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The Oncologist, Vol. 8, No. 6, 521–530, December 2003
© 2003 AlphaMed Press

ORIGINAL PAPER
Breast Cancer

Update on Locally Advanced Breast Cancer

Sharon H. Giordano

University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Correspondence: Sharon H. Giordano, M.D., University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 424, Houston, Texas 77030, USA. Telephone: 713-792-2817; Fax: 713-794-4385; e-mail: sgiordan{at}mdanderson.org


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Diagnosis and Pretreatment...
 Prognostic Factors
 Therapy
 Inflammatory Breast Cancer
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Discuss the heterogeneity of locally advanced breast cancer.
  2. Explain the rationale for the multidisciplinary coordination of care for patients with locally advanced breast cancer.
  3. Identify the current standard of care for the treatment of locally advanced breast cancer.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Diagnosis and Pretreatment...
 Prognostic Factors
 Therapy
 Inflammatory Breast Cancer
 Conclusions
 References
 
Locally advanced breast cancer remains a clinical challenge as the majority of patients with this diagnosis develop distant metastases despite appropriate therapy. Patients with locally advanced disease encompass a wide range of clinical scenarios including advanced primary tumors (stage T4), advanced nodal disease (fixed axillary nodes or involvement of ipsilateral supraclavicular, infraclavicular, or internal mammary nodes), and inflammatory carcinomas. The prognoses of women with locally advanced breast tumors are also heterogeneous and depend on tumor size, extent of lymph node involvement, and the presence or absence of inflammatory carcinoma. Women with locally advanced disease require multimodal therapy, and coordinated treatment planning among the medical oncologist, surgical oncologist, and radiation oncologist is necessary to optimize patient care. In this article, the epidemiology, evaluation, prognostic factors, and treatment for locally advanced breast cancer are discussed. Inflammatory cancer is also reviewed, but is considered separately due to its distinct biology and clinical behavior.

Key Words. Breast cancer • Locally advanced disease • Inflammatory breast cancer


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Diagnosis and Pretreatment...
 Prognostic Factors
 Therapy
 Inflammatory Breast Cancer
 Conclusions
 References
 
Locally advanced breast cancer is a term that refers to most advanced-stage nonmetastatic breast tumors and includes a wide variety of clinical scenarios. These tumors remain a difficult clinical problem as most patients with locally advanced disease will experience disease relapse and eventual death. Investigators have often differed in their precise definition of locally advanced breast cancer. At the M.D. Anderson Cancer Center, we define any tumor that is greater than 5 cm or that involves the skin or chest wall as locally advanced. Locally advanced disease also includes patients with fixed axillary lymph nodes or ipsilateral supraclavicular, infraclavicular, or internal mammary nodal involvement. Thus, all of stage III disease is considered locally advanced, as is a subset of stage IIB (T3N0) [1]. In this article, the current evaluation and treatment of locally advanced breast cancer are reviewed. While inflammatory breast cancer is considered a subtype of locally advanced breast cancer, it has distinct biologic features and clinical behavior, so it is discussed separately. The topic of inflammatory breast cancer was comprehensively covered in a recent update and is considered only briefly here [2].

Since the use of screening mammography has become widespread, the proportion of patients who have locally advanced disease at diagnosis has decreased. Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, which encompasses approximately 14% of the U.S. population, indicate that 7% of patients have stage III disease at diagnosis [3]. In populations that receive regular screening mammography, the percentage of patients with locally advanced disease is less than 5% [4]. However, since only 50%–60% of women have had a recent mammogram, the national rates are higher. According to the SEER data, the 3- and 5-year relative survival rates for women with stage III breast cancer are 70% and 55%, respectively. Median survival for women with stage III disease is 4.9 years [3]. These numbers, however, hide the heterogeneity of the disease and its prognosis, since the survival time for a woman with inflammatory breast cancer is significantly less than for a woman with a 5.1-cm tumor and a single involved axillary lymph node.


