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LOCALLY ADVANCED BREAST CANCER
ADVANCES IN BREAST CANCER THERAPY
0889-8588/99 $8.00 + .OO
LOCALLY ADVANCED BREAST CANCER Francisco J. Esteva, MD, and Gabriel N. Hortobagyi, MD
Locally advanced breast cancer (LABC) accounts for 5% to 15% of new breast cancer cases in the United States and for 40% to 60% of new cases in nonindustrialized countries. The diagnosis of LABC includes tumors classified under TNM classification as stage IIB (T3NO), stage I11 (IIIA and IIIB), and regional stage IV breast cancer (ipsilateral supraclavicular lymph node [LN] metastases), according to the American Joint Committee for Cancer Staging.' Based on the TNM system, LABC tumors must be larger than 5 cm (T3) and/or involve the skin or chest wall (T4) with any node (N), stage. Tumors of any tumor (T) category with N2 (matted axillary LN) or N3 (internal mammary LN) are also considered LABC. Inflammatory breast cancer (IBC) is a particularly aggressive form of LABC that has highly metastatic features, and it is Inflammatory breast cancer classified as stage IIIB in the TNM is a clinical-pathological entity characterized by the rapid development (usually within 3 months) of erythema and edema (also known as peau d'orange sign) and breast ridging (palpable striae in erythematous areas). In many cases no definite mass is found by physical examination or mammography. The typical mammographic finding is diffuse skin thickening. Microscopic examination of involved skin may show invasion of lymphatic vessels, although the typical pathologic findings are not needed to make the diagnosis of IBC. Patients with ipsilateral supraclavicular LN metastases (technically stage IV) and no evidence of dis-
From the Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
HEMATOLOGY/ ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 13 * NUMBER 2 * APRIL 1999
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ESTEVA & HORTOBAGM
tant metastases have a similar prognosis to patients with stage mB disease and are considered in the LABC category? During the first half of the twentieth century, patients with LABC underwent extensive surgical procedures and aggressive radiotherapy. The radical mastectomy was developed by William Halsted at the Johns Hopkins University for LABC patients. In the 1940s, Haagensen and others29revisited the surgical indications for patients with LABC. These authors recognized that patients with extensive skin involvement or fixation to the chest wall (currently classified as T4 lesions) had a high rate of metastases and mortality when treated with surgery alone. For this reason (and not because of technical issues), patients with T4, N3, or regional M1 (stage IIIB/IV) were considered inoperable. Using surgery or radiation therapy (RT) as single-therapy modalities resulted in local control for most patients with LABC. However, more than 80% of patients died of metastatic disease within 5 years of follow-up. The prognosis was particularly poor for patients with IBC treated with local regional therapy only.% INTRODUCTIONOF SYSTEMIC THERAPY
In the 1970s it became apparent that local-regional therapy could not cure most patients with LABC, and systemic therapy was introduced by several research groups in Europe and North America.” 16, 35, 64 The use of chemotherapy (CT) as the initial treatment for patients with LABC was also supported by theoretical and experimental observations. In the 1950s and 1960s, it was hypothesized that breast cancer cells metastasize early and that eradication of microscopic metastatic disease would be associated with improved overall survival (0s).Skipper and colleagues’s mathematical models indicated that anticancer drugs kill a constant fraction of the tumor cell population, regardless of tumor size, and that the chance of eradicating a tumor is greater when the tumor is Goldie and ColdmanZ6hypothesized that the probability of developing drug-resistant clones is proportional to the tumor size, and when the tumor is clinically detectable (greater than lo6 cells), it is likely that at least one cell line is resistant to CT. According to the Goldie-Coldman hypothesis, multiple non-cross-resistant chemotherapeutic agents should be given as soon as possible to achieve a cure. Experimental data indicated that the best outcome was obtained when CT was administered early and that a delay in surgery following tumor transplantation A primary tumor can inhibit the was associated with a lower cure growth of metastatic foci, and removal of the primary tumor is associated with an increased proliferation rate of residual tumors. Fisher and
LOCALLY ADVANCED BREAST CANCER
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associatesU showed that the kinetic changes induced by removal of the primary tumor could be prevented by the administration of CT, tamoxifen, or XRT before surgery. These theoretical considerations, together with the poor prognosis associated with local therapy, led to the introduction of preoperative (also known as induction, primary, and neoadjuvant) systemic therapy in patients with LABC. The use of CT and/or RT before surgery offers several advantages. For patients with stage IIIB/IV breast cancer, surgery is not an option, and neoadjuvant CT is clearly the treatment of choice. In patients with stage Ill3 / IIIA, neoadjuvant CT may effectively downstage previously inoperable tumors or tumors too large to be removed by lumpectomy. This downstaging leads to better local control, improved cosmetic results, and reduction in local recurrence. In addition, neoadjuvant CT permits the in vivo assessment of tumor sensitivity to a particular regimen, allowing optimization of available therapeutic agents. It has been stated that a disadvantage of neoadjuvant CT is the loss of information regarding LN status and other important prognostic factors. Although the LN status is the most important prognostic indicator for patients with primary breast cancer, patients with tumors greater than 1 cm are currently offered postoperative therapy regardless of LN involvement." Furthermore, the presence of LN metastases after neoadjuvant CT has prognostic ~ignificance.~~ RESULTS OF NEOADJUVANT CHEMOTHERAPY
From the initial clinical studies of neoadjuvant CT for LABC, most of which were not randomized, objective responses (either partial or complete) were reported in 50% to 90% of patients (Table 1). Most responses were observed after the first two or three cycles of CT, although some patients required up to 8 to 10 cycles of CT to achieve maximal response.45Despite high overall response rates, clinical complete remissions (CR)were low, in the range of 20% (Table 2). In addition, clinical CR do not always correlate with pathologic CR.20,33 Only 50% to 60% of patients who develop a clinical CR have no evidence of microscopic disease at the time of surgery in the breast tissue and axillary lymph nodes. Conversely, some patients with palpable lesions prior to surgery achieve pathologic CR. The discrepancy observed between clinical and pathologic CR may be due in part to the criteria used to define CR. The optimal timing and duration of CT, both preoperatively and postoperatively, has not been clearly defined. DeLena and associates16 showed that administration of adjuvant therapy after neoadjuvant CT and local treatment is more effective than induction CT alone. The 10-
460
ESTEVA & HORTOBAGYI
Table 1. OBJECTIVE RESPONSES AFTER PRIMARY CHEMOTHERAPY (CT) FOR LOCALLY ADVANCED BREAST CANCER (LABC)
Author
Primary CT Regimen
No. of Patients Treated
Poddubnaya Hortobagyi Hortobagyi Booser DeLena Belembaogo Perloff Ross0 Jacquillat Schwartz Pouillart Calais DeLena Ahern Lippman cocconi Conte Hobar Powles Colozza Morrow Armstrong Cardenas Rubens
AMC/CMF VACP X 3 FAC X 3 FAC X 4 AV X 3 AVC(M)F X 3 CAFVP x 3 FAC X 3 VbTtMAFP X 2-4 CMF+T X 3 WAC X 4 MiVCF AV X 4 AC X 3 CATPMFL X 3-11 CMF +T DESFAC X 3 FAC X 3 MiMMx X 4 CAP1 X 4 cAFx2 CAVMLF X 8 FAC X 4 AV X 4
503 193 174 160 132 126 113 113 98 90 82 80 74 67 51 49 39 36 34 31 31 24 23 12
No. of Patients With Objective Responses
("/I
317 (63) 161 (83) 152 (87) 116 (73) 70 (53) 105 (83) 78 (69) 73 (65) 89 (91) 63 (70) 47 (57) 41 (51) 64 (86) 56 (W 45 (88) 23 (47) 28 (72) 26 (72) 32 (94) 23 (7) 24 (77) 24 (100) 21 (91) 6 (50)
Percent Complete Responses
2 18 17 8 15 10 18 10 23 NR 10 18 4 18 52 8 15 8 44 7 NR 63 30 17
A = doxorubicin (Adriamycin); M = methotrexate; C = cyclophosphamide; F = 5-fluorouracil; vincristine; P = prednisone; Vb = vinblastine; Tt = thiotepa; T = tamoxifen; M 2 = methotrexate + mitomycin; Mi = mitomycin; L = leucovorin; DES = diethylstilbestrol; M x = mitoxantrone; P1 = cisplatin; NR = not reported. V
