Locally Advanced Breast Cancer

Gabriel N. Hortobagyi

Funda Meric-Bernstam

Eric A. Strom

DEFINITION

Locally advanced breast cancer (LABC) remains an important public health problem and a challenging management problem around the world (1). In groups of women who participate in periodic screening programs, the incidence of LABC is lower than 5%, whereas in medically underserved areas of the United States, and in many developing countries, LABC represents 40% to 60% of newly found malignant breast neoplasms (2 and 3). It can be estimated that between 400,000 and 550,000 new cases of LABC are diagnosed around the world every year.

LABC includes large primary tumors (>5 cm, T3 in the AJCC Cancer Staging System) (4), tumors of any size associated with skin or chest wall involvement (T4), tumors with fixed or matted axillary lymph nodes (N2), and those with involvement of the ipsilateral infraclavicular and supraclavicular lymph nodes (N3). Operationally, even moderatesized tumors, 3 to 5 cm in size, located in a small breast are best treated with similar combined-modality approaches. The management of patients with LABC has evolved substantially over the past four decades, and this chapter will summarize current therapeutic options.

HISTORICAL PERSPECTIVE

Adjuvant systemic treatments have become integral components of the curative management of primary breast cancer (5). Postoperative adjuvant chemotherapy, hormone therapy, and trastuzumab produce highly significant reductions in odds of recurrence and death from breast cancer for patients of any age, with node-negative or node-positive tumors. The effectiveness of systemic therapy varied markedly, however, based on predictors of therapeutic benefit. Thus, only patients with estrogen and/or progesterone receptor-positive breast cancer benefit from endocrine therapy; only patients with overexpression or amplification of HER2 benefit from trastuzumab. In addition, the efficacy of chemotherapy is several-fold greater in patients with negative hormone receptors than in patients with positive hormone receptors.

Randomized trials designed for stage III breast cancer suggested that adjuvant systemic therapies also decreased the probability of recurrence and death in this group of patients (6). Most of the information about the management of LABC is based on phase II trials. Therefore, the levels of evidence on which many of the recommendations made in this chapter are based are lower than the levels of evidence that support adjuvant systemic therapy.

Historically, patients with LABC treated with surgery only fared poorly: although surgical resection was technically possible in most patients with LABC, 10 years after diagnosis more than 80% of patients had succumbed to the disease (6). On the basis of this experience, Haagensen and Stout defined the concepts of operable and inoperable breast cancer (7).

Subsequent to Haagensen’s landmark publication, patients with inoperable tumors were treated with radiation therapy alone or associated with surgical resection (6). However, the large doses of radiation necessary to optimize local control, were often associated with long-term complications, including skin and chest wall fibrosis, skin ulceration, pulmonary fibrosis, rib necrosis or resorption, brachial plexopathy, and lymphedema of the arm (8, 9).

It was on this background that the initial combined modality treatment approaches were developed, in parallel with the postoperative adjuvant chemotherapy programs.
There is general agreement that combinations of systemic and local/regional therapies represent the standard of care for all patients with LABC.

DIAGNOSIS AND STAGING

Most LABCs are easily palpable and even visible. Many represent neglected primaries present for months or sometimes years before the initial diagnosis. Patients may be aware of the breast or lymph node abnormality, but because of fear, denial, or lack of access to appropriate healthcare, they delay seeking medical attention. However, some LABCs present with diffuse infiltration of the breast and without a dominant mass. On mammographic or sonographic assessment they often appear as large areas of calcification, or parenchymal distortion; sometimes skin thickening is also present. Occasionally, even large lesions are mammographically and sonographically silent and magnetic resonance imaging (MRI) is needed for definitive imaging.

