence has also been limited, with most approaches being limited to a partial breast reirradiation strategy. Deutsch et al.140 treated 39 women with 50 Gy to the operative area using electrons after a repeat lumpectomy for an intact breast recurrence but reported a rate of second recurrence of 23%. Resch et al.141 treated 17 ipsilateral breast tumor recurrence patients with pulse-dose-rate brachytherapy following repeat lumpectomy and noted a second breast recurrence in 5. Finally, in the largest series to date, Hannoun-Levi et al.142 treated 69 highly selected patients with interstitial brachytherapy after a second lumpectomy for an intact breast recurrence and after a median follow-up of 50 months reported that 11 (16%) developed a second recurrence. Grade 2-3 late complications developed in 0% to 32% of the patients, depending on the radiation dose.
Patients with recurrence in the breast are also at risk of axillary metastases. Patients who initially underwent sentinel lymph node surgery should have an axillary lymph node dissection at the time of recurrence. The use of systemic therapy after breast recurrence needs to be decided on an individual basis according to the risk of metastatic disease, the previous systemic treatments used, and hormone receptor status.
Several investigators have investigated prognostic factors associated with outcome for patients with breast recurrence after treatment for an invasive breast cancer. Quite consistently through these studies is the finding that patients with an interval to development of recurrence of <2 years have a worse outcome than those who develop recurrent disease many years after treatment. In part, this may be explained by the hypothesis that early breast recurrences develop from repopulation of persistent microscopic disease, whereas some late breast recurrences represent a new primary tumor. Investigators from Yale University were among the first to provide insights into the prognostic importance of this distinction. These authors evaluated a series of 136 such patients and used clinical criteria to classify recurrences as either true recurrences or new primary tumors.143 New primary tumors were defined by one of the following: location in the breast remote from the original tumor bed site, a change in histology, or a change from aneuploid to diploid status. Subsequently, investigators from MD Anderson undertook a similar analysis of 139 patients with in-breast recurrences. Both studies found that patients considered to have new primary tumors had significantly longer intervals between their initial primary tumor and the recurrence and had significantly lower rates of distant metastasis and death after the recurrence.144 These data were later validated by this group in a study of 447 patients.145 These findings may be valuable in decisions regarding systemic treatments.
Reconstructive surgery can also be considered for patients treated with mastectomy, but the previous history of breast radiation may limit the success of implant-based procedures. Forman et al.146 reported significant complications in 6 of the 10 patients in whom a tissue expander and implant was attempted after mastectomy in the setting of an ipsilateral breast recurrent treatment. Autologous tissue reconstruction may provide better outcomes. Moran et al.147reported on 14 patients who underwent free TRAM flaps with anastomosis to the thorocodorsal vessels in patients being treated for a breast recurrence. The complication rate was only 14%, and the aesthetic result was rated as excellent.
Local-Regional Recurrence After Mastectomy
Patients with recurrent disease after initial mastectomy have a worse prognosis than those with recurrent disease after initial breast conservation therapy. In the Canadian and the Danish prospective studies that evaluated postmastectomy radiation, patients who developed local-regional recurrence had very high rates of subsequently developing metastatic disease.71,148 In the Danish trial, the 5-year rate of distant metastatic disease development after an isolated local-regional recurrence was 73%, and the rate was no different for those in whom disease recurred after mastectomy only versus those with recurrent disease after mastectomy and radiation.148 Similarly, in the Vancouver trial, of the 39 patients who developed a local-regional recurrence, 37 eventually developed metastatic disease.71
Several publications have provided insights into the factors of prognostic significance for patients with local-regional recurrence after mastectomy. One of the largest series was an analysis of the 535 patients who developed a postmastectomy recurrence after treatment in the Danish 82b and 82c randomized trials.148 In multivariate analyses, the investigators found the following factors to be associated with a poorer outcome: large initial primary tumor and high number of positive lymph nodes, extracapsular extension, recurrence in the infraclavicular or supraclavicular regions, and a disease-free interval of <2 years. Other series have reported similar findings. In general, patients who present with chest wall recurrence, particularly those who have resectable disease and have not undergone radiation, have a greater probability of disease control and improved outcome. Investigators from MD Anderson found that initial nodal status, time to recurrence, and ability to use radiation to treat the recurrence were all independent predictors of outcome for patients with a chest wall recurrence.149 The 19 patients in whom these three factors were favorable had a 5-year overall survival of 86% (median survival time, 141 months). The 5-year survival rate for the 89 patients who had one or two unfavorable features was 48% (median survival time, 54 months), and all 22 of the patients who had all three unfavorable factors died within 5 years of the recurrence (median survival, 16 months). Outcome for patients with T1/T2 disease with one to three positive lymph nodes was as poor after a local-regional recurrence as was the outcome for patients with four or more positive lymph nodes.150 In contrast, patients with initial lymph node–negative disease had a significantly better outcome.
Few data are available to quantify the benefits of systemic therapy for patients with local-regional recurrence. In one of the few series evaluating this issue, authors from British Columbia found in a nonrandomized study that use of chemotherapy at the time of recurrence reduced the probability of death from breast cancer, but this difference was not statistically significant compared with those who did not have chemotherapy at recurrence (p = .07). Finally, a randomized trial that investigated tamoxifen use versus no systemic therapy after salvage local therapy for patients with recurrent disease after mastectomy found improvement in 5-year disease-free survival from 36% to 59% (p = .007),151 supporting the use of systemic treatments in the management of patients with recurrent disease.
Investigators from MD Anderson conducted a series of four prospective single-group protocols evaluating systemic therapies for patients with either local-regional recurrence or metastatic disease that was converted to “no evidence of disease” after surgery, radiation, or both.152 The findings suggest that for patients with anthracycline-naive disease, the introduction of doxorubicin at the time of recurrence can lead to improved survival, and more recently the use of docetaxel also seemed to lead to favorable outcome for patients who had previously had anthracycline treatment. The 3-year disease-free survival rate for such patients was 58%.152
The general management strategy for an isolated local-regional recurrence after mastectomy requires input from a multidisciplinary team. The initial evaluation should define the sites of disease involvement and determine whether the patient is able to undergo resection of all gross disease with negative surgical margins. Surgical therapy is recommended for patients with resectable disease, provided the patients can tolerate the surgery and the morbidity of the surgery is acceptable. After surgery, if the patients had not previously been given radiation therapy, they should receive comprehensive local-regional radiation. A study from Washington University found that patients who had radiation therapy to the chest wall and regional lymphatics had better outcomes than those in whom radiation fields were limited to the site of the recurrent disease.153 Finally, because patients with recurrent disease after mastectomy are at high risk of developing distant metastatic disease, those who have not been previously treated with anthracyclines or taxanes (or trastuzumab if the tumor is HER2/neu–positive) should strongly consider treatment with these agents.154 Patients with ER-positive disease should receive appropriate second-line endocrine therapy.