=
year disease-free survival (DFS) rates were 45% for patients with stage IIIA disease and 33% for patients with stage IIIB disease.loSeveral small randomized clinical trials failed to show an improvement in 0s for preoperative rather than postoperative ~hemotherapy.4~. 53, 56, 59 Only one of these studies56showed an improvement in 0 s for patients receiving preoperative CT; however, there was no change in DFS, and these results are difficult to interpret. Similarly, a large randomized clinical trial by the National Surgical Adjuvant Breast and Bowel Project (NSABP), trial B-18, failed to show a significant difference in 0 s for patients with earlystage breast cancer treated with either preoperative or postoperative CT. In this study, more than 3,000 patients with resectable breast cancer (not with LABC) were randomized to treatment with a combination of doxorubicin and cyclophosphamide (AC) before surgery or to the same regimen after surgery. At 5 years, 0s was identical between the two groups." Although longer follow-up is needed to determine the relative
461
LOCALLY ADVANCED BREAST CANCER
Table 2. COMPLETE REMISSIONS AFTER PRIMARY CHEMOTHERAPY (CT) FOR LOCALLY ADVANCED BREAST CANCER (LABC)
Author
Treatment Regimen
No. of Patients
Hortobagyi Hortobagyi Booser Chollet Machiavelli Namer Schwartz Swain cocconi Closon-Dejardin Conte Hobar Graham Colozza Armstrong Cardenas
CT + S + CT + RT CT? S + RT + CT CT + S + CT + RT CT RT ? S CT + S + CT CT + S + CT fRT CT S CT? RT CT?S+T +CT CT + S + CT + RT CT+S CT(HT) S CT CT + S ? RT + CT CT+S+ CT CT + S + CT/RT CT S ? RT CT + S + RT + CT
193 174 160 148 140 95 90 76 49 40 39 36 34 31 24 23
CT ported
=
+
+ +
+ +
+
chemotherapy; S = surgery; RT
=
Percent Clinical Percent Complete Pathological Response Complete Response
9 8 13 1 18 NR 3 30 14 10 8 11 15 6 17 13
18 17 9 30 8 5 NR 49 8 25 15 8 32 7 37 30
radiotherapy; HT
=
hormone therapy; NR
=
not re-
value of preoperative CT versus postoperative CT in patients with operable breast cancer, neoadjuvant chemotherapy remains the treatment of choice for patients with LABC. CHEMOTHERAPY REGIMENS
Although the CT regimens have varied widely among studies, most clinical trials have used anthracycline-containing regimens. Many of the initial trials used a combination of 5-fluorouracil, doxorubicin and cyclophosphamide (FAC).36In Europe, epirubicin was substituted for doxorubicin (FEC) with similar results. A few trials have used the cyclophosphamide, methotrexate, 5-fluorouracil (CMF) combination, although anthracycline-containing regimens were generally preferred because of the higher response rates observed in the metastatic setting. One approach to improve the results of neoadjuvant CT in patients with LABC is the sequential or concomitant use of non-cross-resistant agents. Bonadonna and colleagues7showed that, in women with extensive nodal involvement, sequential CT with doxorubicin followed by CMF yields superior results compared with the alternating administration of the same regimens or with classical CMF. Recent additions to the CT armamentarium include vinorelbine ( N a ~ e l b i n eand ) ~ ~the taxanes paclitaxel (Tax01)~’and docetaxel (Taxotere).66All three agents produce objective
462
ESTEVA & HOFTOBAGM
responses (either complete or partial) in 50% to 70% of patients with metastatic breast cancer not previously exposed to CT. In addition, both taxanes are effective in patients with anthracycline-resistant breast cancer. Moliterni and associates49showed that the combination of paclitaxel and doxorubicin is safe and results in high response rates in patients with LABC. GradisharZ7reported a 67% partial response (PR) rate and an 18% CR rate using docetaxel100 mg/m2 as a 1-hour intravenous infusion once every 3 weeks followed by surgery in patients with LABC. The M. D. Anderson Cancer Center is conducting a study using doxorubicin and docetaxel as primary CT, followed by surgery. Depending on the pathologic findings at surgery, patients receive either the same CT regimen, or they are crossed over to CMF. Radiation therapy and tamoxifen (if the tumor is estrogen receptor [ER] positive) follow adjuvant CT.
ROLE OF CHEMOTHERAPY DOSE INTENSIFICATION
Although doxorubicin-based CT improves DFS and 0s of patients with LABC, most patients with stage IIIB/IV breast cancer succumb to their disease. The 2- and 5-year DFS for these patients is only 51% and 33%, respectively. One of the major areas of research is the intensification of CT, with or without hematopoietic stem cell support. Dose intensity is defined as the amount of drug administered over a period of time (i.e., mg/m2/week). Hryniuk and Bush showed a correlation between CT dose intensity and response rates in patients with metastatic breast ~ancer.3~ The Cancer and Leukemia Group B (CALGB) protocol 85-41 showed that doses lower than standard dose produce inferior DFS and OS.67On the other hand, CALGB protocol 9344 failed to show a 0 s improvement when doxorubicin dose was intensified over 60 mg/m2 every 21 days,30and, in NSABP protocols B-22 and B-25, intensification of cyclophosphamide over a fourfold range in the AC regimen did not improve DFS or 0 s rates.21Several phase I1 clinical trials have shown higher response rates when anthracyclines are intensified using hematopoietic growth factors.51,58 However, survival data are not available. A randomized phase I1 study recently completed at M. D. Anderson Cancer Center compared standard FAC to FAC administered every 2 weeks instead of every 3 weeks, using granulocyte colony stimulating factor (G-CSF) support. Preliminary data indicate a higher response rate for the higher dose intensity arm (98% versus 76%) but a similar pathologic CR rate.17 Dose density is defined as the administration of CT over short
LOCALLY ADVANCED BREAST CANCER
463
periods of time (e.g., weekly or twice weekly dosing instead of every 3 to 4 weeks).5O In this approach, CT agents are delivered at full dose (with or without growth factor support) in a sequential manner. Theoretically, this model would overcome the problem of regrowth of metastases between cycles. Sikov and associates60reported a 79% response rate using high-dose weekly paclitaxel (175 mg/mz/week) in patients with LABC. In this pilot study, 2 of 14 patients had pathologic CRs confirmed at surgery. All responding patients and two of three patients with stable disease were resectable at the time of surgery. The use of high-dose chemotherapy (HDCT) with hematopoietic stem cell transplantation is an area of active investigation as a treatment for LABC patients at high risk of relapse. This category includes patients who develop progressive disease while or after receiving neoadjuvant conventional CT. High-dose chemotherapy is also being investigated as first-line therapy for patients with stage IIIB / IV disease. Ayash and associates14reported a greater than 90% response rate for patients with IBC treated with induction doxorubicin followed by high-dose CT intensification with cyclophosphamide, thiotepa, and carboplatin. The estimated 30-month DFS rate was 100% for patients who achieved a pathologic CR at the time of surgery, 70% for patients with microscopic residual disease, and less than 40% for patients with gross residual disease. Cagnoni and colleagues" reported similar encouraging results. However, phase I1 clinical trials of HDCT must be analyzed with caution, as patients are highly selected and there is no control group.15,24 The role of HDCT with hematopoietic stem cell support can be determined only by prospective, randomized trials. Hortobagyi and coworkers3*have recently reported the results of a randomized trial of HDCT consolidation for breast cancer patients with more than 10 positive LN. In this study, two courses of HDCT after 8 cycles of FAC were not superior to 8 cycles of FAC alone. Until these issues are resolved, conventional regimens should be delivered at full dose and on time. RESULTS OF NEOADJUVANT HORMONE THERAPY
Endocrine therapy has also been used as primary therapy for patients with LABC. The initial studies used hormone therapy alone for elderly patients thought to be at risk for surgery or XRT. These patients were likely to have ER-positive tumors.53,54 Subsequently, tamoxifen was used as adjuvant to local therapy. More recently, tamoxifen has been used as neoadjuvant therapy in a multidisciplinary fashion (Table 3). Many of the reported clinical trials did not require hormone receptor data. Overall, approximately 33% of patients receiving endocrine therapy