A core needle biopsy usually establishes the histologic diagnosis; incisional biopsies are seldom required. Some recommend a full-thickness skin biopsy (punch biopsy) when inflammatory breast cancer (IBC) is suspected. However, although the presence of dermal lymphovascular tumor emboli is pathognomonic of IBC, lack of dermal involvement does not exclude it. If an experienced cytopathologist is available, the diagnosis of malignancy can be confirmed by fine-needle aspiration cytology (FNAC); nuclear grade, flow cytometry, estrogen- and progesterone-receptor status and HER-2/neu can all be assayed on FNAC samples, and so can most other proposed prognostic indicators (Ki-67, etc.). However, FNAC cannot differentiate invasive from noninvasive tumors. If palpable regional nodes exist, a positive fineneedle aspirate of a node confirms the presence of invasive breast cancer. Once the diagnosis is established, the extent of tumor involvement needs to be ascertained. Bilateral mammogram serves to assess the known primary tumor and to rule out the presence of multifocal and multicentric disease and synchronous bilateral cancer or contralateral metastases. Sonography serves to further define tumor dimensions and to detail any regional lymph node involvement. Sonographic examination preferably should include, in addition to the breast and axillary area, the infraclavicular, supraclavicular, and internal mammary lymph node chains. The extra-axillary nodal basins are commonly involved in LABC. Our recent review of 865 patients with LABC staged by ultrasound showed a 37% probability of infraclavicular, supraclavicular, or internal mammary involvement (10). For lesions poorly defined by mammography or sonography, MRI can be helpful. Bilateral MRI is used at some institutions for baseline assessment of extent of tumor involvement, additional foci of cancer, and following neoadjuvant systemic therapy to assess response to therapy. This is particularly true of some subtypes of breast cancer that are frequently mammographically occult, such as invasive lobular cancer or inflammatory breast cancer. Accurate imaging evaluation at baseline and following systemic therapy is critical to guide optimal local/regional therapy planning and for assessment of response. A biochemical survey, chest radiograph, and bone scan complement a complete physical examination, with quantitative documentation of all palpable abnormalities. Abdominal imaging (computerized tomography [CT] or sonography) is recommended to rule out intraabdominal metastases. Areas of increased radionuclide uptake on bone scan are assessed by radiographs, MRI, or CT scanning. Other tests are indicated only by specific symptoms or for investigational purposes. Increasingly, positron emission tomography (PET) combined with CT is also being employed to assess extent of disease and rule out metastatic deposits at the time of diagnosis.

DEVELOPMENT OF COMBINED MODALITY STRATEGIES

Systemic therapy was introduced in the management of inoperable breast cancers more than 40 years ago (11, 12). Surgery or radiotherapy, or both, followed systemic therapy in these trials. For optimal utilization of all treatment modalities, all interested specialists (radiologist, pathologist, and surgical, radiation, and medical oncologists) should review the diagnostic data, examine the patient, and determine the optimal type and sequence of therapies before any treatment is implemented. Treatment strategies that include neoadjuvant systemic therapy have several potential advantages: early initiation of systemic therapy, in vivo assessment of response, and reduction in the extent of primary tumor and regional lymphatic metastases. The potential (theoretical) shortcomings include delay in local treatment, induction of drug resistance, and unreliability of clinical staging. The practical advantages have exceeded, by far, the disadvantages. The ability to monitor response to therapy by serial measurements of the primary tumor, and the reduction in tumor volume that often permits breast conservation, are the two major clinical advantages of these treatment strategies. However, neoadjuvant systemic therapy also represents an unparalleled research platform, facilitating biomarker discovery, such as identification of predictors of response, pharmacodynamics markers of response (early tumor changes that predict response), and biomarkers associated with residual, therapy-resistant disease. Further, neoadjuvant systemic approach can allow for testing of the efficacy of novel combination therapies, expediting drug development.

Neoadjuvant Chemotherapy (NACT)