Patients presenting with bulky, unresectable disease should be considered for neoadjuvant chemotherapy if active systemic agents are available. If the disease responds favorably, some of these patients may become candidates for surgical resection, which then can be consolidated with comprehensive radiation. The prognosis for those whose disease fails to respond is very poor, and radiation treatments alone are unlikely to render such patients free of disease. Nevertheless, aggressive local-regional radiation is often used to help stabilize the disease and to avoid the significant adverse consequences of uncontrolled growth of local-regional disease. The dose of radiation to be used depends on the presence or absence of gross disease and whether patients have previously undergone radiation therapy. For patients who have not had radiation therapy and do not have gross disease, we recommend comprehensive treatment to the chest wall and draining lymphatics to a dose of 50 to 54 Gy followed by a boost to the chest wall to 60 to 66 Gy. Hyperfractionated chest wall irradiation does not seem to provide any benefit over that of conventional therapy given once daily.155 For patients who develop recurrences in a chest wall that has been previously irradiated, the treatment options are more difficult. Investigators from Duke University have had some success with combining a second course of radiation with chemotherapy and hyperthermia.156
Regional Nodal Relapse
Patients with regional relapse have a less favorable prognosis than patients with intact breast or chest wall recurrences. In general, patients with isolated resectable disease in the low axilla should be treated with axillary dissection, comprehensive radiation to sites not previously treated, including the chest wall, and systemic therapy. Most patients with recurrence in the supraclavicular fossa or internal mammary lymph nodes have unresectable disease. If active chemotherapy agents are available, it is reasonable to consider using neoadjuvant systemic treatment and consolidating with radiation at the point of maximal response. Woodward et al.157 investigated the outcome of 140 patients with local-regional recurrence after mastectomy and doxorubicin chemotherapy and found that the 47 who had supraclavicular disease at the time of recurrence had a worse outcome than the remaining patient with recurrences in other sites (3-year distant disease-free survival of 40% vs. 54%, respectively; p = .003).
GENERAL MANAGEMENT AND TREATMENT RESULTS FOR UNUSUAL PRESENTATIONS OF BREAST CANCER
Axillary Metastases with Unknown Primary
The presentation of metastatic disease within axillary lymph nodes without an identifiable primary source is unusual, accounting for <1% of newly diagnosed breast cancer cases.158–160 Workup for patients who present with axillary disease with an occult primary should initially be aimed at establishing the diagnosis and whether the disease represents a distant metastasis from a different site. Initial evaluation should include a history and physical examination (with particular attention to a skin exam to rule out an unsuspected truncal melanoma), routine serum studies, bilateral mammography, chest radiography, liver imaging, and bone scan. If no primary disease is detected with mammography, ultrasound and MRI scan of the breast is indicated. Cytologic confirmation of disease within axillary lymph nodes can be obtained with ultrasound-guided fine needle aspiration. Tumor markers, including ER, PR, and HER2/neu, can and should be performed on the cytologic specimens. Most individuals present with advanced nodal disease at presentation and are clinically staged as having T0 N2-3 disease.
Modified radical mastectomy and postmastectomy radiation have been the historical local-regional treatments for patients with an occult breast primary and axillary metastases. Studies vary significantly with respect to the frequency with which a primary is found within the breast during pathologic examination. In addition, most of these studies predate the use of MRI screening or other improvements in diagnostic imaging. In general however, approximately two-thirds of the cases are found to have an invasive breast cancer on pathologic examination of a mastectomy specimen.158 Patients with inoperable nodal disease at presentation are treated with neoadjuvant chemotherapy prior to mastectomy. For such individuals, the probability of finding disease within the breast is likely even lower.
More recently, a number of investigators have investigated the safety of breast conservation therapy for patients with occult primary disease. An optimal treatment strategy for such patients can consist of neoadjuvant chemotherapy, reimaging of the breast to evaluate for calcifications resulting from tumor cell death, axillary dissection, and irradiation of the breast and draining lymphatics. Early attempts at breast conservation without breast irradiation resulted in high subsequent breast recurrence rates.161,162 More recent studies that incorporate breast irradiation have yielded better results. In one of the largest series, investigators from MD Anderson evaluated 45 patients treated over a 47-year period and compared the outcome of those treated with mastectomy (n = 13) to those treated with breast conservation (n = 32).159 These authors found equivalent rates of local-regional control, disease-free survival, and overall survival between the mastectomy and breast conservation cohorts. With a median follow-up of 7 years, only 2 of the 25 breast conservation patients who received breast irradiation developed a local recurrence. Similar results have been reported from the Royal Marsden Hospital. In a series of 48 patients, they found a 14% local-regional recurrence rate after breast radiation and an unacceptable rate of 80% if breast radiation was omitted.163
Male Breast Cancer
Breast cancer developing in males is unusual. The American Cancer Society estimated that there would be 2,140 new cases of male breast cancer in the United States in 2011, which would account for only 0.9% of the total new breast cancer cases. It is also estimated that 450 men would die of breast cancer during 2011.5 The ratio of the number of deaths to new cases is 21% for males, compared to a ratio of 17% for females.5
There are several known risk factors for male breast cancer. Similar to female breast cancer, breast cancer is more common in elderly men than in young men. Some conditions that affect testosterone and estrogen levels can increase the risk of breast cancer in men. Examples of some of such conditions include a history of an undescended testicle, history of orchiectomy, and Klinefelter’s syndrome.164 In addition, genetic conditions also can contribute, and men with a family history of female breast cancer have an increased risk. Germline mutations in the BRCA2 gene have been reported in 4% to 16% of men with breast cancer, and, unlike the situation for females, are more common than germline mutations in BRCA1.165,166
Males have a similar histopathologic spectrum of breast cancers, with the exception of having lower rates of invasive lobular disease. In addition, male breast cancers more frequently are ER-positive (estimated rate of 90%) and HER2/neu–negative compared to female breast cancer.167 The presenting symptom for male breast cancer patients is typically a breast mass or axillary adenopathy. Most male breast cancer patients present with locally advanced disease. Diagnostic workup is similar to that for female breast cancer and should include bilateral mammography. Treatment decisions are also similar to those used in women. Men tend to present with more advanced clinical stage disease than females and correspondingly have worse outcome as a population. A study evaluating 1988–2003 SEER Program data found that although men were noted to have more advanced disease compared to females, when comparing outcome specifically for those with stage II or stage III disease there were no gender-specific differences.167
Mastectomy with or without postmastectomy radiation is the most common local-regional treatment approach. Investigators at MD Anderson reviewed 142 patients treated with mastectomy without radiation therapy and found that, similar to female patients, margin status, number of positive nodes, and tumor size predicted local-regional failure.93 Accordingly, decisions concerning postmastectomy radiation should be based on similar criteria used in the treatment of female breast cancer.