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ESTEVA & HORTOBAGM
Table 3. OBJECTIVE RESPONSES AFTER PRIMARY HORMONE THERAPY FOR LOCALLY ADVANCED BREAST CANCER (LABC)
Author
Year
Treatment
Hormone Therapy Alone Pearlman 1976 Ablative therapies 1976 Additive therapies Pearlman Bumma 1976 Nafoxidine 1977 Estrogens Rubens 1977 Androgens Rubens 1985 Hypophysectomy Bum Burn 1985 Oophorectomy 1985 Tamoxifen Bum 1985 Estrogens Bum 1985 Tamoxifen Blamey 1985 Tamoxifen Bradbeer 1990 Tamoxifen Paradiso Gaskell 1992 Tamoxifen 1995 Tamoxifen Bergman 1997 Tamoxifen Willsher Neoadjuvant Hormone Therapy Kennedy 1957 Estrogens 1988 Tamoxifen Ashby 1989 Ovarian ablation Anderson Anderson 1989 Tamoxifen 1989 Aromatase inhibitor Anderson 1989 Tamoxifen Mansi 1989 Leuprolide Mansi 1997 Tamoxifen Valero
NR
=
Mean Percent No. of Response Survival 5-Year Patients Rate (Months) Survival
18 7 7 23 7 20 12 35 3 53 50 29 51 85 53
NR NR 86 NR NR 60 58 46 100 45 59 73 47 38 36
12 6 NR 14 14 NR NR NR NR 32 NR NR 66 48 NR
10 0 NR 13 0 NR NR NR NR NR 62 NR 55 40 NR
23 32 17 10 16 38 4 41
100 31 42
47
NR NR NR NR NR >24
12 NR NR NR NR NR
41
>30
NR
not reported
achieve an objective response and another third achieve stable disease. These results are likely to be improved by patient selection based on ER status. Most clinical trials to date have used tamoxifen as the hormone therapy of choice. Ongoing clinical trials are evaluating the role of novel hormonal agents for patients with LABC. These include specific aromatase inhibitors (e.g., anastrazole, letrozole, formestane), new antiestrogens (e.g., toremifene), progestins (e.g., medroxyprogesterone), and luteinizing hormone-releasing hormone (LHRH) analogs (e.g., goserelin). At the present time, however, tamoxifen remains the treatment of choice if endocrine therapy is indicated. ROLE OF BREAST-CONSERVING SURGERY
Neoadjuvant therapy reduces the tumor size markedly in most patients with LABC, raising the possibility of breast-conserving surgery
LOCALLY ADVANCED BREAST CANCER
465
(BCS) for selected patients. Several groups have reported the feasibility of BCS following primary CT.16,38, 45, 47 However, the selection criteria and surgical techniques for BCS are not clearly defined. At M. D. Anderson Cancer Center, all patients are evaluated by a multidisciplinary team after four cycles of doxorubicin-based chemotherapy. Breast preservation is considered if the tumor is small (relative to the breast size), if the patient is motivated to preserve her breast, and if there is no multifocal disease. Absolute contraindications include the patient’s preference for mastectomy, extensive multifocal disease, extensive persistent skin changes, involved surgical margins, and diffuse microcalcifications on mammogram. Relative contraindications to BCS include a predicted poor cosmetic result, extensive intraductal component, extensive lymphatic invasion, tumor size greater than 3 cm, and a large tumor:breast ratio.37 Following these stringent criteria, Singletary and colleagues61showed that 10% to 40% of patients with LABC can be treated with segmental mastectomy, axillary LN dissection, and XRT. However, only controlled randomized clinical trials will clarify the safety and efficacy of BCS for patients with LABC. INFLAMMATORY BREAST CANCER
Before the introduction of neoadjuvant chemotherapy, IBC was a uniformly lethal disease.36The local recurrence rate was extremely high, most patients developed distant metastases in the first year, and few patients survived beyond 2 years. The addition of systemic CT and hormonal therapy to local-regional treatments resulted in a dramatic improvement in response rates and 0 s (Table 4).127 13, 16, 19, 40-42, 46, 52, 69 Neoadjuvant therapy produced objective response rates of 60% to 8O%, and almost all patients could be rendered disease-free with surgery and XRT.36,42 Today, approximately 30% of patients with IBC and regional stage IV breast cancer are alive and free of disease at 20 years of follow-up.9 PROGNOSTIC FACTORS
Prognostic factors for patients with LABC who are undergoing neoadjuvant CT have been identified (Table 5).37These include the patient’s age, tumor stage, histologic grade, nuclear grade, menopausal status, clinical response to preoperative CT, and the LN status after preoperative CT.57 In a retrospective multivariate analysis, McCready and colleagues48found that the most important prognostic factors were the clinical response to neoadjuvant CT and the LN status following
466
ESTEVA & HORTOBAGYI
Table 4. RESULTS OF COMBINED MODALITY THERAPY FOR INFLAMMATORY BREASTCANCER
Author
Year
Treatment
No. of Patients
Percent Complete Remission
Median Percent Alive At Survival (Months) 3 Years 5 Years
With Hormonal Therapy as Systemic Treatment
Yonemoto Droulias Droulias Lucas Lucas Lucas
1970 1976 1976 1978 1978 1978 1980
HT
14 RT+HT 22 HT+RTfCT 11 S+HT+RT 13 RT+HT or Ct 10 HT 8 ChU RT+HT 14 With Chemotherapy as Systemic Treatment De la Garza 1977 CT+RT+CT 18 1978 CT+RT+CT De Lena 36 Krutchik 1979 CT+RT+CT 32 ChU 1980 RT+CT 16 Pouiuart 1981 CT -RT+ CT 77 Zylberberg 1982 CT+ S+ CT RT 15 Pawlicki, 1983 CT+ S? RT 72 Loprinzi 1984 S+ CT+RT CT 9 Keiling 1985 C T + S + C T 41 Fastenberg 1985 CT + RT 2 S CT 63 JacquiUat 1986 CT+RT+CT 34 Albert0 1986 C T + S + C T +RT 22 FerrieE 1986 CT+ RT f S + CT 75 Poumy 1986 CT+ Sf RT+ CT 33 Israel 1986 C T + S + C T 25 1986 CT+RT+CT Rouessee 91 Rouessee 1986 CT+RT+CT 79 Burton 1987 CT+S+CT+RT 22 Noguchi 1988 CT+S+CT 28 BrUn 1988 CT+ RT+S + CT 26 ThOmS 1989 CTf S + CT + RT 61 Maloisel 1990 C T +S+RT +CT 43 Bilbao 1992 CT +S+RT CT 18 Chevallier 1993 CT + RT 2 CT f S 178 Roth 1993 CT+S+CT 73 Janvier 1993 CT+RT+S+CT 133 Wiseman 13 1995 CT+S+IT+CT+RT Ueno 1997 CT S +CT + RT 72
+ + +
+
+
NR NR
NR NR NR NR NR NR 73 85
NR 51 100 NR 100 100 92 100 95 93 82 96 41 54 86 100
85 100 88 100 83 NR t?4
100 92
22
NR
7
22
NR NR 0
NR NR
13 <12 <12 12 15 21 25 24 >26 34 NR
NR >25 NR 43 NR 43
NR 70 NR 36
NR 18 NR 31 27
NR 33 37 >23 NR 48 34
10 25
0 0 0
NR
NR
NR 24 42
22 NR 35 NR NR 70
NR 45 75 28 60 75 58 77 47 68 70 68 50 80 NR NR 40 NR 85 50 48 NR NR 70 38
NR 55 63 34 66 10 54 60 62 40 66
NR 63 25 35 75
NR 32
NR NR 40 35
= chemotherapy; S = surgery; RT = radiotherapy; HT = hormone therapy; IT = -mothsapy; NR = not reported
doxorubicin-based therapy? Pathologic response has also been associated with 0s. At M. D. Anderson Cancer Center, LABC patients whose mastectomy specimen did not contain gross residual disease had a greater than 75% 5-year DFS. Patients with negative or less than four involved LN after induction CT had a 40% to 50% 5-year DFS; if four or more LN were involved, DFS decreased to 30%; and only 20% of patients were free of disease at 5 years if more than 10 LN contained metastatic carcinoma after neoadjuvant CT.*O
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467
Table 5. PROGNOSTIC FACTORS FOR PATIENTS WITH LOCALLY ADVANCED BREAST CANCER (LABC) TREATED WITH NEOADJUVANT CHEMOTHERAPY (CT) Factor
Favorable
Unfavorable
Stage (TNM) Age Clinical response Pathologic response Inflammatory signs No. positive nodes Premenopausal Estrogen receptor status Progesterone receptor status Histologic grade S-phase fraction
II-IIIA <50 years Complete Complete No <4 Yes Positive Positive High Low
IIIB 250 years Less than complete Less than complete Yes 24
No Negative Negative Low High
MOLECULAR PREDICTORS OF RESPONSE TO CHEMOTHERAPY
One of the advantages of neoadjuvant CT is the opportunity to evaluate tumor sensitivity to a particular CT regimen in vivo by assessing clinical and pathologic response. In addition, molecular markers can be analyzed before and after preoperative CT. Retrospective data from large adjuvant CT trials have revealed associations between oncogene expression and resistance to CT. Gusterson and colleagues**showed that women with early-stage breast cancer undergoing CMF CT in the adjuvant setting did not benefit if their tumors overexpressed the HER2 / neu protein. The CALGB protocol 85-41 evaluated a combination of cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) to determine the role of dose intensity in the adjuvant setting. In this study, patients whose tumors overexpressed HER2/neu had an improved 0 s with higher (full) doses of CAF?7 These data suggest that HER2 / neu-mediated drug resistance may be overcome by full doses of doxorubicin. The role of HER2/ neu overexpression and response to paclitaxel is controversial. Retrospective data from Memorial Sloan-Kettering Cancer Center indicate increased sensitivity to paclitaxel in patients with metastases and HER2/ neu overexpressing tumor^.^ However, randomized clinical trials showed a poor response (14%) to paclitaxel for this patient population and improved response rates and DFS for patients treated with paclitaxel in combination with an anti-HER2 antibody (Her~eptin).~~ Experimental in vivo data indicate that tumors overexpressing HER2 / neu are resistant to paclitaxel-induced apoptosis,68 supporting the results observed in randomized clinical trials of Herceptin in combination with paclitaxel. Apoptosis is one of the most important mechanisms of CT-induced cytotoxicity. Ellis and coworkers18showed that doxorubicin-based neoadjuvant CT can induce apoptosis in primary tumors in patients under-
