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Keywords:

  • breast cancer;
  • primary systemic therapy;
  • inflammatory breast cancer;
  • locally advanced breast cancer;
  • taxanes;
  • anthracylines;
  • CMF regimen

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

BACKGROUND:

This study was performed to evaluate the outcomes of patients with locally advanced breast cancer (LABC) who were treated with a multidisciplinary approach including primary systemic chemotherapy and noncross-resistant adjuvant chemotherapy.

METHODS:

Patients with LABC received 4 or 6 cycles of doxorubicin and docetaxel (DT) as primary systemic chemotherapy (PST) every 21 days. Patients with adequate response underwent surgery followed by adjuvant chemotherapy according to pathologic response: complete (pCR), 2 more cycles of DT; partial (pPR), 2 more cycles of DT followed by 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF); and minor (pMR), 6 cycles of CMF. Patients then received radiation and tamoxifen (hormone receptor-positive patients only).

RESULTS:

Eighty-eight patients were evaluable. Seventy-four patients had an adequate response to DT and were considered operable, and 72 underwent surgery. Ten patients (13.9%) achieved a pCR, 22 (30.5%) achieved a pPR, and 40 achieved a pMR (55.5%). Fourteen patients were considered nonoperable after DT and underwent salvage CMF therapy. Five of these patients underwent surgery and 1 had achieved a pCR. The estimated 5-year recurrence-free survival (RFS) rates for patients with pCR, pPR, and pMR were 80%, 77%, and 59%, respectively, and the estimated 5-year overall survival (OS) rates were 90%, 91%, and 74%, respectively. The 5-year OS rates were 82% for initially operable and 21% for initially inoperable patients (P ≤ .001)

CONCLUSIONS:

Multidisciplinary therapy that includes PST with DT and adjuvant therapy with CMF administered according to the clinical and pathologic response is associated with high long-term RFS and OS rates in patients with LABC. Clinical or pathologic PR or CR to DT predicts improved RFS and OS. Cancer 2010. Published 2010 by the American Cancer Society.

Although locally advanced breast cancer (LABC) is uncommon (approximately 5-10%) in the United States and Western Europe, it represents the most common presentation (between 30% and 50%) in many developing countries.1 Currently, the standard initial therapy for LABC, including inflammatory breast cancer (IBC), is primary systemic therapy (PST). The aims of PST are to reduce the risk of disease recurrence by treating potential areas of distant microscopic metastatic disease, to reduce breast and lymph node tumor burden, to improve surgical respectability, and provide early information or surrogate markers for long-term outcome.2 The response to PST and, in particular, the achievement of a pathologic complete response (pCR) has been established in prospective clinical trials as an early predictor of recurrence-free survival (RFS) and overall survival (OS).2-5

In the 1990s, many investigators attempted to improve the pCR rate after PST by adding taxanes (paclitaxel and docetaxel) to anthracyclines. Docetaxel given concomitantly or sequentially with doxorubicin as PST has been shown to have meaningful efficacy,6 and in 1 large trial (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-27), docetaxel administered in sequence after a doxorubicin-containing regimen resulted in improved pCR rates.7

Due to the activity of the anthracyclines and taxanes as well as cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF) in metastatic breast cancer, in 1997 we designed a trial to determine whether adding the noncross-resistant CMF regimen as adjuvant (postoperative) therapy improves pCR, as well as RFS and OS in patients who achieve less than a pCR after PST with doxorubicin and docetaxel (DT).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Patient Eligibility