   DIAGNOSIS AND PRETREATMENT EVALUATION
Top
 Learning Objectives
 Abstract
 Introduction
 Diagnosis and Pretreatment...
Prognostic Factors
 Therapy
 Inflammatory Breast Cancer
 Conclusions
 References
 
If breast cancer is suspected, a biopsy is necessary to confirm the diagnosis. Estrogen-receptor (ER) and progesterone-receptor (PR) status, HER-2/neu status, p53 status, nuclear grade, and Ki67 can all be determined from either fine-needle aspiration or core biopsy. The National Comprehensive Cancer Network has published guidelines for the workup of women with newly diagnosed breast cancer [5]. For women with stage III disease, the recommended evaluation includes: history and physical examination; laboratory evaluation with CBC, platelets, and liver enzymes; diagnostic bilateral mammogram and ultrasound as necessary; chest x-ray; pathology review, determination of ER, PR, and HER-2 status; optional breast magnetic resonance imaging (MRI), if borderline candidate for breast conservation; bone scan; and abdominal computerized tomography (CT) scan, ultrasound, or MRI. These tests will establish the extent of disease for further treatment planning.


   PROGNOSTIC FACTORS
Top
 Learning Objectives
 Abstract
 Introduction
 Diagnosis and Pretreatment...
 Prognostic Factors
Therapy
 Inflammatory Breast Cancer
 Conclusions
 References
 
The prognostic factors for locally advanced tumors are similar to the prognostic factors for earlier stage breast cancer, with lymph node status and tumor size having the strongest effects on survival. Most patients with locally advanced disease have axillary lymph nodes involved with their tumors, but a subset of patients has large primary tumors without lymph node involvement. The prognosis for patients without lymph node metastases is better than for those patients with lymph node involvement [6, 7]. For patients with lymph node metastases, a greater number of lymph nodes involved and higher nodal stage predict poorer survival [7, 8]. The size of the primary tumor also is associated with survival; patients with larger cancers have poorer survival rates. Valagussa et al. found that 5-year survival rates were 65%, 36%, and 16% for breast tumors measuring <5 cm, 5–10 cm, and >10 cm, respectively [8].

The role of hormone receptor status as a prognostic factor is less clear, but most studies have found that hormone receptor positivity is associated with a longer survival time. One study found that estrogen receptor positivity predicted a significantly longer disease-free interval and overall survival, but only in the subset of patients with operable breast cancer [9]. Another study of 187 patients with locally advanced breast tumors found that ER and PR negativity was associated with shorter overall survival times in univariate analyses [10]. In a multivariate analysis, PR status was still significantly associated with survival (hazard ratio = 0.54, 95% confidence interval = 0.35–0.83) [10].

Other variables that have been investigated as possible prognostic markers in locally advanced breast cancer include measures of proliferation, p53, HER-2, and nuclear grade. Several studies have found that the thymidine labeling index (TLI) was an independent prognostic factor, with a high TLI predicting poorer survival [11, 12]. Another group of investigators reported that p53 positivity was associated with a shorter overall survival time [10]. HER-2 status and nuclear grade have not consistently emerged in multivariate analyses as independent predictors of survival [10, 11].


   THERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 Diagnosis and Pretreatment...
 Prognostic Factors
 Therapy
Inflammatory Breast Cancer
 Conclusions
 References
 
The treatment of locally advanced breast cancer requires a combination of systemic chemotherapy, surgery, and radiotherapy to optimize the chance of cure. The earliest therapy for locally advanced breast cancer was radical mastectomy [13]. However, patients with supraclavicular involvement, edema of the arm, satellite skin nodules, and extensive breast edema were all found to develop recurrences, and these signs were considered markers of inoperable disease. Patients who were treated with primary radiotherapy also had a high risk for disease recurrence and death, as well as the complications of chest wall fibrosis, brachial plexopathy, lymphedema, skin ulceration, and skin necrosis [14–16]. The first reports of the use of induction chemotherapy for locally advanced disease were published in the 1970s [17]. Since then, the use of systemic chemotherapy has become standard and has substantially improved the prognosis of locally advanced breast cancer.