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ESTEVA & HORTOBAGYI
going doxorubicin-based primary CT. Anthracyclines induce apoptosis through the p53 protein, and experimental tumors with a mutated (inactive) p53 gene are resistant to anthracyclines. Berruti and colleagues5 reported an association between wild-type p53 protein and response to neoadjuvant doxorubicin-based CT, suggesting that an intact p53 gene may be required for CT-induced cytotoxicity. In contrast, the taxanes induce cell death in a p53 gene-independent manner. In one study, paclitaxel was more effective for patients whose tumors overexpressed the p53 protein4 The Bcl-2 protein is another important molecule in the control of apoptosis. Bcl-2 expression has been associated with ERpositive status and low proliferation rates: Archer and colleagues2 showed that Bcl-2-negative patients were more likely to respond to anthracycline-based CT than Bcl-2-positive patients. Bonetti and associate# reported an association between Bcl-2 expression and response to CT in advanced breast cancer by a multivariate logistic regression analysis. In this study, 42% of patients with Bcl-2-negative tumors responded to CT, but in Bcl-2-positive patients only 13% responded. This effect was independent of ER status, P-glycoprotein expression, age, menopausal status, dominant disease site, DFS, and type of first-line therapy. Another gene undergoing evaluation is the multi-drug-resistant gene (MDR-1). The MDR-1 protein is located at the cell membrane and functions as a pump that detoxifies the cell from noxious agents. Overexpression of the MDR-1 protein has been associated with resistance to anthracycline- and taxane-based CT in vitro. However, the clinical value of MDR-1 expression in breast cancer has not been clearly defined.65
CONCLUSION
In summary, neoadjuvant systemic therapy results in improved local control and 0s for patients with LABC. A multidisciplinary approach that includes preoperative CT or endocrine therapy, surgery, adjuvant systemic therapy, and XRT is now considered the standard of care for patients with LABC. Novel cytotoxic, hormonal, and biological agents are rapidly being integrated into the management of LABC. The role of HDCT, with or without autologous peripheral stem cell transplantation, remains experimental. Prospective clinical trials are evaluating the role of oncogenes and tumor suppressor genes in drug sensitivity and resistance, using the neoadjuvant setting as a model to study molecular changes induced by different drugs and biologics in breast cancer cells.
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21. Fisher B, Anderson S, Wickerham DL, et al: Increased intensification and total dose of cyclophosphamide in a doxorubidn-cyclophosphamideregimen for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project 8-22. J Clin Oncol 151858,1997 22. Fisher 8, Brown A, Mamounas E, et ak Effect of preoperative therapy for primary breast cancer (BC) on local-regional disease, disease-free survival (DFS) and survival (S): Results from NSABP B-18 [abstract]. Proceedings of the American Society of Clinical Oncology 16:127, 1997 23. Fisher 8, Gunduz N, Saffer EA: Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res 43:1488, 1983 24. Garcia-Carbonero R, Hidalgo M, Paz-Ares L, et al: Patient selection in high-dose chemotherapy trials: Relevance in high-risk breast cancer. J Clin Oncol 15:3178, 1997 25. Goldhirsch A, Wood WC, Senn HJ, et ak Fifth International Conference on Adjuvant Therapy of Breast Cancer, St Gallen, March 1995. International Consensus Panel on the Treatment of Primary Breast Cancer. Eur J Cancer 31A1754, 1995 26. Goldie JH, Coldman AJ: A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treatment Reports 631727,1979 27. Gradishar WJ: Docetaxel as neoadjuvant chemotherapy in patients with stage III breast cancer. Oncology (Huntingt) 11:15, 1997 28. Gusterson BA, Gelber RD, Goldhirsch A, et al: Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group. J Clin Oncol 101049, 1992 29. Haagensen CD,Stout Al? Carcinoma of the breast. Criteria of inoperability. Am Surg 118859,1943 30. Henderson IC, Berry D, Demetri G, et ak Improved disease-free (DFS) and overall survival (0s)from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients with nodepositive primary breast cancer [abstract]. Proceedings of the Annual Meeting of the Society of Clinical Oncology 17390, Los Angeles, CA, May 16-19, 1998 31. Holmes FA, Walters RS, Theriault RL, et ak Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83:1797, 1991 32. Hortobagyi GN, Buzdar AU, Champlin R, et al: Lack of efficacy of adjuvant high-dose tandem combination chemotherapy for high-risk primary breast cancer-A randomized trial. Proceedings of the Annual Meeting of the Society of Clinical Oncology 17471a, Los Angeles, CA, May 16-19, 1998 33. Hortobagyi GN, Singletary SE, McNeese MD: Treatment of locally advanced and inflammatory breast cancer. In Harris JR, Lippman ME, Morrow M, et a1 (eds): Diseases of the Breast. Philadelphia, Lippincott-Raven, 1996 34. Hortobagyi GN, Ames FC, Buzdar AU, et ak Management of stage I11 primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer 622507, 1988 35. Hortobagyi GN, Blumenschein GR, Spanos W, et al: Multimodal treatment of locoregionally advanced breast cancer. Cancer 51:763, 1983 36. Hortobagyi GN, Buzdar AU. Locally advanced breast cancer: A review including the M. D. Anderson experience. In Ragaz J, Ariel IM (eds): High-risk Breast Cancer. Berlin, Springer-Verlag, 1991 37. Hortobagyi GN, Buzdar AU, Strom EA, et al: Primary chemotherapy for early and advanced breast cancer. Cancer Lett 90103, 1995 38. Hortobagyi GN, Spanos W, Montague ED, et al, Treatment of locoregionally advanced breast cancer with surgery, radiotherapy, and combination chemoimrnunotherapy. Int J Radiat Oncol Biol Phys 9:643, 1983 39. Hryniuk W, Bush H The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol21281, 1984 40. Israel L, Breau JL, Morere JF:Two years of high-dose cyclophosphamide and 5fluorourad followed by surgery after 3 months for acute inflammatory breast carcinomas. A phase 11 study of 25 cases with a median follow-up of 35 months. Cancer 5724, 1986
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41. Jacquillat C, Weil M, Auclerc G, et al: Neoadjuvant chemotherapy in the conservative management of breast cancer: A study of 252 patients. Recent Results Cancer Res 115:36, 1989 42. Jaiyesimi IA, Buzdar AU, Hortobagyi G: Inflammatory breast cancer: A review. J Clin Oncol 10:1014, 1992 43. Johnson SA, Harper P, Hortobagyi GN, et al: Vinorelbine: An overview. Cancer Treat Rev 22:127, 1996 44. Kandioler-EckersbergerD, Taucher S, Steiner B, et al: p53 genotype and major response to anthracyclin or paclitaxel based neoadjuvant treatment in breast cancer patients [abstract]. Proceedings of the American Society of Clinical Oncology 392, Los Angeles, CA, May 16-19, 1998 45. Lippman ME, Sorace RA, Bagley CS, et al: Treatment of locally advanced breast cancer using primary induction chemotherapy with hormonal synchronization followed by radiation therapy with or without debulking surgery. National Cancer Institute Monographs 153, 1986 46. Loprinzi CL, Carbone PP, Tormey DC, et al: Aggressive combined modality therapy for advanced local-regional breast carcinoma. J Clin Oncol 2157, 1984 47. Mauriac L, Durand M, Avril A, et al: Effects of primary chemotherapy in conservative treatment of breast cancer patients with operable tumors larger than 3 cm. Results of a randomized trial in a single centre. Ann Oncol 2:347, 1991 48. McCready DR, Hortobagyi GN, Kau SW, et al: The prognostic significance of lymph node metastases after preoperative chemotherapy for locally advanced breast