The first clinical trials with NACT (also called induction chemotherapy, primary chemotherapy, or preoperative chemotherapy) started in the late 1960s, but the earliest reports were published in the 1970s (11, 12). Since then, multiple reports have documented the effectiveness of primary systemic therapy in patients with LABC (summarized in reference 6). Most reports of combined modality therapy of locally advanced breast cancer are based on anthracycline-containing combination chemotherapy regimens (see also Chapter 44, Adjuvant Chemotherapy). Administration of combination chemotherapy produces major reductions in tumor volume in 60% to 90% of patients. Tumor reduction has been consistently documented in both the primary tumor and the enlarged regional lymph nodes (6, 11, 12, 13, 14, 15, 16, 17 and 18, ). Although mixed responses (response in the primary tumor and no response in the regional lymph nodes, or vice versa) have been reported, they are uncommon (18, 19 and 20). Clinical complete remissions have been reported in 10% to 20% of patients with LABC treated with anthracycline-containing combination chemotherapy regimens (6, 18, 19, 20 and 21). Response rates, and especially complete response rates, improve if a taxane is added, especially in sequential regimens. The median number of cycles required to achieve a partial remission was reported to be four, and for a complete remission, five (13). Pathological complete remission (pCR) (20 and 21) is uncommonly obtained with chemotherapy in ER positive tumors, and is rare after neoadjuvant endocrine therapy. Since the introduction of trastuzumab, a number of reports indicated that, in combination with chemotherapy, trastuzumab produces pCR rates ranging from 20% to 70% in HER2-amplified or overexpressing breast cancers (22). Clinical measurements of breast masses
are often inaccurate, and there is substantial interindividual variation among examiners (23). Therefore, imaging methods are often used to more reliably document extent of disease (24). The combination of physical examination with either mammography or ultrasound gives measurements that closely approach those achieved by histopathology, and it reduces error rates in serial monitoring of response to systemic therapy (24). MRI may also be used to determine extent of disease (25). The determination of clinical complete remission requires that no residual disease be present by physical examination and by imaging (mammography and/or ultrasound) in the breast or regional lymph nodes (17). Even following these criteria, only half to two-thirds of patients thought to have a clinical complete remission are found to have a pathologic complete remission (i.e., no residual disease) (17, 18, 20, 21, 24). Furthermore, a third of patients with no residual disease by histologic examination will have residual clinical or imaging abnormalities that preclude the diagnosis of clinical complete remission. Patients who achieve a histologically documented complete remission have a markedly improved long-term prognosis compared with patients who achieve incomplete or no responses (17, 21, 26). Furthermore, these patients are often excellent candidates for breast-conserving strategies, with or without surgical intervention (27). In recent years, in addition to refinements to the sequential evaluation of extent of disease during therapy utilizing mammography, sonography, and MRI, positron emission tomography (PET) has been evaluated. Several authors have reported that not only does PET (usually in combination with CT, PET/CT) identify metastatic lesions not found by other imaging modalities (28) but also it is a very sensitive tool to monitor the functional status of the tumor. Thus, changes in PET imaging, such as marked reductions in standardized uptake values, are under evaluation for early determination of response to neoadjuvant systemic therapy (29).

Most initial reports of combined-modality treatment of LABC were based on anthracycline-containing combination chemotherapy regimens, such as doxorubicin, and cyclophosphamide (AC) or fluorouracil, doxorubicin/epirubicin, and cyclophosphamide (FAC or FEC). Over the past two decades, multiple reports have documented the benefits of the use of anthracycline and taxane combinations (27, 30, 31). These newer regimens were reported to have marked antitumor activity, with overall response rates in the 80% to 95% range. Unfortunately, the reported clinical and pathologic complete remission rates were only modestly higher than those reported with older combinations. Table 58-1 summarizes prospective randomized trials that compare anthracycline- and taxane-containing regimens with anthracycline-containing combinations without a taxane (26 and 27, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 and 40). In several randomized trials in which a taxane was administered sequentially, after the initial four cycles of an anthracycline/cyclophosphamide-containing neoadjuvant regimen, a significant increase in pathologic complete remission was reported (26, 32). In a small, multicenter trial conducted on patients with LABC, the increase in clinical and pathologic complete response rate was associated with improved disease-free and overall survival rates (32, 33, 34, 35, 36, 37, 38, 39, 40 and 41). Of note, both responders and nonresponders to the initial anthracycline-containing combination benefited from crossover to docetaxel. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-27 included a crossover to docetaxel after four cycles of neoadjuvant doxorubicin and cyclophosphamide (AC); the addition of docetaxel resulted in significant increases in overall and complete response rates, pathologic complete response rates, and increased breast-conserving surgery rates (26). However, while there was a borderline improvement in relapse-free survival, the primary endpoint of the study, improved disease-free survival, was not significantly altered. However, this study was underpowered to detect clinically significant differences in survival. It is estimated that for each 10% increase in pCR rate a 2.6% improvement in survival might be observed (26). Other drugs under investigation in the neoadjuvant setting are gemcitabine, vinorelbine, platinum analogs, ixabepilone, eribulin, trastuzumab, pertuzumab, trastuzumab emtansine, bevacizumab, and lapatinib. Single-agent trastuzumab was reported to achieve a 23% partial response rate after three weeks of treatment in patients with LABC in one study and a 45% response rate in another (42, 43). In combination with a taxane or vinorelbine, or two-drug combination chemotherapy regimens, clinical CR rates of 24% to 59% were reported (22, 44, 45). The corresponding pCR rates ranged from 18% to 45%. In a small randomized trial of sequential paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide, with or without trastuzumab, pCR rate increased from 26% to 65% with the addition of trastuzumab (46). These results
were confirmed by a larger randomized trial that included 235 patients with HER-2/neu-positive primary breast cancer (47). A large, multicenter confirmatory study has completed accrual patients with T2 and T3, HER-2-positive breast cancer (ACOSOG protocol Z1041). Gianni and collaborators also reported the initial results of a four-arm randomized trial comparing neoadjuvant docetaxel plus trastuzumab with docetaxel plus pertuzumab, docetaxel plus both antibodies, or the two antibodies without chemotherapy (48). Pathological complete remission rates were 31%, 23%, 49%, and 18%, for the four arms, respectively, indicating that combining the two antibodies with chemotherapy provides the best result, while the two antibodies without chemotherapy were able to eradicate the primary tumor in almost 20% of patients.