Similarly, systemic treatments are indicated for male breast cancer patients who have a clinically relevant risk of distant metastases. Data supporting the use of particular chemotherapy regimens are lacking, given the rarity of the disease. In addition to chemotherapy, because most male breast cancers are hormonally responsive, tamoxifen is indicated for the majority of cases. Retrospective series suggested that tamoxifen use can reduce the risk of recurrence and death.168 The role of aromatase inhibitors in males is under investigation.
TABLE 57.11 RATE OF PATHOLOGIC INVOLVEMENT OF INTERNAL MAMMARY LYMPH NODES IN PATIENTS WHO UNDERWENT EXTENDED RADICAL MASTECTOMY172
RADIATION TREATMENT TECHNIQUES AFTER MASTECTOMY
Target Definitions
Traditionally, postmastectomy radiation therapy included treatment to the chest wall and draining lymphatics in the undissected axillary apex/supraclavicular fossa. It is clear from pattern-of-failure studies from patients treated with mastectomy without radiation that the chest wall is the most common site of recurrent disease, accounting for two-thirds to three-fourths of all local-regional recurrences. It is also clear that patients with stage III disease (T3 N1, T4, or pathologic N2-3 disease) have a clinically relevant risk of recurrence in the axillary apex/supraclavicular fossa. A study of >1,000 patients who did not receive radiation after treatment with mastectomy and chemotherapy found the 10-year risk of recurrence in the axillary apex/supraclavicular fossa to be 14% to 19% for patients with four or more positive lymph nodes, 20% or greater positive lymph nodes, or extracapsular extension of disease that measured >2 mm.169
The benefit or radiation for treatment of the dissected level I/II axilla is less clear. In this same study, in which all patients had a standard axillary lymph node dissection (median number of lymph nodes recovered, 17), the 10-year risk of recurrence in this region was only 3% and not predicted by the extent of axillary disease or extracapsular extension.169 In contrast, 43% of the patients treated in the no-radiation arms of the Danish postmastectomy radiation trials and who developed a local-regional recurrence had the axilla as a component of their local-regional recurrence.72 The higher recurrence rate in the axilla likely was a consequence of a less extensive axillary level I/II dissection (median number of lymph nodes recovered was 7) in the Danish studies. These data, taken together, suggest that the decision to include the level I/II as a target for postmastectomy radiation in large part is determined by the completeness of the axillary dissection.
The treatment of the internal mammary lymph nodes for patients treated with postmastectomy radiation is controversial and the subject of ongoing phase III studies. The justification for including this region is based on previous experiences of dissecting the internal mammary chain, which found that up to 35% to 50% of patients with clinically advanced disease will have microscopic involvement of lymph nodes within this region.170,171 Table 57.11 shows the rates of internal mammary lymph nodes involvement from a more recent study of 2,269 patients from China who underwent resection of these nodes as a component of an extended radical mastectomy.172 The randomized trials that have shown a survival advantage for postmastectomy radiation included the internal mammary lymph nodes within their treatment target volume.69,70,73 Finally, inclusion of the internal mammary lymph nodes provides a broader coverage of the chest wall, which may prove to be secondary benefit in avoiding marginal misses.
When radiation is used after mastectomy for patients with stage II breast cancer, the appropriate target volumes are less clear. Patients with stage II breast cancer with one to three positive lymph nodes fail predominantly on the chest wall and have a much lower risk of recurrence in the axillary apex/supraclavicular fossa. In a site of failure analysis cited earlier, the risk of recurrence in the axilla/supraclavicular fossa for patients with one to three positive lymph nodes and no extracapsular extension was only 4%.169 For these reasons, some have advocated treatment of the chest wall only in such patients. However, the trials showing a survival advantage for the use of postmastectomy radiation included the axillary apex/supraclavicular fossa within the treatment fields, and more recent data of the MA-20 trial discussed in Chapter 56, suggests some benefits of lymphatic drainage for patients with stage II disease.
CT simulation is very useful to precisely delineate target volumes. For example, the internal mammary vessels within the first three intercostal interspaces, which are where lymph nodes at risk within this region are located, can be easily identified and contoured. Likewise, the depth of the level III axilla and supraclavicular fossa varies greatly according to individual anatomy and patient weight. Contouring the region helps to ensure that these targets fall within the desired isodose lines. A recent analysis that evaluated various dose prescriptions used for supraclavicular field treatments found that 6-MV photons prescribed to Dmax or a depth of 3 cm significantly underdosed contoured lymph node regions at risk in overweight and obese patients (defined according to patient body mass index).173 Finally, for patients who require treatment to the low axilla, contouring the region at risk also helps to more precisely conform the dose distribution to the area in need of treatment.
Technique
Patients should be immobilized with their ipsilateral arm abducted (90 to 120 degrees) and externally rotated. In assessing arm position, it is important to have the soft tissues of the arm cranial to the junction of the tangent and supraclavicular fossa field. In addition, skin folds within the supraclavicular fossa should be avoided if possible. Patients are placed on a 10- to 15-degree angle board to flatten the slope of the chest wall in the region of the sternum. Radiopaque wires are placed on the mastectomy scar, and the patient undergoes a treatment-planning noncontrast CT scan. The border between the chest wall and the supraclavicular fields is typically placed at the bottom of the clavicular head. Appropriate isocenters and setup points are determined and marked. Targeted areas of interest are then contoured on the CT slices.
Several techniques are available treat the chest wall and internal mammary lymph nodes. One of the more common methods is to use a 15- to 25-degree obliqued electron field to treat the medial chest wall and internal mammary lymph nodes. The lateral border of this field is then matched on the skin to a pair of photon tangent fields that treat the lateral chest wall and are created with matched nondivergent deep and cranial borders. A nondivergent cranial border is created through rotation of the couch, and a nondivergent deep border is achieved by overrotating the gantry or a half-beam block. The collimators are rotated to match the chest wall slope, and any volume that extends into the supraclavicular field is blocked. An alternative technique that is particularly of benefit for patients with very little tissue between the lung and skin is to use three electron fields. The junction of such fields should be moved every week to minimize the consequences of the required gantry rotation necessary to make the fields apposition for the lateral chest wall. These fields are then match to a supraclavicular/axillary apex field, which has been described in Chapter 56. For patients with advanced disease, the supraclavicular lateral field edge is often extended to give margin on the superior-lateral chest wall and to provide treatment of the anterior interpectoral Rotter’s lymph nodes.
FIGURE 57.7. Images of radiation treatment fields to treat the chest wall and internal mammary lymph nodes. In this case, two medial electron fields were angled 15 degrees toward a matched pair of photon fields. The energy of the upper electron field is higher than that of the lower electron field in order to achieve coverage of the contoured internal mammary target while minimizing the dose to the heart. A: Skin surface rendering of the fields. B: Upper axial image. C: Lower axial image in the region of the heart. (From Buchholz TA. Locally advanced breast cancer. In Haffty BG, Wilson L, eds. Handbook of radiation oncology. Sudbury, MA: Jones and Bartlett, 2008.)