cancer. Arch Surg 12421, 1989 49. Moliterni A, Tarenzi E, Capri G, et a1 Pilot study of primary chemotherapy with doxorubicin plus paclitaxel in women with locally advanced or operable breast cancer. Semin Oncol24:S17, 1997 50. Norton L: Kinetic concepts in the treatment of breast cancer. Recent Results Cancer Res 1271, 1993 51. Piccart MJ, Bruning P, Wildiers J, et al: An EORTC pilot study of Filgrastim (recombinant human granulocyte colony stimulating factor) as support to a high dose-intensive epiadriamycin-cyclophosphamide regimen in chemotherapy-naive patients with locally advanced or metastatic breast cancer. Ann Oncol 6:673, 1995 52. Rouesse J, Friedman S, Sarrazin D, et al: Primary chemotherapy in the treatment of inflammatory breast carcinoma: A study of 230 cases from the Institut Gustave-Roussy. J Clin Oncol4:1765, 1986 53. Rubens RD, Bartelink H, Engelsman E, et a1 Locally advanced breast cancer: The contribution of cytotoxic and endocrine treatment to radiotherapy. An EORTC Breast Cancer Co-operative Group Trial (10792). European Journal of Cancer and Clinical Oncology 25:667, 1989 54. Rubens RD, Tinson CL, Coleman RE, et al: Prednisolone improves the response to primary endocrine treatment for advanced breast cancer. Br J Cancer 58:626, 1988 55. Schabel FM, Jr.: Surgical adjuvant chemotherapy of metastatic murine tumors. Cancer 40:558, 1977 56. Scholl SM, Fourquet A, Asselain B, et al: Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: Preliminary results of a randomised trial: 56. Eur J Cancer 30A645, 1994 57. Scholl SM, Pierga JY, Asselain B, et al: Breast tumour response to primary chemotherapy predicts local and distant control as well as survival. Eur J Cancer 31A1969, 1995 58. Scinto AF, Ferraresi V, Campioni N, et al: Accelerated chemotherapy with highdose epirubicin and cyclophosphamide plus r-met-HUG-CSF in locally advanced and metastatic breast can&. h n 6ncol 6665, 1995 59. Semiglazov VF, Topuzov EE, Bavli JL, et al: Primary (neoadjuvant) chemotherapy and radiotherapy compared with primary radiotherapy alone in stage 1%-IIIa breast cancer. Ann Oncol 5:591, 1994 60. Sikov W, Akerley W, Cummings F, et al: High-dose weekly paclitaxel for locally advanced (LABC) and metastatic breast cancer (MBC) [abstract]. Proceedings of the American Society of Clinical Oncology 16:669, 1997 61. Singletary SE, McNeese MD, Hortobagyi GN: Feasibility of breast-conservation surgery
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62. 63.
64. 65. 66. 67. 68. 69.
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after induction chemotherapy for locally advanced breast carcinoma. Cancer 692849, 1992 Skipper H E Experimental evaluation of potential anticancer agents. XIII. On the criteria and kinetics associated with “curability” of experimental leukemia. Cancer Chemotherapy Reports 351, 1964 Slamon DJ, Leyland-Jones B, Shak S, et ak Addition of Herceptin”” (humanized antiHER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2 + /MBC) markedly increases anticancer activity: A randomized, multinational controlled phase Ill trial [abstract]. Proceedings of the American Society of Clinical Oncology 17377, Los Angeles, CA, May 16-19, 1998 Swain SM, Sorace RA, Bagley CS, et al: Neoadjuvant chemotherapy in the combined modality approach of locally advanced nonmetastatic breast cancer. Cancer Res 473889, 1987 Trock BJ, Leonessa F, Clarke R Multidrug resistance in breast cancer: A meta-analysis of MDRl/gpl70 expression and its possgle functional significance. J Natl Cancer - h t 89:917. 1997 Valero V, Holmes FA, Walters RS, et a1 Phase II trial of docetaxel: A new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 132886, 1995 Wood WC, Budman DR, Korzun AH, et al: Dose and dose intensity of adjuvant chemotherapy for stage 11, node-positive breast carcinoma. N Engl J Med 330:1253,1994 Yu D, Liu B, Sun D, et ak Overexpression of both p185 c-erbB-2 and p170 MDR-1 renders breast cancer cells highly resistant to Taxol. Proceedings of the American Association for Cancer Research 39:1470, New Orleans, LA, Mar 28-April 1, 1998 Zylberberg B, Salat-Baroux J, Ravina JH, et ak Initial chemoimmunotherapy in inflammatory carcinoma of the breast. Cancer 49:1537, 1982
Address reprint requests to Francisco J. Esteva, MD Assistant Professor of Medicine Department of Breast Medical Oncology The University of Texas M. D. Anderson Cancer Center 1515 Holcombe Blvd., Box 56 Houston, TX 77030
0889-8588/99 $8.00 + .OO
LOCALLY ADVANCED BREAST CANCER Francisco J. Esteva, MD, and Gabriel N. Hortobagyi, MD
Locally advanced breast cancer (LABC) accounts for 5% to 15% of new breast cancer cases in the United States and for 40% to 60% of new cases in nonindustrialized countries. The diagnosis of LABC includes tumors classified under TNM classification as stage IIB (T3NO), stage I11 (IIIA and IIIB), and regional stage IV breast cancer (ipsilateral supraclavicular lymph node [LN] metastases), according to the American Joint Committee for Cancer Staging.' Based on the TNM system, LABC tumors must be larger than 5 cm (T3) and/or involve the skin or chest wall (T4) with any node (N), stage. Tumors of any tumor (T) category with N2 (matted axillary LN) or N3 (internal mammary LN) are also considered LABC. Inflammatory breast cancer (IBC) is a particularly aggressive form of LABC that has highly metastatic features, and it is Inflammatory breast cancer classified as stage IIIB in the TNM is a clinical-pathological entity characterized by the rapid development (usually within 3 months) of erythema and edema (also known as peau d'orange sign) and breast ridging (palpable striae in erythematous areas). In many cases no definite mass is found by physical examination or mammography. The typical mammographic finding is diffuse skin thickening. Microscopic examination of involved skin may show invasion of lymphatic vessels, although the typical pathologic findings are not needed to make the diagnosis of IBC. Patients with ipsilateral supraclavicular LN metastases (technically stage IV) and no evidence of dis-
From the Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
HEMATOLOGY/ ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 13 * NUMBER 2 * APRIL 1999
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tant metastases have a similar prognosis to patients with stage mB disease and are considered in the LABC category? During the first half of the twentieth century, patients with LABC underwent extensive surgical procedures and aggressive radiotherapy. The radical mastectomy was developed by William Halsted at the Johns Hopkins University for LABC patients. In the 1940s, Haagensen and others29revisited the surgical indications for patients with LABC. These authors recognized that patients with extensive skin involvement or fixation to the chest wall (currently classified as T4 lesions) had a high rate of metastases and mortality when treated with surgery alone. For this reason (and not because of technical issues), patients with T4, N3, or regional M1 (stage IIIB/IV) were considered inoperable. Using surgery or radiation therapy (RT) as single-therapy modalities resulted in local control for most patients with LABC. However, more than 80% of patients died of metastatic disease within 5 years of follow-up. The prognosis was particularly poor for patients with IBC treated with local regional therapy only.% INTRODUCTIONOF SYSTEMIC THERAPY
In the 1970s it became apparent that local-regional therapy could not cure most patients with LABC, and systemic therapy was introduced by several research groups in Europe and North America.” 16, 35, 64 The use of chemotherapy (CT) as the initial treatment for patients with LABC was also supported by theoretical and experimental observations. In the 1950s and 1960s, it was hypothesized that breast cancer cells metastasize early and that eradication of microscopic metastatic disease would be associated with improved overall survival (0s).Skipper and colleagues’s mathematical models indicated that anticancer drugs kill a constant fraction of the tumor cell population, regardless of tumor size, and that the chance of eradicating a tumor is greater when the tumor is Goldie and ColdmanZ6hypothesized that the probability of developing drug-resistant clones is proportional to the tumor size, and when the tumor is clinically detectable (greater than lo6 cells), it is likely that at least one cell line is resistant to CT. According to the Goldie-Coldman hypothesis, multiple non-cross-resistant chemotherapeutic agents should be given as soon as possible to achieve a cure. Experimental data indicated that the best outcome was obtained when CT was administered early and that a delay in surgery following tumor transplantation A primary tumor can inhibit the was associated with a lower cure growth of metastatic foci, and removal of the primary tumor is associated with an increased proliferation rate of residual tumors. Fisher and