This trial was conducted at The University of Texas M. D. Anderson Cancer Center after Institutional Review Board approval (Protocol ID97-099). All patients provided written informed consent. Patients were enrolled between January 1998 and June 2000. Eligible patients had newly diagnosed, biopsy-proven LABC (stage IIB and stage IIIA, B, and C) according to the sixth edition of the American Joint Committee on Cancer Staging System.8 Inclusion criteria were as follows: Karnofsky performance status ≥70% and normal cardiac function (left ventricular ejection fraction >50%), bone marrow function (absolute neutrophil count ≥1500/μL, platelet count >100,000/μL), liver function (bilirubin level ≤1.5 times the upper limit of normal), renal function (creatinine level <2.0 mg/dL), and neurologic function (peripheral neuropathy < grade 2). Exclusion criteria were history of unstable cardiac disorder (eg, unstable angina or recent myocardial infarction), congestive heart failure, or a left ventricular ejection fraction detected by cardiac blood pool scan or echocardiogram of ≤50%. The study was conducted in accordance with the Declaration of Helsinki.

Clinical Response Assessment After PST With DT

The trial design is outlined in Figure 1. Patients received 2 cycles of PST with DT and were then re-evaluated by a multidisciplinary team, including a medical oncologist, radiation oncologist, breast surgeon, and breast radiologist. Evaluation was comprised of physical examination, breast ultrasound, and mammography. After this, if patients achieved a clinical CR or a clinical partial response (PR) (>50% reduction in the product of the 2 longest perpendicular tumor dimensions), 2 additional cycles of DT were administered preoperatively; if insufficient response was observed, the patients were crossed over to CMF. Progressive disease (PD) was defined as a >50% increase in size in the bidimensional tumor dimensions.

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Figure 1. Study design showing the chemotherapy treatment schema for The University of Texas M. D. Anderson Cancer Center Locally Advanced Protocol ID97-099 is shown. DT indicates docetaxel; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; ER+, estrogen receptor positive.

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Pathologic Response Assessment After Surgery

The pCR was defined as no residual invasive tumor (breast and axillary lymph nodes). Pathologic PR (pPR) was defined as a >50% reduction in the product of the 2 longest perpendicular tumor dimensions and ≤3 positive lymph nodes. Pathologic minor response (pMR) was defined as a <50% reduction in the primary breast tumor and/or ≥4 positive lymph nodes.'

DT and CMF Regimens

The DT regimen was comprised of doxorubicin at a dose of 60 mg/m2 intravenously (iv) on Day 1 followed by docetaxel at a dose of 60 mg/m2 iv on Day 1. Cycles were administered every 21 days. All patients received prophylactic granulocyte-macrophage—colony-stimulating factor (GM-CSF) at a dose of 250 μg/m2/day subcutaneously. GM-CSF was initiated on Day 3 of therapy and was given for 5 days (Days 3-7) or until the absolute neutrophil count was >2000/μL.

The CMF regimen was comprised of cyclophosphamide at a dose of 600 mg/m2 iv, methotrexate at a dose of 40 mg/m2 iv, and 5-FU at a dose of 600 mg/m2 iv; all drugs were administered on Days 1 and 8. Cycles were administered every 21 days. Patients who had grade 3 to 4 toxicities (according to National Cancer Institute Common Toxicity Criteria [NCI CTC]) on Day 21, neutropenic fever, or documented infection received prophylactic GM-CSF during subsequent cycles. GM-CSF was administered at a dose of 250 μg/m2/day subcutaneously from Day 9 of therapy until Day 13 or until the absolute neutrophil count was >2000/μL, whichever occurred later.

Surgery

After 4 cycles of DT, patients with a clinical response were considered candidates for surgery and assessed at a Multidisciplinary Breast Cancer Planning Clinic. Patients whose disease met the following criteria underwent segmental mastectomy with axillary lymph node dissection: 1) single breast mass measuring ≤4 cm in largest dimension (or 2 primary tumors in the same quadrant of the breast); 2) no residual involvement of skin or chest wall; 3) tumor/breast size ratio small enough for a good cosmetic result; 4) no evidence of matted or fixed axillary lymph nodes (by physical examination, mammography, and ultrasound); and 5) patient desiring a breast conservative approach. Patients whose disease did not fulfill these criteria underwent modified radical mastectomy.