Figures 57.7 to 57.9 show examples of matched electron, tangent fields; chest wall electron-only fields; and a supraclavicular/axillary apex field. All chest wall radiation fields should be designed to avoid irradiating the heart. The advantages of the field designs described here is that with the use of CT treatment planning, the beam arrangement and selection of electron energies can be determined so that cardiac irradiation is avoided or minimized.
FIGURE 57.8. Images of radiation treatment fields using a matched electron field technique to treat the chest wall and internal mammary lymph nodes. Three medial electron fields are matched on the skin. The junction between the middle and lateral fields is shifted weekly due to the differences in gantry angle. A: Skin surface rendering of the fields. B: Axial image of the fields.
FIGURE 57.9. Images of a radiation treatment field used to treat the axillary apex/supraclavicular fossa. The level III region of the axillary and the upper internal mammary vessels have been contoured on axial computed tomography images and reconstructed on this image. These contours are used to determine depth of dose prescription. (From Buchholz TA. Locally advanced breast cancer. In Haffty BG, Wilson L, eds. Handbook of radiation oncology. Sudbury, MA: Jones and Bartlett, 2008.)
Dosimetry and Dose
Initial fields and target volumes should be treated to a total dose of 50 Gy in 25 fractions over 5 weeks. A 3- to 5-mm bolus is used over the chest wall every other day or every day for 2 weeks (20 Gy total dose) and then as needed to ensure that a brisk radiation dermatitis develops. However, this dermatitis should not lead to a treatment interruption. There are no studies evaluating the optimal total dose, but in our institution we boost the chest wall with electron fields (5 to 10 cm beyond the mastectomy scar and covering the tumor bed location of the original primary) for an additional 10 Gy in 5 fractions over 1 week beyond the initial 50-Gy course. In addition, we boost all sites of unresected but initially involved adenopathy in the internal mammary, infraclavicular, and supraclavicular regions with a radiation boost. If ultrasonography has shown a resolution of disease in these areas to ≤1 cm, we treat this region with an additional boost of 10 Gy. If >1 cm of disease persists, we increase the boost dose to 16 Gy.
Three-dimensional treatment-planning systems allow for evaluation of dose distributions in multiple off-axis slices and calculations of dose using heterogeneity correction factors. Dose distributions can be modulated through standard wedge compensators or field-in-field techniques. Electron energies for the medial chest wall/internal mammary lymph node fields should ensure that the 90% isodose curve covers the contoured volume and avoids irradiation of the heart. In addition, the supraclavicular dosimetry should be checked to verify that the 90% isodose curve fully covers the undissected level III axilla.
POSTMASTECTOMY RADIATION AND BREAST RECONSTRUCTION
Coordination of radiation and breast reconstruction is a commonly encountered issue for patients treated with mastectomy and requires clear communication between surgical oncologist, reconstructive/plastic surgeon, radiation oncologist, and the patient. There are many factors to consider regarding the issue of reconstruction and postmastectomy radiation, including ensuring the safety and efficacy of radiation treatments, ensuring the maximal quality of life for the patients, and achieving the optimal long-term aesthetic result from the procedure.
The two major classes of reconstruction are implant-based approaches and autologous tissue reconstruction. The two options for timing for the reconstruction are immediate—done at the time of mastectomy—or delayed—done after completion of radiation. There are advantages and disadvantages of both approaches and both timings. Implant-based approaches are simpler surgical procedures that avoid the donor-site morbidities of autologous tissue transfers. In addition, implants can be used in thin women who do not have adequate volume of autologous tissue in donor sites. Typically, for this procedure, a tissue expander is placed under the pectoralis major muscle and, after full expansion is achieved, replaced with an implant. Most women treated with postmastectomy radiation who undergo implant-based reconstruction require an immediate reconstruction procedure. This is because after radiation the normal tissues are less compliant, and tissue expanders are often unsuccessful and may cause rib fractures and other injuries. For women treated with autologous tissues, the reconstruction can be immediate or delayed. Immediate reconstruction has the benefit of being accompanied by a skin-sparing mastectomy, which preserves a significant component of the normal breast skin and preserves the natural inframammary sulcus and other skin envelopes. These elements are important to achieving the optimal cosmetic outcome. The downsides of immediate reconstruction relative to delayed reconstruction are twofold: radiation has adverse effects on the long-term aesthetics of breast reconstructions, particularly implant-based reconstruction, and reconstruction has a negative effect on the design and delivery of radiation treatment fields.
Effects of Radiation on Reconstruction
The majority of patients who undergo an immediate reconstruction and require postmastectomy radiation will have an aesthetic change as a consequence of treatments. In general, implant-based reconstruction has high rates of late contraction, fibrosis, implant fixation, and poor aesthetic outcome. Many of these changes begin 6 months after treatment and insidiously progress over time. Spear et al.174 reviewed the data on breast reconstruction with implants and found that 53% complication rate after radiation compared to a 10% rate in those who did not require radiation (p < .001). Fox Chase investigators reported a 27% rate of significant complication after irradiation of tissue expander or implant.175 MD Anderson investigators reported and even higher rate of 40% to 50% unless the implant was combined with an autologous tissue flap.176
Complications also develop for patients treated with an immediate autologous tissue reconstruction followed by radiation, although the effects, although common, may be less severe than implant-based approaches. Investigators from MD Anderson compared complications in patients treated with radiation and autologous tissue reconstruction. Those with an immediate reconstruction had a higher rate of complications compared to those with a delayed reconstruction (87.5% vs. 8.6%, respectively; p < .001).177 Furthermore, 28% of the patients with immediate reconstruction required an additional flap to improve aesthetics.
Effects of Reconstruction on Radiation Treatment and Delivery
Reconstruction affects the contour of the chest and can make the delivery of radiation to the appropriate targeted areas more challenging. Overinflated tissue expanders can cause significantly sloping contours at field junction between chest wall and internal mammary fields and between chest wall and supraclavicular/axillary apex fields. As a consequence, compromises are sometimes necessary in order to deliver the treatment safely. A study evaluated the effects reconstruction had in radiation treatment field designs in 112 postmastectomy radiation plans.178 These authors reported that compromises in the field design were made in 52% of these cases because of the geometric constraints caused by the reconstruction (33% were considered moderate compromises and 19% major compromises). In a matched control set treated with mastectomy without reconstruction, only 7% of cases had compromises in plans due to patient anatomy.179,180
REFERENCES
1. Haagensen CD, Cooley E. Radical mastectomy for mammary carcinoma. Ann Surg 1969;170:884.
2. Haagensen CD, Stout AP. Carcinoma of the breast: criteria of inoperability. Ann Surg 1943;118:859–870.
3. Fracchia AA, Evans JF, Eisenberg BC. Stage III carcinoma of the breast - A detailed analysis. Ann Surg 1980;192:705.
4. American Cancer Society. Breast cancer facts and figures 2009–2010. Atlanta, GA: American Cancer Society, 2009:1–6.
5. American Cancer Society. Cancer facts and figures 2011. Atlanta, GA: American Cancer Society, 2011:1–10.
6. Li CL, Malone KE, Daling JR. Differences in breast cancer hormone receptor status and histology by race and ethnicity among women 50 years of age and older. Cancer Epidemiol Biomarkers Prev 2002;11:601–607.