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associatesU showed that the kinetic changes induced by removal of the primary tumor could be prevented by the administration of CT, tamoxifen, or XRT before surgery. These theoretical considerations, together with the poor prognosis associated with local therapy, led to the introduction of preoperative (also known as induction, primary, and neoadjuvant) systemic therapy in patients with LABC. The use of CT and/or RT before surgery offers several advantages. For patients with stage IIIB/IV breast cancer, surgery is not an option, and neoadjuvant CT is clearly the treatment of choice. In patients with stage Ill3 / IIIA, neoadjuvant CT may effectively downstage previously inoperable tumors or tumors too large to be removed by lumpectomy. This downstaging leads to better local control, improved cosmetic results, and reduction in local recurrence. In addition, neoadjuvant CT permits the in vivo assessment of tumor sensitivity to a particular regimen, allowing optimization of available therapeutic agents. It has been stated that a disadvantage of neoadjuvant CT is the loss of information regarding LN status and other important prognostic factors. Although the LN status is the most important prognostic indicator for patients with primary breast cancer, patients with tumors greater than 1 cm are currently offered postoperative therapy regardless of LN involvement." Furthermore, the presence of LN metastases after neoadjuvant CT has prognostic ~ignificance.~~ RESULTS OF NEOADJUVANT CHEMOTHERAPY
From the initial clinical studies of neoadjuvant CT for LABC, most of which were not randomized, objective responses (either partial or complete) were reported in 50% to 90% of patients (Table 1). Most responses were observed after the first two or three cycles of CT, although some patients required up to 8 to 10 cycles of CT to achieve maximal response.45Despite high overall response rates, clinical complete remissions (CR)were low, in the range of 20% (Table 2). In addition, clinical CR do not always correlate with pathologic CR.20,33 Only 50% to 60% of patients who develop a clinical CR have no evidence of microscopic disease at the time of surgery in the breast tissue and axillary lymph nodes. Conversely, some patients with palpable lesions prior to surgery achieve pathologic CR. The discrepancy observed between clinical and pathologic CR may be due in part to the criteria used to define CR. The optimal timing and duration of CT, both preoperatively and postoperatively, has not been clearly defined. DeLena and associates16 showed that administration of adjuvant therapy after neoadjuvant CT and local treatment is more effective than induction CT alone. The 10-
460
ESTEVA & HORTOBAGYI
Table 1. OBJECTIVE RESPONSES AFTER PRIMARY CHEMOTHERAPY (CT) FOR LOCALLY ADVANCED BREAST CANCER (LABC)
Author
Primary CT Regimen
No. of Patients Treated
Poddubnaya Hortobagyi Hortobagyi Booser DeLena Belembaogo Perloff Ross0 Jacquillat Schwartz Pouillart Calais DeLena Ahern Lippman cocconi Conte Hobar Powles Colozza Morrow Armstrong Cardenas Rubens
AMC/CMF VACP X 3 FAC X 3 FAC X 4 AV X 3 AVC(M)F X 3 CAFVP x 3 FAC X 3 VbTtMAFP X 2-4 CMF+T X 3 WAC X 4 MiVCF AV X 4 AC X 3 CATPMFL X 3-11 CMF +T DESFAC X 3 FAC X 3 MiMMx X 4 CAP1 X 4 cAFx2 CAVMLF X 8 FAC X 4 AV X 4
503 193 174 160 132 126 113 113 98 90 82 80 74 67 51 49 39 36 34 31 31 24 23 12
No. of Patients With Objective Responses
("/I
317 (63) 161 (83) 152 (87) 116 (73) 70 (53) 105 (83) 78 (69) 73 (65) 89 (91) 63 (70) 47 (57) 41 (51) 64 (86) 56 (W 45 (88) 23 (47) 28 (72) 26 (72) 32 (94) 23 (7) 24 (77) 24 (100) 21 (91) 6 (50)
Percent Complete Responses
2 18 17 8 15 10 18 10 23 NR 10 18 4 18 52 8 15 8 44 7 NR 63 30 17
A = doxorubicin (Adriamycin); M = methotrexate; C = cyclophosphamide; F = 5-fluorouracil; vincristine; P = prednisone; Vb = vinblastine; Tt = thiotepa; T = tamoxifen; M 2 = methotrexate + mitomycin; Mi = mitomycin; L = leucovorin; DES = diethylstilbestrol; M x = mitoxantrone; P1 = cisplatin; NR = not reported. V
=
year disease-free survival (DFS) rates were 45% for patients with stage IIIA disease and 33% for patients with stage IIIB disease.loSeveral small randomized clinical trials failed to show an improvement in 0s for preoperative rather than postoperative ~hemotherapy.4~. 53, 56, 59 Only one of these studies56showed an improvement in 0 s for patients receiving preoperative CT; however, there was no change in DFS, and these results are difficult to interpret. Similarly, a large randomized clinical trial by the National Surgical Adjuvant Breast and Bowel Project (NSABP), trial B-18, failed to show a significant difference in 0 s for patients with earlystage breast cancer treated with either preoperative or postoperative CT. In this study, more than 3,000 patients with resectable breast cancer (not with LABC) were randomized to treatment with a combination of doxorubicin and cyclophosphamide (AC) before surgery or to the same regimen after surgery. At 5 years, 0s was identical between the two groups." Although longer follow-up is needed to determine the relative
461
LOCALLY ADVANCED BREAST CANCER
Table 2. COMPLETE REMISSIONS AFTER PRIMARY CHEMOTHERAPY (CT) FOR LOCALLY ADVANCED BREAST CANCER (LABC)
Author
Treatment Regimen
No. of Patients
Hortobagyi Hortobagyi Booser Chollet Machiavelli Namer Schwartz Swain cocconi Closon-Dejardin Conte Hobar Graham Colozza Armstrong Cardenas
CT + S + CT + RT CT? S + RT + CT CT + S + CT + RT CT RT ? S CT + S + CT CT + S + CT fRT CT S CT? RT CT?S+T +CT CT + S + CT + RT CT+S CT(HT) S CT CT + S ? RT + CT CT+S+ CT CT + S + CT/RT CT S ? RT CT + S + RT + CT
193 174 160 148 140 95 90 76 49 40 39 36 34 31 24 23
CT ported
=
+
+ +
+ +
+
chemotherapy; S = surgery; RT
=
Percent Clinical Percent Complete Pathological Response Complete Response
9 8 13 1 18 NR 3 30 14 10 8 11 15 6 17 13
18 17 9 30 8 5 NR 49 8 25 15 8 32 7 37 30
radiotherapy; HT
=
hormone therapy; NR
=
not re-
value of preoperative CT versus postoperative CT in patients with operable breast cancer, neoadjuvant chemotherapy remains the treatment of choice for patients with LABC. CHEMOTHERAPY REGIMENS
Although the CT regimens have varied widely among studies, most clinical trials have used anthracycline-containing regimens. Many of the initial trials used a combination of 5-fluorouracil, doxorubicin and cyclophosphamide (FAC).36In Europe, epirubicin was substituted for doxorubicin (FEC) with similar results. A few trials have used the cyclophosphamide, methotrexate, 5-fluorouracil (CMF) combination, although anthracycline-containing regimens were generally preferred because of the higher response rates observed in the metastatic setting. One approach to improve the results of neoadjuvant CT in patients with LABC is the sequential or concomitant use of non-cross-resistant agents. Bonadonna and colleagues7showed that, in women with extensive nodal involvement, sequential CT with doxorubicin followed by CMF yields superior results compared with the alternating administration of the same regimens or with classical CMF. Recent additions to the CT armamentarium include vinorelbine ( N a ~ e l b i n eand ) ~ ~the taxanes paclitaxel (Tax01)~’and docetaxel (Taxotere).66All three agents produce objective
462
ESTEVA & HOFTOBAGM
responses (either complete or partial) in 50% to 70% of patients with metastatic breast cancer not previously exposed to CT. In addition, both taxanes are effective in patients with anthracycline-resistant breast cancer. Moliterni and associates49showed that the combination of paclitaxel and doxorubicin is safe and results in high response rates in patients with LABC. GradisharZ7reported a 67% partial response (PR) rate and an 18% CR rate using docetaxel100 mg/m2 as a 1-hour intravenous infusion once every 3 weeks followed by surgery in patients with LABC. The M. D. Anderson Cancer Center is conducting a study using doxorubicin and docetaxel as primary CT, followed by surgery. Depending on the pathologic findings at surgery, patients receive either the same CT regimen, or they are crossed over to CMF. Radiation therapy and tamoxifen (if the tumor is estrogen receptor [ER] positive) follow adjuvant CT.