The benefit of adjuvant chemotherapy for the treatment of breast cancer has been clearly established, although most trials have not been specifically focused on patients with locally advanced disease. Initially, Bonadonna et al. demonstrated a survival benefit for women with node-positive breast cancer treated with CMF chemotherapy [18]. The Early Breast Trialists’ Collaborative Group published a meta-analysis of all known randomized trials of adjuvant chemotherapy and demonstrated a significantly lower mortality rate for women treated with chemotherapy [19]. The benefit was independent of tumor size or nodal status, indicating that women with locally advanced disease are likely to receive the same proportional reduction in risk of recurrence as women with early breast cancer. A few trials have attempted to address the benefit of chemotherapy in women with locally advanced disease [20–22]. While most have suggested a survival benefit, only a few studies have had sufficient power to reach statistical significance [20]. However, the data in aggregate clearly support the use of systemic chemotherapy for women with locally advanced breast cancer.

Neoadjuvant chemotherapy was pioneered in the setting of locally advanced breast cancer [17]. The administration of systemic chemotherapy prior to definitive local therapy is advantageous for women with locally advanced disease, since induction chemotherapy can render inoperable tumors (stage T4, N2, or N3) resectable and can increase rates of breast-conserving therapy [23–26]. Induction chemotherapy also has the theoretical advantages of early initiation of systemic therapy, delivery of drugs through intact vasculature, in vivo assessment of response to therapy, and the opportunity to study the biologic effects of chemotherapy. However, the use of neoadjuvant chemotherapy does result in the loss of standard and well-validated pathologic prognostic markers such as initial tumor size and the number of axillary lymph nodes involved. Most importantly, the survival rates of women treated with adjuvant or neoadjuvant chemotherapy are equivalent, making either approach reasonable for a woman with operable breast cancer [25–28]. For inoperable disease, the initial approach should be chemotherapy with the goal of achieving resectability.

Many standard chemotherapy regimens exist for the adjuvant and neoadjuvant treatments of breast cancer. The Early Breast Cancer Trialists’ Group established the superiority of anthracycline-based chemotherapy regimens [19]. For patients with node-positive breast cancer, the addition of a taxane to an anthracycline-based regimen improves overall survival [29, 30]. Whether or not the anthracycline and taxane should be given in sequence or in combination is more controversial. Using doxorubicin and docetaxel in combination produces a higher rate of febrile neutropenia than when these drugs are given in sequence [31]. However, in patients with metastatic disease, the response rates are higher from combination therapy than from sequential treatment, although survival rates are similar [31, 32]. For the treatment of locally advanced disease, particularly in the setting of inoperable disease, using a regimen with the highest likelihood of shrinking the tumor should improve the chances of converting the disease to operable breast cancer. A phase II trial has evaluated the combination of docetaxel and epirubicin in patients with locally advanced breast cancer and found a response rate of 77%, showing that combination therapy is effective in patients with locally advanced disease [33]. Our approach at The University of Texas M.D. Anderson Cancer Center has been to use anthracycline and taxane combinations for the initial treatment of locally advanced disease.

For women with HER-2 positive metastatic breast cancer, treatment with trastuzumab in combination with chemotherapy can improve survival [34]. Therefore, the potential use of trastuzumab in the adjuvant and neoadjuvant settings has generated much interest. While many studies are ongoing, the benefit of trastuzumab has not been demonstrated for women with curable breast cancer. One pilot study described the use of preoperative trastuzumab and paclitaxel followed by doxorubicin and cyclophosphamide in women with HER-2-positive stage II and III breast cancers [35]. Of the 40 women enrolled in the study, 75% had a clinical response to paclitaxel and trastuzumab. When the analysis was limited to women with 3+ HER-2 overexpression, the clinical response rate was greater at 84%. Four of the 40 women had asymptomatic declines in left ventricular ejection fraction. That small study demonstrated the feasibility of neoadjuvant trastuzumab, and larger studies are ongoing to determine efficacy. Currently, trastuzumab is not indicated in the adjuvant or neoadjuvant settings outside the context of a clinical trial.