7. Elledge RM, et al. Tumor biologic factors and breast cancer prognosis among white, Hispanic, and black women in the United States. J Natl Cancer Inst 1994; 86:705–712.
8. Levine P, et al. Inflammatory breast cancer. The experience of the Surveillance Epidemiology and End Results (SEER) Program. J Natl Cancer Inst 1985;74:291–297.
9. Hortobagyi GN, Singletary SE, Buchholz TA. Locally advanced breast cancer. In: Singletary SE, Robb GL, Hortobagyi GN, eds. Advanced therapy of breast disease, 2nd ed. Hamilton, Canada: BC Decker, Inc., 2004:498–508.
10. Dawood S, et al. Differences in survival among women with stage III inflammatory and noninflammatory locally advanced breast cancer appear early: a large population-based study. Cancer 117(9):1819–1826.
11. Woodward WA, et al. Changes in the 2003 American Joint Committee on Cancer staging for breast cancer dramatically affect stage-specific survival. J Clin Oncol 2003;21(17):3244–3248.
12. Haagensen C. Diseases of the breast, 2nd ed. Phialdelphia, PA: WB Saunders, 1971:576–584.
13. Bozzetti F, et al. Inflammatory cancer of the breast: analysis of 114 cases. J Surg Oncol 1981;18(4):355–361.
14. Wingo PA, et al. Population-based statistics for women diagnosed with inflammatory breast cancer (United States). Cancer Causes Control 2004;15(3):321–328.
15. Zucali R, et al. Natural history and survival of inoperable breast cancer treated with radiotherapy and radiotherapy followed by radical mastectomy. Cancer 1976;37(3):1422–1431.
16. Barker JL, Nelson AJ, Montague ED. Inflammatory carcinoma of the breast. Radiology 1976;121(1):173–176.
17. Krutchik AN, et al. Combined chemoimmunotherapy and radiation therapy of inflammatory breast carcinoma. J Surg Oncol 1979;11(4):325–332.
18. Fields JN, et al. Inflammatory carcinoma of the breast: treatment results on 107 patients. Int J Radiat Oncol Biol Phys 1989;17(2):249–255.
19. Hance KW, et al. Trends in inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program at the National Cancer Institute. J Natl Cancer Inst 2005;97(13):966–975.
20. Baker RR, et al. An evaluation of bone scans as screening procedures for occult metastases in primary breast cancer. Ann Surg 1977;186(3):363–368.
21. Carkaci S, et al. Retrospective study of 18 F-FDG PET/CT in the diagnosis of inflammatory breast cancer: preliminary data. J Nucl Med 2009;50(2):231–238.
22. Singletary SE, Greene FL. Revision of breast cancer staging: the 6th edition of the TNM Classification. Semin Surg Oncol 2003;21(1):53–59.
23. Guerin M, et al. Structure and expression c-erB-2 and EGFR receptor genes in inflammatory and non-inflammatory breast cancer: prognostic significance. Int J Cancer 1989;43:201–208.
24. Pro B, et al. The evaluation of p53, HER-2/neu, and serial MDR protein expression as possible markers of chemoresistance and their use as prognostic markers in inflammatory breast cancer. Proc Am Soc Clin Oncol1998;17:553a.
25. Chang S, et al. Inflammatory breast carcinoma incidence and survival. The Surveillance Epidemiology and End Results (SEER) Program of the National Cancer Institute, 1975-1992. Cancer 1998;82:2366–2372.
26. van Golen KL, et al. A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin Cancer Res 1999;5(9):2511–2519.
27. Kleer CG, et al. WISP3 and RhoC guanosine triphosphatase cooperate in the development of inflammatory breast cancer. Breast Cancer Res 2004;6(2):R110–R115.
28. Dong HM, et al. Dominant-negative E-cadherin inhibits the invasiveness of inflammatory breast cancer cells in vitro. J Cancer Res Clin Oncol 2007;133(2):83–92.
29. Tomlinson JS, Alpaugh ML, Barsky SH. An intact overexpressed E-cadherin/alpha,beta-catenin axis characterizes the lymphovascular emboli of inflammatory breast carcinoma. Cancer Res 2001;61(13):5231–5241.
30. Elkin EB, et al. The effect of changes in tumor size on breast carcinoma survival in the U.S.: 1975–1999. Cancer 2005;104(6):1149–1157.
31. Giordano SH, et al. Is breast cancer survival improving? Cancer 2004;100(1):44–52.
32. Fisher B, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowell Project B-18. J Clin Oncol 1997;15:2483–2493.
33. Kuerer HM, et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 1999;17:460–469.
34. Wolmark N, et al. Preoperative chemotherapy in patients withoperable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. Cancer 2001;30:96–102.
35. Fisher ER, et al. Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 2002;95:681–695.
36. van der Hage JA, et al. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 2001;19:4224–4237.
37. Buchholz TA, et al. Global gene expression changes during neoadjuvant chemotherapy for human breast cancer. Cancer J 2002;8(6):461–468.
38. Fisher B, et al. Effect of local or systemic treatment prior to primary tumor removal on the production and response to a serum growth-stimulating factor in mice. Cancer Res 1989;49(8):2002–2004.
39. Rastogi P, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008;26(5):778–785.
40. van Nes JG, et al. Preoperative chemotherapy is safe in early breast cancer, even after 10 years of follow-up; clinical and translational results from the EORTC trial 10902. Breast Cancer Res Treat 2009;115(1):101–113.
41. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005;97(3):188–194.
42. Kuerer HM, et al. Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg 1999;230(1):72–78.
43. Hunt KK, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients. Ann Surg 2009;250(4):558–566.
44. Mamounas EP, et al. Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2005;23(12):2694–2702.
45. Xing Y, et al. Meta-analysis of sentinel lymph node biopsy after preoperative chemotherapy in patients with breast cancer. Br J Surg 2006;93(5):539–546.
46. Rouzier R, et al. Nomograms to predict pathologic complete response and metastasis-free survival after preoperative chemotherapy for breast cancer. J Clin Oncol 2005;23(33):8331–8339.
47. Cristofanilli M, et al. Invasive lobular carcinoma classic type: response to primary chemotherapy and survival outcomes. J Clin Oncol 2005;23(1):41–48.
48. Kaufmann M, et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: an update. J Clin Oncol 2006;24(12):1940–1949.
49. Smith IE, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 2005;23(22):5108–5116.
50. Cataliotti L, et al. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the Pre-Operative “Arimidex” Compared to Tamoxifen (PROACT) trial. Cancer2006;106(10):2095–2103.