TABLE 58-1 Randomized Phase III Studies Comparing Anthracycline- and Taxane-Containing Regimens with Anthracycline-Containing Combinations without Taxanes

Author (Ref. no)	n	Clinical stage	Treatment	ORR (%)	pCR (%)
Smith et al. (32)	162	IIB, III	CVAP vs. CVAP + docetaxel	64 vs. 85 (p = .03)	15 vs. 31 (p = .06)
Vinholes et al. (33)	407	IIIA, IIIB	Docetaxel + doxorubicin vs. FAC	72 vs. 63 (p = .0056)	16 vs. 11
Luporsi et al. (34)	90	II, III	FEC vs. ET	72 vs. 84	24 vs. 24
NSABP B-27 (26)	2411	II	AC vs. AC + T + surgery vs. AC + surgery + T	85 vs. 91	14 vs. 25
Evans et al. (35)	365	II, III	AC vs. AT	78 vs. 88	12 vs. 8
Buzdar et al. (36)	174	II-IIIA	Paclitaxel vs. FAC	80 vs. 79	8 vs. 14
Dieras et al. (37)	247	IIA, IIB, IIIA	AC vs. AT	10 vs. 16	66 vs. 83
Green et al. (38)	127	I, II, IIIA	T q 3 weeks vs. weekly T	18 vs. 31	N/A N/A
Untch et al. (39)	475	II, IIIA+B	Dose-dense sequential E to T, vs. standard ET	18 vs. 10	N/A N/A
CVAP, cyclophosphamide, vincristine, doxorubicin, prednisone; FAC, 5-fluorouracil, Adriamycin (doxorubicin), cyclophosphamide; FEC, fluorouracil, Epirubicin, cyclophosphamide; ET, Epirubicin, paclitaxel; AC, Adriamycin (doxorubicin) and cyclophosphamide; AT, doxorubicin, docetaxel; T, paclitaxel; ORR, overall response rate; N/A, not available.