ROLE OF CHEMOTHERAPY DOSE INTENSIFICATION
Although doxorubicin-based CT improves DFS and 0s of patients with LABC, most patients with stage IIIB/IV breast cancer succumb to their disease. The 2- and 5-year DFS for these patients is only 51% and 33%, respectively. One of the major areas of research is the intensification of CT, with or without hematopoietic stem cell support. Dose intensity is defined as the amount of drug administered over a period of time (i.e., mg/m2/week). Hryniuk and Bush showed a correlation between CT dose intensity and response rates in patients with metastatic breast ~ancer.3~ The Cancer and Leukemia Group B (CALGB) protocol 85-41 showed that doses lower than standard dose produce inferior DFS and OS.67On the other hand, CALGB protocol 9344 failed to show a 0 s improvement when doxorubicin dose was intensified over 60 mg/m2 every 21 days,30and, in NSABP protocols B-22 and B-25, intensification of cyclophosphamide over a fourfold range in the AC regimen did not improve DFS or 0 s rates.21Several phase I1 clinical trials have shown higher response rates when anthracyclines are intensified using hematopoietic growth factors.51,58 However, survival data are not available. A randomized phase I1 study recently completed at M. D. Anderson Cancer Center compared standard FAC to FAC administered every 2 weeks instead of every 3 weeks, using granulocyte colony stimulating factor (G-CSF) support. Preliminary data indicate a higher response rate for the higher dose intensity arm (98% versus 76%) but a similar pathologic CR rate.17 Dose density is defined as the administration of CT over short
LOCALLY ADVANCED BREAST CANCER
463
periods of time (e.g., weekly or twice weekly dosing instead of every 3 to 4 weeks).5O In this approach, CT agents are delivered at full dose (with or without growth factor support) in a sequential manner. Theoretically, this model would overcome the problem of regrowth of metastases between cycles. Sikov and associates60reported a 79% response rate using high-dose weekly paclitaxel (175 mg/mz/week) in patients with LABC. In this pilot study, 2 of 14 patients had pathologic CRs confirmed at surgery. All responding patients and two of three patients with stable disease were resectable at the time of surgery. The use of high-dose chemotherapy (HDCT) with hematopoietic stem cell transplantation is an area of active investigation as a treatment for LABC patients at high risk of relapse. This category includes patients who develop progressive disease while or after receiving neoadjuvant conventional CT. High-dose chemotherapy is also being investigated as first-line therapy for patients with stage IIIB / IV disease. Ayash and associates14reported a greater than 90% response rate for patients with IBC treated with induction doxorubicin followed by high-dose CT intensification with cyclophosphamide, thiotepa, and carboplatin. The estimated 30-month DFS rate was 100% for patients who achieved a pathologic CR at the time of surgery, 70% for patients with microscopic residual disease, and less than 40% for patients with gross residual disease. Cagnoni and colleagues" reported similar encouraging results. However, phase I1 clinical trials of HDCT must be analyzed with caution, as patients are highly selected and there is no control group.15,24 The role of HDCT with hematopoietic stem cell support can be determined only by prospective, randomized trials. Hortobagyi and coworkers3*have recently reported the results of a randomized trial of HDCT consolidation for breast cancer patients with more than 10 positive LN. In this study, two courses of HDCT after 8 cycles of FAC were not superior to 8 cycles of FAC alone. Until these issues are resolved, conventional regimens should be delivered at full dose and on time. RESULTS OF NEOADJUVANT HORMONE THERAPY
Endocrine therapy has also been used as primary therapy for patients with LABC. The initial studies used hormone therapy alone for elderly patients thought to be at risk for surgery or XRT. These patients were likely to have ER-positive tumors.53,54 Subsequently, tamoxifen was used as adjuvant to local therapy. More recently, tamoxifen has been used as neoadjuvant therapy in a multidisciplinary fashion (Table 3). Many of the reported clinical trials did not require hormone receptor data. Overall, approximately 33% of patients receiving endocrine therapy
464
ESTEVA & HORTOBAGM
Table 3. OBJECTIVE RESPONSES AFTER PRIMARY HORMONE THERAPY FOR LOCALLY ADVANCED BREAST CANCER (LABC)
Author
Year
Treatment
Hormone Therapy Alone Pearlman 1976 Ablative therapies 1976 Additive therapies Pearlman Bumma 1976 Nafoxidine 1977 Estrogens Rubens 1977 Androgens Rubens 1985 Hypophysectomy Bum Burn 1985 Oophorectomy 1985 Tamoxifen Bum 1985 Estrogens Bum 1985 Tamoxifen Blamey 1985 Tamoxifen Bradbeer 1990 Tamoxifen Paradiso Gaskell 1992 Tamoxifen 1995 Tamoxifen Bergman 1997 Tamoxifen Willsher Neoadjuvant Hormone Therapy Kennedy 1957 Estrogens 1988 Tamoxifen Ashby 1989 Ovarian ablation Anderson Anderson 1989 Tamoxifen 1989 Aromatase inhibitor Anderson 1989 Tamoxifen Mansi 1989 Leuprolide Mansi 1997 Tamoxifen Valero
NR
=
Mean Percent No. of Response Survival 5-Year Patients Rate (Months) Survival
18 7 7 23 7 20 12 35 3 53 50 29 51 85 53
NR NR 86 NR NR 60 58 46 100 45 59 73 47 38 36
12 6 NR 14 14 NR NR NR NR 32 NR NR 66 48 NR
10 0 NR 13 0 NR NR NR NR NR 62 NR 55 40 NR
23 32 17 10 16 38 4 41
100 31 42
47
NR NR NR NR NR >24
12 NR NR NR NR NR
41
>30
NR
not reported
achieve an objective response and another third achieve stable disease. These results are likely to be improved by patient selection based on ER status. Most clinical trials to date have used tamoxifen as the hormone therapy of choice. Ongoing clinical trials are evaluating the role of novel hormonal agents for patients with LABC. These include specific aromatase inhibitors (e.g., anastrazole, letrozole, formestane), new antiestrogens (e.g., toremifene), progestins (e.g., medroxyprogesterone), and luteinizing hormone-releasing hormone (LHRH) analogs (e.g., goserelin). At the present time, however, tamoxifen remains the treatment of choice if endocrine therapy is indicated. ROLE OF BREAST-CONSERVING SURGERY
Neoadjuvant therapy reduces the tumor size markedly in most patients with LABC, raising the possibility of breast-conserving surgery
LOCALLY ADVANCED BREAST CANCER
465
(BCS) for selected patients. Several groups have reported the feasibility of BCS following primary CT.16,38, 45, 47 However, the selection criteria and surgical techniques for BCS are not clearly defined. At M. D. Anderson Cancer Center, all patients are evaluated by a multidisciplinary team after four cycles of doxorubicin-based chemotherapy. Breast preservation is considered if the tumor is small (relative to the breast size), if the patient is motivated to preserve her breast, and if there is no multifocal disease. Absolute contraindications include the patient’s preference for mastectomy, extensive multifocal disease, extensive persistent skin changes, involved surgical margins, and diffuse microcalcifications on mammogram. Relative contraindications to BCS include a predicted poor cosmetic result, extensive intraductal component, extensive lymphatic invasion, tumor size greater than 3 cm, and a large tumor:breast ratio.37 Following these stringent criteria, Singletary and colleagues61showed that 10% to 40% of patients with LABC can be treated with segmental mastectomy, axillary LN dissection, and XRT. However, only controlled randomized clinical trials will clarify the safety and efficacy of BCS for patients with LABC. INFLAMMATORY BREAST CANCER
Before the introduction of neoadjuvant chemotherapy, IBC was a uniformly lethal disease.36The local recurrence rate was extremely high, most patients developed distant metastases in the first year, and few patients survived beyond 2 years. The addition of systemic CT and hormonal therapy to local-regional treatments resulted in a dramatic improvement in response rates and 0 s (Table 4).127 13, 16, 19, 40-42, 46, 52, 69 Neoadjuvant therapy produced objective response rates of 60% to 8O%, and almost all patients could be rendered disease-free with surgery and XRT.36,42 Today, approximately 30% of patients with IBC and regional stage IV breast cancer are alive and free of disease at 20 years of follow-up.9 PROGNOSTIC FACTORS