51. Singletary SE, McNeese MD, Hortobagyi GN. Feasibility of breast-conservation surgery after induction chemotherapy for locally advanced breast carcinoma. Cancer 1992;69(11):2849–2852.
52. Mauriac L, et al. Neoadjuvant chemotherapy for operable breast carcinoma larger than 3 cm: a unicentre randomized trial with a 124-month median follow-up. Ann Oncol 1999;10:47–52.
53. Rouizer R, et al. Primary chemotherapy for operable breast cancer: incidence and prognostic significance of ipsilateral breast tumor recurrence after breast-conserving surgery. J Clin Oncol 2001;19:3828–3835.
54. Swain SM, et al. Neoadjuvant chemotherapy in the combined modality approach of locally advanced nonmetastatic breast cancer. Cancer Res 1987;47(14):3889– 3894.
55. Bonadonna G, et al. Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 1998;16(1):93–100.
56. Chen AM, et al. Breast-conserving therapy after neoadjuvant chemotherapy: the M. D. Anderson Cancer Center experience. J Clin Oncol 2004;22:2303–2312.
57. Chen AM, et al. Breast conservation after neoadjuvant chemotherapy: a prognostic index for clinical decision-making. Cancer 2005;103(4)689–695.
58. Akay CL, et al. Evaluation of the MD Anderson prognostic index for local-regional recurrence after breast conserving therapy in patients receiving neoadjuvant chemotherapy. Ann Surg Oncol 2012;19(3):901–907.
59. Mittendorf EA, et al. Impact of chemotherapy timing on local-regional failures in breast cancer patients undergoing breast conserving therapy. Proc Annu Meet Am Soc Clin Oncol Breast Symp 2012;14(3):R83.
60. Huang EH, et al. Comparison of risk of local-regional recurrence after mastectomy or breast conservation therapy for patients treated with neoadjuvant chemotherapy and radiation stratified according to a prognostic index score. Int J Radiat Oncol Biol Phys 2006;66(2):352–357.
61. Cuzick J, et al. Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep 1987;71(1):15–29.
62. Cuzick J, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 1994;12(3):447–453.
63. Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355(9217):1757–1770.
64. Early Breast Cancer Trialists’ Collaborative Group. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet2005;366(9503):2087–2106.
65. 2006 Update from the Early Breast Cancer Trialists’ Collaborative Group Overview of Radiation Therapy for Early Breast Cancer. presentation by Darby S, at the 2007 ASCO annual meeting, Chicago, IL, June 2007 2007. Available at: http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Speaker?& spk=Darby%2 C+Sarah+%5Bfau%5D.
66. Van de Steene J, Soete G, Storme G. Adjuvant radiotherapy for breast cancer significantly improves overall survival: the missing link. Radiother Oncol 2000; 55(3):263–272.
67. Whelan TJ, et al. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000;18(6):1220–1229.
68. Gebski V, et al. Survival effects of postmastectomy adjuvant radiation therapy using biologically equivalent doses: a clinical perspective. J Natl Cancer Inst 2006; 98(1):26–38.
69. Overgaard M, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949–955.
70. Overgaard M, et al. Randomized trail evaluating postoperative radiotherapy in high risk postmenopausal breast cancer patients given adjuvant tamoxifen: results from the DBCG 82c trial. Lancet 1999;353:1641–1648.
71. Ragaz J, et al. Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst 2005;97(2):116–126.
72. Nielsen HM, et al. Study of failure pattern among high-risk breast cancer patients with or without postmastectomy radiotherapy in addition to adjuvant systemic therapy: long-term results from the Danish Breast Cancer Cooperative Group DBCG 82b and c randomized studies. J Clin Oncol 2006;24(15):2268–2275.
73. Ragaz J, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997;337(14):956–962.
74. Overgaard M, Nielsen HM, Overgaard J. Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials. Radiother Oncol 2007;82(3):247–253.
75. Katz A, et al. Loco-regional recurrence patterns following mastectomy and doxorubicin-based chemotherapy: implications for postoperative irradiation. J Clin Oncol 2000;18:2817–2827.
76. Recht A, et al. Locoregional failure ten years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: experience of the Eastern Cooperative Oncology Group. J Clin Oncol 1999;17:1689–1700.
77. Wallgren A, et al. Risk factors for locoregional recurrence among breast cancer patients: results from International Breast Cancer Study Group Trials I through VII. J Clin Oncol 2003;21(7):1205–1213.
78. Taghian A, et al. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol 2004;22(21):4247–4254.
79. Truong PT, Olivotto, IA, Kader HA, et al. Selecting breast cancer patients with T1-T2 tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys2005;61:1337–1347.
80. Cheng JC, et al. Locoregional failure of postmastectomy patients with 1-3 positive axillary lymph nodes without adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 2002;52(4):980–988.
81. Freedman GM, et al. A close or positive margin after mastectomy is not an indication for chest wall irradiation except in women aged fifty or younger. Int J Radiat Oncol Biol Phys 1998;41(3):599–605.
82. Katz A, et al. The influence of pathologic tumor characteristics on locoregional recurrence rates following mastectomy. Int J Radiat Oncol BIol Phys 2001;50(3):735–742.
83. Fowble B, et al. The role of mastectomy in patients with stage I-II breast cancer presenting with gross multifocal or multicentric disease or diffuse microcalcifications. Int J Radiat Oncol Biol Phys 1993;27(3):567–573.
84. Sharma R, et al. Present-day locoregional control in patients with t1 or t2 breast cancer with 0 and 1 to 3 positive lymph nodes after mastectomy without radiotherapy. Ann Surg Oncol 17(11):2899–2908.
85. Woodward WA, et al. Locoregional recurrence after doxorubicin-based chemotherapy and postmastectomy radiation: implications for patients with early stage disease and predictors for recurrence after radiation. Int J Radiat Oncol BIol Phys 2003;57:336–344.
86. Smith BD, Smith GL, Haffty BG. Postmastectomy radiation and mortality in women with T1-2 node-positive breast cancer. J Clin Oncol 2005;23(7):1409–1419.
87. Buchholz TA, et al. Radiation use and long-term survival in breast cancer patients with T1,T2 primary tumors and 1-3 positive axillary lymph nodes. Int J Radiat Oncol BIol Phys 2006 (in press).
88. Kyndi M, et al. High local recurrence risk is not associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of DBCG 82 b& c. Radiother Oncol 2009;90(1):74–79.
89. Floyd SR, et al. Low local recurrence rate without postmastectomy radiation in node-negative breast cancer patients with tumors 5 cm and larger. Int J Radiat Oncol Biol Phys 2006;66(2):358–364.
90. Taghian AG, et al. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol 2006;24(24):3927–3932.
91. Harris JR, et al. Consensus statement on postmastectomy radiation therapy. Int J Radiat Oncol Biol Phys 1999;44(5):989–990.