Adjuvant Chemotherapy

In patients who underwent surgery, different types of adjuvant chemotherapy were administered depending on the magnitude of the pathologic response (Fig. 1). The regimens were as described as above. Trastuzumab was not used in this clinical trial.

Radiotherapy

Radiotherapy was given within 6 weeks after the completion of adjuvant chemotherapy. Patients were treated with 50.4 grays (Gy) (1.8 Gy per fraction; 28 fractions) or 50 Gy (2 Gy per fraction; 25 fractions) to the chest wall (after modified radical mastectomy) or breast (after breast-conserving surgery [BCS]); supraclavicular region, and internal mammary lymph nodes. The midaxilla was treated with a dose of 40 to 50 Gy if the pathologic findings included any 1 of the following: a lymph node measuring ≥2.5 cm, fixed or matted lymph nodes, undissected axilla, or pathologic evidence of extracapsular extension >2 mm. A boost of 10 Gy (2 Gy per fraction; 5 fractions) was administered to the chest wall (after mastectomy) or the location of the primary breast tumor (demarcated by surgical clips) after delivery of 50.4 or 50 Gy to the chest wall or breast. Patients with IBC were treated with accelerated, hyperfractionated irradiation.

Tamoxifen

Patients with estrogen receptor (ER) -positive tumors or unknown ER status received tamoxifen at a dose of 20 mg/day by mouth, beginning at the conclusion of all systemic chemotherapy and continuing for 5 years or until disease recurrence.

Statistical Analysis

The primary endpoints were the clinical objective response rate and pathologic response after PST with DT. Secondary endpoints included RFS and OS. Two earlier protocols that investigated treatment of LABC patients in our institution with multidisciplinary management (DM 85-01 and DM 89-007) reported objective response rates of 70% to 85%, respectively.9, 10 Two hypotheses were evaluated using the method recommended by Simon11: P1 with an overall response rate (ORR) <0.70 (ie, a rate at this level or below would not be of interest for further study), and P2: ORR >0.85 (ie, a rate at this level or above would be of considerable interest). An interim analysis was planned after treatment of the first 20 patients. If <14 patients (70%) had achieved objective response, the trial would be terminated; otherwise, accrual would continue to 88 patients. RFS was measured from the date of first treatment to the date of disease recurrence or last follow-up visit. OS was calculated from the date of diagnosis to death. The Kaplan-Meier product-limit method was used to compute freedom from distant metastasis. The log-rank test was also used to compare the survival estimates in the 2 groups. P values < .05 were considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

From January 1998 through June 2000, 88 female patients were enrolled in this phase 2 study. All 88 patients completed the initial 2 cycles of DT. A total of 74 patients (84%) had an adequate response to 4 or 6 cycles of PST with DT, and were considered candidates for surgery; 72 patients actually underwent surgery. Patient and tumor characteristics are summarized in Table 1. Four patients had IBC. The median Karnofsky performance status score was 90.

Table 1. Patient Characteristics
CharacteristicNo. of Patients%
  1. HER-2 indicates human epidermal growth factor receptor 2; AJCC, American Joint Committee on Cancer.

Age, y  
 Median51 
 Range28-73 
Karnofsky performance status  
 Median90 
 Range70-90 
Menopausal status  
 Premenopausal4146
 Postmenopausal4753
Ethnic background  
 Asian11
 African-American1921
 Hispanic89
 Caucasian6068
Nuclear grade  
 1-21215
 37585
 Unknown11
Estrogen receptor status  
 Positive3439
 Negative5360
 Unknown11
HER-2 status  
 Positive2630
 Negative4854
 Unknown1416
Triple-negative1618
AJCC stage of disease  
 IIB11
 IIIA2528
 IIIB4146
 IIIC2124

Clinical Response After PST With DT

On clinical assessment after 4 to 6 cycles of DT, 3 patients (3.4%) achieved a clinical CR, 76 patients (86.4%) a clinical PR, 4 patients (4.5%) a clinical MR, and 5 patients (5.7%) had clinical PD. Overall clinical response rate was 89.8%.

