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Journal of Clinical Oncology, Vol 20, Issue 5 (March), 2002: 1304-1310
© 2002 American Society for Clinical Oncology

Incidence and Prognostic Significance of Complete Axillary Downstaging After Primary Chemotherapy in Breast Cancer Patients With T1 to T3 Tumors and Cytologically Proven Axillary Metastatic Lymph Nodes

By Roman Rouzier, Jean-Marc Extra, Jerzy Klijanienko, Marie-Christine Falcou, Bernard Asselain, Anne Vincent-Salomon, Philippe Vielh, Edwige Bourstyn

From the Departments of Surgery, Biostatistics, Oncology, and Pathology, Institut Curie, Paris, France.

Address reprint requests to Edwige Bourstyn, MD, Department of Surgery, 26 rue d’Ulm, 75005 Paris, France; email: edwige.bourstyn@ wanadoo.fr.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To determine the incidence and prognostic significance of eradication of cytologically proven axillary lymph node metastases in breast cancer patients treated with primary chemotherapy.

PATIENTS AND METHODS: Between January 1985 and December 1994, 152 breast cancer patients with invasive T1 to T3 tumors and axillary metastases cytologically proven by fine-needle sampling underwent primary chemotherapy followed by lumpectomy or mastectomy, level I and II axillary lymph node dissection, and irradiation. We studied pathologic complete responses (pCRs) of axillary nodes and breast tumors, as well as predictors of distant metastases.

RESULTS: Thirty-five patients (23%) had axillary pCRs, and 20 patients (13.2%) had pCRs of primary breast tumors. Scarff-Bloom-Richardson grade 3 tumors (P = .04) and a clinical response to chemotherapy >= 50% (P = .003) were associated with negative axillary status at dissection. An initial tumor size <= 3 cm (63 patients) was associated with pCR of the primary tumor (P = .02) but not with complete histologic clearance of axillary lymph nodes. The median length of follow-up was 75 months. In the univariate analysis, age greater than 40 years (P = .003), absence of residual nodal disease (P = .01), and pCR of the tumor (P = .05) were associated with better distant disease-free survival. Five-year distant disease-free survival rates were 73.5% ± 14.9% among patients with no involved nodes at the time of surgery and 48.7% ± 9.2% among patients with residual nodal disease. In the multivariate Cox regression analysis, parameters associated with poor distant disease-free survival were age <= 40 years (P = .002), persistence of nodal involvement (P = .03), and S-phase fraction greater than 4% (P = .02).

CONCLUSION: Our results suggest that axillary status is a better prognostic factor than response of the primary tumor to primary chemotherapy.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
METASTATIC INVOLVEMENT of axillary lymph nodes in breast carcinoma is highly associated with subsequent development of distant metastases and death.1,2 Since the early 1980s, primary chemotherapy has been part of the multidisciplinary approach to locally advanced breast carcinoma.3 The prognostic value of clinical regression of the primary tumor and nodes has been clearly demonstrated, and pathologic complete response (pCR) of the tumor has also been studied. Axillary nodes, rarely evaluated by cytology before treatment, can be clinically overestimated in 7.4% to 51% of cases.4-6 False-positives are a limitation in the assessment of axillary downstaging and further evaluation of the significance of such downstaging. The incidence and effect of eradication of axillary lymph node metastases in breast cancer patients have been reported only once in the literature.7 In that study, the value of complete axillary downstaging was not controlled in a multivariate analysis, and only patients with tumors >= 4 cm were evaluated. In the current study, we analyzed data from 152 breast cancer patients with T1 to T3 tumors and cytologically proven axillary metastases treated with primary chemotherapy and surgery. We evaluated the incidence, predictive factors, and prognostic significance of histologic clearance of breast tumors and axillary lymph nodes.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
One hundred fifty-two consecutive breast cancer patients treated between January 1, 1985, and December 30, 1994, at the Institut Curie were selected from a database into which initial clinical, pathologic, and follow-up data were prospectively entered. Patients were considered for the study if they met the following criteria: T1, T2, or T3 primary tumor; clinically and cytologically proven metastatic nodes (none of the patients had undergone disease staging with axillary ultrasound; fine-needle sampling (FNS) was performed at the Institut Curie); M0; and primary chemotherapy followed by surgery. The median age was 46 years (range, 27 to 66 years). The mean size of the tumor (± SE) was 40 ± 2.4 mm. According to the International Union Against Cancer (UICC) classification, 19 patients (12.5%) had T1 tumors, 111 (73%) had T2 tumors, and 22 (14.4%) had T3 tumors. One hundred forty-five patients (95.4%) had clinically staged N1 carcinoma, and seven (4.6%) had clinically staged N2 carcinoma. All patients underwent drill biopsy and FNS of the primary tumor and FNS of clinically involved axillary nodes. Drill biopsy was performed under local anesthesia with a 2-mm-diameter rotating drill needle. FNS was performed with a 23-gauge needle without aspiration.8 Nodes to be sampled were identified clinically and never under ultrasound guidance. The Scarff-Bloom-Richardson (SBR) histologic grading system9 was used. Thirty-seven patients had SBR grade 1 tumors, 75 had SBR grade 2 tumors, and 40 had SBR grade 3 tumors. Estrogen receptor status and S-phase fractions were determined as previously described.10,11 Seventy-one patients were estrogen receptor–positive and 58 were estrogen receptor–negative; the estrogen receptor status of the remaining 23 patients was unknown. The median S phase was 4%, and 4% was chosen as the cutoff value, above which the proliferative index was considered to be high (49 patients made up this group). S-phase fractions were missing for 57 patients.