92. Recht A, et al. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19(5):1539–1569.
93. Buchholz TA, et al. Pathologic tumor size and lymph node status predict for different rates of locoregional recurrence after mastectomy for breast cancer patients treated with neoadjuvant versus adjuvant chemotherapy. Int J Radiat Oncol Biol Phys2002;53(4):880–888.
94. Huang EH, et al. Radiation treatment improves local-regional control and cause-specific survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy. J Clin Oncol2004;(in press).
95. Nagar H, et al. Local-regional recurrence with and without radiation therapy after neoadjuvant chemotherapy and mastectomy for clinically staged T3N0 breast cancer. Int J Radiat Oncol Biol Phys 2011;81(3):782–787.
96. Garg A, et al. T3 disease at presentation or pathologic involvement of four or more lymph nodes predict for local-regional recurrence in stage II breast cancer treated with neoadjuvant chemotherapy and mastectomy without radiation. Int J Radiat Oncol BIol Phys 2004;59:138–145.
97. Mamounas E, et al. Predictors of locoregional failure (LRF) in patients receiving neoadjuvant chemotherapy (NC): Results from combined analysis of NSABP B-18 and NSABP B-27. Abstracts from the ASCO 2010 Breast Cancer Symposium, 2010. Available at: http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=100&abstractID=60279.
98. Early Breast Cancer Trialists’ Collaborative Group, et al. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet2005;365(9472):1687–1717.
99. Davies C, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011;378(9793):771–784.
100. Dowsett M, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010;28(3):509–518.
101. Henderson IC, et al. Improved outcomes from adding sequential Paclitaxel but not from escalating Dosorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol2003;21(6):976–983.
102. Mamounas EP, et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 2005;23(16):3686–3696.
103. Martin M, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005;352(22):2302–2313.
104. De Laurentiis M, et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 2008;26(1):44–53.
105. Citron ML, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21(8):1431–1439.
106. Jones S, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of us oncology research trial 9735. J Clin Oncol2009;27(8):1177–1183.
107. Howell A, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005;365(9453):60–62.
108. Goss PE, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349(19):1793–1802.
109. Coombes RC, et al; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350(11):1081–1092.
110. Thurlimann B, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353(26):2747–2757.
111. Burstein HJ, et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010;28(23):3784–3796.
112. Perez EA, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2010; 29(25):3366–3373.
113. Piccart-Gebhart MJ, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353(16):1659–1672.
114. Joensuu H, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354(8):809–820.
115. Slamon D, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early bereast cancer patients: BCIRG 006 study. Breast Cancer Res Treat 2005;94(suppl 1)(S5):(abst 1).
116. Romond EH, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353(16):1673–1684.
117. Perez EA, et al. Effect of doxorubicin plus cyclophosphamide on left ventricular ejection fraction in patients with breast cancer in the North Central Cancer Treatment Group N9831 Intergroup Adjuvant Trial. J Clin Oncol2004;22(18):3700–3704.
118. Buchholz TA, et al. Factors predictive of outcome in patients with breast cancer refractory to neoadjuvant chemotherapy. Cancer J 2001;7(5):413–420.
119. Huang E, et al. Locoregional treatment outcomes for inoperable anthracycline-resistant breast cancer. Int J Radiat Oncol Biol Phys 2002;53(5):1225–1233.
120. Chakravarthy AB, et al. Neoadjuvant concurrent paclitaxel and radiation in stage II/III breast cancer. Clin Cancer Res 2006;12(5):1570–1576.
121. Adams S, et al. Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: pathologic response correlates with five-year overall survival. Breast Cancer Res Treat 2010;124(3):723–732.
122. Brito RA, et al. Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: the University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol2001;19(3):628–633.
123. Cristofanilli M, et al. Paclitaxel improves the prognosis in estrogen receptor negative inflammatory breast cancer: the M. D. Anderson Cancer Center experience.Clin Breast Cancer 2004;4(6):415–419.
124. De Boer RH, et al. Multimodality therapy in inflammatory breast cancer: is there a place for surgery? Ann Oncol 2000;11(9):1147–1153.
125. Perez CA, et al. Management of locally advanced carcinoma of the breast. II. Inflammatory carcinoma. Cancer 1994;74(1 Suppl):466–476.
126. Panades M, et al. Evolving treatment strategies for inflammatory breast cancer: a population-based survival analysis. J Clin Oncol 2005;23(9):1941–1950.
127. Fleming RY, et al. Effectiveness of mastectomy by response to induction chemotherapy for control in inflammatory breast carcinoma. Ann Surg Oncol 1997;4(6):452–461.
128. Low JA, et al. Long-term follow-up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy. J Clin Oncol 2004;22(20):4067–4074.
129. Brun B, et al. Treatment of inflammatory breast cancer with combination chemotherapy and mastectomy versus breast conservation. Cancer 1988;61(6):1096–1103.
130. Arthur DW, et al. Accelerated superfractionated radiotherapy for inflammatory breast carcinoma: complete response predicts outcome and allows for breast conservation. Int J Radiat Oncol Biol Phys 1999;44(2):289–296.
131. Swain SM, Lippman ME. Treatment of patients with inflammatory breast cancer. Important Adv Oncol 1989:129–150.
132. Chevallier B, et al. Inflammatory breast cancer. Determination of prognostic factors by univariate and multivariate analysis. Cancer 1987;60(4):897–902.
133. Liao Z, et al. Locoregional irradiation for inflammatory breast cancer: effectiveness of dose escalation in decreasing recurrence. Int J Radiat Oncol Biol Phys 2000;47(5):1191–1200.
134. Bristol IJ, et al. Locoregional treatment outcomes after multimodality management of inflammatory breast cancer. Int J Radiat Oncol Biol Phys 2008;72(2):474–484.
135. Li J, et al. Triple-negative/basal subtype predicts poor overall survival and high locoregional relapse in inflammatory breast cancer. Oncologist 2011 (in press).
136. Robertson FM, et al. Inflammatory breast cancer: the disease, the biology, the treatment. CA Cancer J Clin 2010;60(6):351–375.
137. Dawood S, et al. International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Ann Oncol. 2011;22(3):515–523.
138. Salvadori B, et al. Reoperation for locally recurrent breast cancer in patients previously treated with conservative surgery. Br J Surg 1999;86(1):84–87.
139. Komoike Y, et al. Repeat lumpectomy for patients with ipsilateral breast tumor recurrence after breast-conserving surgery. Preliminary results. Oncology 2003;64(1):1–6.
140. Deutsch M. Repeat high-dose external beam irradiation for in-breast tumor recurrence after previous lumpectomy and whole breast irradiation. Int J Radiat Oncol Biol Phys 2002;53(3):687–691.
141. Resch A, et al. Locally recurrent breast cancer: pulse dose rate brachytherapy for repeat irradiation following lumpectomy– a second chance to preserve the breast. Radiology 2002;225(3):713–718.
142. Hannoun-Levi JM, et al. Partial breast irradiation as second conservative treatment for local breast cancer recurrence. Int J Radiat Oncol Biol Phys 2004;60(5): 1385–1392.