Surgery and Pathologic Response

Of the 74 patients who were considered candidates for surgery after PST with DT, 2 did not actually undergo surgery and were treated with radiotherapy. One patient with baseline T0N2M1 achieved a clinical PR from DT and received radiotherapy only; at the time of last follow–up, the patient remained with no evidence of disease (NED). Another patient with a clinical PR after DT with extensive supraclavicular and infraclavicular lymph node involvement received radiation only and was considered to have NED at the time of last follow–up. Thirteen (18%) patients underwent BCS and 59 (82%) patients underwent modified radical mastectomy. On pathologic evaluation, 10 patients (13.9%) had a pCR, 22 patients (30.5%) had a pPR, and 40 patients (55.5%) had a pMR. Fourteen patients (19%) had negative axillary lymph nodes, 19 patients (26%) had 1 to 3 positive lymph nodes, 23 patients (32%) had 4 to 9 positive lymph nodes, and 15 patients (21%) had ≥ 10 positive lymph nodes. One pathologic sample (1.3%) was not available for analysis.

Outcomes in Patients Treated With Salvage CMF

Overall, 14 patients (16%) were crossed over to CMF salvage regimen without surgery because of a suboptimal response to PST with DT. Six of these 14 patients achieved a PR but remained inoperable, 3 patients had SD, and 5 patients had PD. After salvage therapy with CMF, 5 patients became surgical candidates (36%). One patient achieved a pCR and was alive with NED at the time of last follow–up. This patient had IBC and had achieved a clinical PR but had residual edema after CMF. One patient became operable, 1 underwent high-dose chemotherapy with bone marrow transplantation, 3 received preoperative radiotherapy, and 1 had PD. Five patients were crossed over to salvage CMF after 4 cycles of DT. Two became operable, and 3 received radiotherapy.

Three patients had an inadequate response after 4 cycles of DT, and had the regimen extended to 6 cycles and then were crossed over to salvage CMF. Two of these patients became operable; 1 patient received radiotherapy only.

Adjuvant Chemotherapy

Among the 72 patients who underwent surgery after PST with DT, adjuvant treatment was as follows: DT only in 9 patients (10%), DT followed by CMF in 21 patients (29%), CMF only in 41 patients (57%), and paclitaxel in 1 patient (1.4%).

Radiotherapy

Eighty-six patients (98%) received radiotherapy; 2 patients did not receive radiotherapy because they were found to have metastatic disease. Seventy-four patients received adjuvant radiotherapy after surgery. Seven patients received preoperative radiotherapy after an inadequate response to salvage CMF and 5 of these patients became surgical candidates after irradiation. Two patients were treated with definitive radiotherapy without surgery: 1 patient with baseline T0N3 disease achieved a PR after DT and received radiotherapy only; the second patient had extensive supraclavicular and infraclavicular lymph node involvement, achieved a PR after DT, and also received radiotherapy. Both patients remained withNED at the time of last follow–up.

Hormonal Therapy

Thirty-five patients were treated with tamoxifen at a dose of 20 mg daily × 5 years after adjuvant chemotherapy.

Safety Profile

All patients were evaluable for toxicity. For PST with DT, the median number of cycles was 4.3 cycles. Rates of grade 3 and 4 hematologic side effects according to the NCI CTC were as follows: leukopenia, 37.5% and 44%; neutropenia, 12.5% and 81%; thrombocytopenia, 3.4% and 2.2%; and anemia, 10.2% and 2.2%, respectively.

For CMF, the median number of cycles was 5.6 cycles (either salvage or adjuvant); rates of grade 3 and 4 side effects were as follows: leukopenia, 30.6% and 11.3%; neutropenia, 27.2% and 19.3%; thrombocytopenia, 5.6% and 5.6%; and anemia, 2.2% and 6.8%, respectively.