Treatment consisted of three (n = 39) or four (n = 113) monthly courses of an intravenous drug combination: 1) fluorouracil 500 mg/m2 days 1, 3, 5, and 8; 2) cyclophosphamide 500 mg/m2 days 1 and 8; and 3) doxorubicin 25 mg/m2 days 1 and 8 or methotrexate 40 mg/m2 days 1 and 8 or thiotepa 10 mg/m2 days 1 and 8. Clinical response was assessed as previously described.12 Local-regional treatment depended on tumor regression during chemotherapy. Tumor size after primary chemotherapy was compatible with a cosmetically acceptable breast-conserving surgery for 78 patients who underwent lumpectomy and breast irradiation (54 Gy). A total of 75 patients underwent mastectomy. All patients underwent level I and II axillary dissection.

For the pathologic analysis of the tumor response, the amount of residual epithelial neoplastic cells in the tumor mass, the mitotic index in malignant epithelial cells, and the location of the malignant component (invasive v intraductal) were taken into account.13 Patients with breast tissue without residual invasive malignant epithelial cells or with residual invasive malignant epithelial cells representing less than 5%% of the tumor mass and without mitosis were considered to exhibit pCRs. Tumors with malignant residual components strictly in situ were classified as in situ. The response was considered absent when no histologic modification of the tumor tissue could be related to therapy (residual invasive malignant epithelial cells representing > 20% of the tumor mass). Responses were classified as partial in the remaining cases. Patients having tumors with malignant residual components strictly in situ were not included in the pCR group. Nodal involvement status was determined by analyzing multiple hematoxylin and eosin–stained sections from all nodes removed during axillary dissection. The axillary downstaging was considered complete if no neoplastic cells could be found in the nodes.

All patients underwent irradiation of the supraclavicular fossa and the axillary apex (50 Gy). When the tumor was located in the inner quadrants or in the central region of the breast, the internal mammary lymph nodes were irradiated at a dose of 50 Gy. Hormonal therapy (tamoxifen 20 mg/d) was prescribed to 35 postmenopausal patients. At our institution, premenopausal patients and estrogen receptor–negative patients were not eligible for treatment with tamoxifen during this period. After completion of all treatment, patients were observed every 4 months for 2 years, every 6 months during the next 3 years, and then at least yearly.