143. Smith TE, et al. True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management. Int J Radiat Oncol Biol Phys2000;48(5):1281–1289.
144. Huang E, et al. Classifying local disease recurrences after breast conservation therapy based on location and histology: new primary tumors have more favorable outcomes than true local disease recurrences. Cancer2002;95(10):2059–2067.
145. Yi M, et al. Classification of ipsilateral breast tumor recurrences after breast conservation therapy can predict patient prognosis and facilitate treatment planning. Ann Surg 2011;253(3):572–579.
146. Forman DL, et al. Breast reconstruction in previously irradiated patients using tissue expanders and implants: a potentially unfavorable result. Ann Plast Surg 1998;40(4):360–363; discussion 363–364.
147. Moran SL, Serletti JM, Fox I. Immediate free TRAM reconstruction in lumpectomy and radiation failure patients. Plast Reconstr Surg 2000;106(7):1527–1531.
148. Nielsen HM, et al. Loco-regional recurrence after mastectomy in high-risk breast cancer–risk and prognosis. An analysis of patients from the DBCG 82 b& c randomization trials. Radiother Oncol 2006;79(2):147–155.
149. Chagpar A, et al. Chest wall recurrence after mastectomy does not always portend a dismal outcome. Ann Surg Oncol 2003;10(6):628–634.
150. Chagpar A, et al. Outcome of treatment for breast cancer patients with chest wall recurrence according to initial stage: implications for post-mastectomy radiation therapy. Int J Radiat Oncol Biol Phys 2003;57(1):128–135.
151. Borner M, et al. First isolated locoregional recurrence following mastectomy for breast cancer: results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. Swiss Group for Clinical Cancer Research. J Clin Oncol 1994;12(10):2071–2077.
152. Hanrahan EO, et al. Combined-modality treatment for isolated recurrences of breast carcinoma: update on 30 years of experience at the University of Texas M.D. Anderson Cancer Center and assessment of prognostic factors. Cancer 2005;104(6):1158–1171.
153. Halverson KJ, et al. Isolated local-regional recurrence of breast cancer following mastectomy: radiotherapeutic management. Int J Radiat Oncol Biol Phys 1990;19(4):851–858.
154. Haylock BJ, et al. Locoregional first recurrence after mastectomy: prospective cohort studies with and without immediate chemotherapy. Int J Radiat Oncol Biol Phys 2000;46(2):355–362.
155. Ballo MT, et al. Local-regional control of recurrent breast carcinoma after mastectomy: does hyperfractionated accelerated radiotherapy improve local control? Int J Radiat Oncol Biol Phys 1999;44(1):105–112.
156. Zagar TM, et al. Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy. Radiother Oncol 2010;97(3):535–540.
157. Reddy JP, et al. Long-term outcomes in patients with isolated supraclavicular nodal recurrence after mastectomy and doxorubicin-based chemotherapy for breast cancer. Int J Radiat Oncol Biol Phys 2011;80(5):1453–1457.
158. Knapper WH. Management of occult breast cancer presenting as an axillary metastasis. Semin Surg Oncol 1991;7(5):311–313.
159. Vlastos G, et al. Feasibility of breast preservation in the treatment of occult primary carcinoma presenting with axillary metastases. Ann Surg Oncol 2001;8(5):425–431.
160. Vezzoni P, et al. Axillary lymph node metastases from occult carcinoma of the breast. Tumori 1979;65(1):87–91.
161. Bhatia SK, et al. Hormone receptor studies in axillary metastases from occult breast cancers. Cancer 1987;59(6):1170–1172.
162. Ellerbroek N, et al. Treatment of patients with isolated axillary nodal metastases from an occult primary carcinoma consistent with breast origin. Cancer 1990;66(7):1461–1467.
163. Barton SR, et al. The role of ipsilateral breast radiotherapy in management of occult primary breast cancer presenting as axillary lymphadenopathy. Eur J Cancer 2011;47(14):2099–2106.
164. Giordano SH. A review of the diagnosis and management of male breast cancer. Oncologist 2005;10(7):471–479.
165. Friedman LS, et al. Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population. Am J Hum Genet 1997;60(2):313–319.
166. Ottini L, et al. BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. Cancer Res 2003;63(2):342–347.
167. Gnerlich JL, et al. Poorer survival outcomes for male breast cancer compared with female breast cancer may be attributable to in-stage migration. Ann Surg Oncol 2011;18(7):1837–1844.
168. Ribeiro G, Swindell R. Adjuvant tamoxifen for male breast cancer (MBC). Br J Cancer 1992;65(2):252–254.
169. Strom EA, et al. Clinical investigation: regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy. Int J Radiat Oncol Biol Phys 2005;63(5):1508–1513.
170. Handley RS. Carcinoma of the breast. Ann R Coll Surg Engl 1975;57:59–66.
171. Urban JA, Marjani MA. Significance of internal mammary lymph node metastases in breast cancer. Am J Roentgenol Radium Ther Nucl Med 1971;111(1):130–136.
172. Huang O, et al. Breast cancer subpopulation with high risk of internal mammary lymph nodes metastasis: analysis of 2,269 Chinese breast cancer patients treated with extended radical mastectomy. Breast Cancer Res Treat2008;107(3):379–387.
173. Liengsawangwong R, et al. Treatment optimization using Computed Tomography delineated targets should be used for supraclavicular radiation in breast cancer. Int J Radiat Oncol Biol Phys 2006;in press.
174. Spear SL, Onyewu C. Staged breast reconstruction with saline-filled implants in the irradiated breast: recent trends and therapeutic implications. Plast Reconstr Surg 2000;105(3):930–942.
175. Anderson PR, et al. Postmastectomy chest wall radiation to a temporary tissue expander or permanent breast implant–is there a difference in complication rates? Int J Radiat Oncol Biol Phys 2009;74(1):81–85.
176. Chang DW, Barnea Y, Robb GL. Effects of an autologous flap combined with an implant for breast reconstruction: an evaluation of 1000 consecutive reconstructions of previously irradiated breasts. Plast Reconstr Surg2008;122(2):356–362.
177. Tran NV, et al. Comparison of immediate and delayed free TRAM flap breast reconstruction in patients receiving postmastectomy radiation therapy. Plast Reconstr Surg 2001;108(1):78–82.
178. Motwani SB, et al. The impact of immediate breast reconstruction on the technical delivery of postmastectomy radiotherapy. Int J Radiat Oncol Biol Phys 2006;66(1):76–82.
179. Buchholz TA. Locally advanced breast cancer. In: Haffty BG, Wilson LD, eds. Handbook of radiation oncology: Basic principles and clinical protocols. Burlington, MA: Jones and Bartlett; 2006.
180. Buchholz TA, et al. Neoadjuvant chemotherapy for breast carcinoma: multidisciplinary considerations of benefits and risks. Cancer 2003;98(6):1150–1160.