Twelve patients (13.6%) had documented grade 3 infection and 1 (1.1%) had a grade 4 infection. Twenty-seven events of neutropenic fever (30.6% of patients) were documented. Grade 3 fatigue and grade 3 paresthesias occurred in 52.2% and 1.1% of patients, respectively. One patient who received 6 cycles of DT followed by 4 cycles of adjuvant CMF developed congestive heart failure with a left ventricular ejection fraction of 29% and died of brain metastasis. No secondary malignancies, such as acute myelogenous leukemia, were observed.

Survival

At a median follow-up of 107 months (range, 18-133 months), 48 patients (54%) were alive and free of breast cancer, 6 patients (7%) were alive with breast cancer, 2 patients had died without evidence of disease (1 of chronic obstructive pulmonary disease and 1 of with multiple comorbidities), and 32 patients (36%) had died of breast cancer. Survival analysis according to the response category demonstrated the following: pCR (10 patients treated with PST with DT) in 10 patients (13.8%), pPR in 22 patients (30.5%), and pMR in 40 patients (55.5%). The 5-year estimated RFS rates for patients with pCR, pPR, and pMR were 80%, 77%, and 59%, respectively (P = .078) (Fig. 2 Top). The 5-year estimated OS rates for patients with pCR, pPR, and pMR were 90%, 91%, and 74%, respectively (P = .022) (Fig. 2 Bottom). The 5-year estimated RFS rate for responders to PST with DT was 68% and was 14% for nonresponders (P <0.001) (Fig. 3 Top). The estimated 5-year OS rate was better for the 74 responders to PST with DT than for the 14 nonresponders (82% vs 21%; P <.001) (Fig. 3 Bottom).

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Figure 2. (Top) Estimated 5-year recurrence-free survival is shown, comparing the pathologic responses of the 3 groups of operable patients. (Bottom) Estimated 5-year overall survival comparing the pathologic responses of the 3 groups of operable patients is shown. pCR indicates pathologic complete response; pPR, pathologic partial response; pMR, pathologic minor response.

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thumbnail image

Figure 3. (Top) Estimated 5-year recurrence-free survival is shown for responders to chemotherapy and nonresponders. (Bottom) Estimated 5-year overall survival is shown for responders to chemotherapy and nonresponders.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

The results of the current study demonstrate that patients with LABC who responded to PST with the combination of an anthracycline and a taxane, and had multidisciplinary management including surgery, radiotherapy, and adjuvant chemotherapy (DT or noncross-resistant regimen CMF), achieved an excellent RFS and OS.

PST has become the standard of care for patients with LABC and large operable stage II breast cancer. The study published by Thomas et al12 from our institution used early clinical response as a decision aid. A total of 193 evaluable patients with LABC (of whom 80% had stage III disease) received PST comprised of 3 cycles of vincristine, doxorubicin, cyclophosphamide, and prednisone (VACP). After surgery, patients were stratified on the basis of pathologic response. Patients with <1 cm3 of residual tumor present at mastectomy received an additional 5 cycles of VACP. Patients with >1 cm3 of residual tumor present were randomly assigned to an additional 5 cycles of VACP or 5 cycles of vinblastine, methotrexate, leucovorin, and 5-fluorouracil (VbMF). Patients who achieved a clinical CR or pCR after VACP had improved survival compared with patients with less response. The absolute improvements in 5-year RFS and OS rates with the use of VbMF in addition to VACP were 10% and 18%, respectively.

The current trial was designed to evaluate early response to 2 initial cycles of DT in a group of patients with inoperable LABC, including IBC. Evaluation of tumor response was performed by clinical examination by a multidisciplinary team and imaging. In designing this study, we took into consideration that patients could require longer administration of chemotherapy before surgery; therefore, patients were allowed receive 4 or 6 cycles of PST with DT. Our results were very promising because, despite all patients being initially inoperable at baseline, 74 patients (84%) became surgical candidates.