The role of dose-dense therapy has also recently been explored for patients with node-positive and locally advanced breast cancer. Citron et al. reported a higher survival rate in node-positive patients who were treated with dose-dense chemotherapy [36]. In that trial, women who were treated with chemotherapy every 2 weeks with filgrastim support had better disease-free and overall survival rates than women treated with a conventional 3-week regimen. It remains unclear whether the survival benefit seen in that trial reveals a general principle of dose-dense chemotherapy scheduling or reflects the known schedule-dependent effects of the drug paclitaxel. A trial from the M.D. Anderson Cancer Center previously demonstrated a doubling of pathologic response rates when paclitaxel was administered on a weekly versus 3-weekly schedule [37]. Two trials have evaluated dose-dense chemotherapy in patients with locally advanced breast cancer, and neither found a significant difference in response rate or survival between the dose-dense and standard arms [38, 39]. The role of dose-dense therapy remains a promising area for continued research, but has not been clearly established as superior in patients with locally advanced disease.

Most patients who are treated with induction chemotherapy show a response to therapy. Approximately 10%–20% of patients achieve a clinical complete response (CR), and 50%–60% achieve a partial response (PR) (Table 1Go) [23, 25, 27, 28, 40–46]. Clinical CR often does not correlate with pathologic response, as approximately one-third of patients with a clinical CR are found to have pathologic evidence of residual disease [27, 28, 41, 42]. Similarly, the clinical assessment of axillary metastasis is not accurate in predicting the pathologic response of the axillary nodes. Kuerer et al. found that, of 55 patients with locally advanced breast cancer who appeared to have had complete resolutions of axillary disease by both physical examination and ultrasonography, 29 (53%) had pathologic evidence of axillary metastases [47]. Due to the limitations of physical examination, mammography, and ultrasonography in accurately predicting response to chemotherapy, MRI is currently being investigated as an alternate and potentially more accurate imaging modality [48–51].


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  		Table 1. Clinical and pathologic response rates to induction chemotherapy in locally advanced breast cancer
 
Despite the difficulty in accurately assessing response, patients who have complete clinical or pathologic responses to neoadjuvant chemotherapy have better outcomes [41, 52, 53]. Kuerer et al. reported a series of 372 patients with locally advanced breast cancer who were all treated with neoadjuvant anthracycline-based chemotherapy. A total of 43 (12%) patients achieved a pathologic CR, and those patients had a significantly better survival rate [53]. Although the survival time of responders was better than that of nonresponders, 13% of the complete responders had relapsed or died by 5 years.

Since response to chemotherapy is an important predictor of survival, many investigators have studied markers that may predict response to chemotherapy. For patients treated with anthracycline-based induction chemotherapy, small tumor size, high nuclear grade, high proliferation index (Ki67), and coexpression of HER-2/neu and topoisomerase II have been associated with greater response rates [53–58]. Conversely, mutation of the p53 gene is associated with a lower response rate to chemotherapy [59, 60]. Much less data are available regarding predictors of response to taxane-based therapy. However, one study found that tumors with low levels of HER-2 expression were more likely to respond to concurrent paclitaxel and radiotherapy [61]. In a study presented at the American Society of Clinical Oncology 2003 meeting, Pusztai et al. demonstrated the potential of gene-expression profiling to predict pathologic CR in patients receiving neoadjuvant chemotherapy [62]. The study of predictors of response to chemotherapy is an exciting avenue for future investigation, but the data are too preliminary at this point to be used in clinical decision making.