Prognostic factors for patients with LABC who are undergoing neoadjuvant CT have been identified (Table 5).37These include the patient’s age, tumor stage, histologic grade, nuclear grade, menopausal status, clinical response to preoperative CT, and the LN status after preoperative CT.57 In a retrospective multivariate analysis, McCready and colleagues48found that the most important prognostic factors were the clinical response to neoadjuvant CT and the LN status following
466
ESTEVA & HORTOBAGYI
Table 4. RESULTS OF COMBINED MODALITY THERAPY FOR INFLAMMATORY BREASTCANCER
Author
Year
Treatment
No. of Patients
Percent Complete Remission
Median Percent Alive At Survival (Months) 3 Years 5 Years
With Hormonal Therapy as Systemic Treatment
Yonemoto Droulias Droulias Lucas Lucas Lucas
1970 1976 1976 1978 1978 1978 1980
HT
14 RT+HT 22 HT+RTfCT 11 S+HT+RT 13 RT+HT or Ct 10 HT 8 ChU RT+HT 14 With Chemotherapy as Systemic Treatment De la Garza 1977 CT+RT+CT 18 1978 CT+RT+CT De Lena 36 Krutchik 1979 CT+RT+CT 32 ChU 1980 RT+CT 16 Pouiuart 1981 CT -RT+ CT 77 Zylberberg 1982 CT+ S+ CT RT 15 Pawlicki, 1983 CT+ S? RT 72 Loprinzi 1984 S+ CT+RT CT 9 Keiling 1985 C T + S + C T 41 Fastenberg 1985 CT + RT 2 S CT 63 JacquiUat 1986 CT+RT+CT 34 Albert0 1986 C T + S + C T +RT 22 FerrieE 1986 CT+ RT f S + CT 75 Poumy 1986 CT+ Sf RT+ CT 33 Israel 1986 C T + S + C T 25 1986 CT+RT+CT Rouessee 91 Rouessee 1986 CT+RT+CT 79 Burton 1987 CT+S+CT+RT 22 Noguchi 1988 CT+S+CT 28 BrUn 1988 CT+ RT+S + CT 26 ThOmS 1989 CTf S + CT + RT 61 Maloisel 1990 C T +S+RT +CT 43 Bilbao 1992 CT +S+RT CT 18 Chevallier 1993 CT + RT 2 CT f S 178 Roth 1993 CT+S+CT 73 Janvier 1993 CT+RT+S+CT 133 Wiseman 13 1995 CT+S+IT+CT+RT Ueno 1997 CT S +CT + RT 72
+ + +
+
+
NR NR
NR NR NR NR NR NR 73 85
NR 51 100 NR 100 100 92 100 95 93 82 96 41 54 86 100
85 100 88 100 83 NR t?4
100 92
22
NR
7
22
NR NR 0
NR NR
13 <12 <12 12 15 21 25 24 >26 34 NR
NR >25 NR 43 NR 43
NR 70 NR 36
NR 18 NR 31 27
NR 33 37 >23 NR 48 34
10 25
0 0 0
NR
NR
NR 24 42
22 NR 35 NR NR 70
NR 45 75 28 60 75 58 77 47 68 70 68 50 80 NR NR 40 NR 85 50 48 NR NR 70 38
NR 55 63 34 66 10 54 60 62 40 66
NR 63 25 35 75
NR 32
NR NR 40 35
= chemotherapy; S = surgery; RT = radiotherapy; HT = hormone therapy; IT = -mothsapy; NR = not reported
doxorubicin-based therapy? Pathologic response has also been associated with 0s. At M. D. Anderson Cancer Center, LABC patients whose mastectomy specimen did not contain gross residual disease had a greater than 75% 5-year DFS. Patients with negative or less than four involved LN after induction CT had a 40% to 50% 5-year DFS; if four or more LN were involved, DFS decreased to 30%; and only 20% of patients were free of disease at 5 years if more than 10 LN contained metastatic carcinoma after neoadjuvant CT.*O
LOCALLY ADVANCED BREAST CANCER
467
Table 5. PROGNOSTIC FACTORS FOR PATIENTS WITH LOCALLY ADVANCED BREAST CANCER (LABC) TREATED WITH NEOADJUVANT CHEMOTHERAPY (CT) Factor
Favorable
Unfavorable
Stage (TNM) Age Clinical response Pathologic response Inflammatory signs No. positive nodes Premenopausal Estrogen receptor status Progesterone receptor status Histologic grade S-phase fraction
II-IIIA <50 years Complete Complete No <4 Yes Positive Positive High Low
IIIB 250 years Less than complete Less than complete Yes 24
No Negative Negative Low High
MOLECULAR PREDICTORS OF RESPONSE TO CHEMOTHERAPY
One of the advantages of neoadjuvant CT is the opportunity to evaluate tumor sensitivity to a particular CT regimen in vivo by assessing clinical and pathologic response. In addition, molecular markers can be analyzed before and after preoperative CT. Retrospective data from large adjuvant CT trials have revealed associations between oncogene expression and resistance to CT. Gusterson and colleagues**showed that women with early-stage breast cancer undergoing CMF CT in the adjuvant setting did not benefit if their tumors overexpressed the HER2 / neu protein. The CALGB protocol 85-41 evaluated a combination of cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) to determine the role of dose intensity in the adjuvant setting. In this study, patients whose tumors overexpressed HER2/neu had an improved 0 s with higher (full) doses of CAF?7 These data suggest that HER2 / neu-mediated drug resistance may be overcome by full doses of doxorubicin. The role of HER2/ neu overexpression and response to paclitaxel is controversial. Retrospective data from Memorial Sloan-Kettering Cancer Center indicate increased sensitivity to paclitaxel in patients with metastases and HER2/ neu overexpressing tumor^.^ However, randomized clinical trials showed a poor response (14%) to paclitaxel for this patient population and improved response rates and DFS for patients treated with paclitaxel in combination with an anti-HER2 antibody (Her~eptin).~~ Experimental in vivo data indicate that tumors overexpressing HER2 / neu are resistant to paclitaxel-induced apoptosis,68 supporting the results observed in randomized clinical trials of Herceptin in combination with paclitaxel. Apoptosis is one of the most important mechanisms of CT-induced cytotoxicity. Ellis and coworkers18showed that doxorubicin-based neoadjuvant CT can induce apoptosis in primary tumors in patients under-
468
ESTEVA & HORTOBAGYI
going doxorubicin-based primary CT. Anthracyclines induce apoptosis through the p53 protein, and experimental tumors with a mutated (inactive) p53 gene are resistant to anthracyclines. Berruti and colleagues5 reported an association between wild-type p53 protein and response to neoadjuvant doxorubicin-based CT, suggesting that an intact p53 gene may be required for CT-induced cytotoxicity. In contrast, the taxanes induce cell death in a p53 gene-independent manner. In one study, paclitaxel was more effective for patients whose tumors overexpressed the p53 protein4 The Bcl-2 protein is another important molecule in the control of apoptosis. Bcl-2 expression has been associated with ERpositive status and low proliferation rates: Archer and colleagues2 showed that Bcl-2-negative patients were more likely to respond to anthracycline-based CT than Bcl-2-positive patients. Bonetti and associate# reported an association between Bcl-2 expression and response to CT in advanced breast cancer by a multivariate logistic regression analysis. In this study, 42% of patients with Bcl-2-negative tumors responded to CT, but in Bcl-2-positive patients only 13% responded. This effect was independent of ER status, P-glycoprotein expression, age, menopausal status, dominant disease site, DFS, and type of first-line therapy. Another gene undergoing evaluation is the multi-drug-resistant gene (MDR-1). The MDR-1 protein is located at the cell membrane and functions as a pump that detoxifies the cell from noxious agents. Overexpression of the MDR-1 protein has been associated with resistance to anthracycline- and taxane-based CT in vitro. However, the clinical value of MDR-1 expression in breast cancer has not been clearly defined.65
CONCLUSION
In summary, neoadjuvant systemic therapy results in improved local control and 0s for patients with LABC. A multidisciplinary approach that includes preoperative CT or endocrine therapy, surgery, adjuvant systemic therapy, and XRT is now considered the standard of care for patients with LABC. Novel cytotoxic, hormonal, and biological agents are rapidly being integrated into the management of LABC. The role of HDCT, with or without autologous peripheral stem cell transplantation, remains experimental. Prospective clinical trials are evaluating the role of oncogenes and tumor suppressor genes in drug sensitivity and resistance, using the neoadjuvant setting as a model to study molecular changes induced by different drugs and biologics in breast cancer cells.
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469
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Address reprint requests to Francisco J. Esteva, MD Assistant Professor of Medicine Department of Breast Medical Oncology The University of Texas M. D. Anderson Cancer Center 1515 Holcombe Blvd., Box 56 Houston, TX 77030