Several trials have tested a similar hypothesis on the basis of clinical rather than pathologic response. In the Aberdeen trial,13 162 patients were enrolled and treated with cyclophosphamide, vincristine, doxorubicin, and prednisone (CVAP). Responders (66.1%) were randomly assigned to 4 additional cycles of CVAP or docetaxel; nonresponders (34.1%) received docetaxel. The combination of CVAP and docetaxel was found to be superior to that of CVAP and additional cycles of CVAP, and complete eradication of invasive tumor cells was achieved in 30.8% of the CVAP-docetaxel group and 15.4% of the CVAP-CVAP group. Patients with an initial response to CVAP who crossed over to docetaxel were found to have a significantly higher survival rate at 5 years (90% vs 70%). Conversely, patients in whom CVAP failed did not have significant benefit after the crossover to docetaxel.

The German GeparTrio study14 tested the role of using a noncross-resistant regimen in nonresponders. In that study, patients with operable breast cancer were evaluated after 2 cycles of PST with docetaxel, doxorubicin, and cyclophosphamide every 21 days (TAC). Patients with chemosensitive disease (decrease in tumor size ≥50% as defined by clinical examination and breast ultrasonography) were randomized to receive 4 or 6 additional cycles of TAC. Patients with chemoinsensitive tumors were randomly assigned to 4 cycles of a noncross-resistant chemotherapy regimen, vinorelbine and capecitabine, versus 4 additional cycles of TAC. For the early responding patients, the primary objective of the study was to compare the rate of pCR after 6 cycles of TAC with that after 8 cycles of TAC. There was no statistically significantly difference noted with regard to the pCR rates between the groups (21.0% vs 23.5% [difference of 2.5%]; 95% confidence interval, 1.8-6.8% [P = .27]). Approximately one–third of the patients did not respond to the initial 2 cycles of TAC. They were randomly assigned to an additional 4 cycles of TAC or 4 cycles of vinorelbine and capecitabine (NX).15 There were no significant differences noted between the TAC and NX regimens with respect to the pCR rate (5.3% and 6.0%, respectively).

Other clinical trials have shown that patients who do not respond to the initial cycles of PST have an unfavorable prognosis.7, 16

In the current study, we described 14 patients who were considered inoperable after PST with DT; after crossover to CMF, 5 of these patients (36%) became operable, and 1 of them (7.4%), who achieved a PR after DT, achieved a pCR.

Data from others noncross-resistant regimens used in clinical trials as part of adjuvant treatment revealed an improvement in the RFS and OS rates of approximately 10% and 20%, respectively.12, 13 The CMF regimen was chosen as a part of the adjuvant program because its popularity in the adjuvant setting and low toxicity. These results are similar to those from GeparTrio.16 Furthermore, the results of the current study indicate that crossover to CMF could be considered for patients with LABC who achieve only a MR or PR after anthracycline-based and taxane-based PST. This is particularly relevant for developing countries, in which this alternative noncross-resistant regimen (CMF) is widely available. Another therapeutic option for this situation is the use of capecitabine and, more recently, ixabepilone.

In conclusion, the results of the current study provide mature data demonstrating excellent OS and RFS for patients with initially inoperable LABC who responded to PST with a combination of an anthracycline and a taxane. Adjuvant CMF in patients who initially achieved a PR, indicating partial sensitivity to chemotherapy, may add to the initial benefit from PST with DT. For patients with residual disease after surgery, the prognosis is ominous; newer, potentially more effective therapies, including other chemotherapies and targeted therapies, should be studied to improve response and ultimately survival in women with LABC.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

We gratefully acknowledge Stephanie P. Deming, Scientific Editor, for excellent technical assistance.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Supported by a grant of Sanofi-Aventis and Immunex Corporation.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
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    von Minckwitz G, Kummel S, Vogel P, et al. Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study. J Natl Cancer Inst. 2008; 100: 552-562.
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