After patients complete neoadjuvant chemotherapy, they should proceed with definitive local therapy. The traditional approach has been to treat women with locally advanced tumors with modified radical mastectomy. However, after induction chemotherapy, many of these women become candidates for breast-conserving therapy. Singletary et al. reviewed a series of 143 patients treated at the M.D. Anderson Cancer Center for locally advanced disease to determine whether breast conservation was a feasible option after chemotherapy [63]. Strict criteria were applied to determine which patients would, theoretically, be good candidates for breast conservation. All patients were treated with a standard approach of mastectomy and axillary lymph node dissection. Of the 33 patients who would have been candidates for breast conservation, 42% were found to have a pathologic CR to chemotherapy, and none had multicentric disease, which suggested that breast conservation would have been a safe approach. Other trials have confirmed the safety of breast conservation in select groups of patients with locally advanced disease [26, 64, 65]. An alternate approach to breast conservation has been the use of primary radiation therapy in place of surgery, as most studies that have compared primary radiation therapy with primary surgical therapy have shown equivalent outcomes [17, 40].

In summary, patients with locally advanced breast cancer should receive induction chemotherapy as the initial component of therapy to enhance their chances of breast-conserving surgery and to make inoperable tumors amenable to resection (Fig. 1Go). For operable tumors, initial mastectomy followed by adjuvant chemotherapy is also a reasonable option. In total, patients should receive between six and eight cycles of anthracycline- and taxane-based regimens, given in sequence or in combination. Chemotherapy should be followed by segmental or modified radical mastectomy for tumors that are operable. Patients with inoperable tumors after induction chemotherapy can be crossed over to alternate chemotherapy (i.e., a taxane, if initial therapy was anthracycline based) or can proceed with definitive radiation therapy. Patients who are treated with surgery should receive postoperative radiation therapy to minimize the risk of local recurrence [66]. Finally, women with hormone-receptor-positive tumors should receive additional benefits from 5 years of hormonal therapy.



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  		Figure 1. Treatment algorithm for locally advanced breast cancer.

 

   INFLAMMATORY BREAST CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Diagnosis and Pretreatment...
 Prognostic Factors
 Therapy
 Inflammatory Breast Cancer
Conclusions
 References
 
Inflammatory breast cancer is a distinct clinical subtype of locally advanced breast cancer, with a particularly aggressive behavior and poor prognosis. Clinically, inflammatory breast cancer typically presents with the rapid onset of breast erythema, warmth, and edema, often without a discrete underlying mass (Fig. 2Go). The swelling of the breast can be quite pronounced, producing significant tenderness. The characteristic pathology is invasion of the dermal lymphatic by tumor emboli, which results in blockage of the breast lymphatics and can lead to breast edema. Neglected locally advanced breast cancer can develop secondary inflammatory characteristics, but should be distinguished from primary inflammatory carcinoma as these secondary inflammatory breast cancers may follow a more indolent course and can be treated as other locally advanced breast tumors [67].



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  		Figure 2. Clinical presentation of inflammatory breast cancer.

 
The biology of inflammatory carcinoma has some important differences from other breast cancers. van Golen et al. found that overexpression of RhoC GTPase and the lost in inflammatory breast cancer (LIBC) protein were highly correlated with an inflammatory breast cancer phenotype [68]. Inflammatory breast cancer also can be distinguished by its highly angiogenic characteristics [69, 70]. These tumors are more likely to be high grade, aneuploid, and hormone-receptor negative and have a high S-phase fraction and p53 mutations [71–73]. Despite these differences in biologic characteristics, prognostic factors for inflammatory breast cancer are similar to those for locally advanced disease, with axillary lymph node involvement predicting poorer survival [74, 75]. Other negative prognostic factors for inflammatory carcinoma include negative ER status [72, 76], extensive erythema of the breast [74, 75], and p53 mutations [77].