TABLE 58-2 Effective and Well-Tolerated Induction Chemotherapy Regimens

Regimen—Drugs		Doses, Route, and Day of Administration	Frequency and Number of Cycles
Dose Dense AC-T
Cycles 1-4
	Doxorubicin	60 mg/m² IV, day 1	Every 2 weeks × 4 cycles
	Cyclophosphamide	600 mg/m² IV, day 1	Every 2 weeks × 4 cycles
	Perfilgrastim	6 mg SQ, day 2	Every 2 weeks × 4 cycles
Cycles 5-8
	Paclitaxel^a	175 mg/m² IV, day 1	Every 2 weeks × 4 cycles
PACLITAXEL/FAC
First 3 months
	Paclitaxel^b	80 mg/m² IV, day 1	Every week × 12 weeks
Final 3 months
	5-Fluorouracil	500 mg/m² IV, day 1	Every 3 weeks × 4 cycles
	Doxorubicin	50 mg/m² IV, day 1	Every 3 weeks × 4 cycles
	Cyclophosphamide	500 mg/m² IV, day 1	Every 3 weeks × 4 cycles
TAC
	Docetaxel	75 mg/m² IV, day 1
	Doxorubicin	50 mg/m² IV, day 1	Every 3 weeks × 6 cycles
	Cyclophosphamide	500 mg/m² IV, day 1	Every 3 weeks × 6 cycles
	Perfilgrastim	6 mg SQ, day 2	Every 3 weeks × 4-6 cycles
TC
	Docetaxel	75 mg/m² IV, day 1	Every 3 weeks × 4-6 cycles
	Cyclophosphamide	600 mg/m² IV, day 1	Every 3 weeks × 4-6 cycles
REGIMENS WITH TRASTUZUMAB
DOSE DENSE AC-TH
Cycles 1-4
	Doxorubicin	60 mg/m² IV, day 1	Every 2 weeks × 4 cycles
	Cyclophosphamide	600 mg/m² IV, day 1	Every 2 weeks × 4 cycles
	Perfilgrastim	6 mg SQ, day 2	Every 2 weeks × 4 cycles
Cycles 5-8
	Paclitaxel	175 mg/m² IV, day 1	Every 2 weeks × 4 cycles
	Trastuzumab	4 mg/kg IV, day 1, followed by 2 mg/kg IV	Weekly for 1 year
TCbH
	Docetaxel	75 mg/m² IV, day 1	Every 3 weeks × 6 cycles
	Carboplatin	AUC = 6 IV, day 1	Every 3 weeks × 6 cycles
	Trastuzumab	8 mg/kg IV, day 1, followed by 6 mg/kg	Every 3 weeks for 1 year
^aPaclitaxel, 80 mg/m² IV every week × 12 weeks can be substituted. ^bDocetaxel, 100 mg/m² IV every 3 weeks × 4 cycles can be substituted (before or after FAC).

Table 58-2 lists the more commonly used effective and well-tolerated neoadjuvant chemotherapy regimens.

NEOADJUVANT ENDOCRINE THERAPY

Most of the clinical investigation with neoadjuvant systemic therapy was conducted with cytotoxic therapy. More limited information is available about neoadjuvant endocrine therapy (see also Chapter 55, Preoperative Endocrine Therapy for Operable Breast Cancer). For patients with estrogen receptor-positive (ER+) breast cancer neoadjuvant endocrine therapy is an appropriate option. The initial trials used tamoxifen and included patients selected on the basis of old age or comorbidity that precluded chemotherapy (49, 50). The
results suggested that neoadjuvant endocrine therapy was therapeutically effective and produced marked reduction in tumor volume in 40% to 60% of patients. A significant minority of tumors progressed during neoadjuvant endocrine therapy; thus, close monitoring is required so that early progressors are identified promptly and appropriate regional therapy (or crossover to chemotherapy) can be implemented. Several studies also concluded that tamoxifen alone was insufficient therapy for patients with primary and locally advanced breast cancer, and that appropriate surgery and/or radiation therapy was needed for optimal local and systemic control (51, 52). Endocrine therapy should be restricted to patients with hormone receptor-positive breast cancer. More recent trials compared selective aromatase inhibitors with drugs in the same family or with tamoxifen (53). Greater antitumor efficacy was observed with aromatase inhibitors compared to tamoxifen (53). In general, response to neoadjuvant endocrine therapy occurs in 35% to 50% of patients with hormone receptor-positive breast cancer, but fewer than 5% achieve pCR. Response rates to neoadjuvant endocrine therapies in this setting are lower than response rates to anthracycline/taxane based chemotherapy in unselected patients with LABC (52); pCR rates with neoadjuvant chemotherapy for patients with ER+ breast cancer are observed in 5% to 14%, several-fold lower than for patients with ER- breast cancer. Early progression is observed more frequently after neoadjuvant endocrine therapy (12% to 17%) (53) than after neoadjuvant chemotherapy (5% to 10%) (6). The poor prognosis for patients with LABC indicates that all treatment modalities are needed for optimal results, so all patients with positive estrogen and/or progesterone receptor assays should receive adjuvant endocrine treatment as part of multidisciplinary therapy. Whether there is a subset of patients with hormone receptor-positive LABC that does not benefit from, and therefore does not require, NACT is under active investigation.

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