Historically, patients with inflammatory breast cancer have had dismal outcomes with single modality local therapies such as surgery or radiotherapy [78–85]. The prognosis did not improve until the advent of active chemotherapy regimens in the 1970s [86]. Experience at the M.D. Anderson Cancer Center over the past 20 years was reported by Ueno et al. [87]. One hundred seventy patients had combined modality therapy consisting of doxorubicin-based induction chemotherapy, local therapy with either radiation or mastectomy, and adjuvant chemotherapy. Patients who underwent mastectomy also had adjuvant radiotherapy. In that series, overall survival was 40% at 5 years and 33% at 10 years, which was a significant improvement over historical controls. Seventy-one percent of patients had responses to induction chemotherapy. Other studies have also reported high response rates to neoadjuvant chemotherapy (Table 2Go) [17, 87–96]. The study by Ueno et al. also showed the importance of response to induction chemotherapy. Patients who had a CR to chemotherapy had a 44% disease-free survival rate at 15 years compared with a 7% rate in those patients who were nonresponders. Other large series of patients with inflammatory carcinoma have shown similar survival rates, demonstrating the clear impact of systemic chemotherapy on the prognosis of this disease [88–90, 97, 98]. Dose-intensive therapy and bone marrow transplantation have been studied, but have not been shown to have an impact on survival and cannot be recommended outside the context of a clinical trial [88, 99].


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  		Table 2. Response rates to anthracycline-based induction chemotherapy in inflammatory breast cancer
 
The optimal treatment of inflammatory breast cancer requires careful coordination of multimodal therapy among medical, radiation, and surgical oncologists. The initial component of treatment should be induction chemotherapy with an anthracycline-based regimen or an anthracycline and taxane combination. Definitive local therapy can then be achieved with radiation therapy, mastectomy, or both [91, 100–103]. For patients who are treated with mastectomy, limited data suggest that sentinel node biopsy is not reliable for patients with inflammatory carcinoma [104]. After local therapy, patients should receive further adjuvant chemotherapy, as the risk of relapse remains high, followed by adjuvant radiotherapy, if not previously given. Patients with hormone-receptor-positive tumors should be treated with 5 years of adjuvant hormonal therapy to minimize the risk of recurrence.

Despite the progress that has been made in the treatment of this disease, only one-third of women are cured. While the advent of systemic chemotherapy has made the cure of more patients possible, further advances in the understanding and treatment of inflammatory carcinoma are clearly needed. Recent discoveries of the distinct biologic features that characterize inflammatory carcinoma can lead the way toward the development of new therapies. For instance, farnesyl transferase inhibitors have been shown to reverse the invasive phenotype of RhoC GTPase-overexpressing cell lines [105]. Other possible therapeutic targets include mediators of angiogenesis such as vascular endothelial growth factor, basic fibroblast growth factor, and Flt-1, which are overexpressed in inflammatory breast cancers.


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Diagnosis and Pretreatment...
 Prognostic Factors
 Therapy
 Inflammatory Breast Cancer
 Conclusions
References
 
Although screening mammography has resulted in proportionally fewer cases, locally advanced breast cancer remains a difficult clinical problem due to the high rate of relapse and low rate of overall survival. The range of disease encompassed by the term locally advanced is wide and includes patients with large, but operable, primary tumors to patients with rapidly progressing inflammatory carcinomas, who have very different prognoses. Thus, treatment decisions must be tailored to the individual patient. Of critical importance in all cases of locally advanced breast tumors is coordination of care among medical oncology, surgical oncology, and radiation oncology, as the vast majority of patients need chemotherapy, surgery, and radiotherapy. Progress continues to be made in the management of locally advanced breast cancer as improvements are being made in chemotherapy regimens, predictors of response to chemotherapy, and imaging techniques. Strides are also being made in the understanding of the biology of inflammatory breast cancer, and new therapeutic targets are emerging. With continued support of basic and clinical research, further advances in the treatment and prognosis of women with locally advanced breast cancer will occur.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Diagnosis and Pretreatment...
 Prognostic Factors
 Therapy
 Inflammatory Breast Cancer
 Conclusions
 References
 

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Received May 2, 2003; accepted for publication August 5, 2003.




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