Statistical analysis was performed using the {chi}2 test or Fisher’s exact test for categorical variables and the Student’s t test for means. All comparisons were two-tailed. Age (<= 40 v > 40 years), initial tumor size, SBR grade, estrogen receptor status, S-phase fraction, and clinical response were tested as possible predictors of pCR of the tumor and conversion from cytologically proven axillary metastases to histologically negative axillary status at dissection. Survival curves were calculated using the Kaplan-Meier14 method and compared using the log-rank test.15 Multivariate analysis was performed using the Cox proportional hazards model.16 The end point was any metastatic event, measured from the date of first treatment to the time of the last follow-up visit or metastases. Clinical and pathologic factors tested by univariate and multivariate analysis included patient age, initial tumor size (clinical), SBR grade, estrogen receptor status, S-phase fraction, clinical regression, pathologic residual disease, and pathologic nodal status. P <= .05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The median number of lymph nodes removed from the 152 patients was 15 (range, five to 39). Thirty-five patients (23%) had complete axillary downstaging. One to three nodes were involved in 54 cases (35.5%), four to seven nodes were involved in 29 cases (19.1%), and >= eight nodes were involved in 34 cases (22.4%). According to the UICC classification, 11 patients had pN1a disease (only residual axillary micrometastases), 25 patients had pN1bi disease (one to three axillary metastases between 0.2 and 2 cm), 27 patients had pN1bii disease (> three axillary metastases between 0.2 and 2 cm), 47 patients had pN1biii disease (extranodal tumor growth), and seven had pN1biv disease (at least one axillary metastasis > 2 cm). Pathologic examination of breast tissue showed pCRs in 13.2% of cases (20 of 152) and ductal carcinoma-in-situ in 5.9% (nine of 152). The relationship between various parameters and pathologic response to therapy is shown in Table 1. SBR grade 3 tumors (P = .04) and a clinical response >= 50% to chemotherapy (P = .003) were associated with negative axillary status at dissection. High S-phase fraction and estrogen receptor–negative status fell short of reaching statistical significance (P = .06 and P = .10, respectively). Initial primary tumor size was not significantly correlated with complete axillary downstaging. An initial tumor size <= 3 cm (P = .02) and clinical regression >= 50% (P = .001) were associated with pCR of the primary tumor. As shown in Table 2, breast pCR and complete axillary downstaging were highly correlated: 14 of the 20 patients with pCRs of primary tumors had complete axillary downstaging (P < .001).


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  		Table 1.  Patient Characteristics and Pathologic Responses to Chemotherapy
 

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  		Table 2.  Correlation Between Tumor Response and Axillary Downstaging (P < .001)
 
The median follow-up time was 75 months. The five-year distant disease-free and overall survival rates for the whole population were 54.4% ± 8.0% and 68.5% ± 7.5%, respectively (Fig 1). Twenty-two patients had local recurrence (17 ipsilateral breast tumor recurrences and five appearances of tumor on the ipsilateral chest wall or in the mastectomy scar) and 65 had distant metastases. Regional nodal failure occurred in 19 patients (axillary in eight patients and supraclavicular in 11 patients). In the univariate analysis of survival, age greater than 40 years (P = .003), complete axillary downstaging (P = .01), and pCR of the breast tumor (P = .05) were associated with improvement of distant disease-free survival (Table 3). Five-year distant disease-free survival rates were 73.5% ± 14.9% for the group of patients with no involved nodes at the time of surgery and 48.7% ± 9.2% for the group of patients with residual nodal disease (Fig 2). There was a marked trend toward decreased survival with increased numbers of involved nodes: 5-year distant disease-free survival rates were 65.3% ± 12.7% among patients with one to three involved nodes, 46.6% ± 18.4% among patients with four to seven involved nodes, and 25.7% ± 14.9% among patients with >= eight involved nodes (P < .001). Survival also was correlated with postoperative UICC classification: 5-year distant disease-free survival rates were 81.8% ± 22.7% among patients with pN1a disease, 58.5% ± 19.6% among patients with pN1bi disease, 36.5% ± 19% among patients with pN1bii disease, 43.8% ± 14.3% among patients with pN1biii disease, and 42.9% ± 36.7% among patients with pN1biv disease (P < .02).



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  		Fig 1. Distant disease-free survival and overall survival in the entire population. —, Overall survival; ---, metastasis-free survival.

 

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  		Table 3.  Univariate Analysis of Predictors of Distant Disease-Free Survival
 


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  		Fig 2. Distant disease-free survival according to the axillary nodal status after primary chemotherapy. —, No residual nodal disease; ---, residual nodal disease.

 
Distant disease-free survival rates were 74.7% ± 14.9% among women with breast tumors that showed pCRs and 51.3% ± 8.8% among other patients (Fig 3). The distant disease-free survival rates were similar among patients with in situ residual disease in the breast (50.0% ± 34.7%) and patients with partial or no responses (50.9% ± 9.0%). Distant disease-free survival rates according to both axillary and breast status at surgery are shown in Fig 4: the 5-year distant disease-free survival rates were 85.7% ± 18.4% among patients with breast and axillary pCRs and 65.8% ± 20.6% among patients with residual disease in the breast only. Five-year distant disease-free survival rates were similar among patients with residual disease in the axilla only and in both breast and axilla (50% ± 40.0% and 48.2% ± 9.4%, respectively).



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  		Fig 3. Distant disease-free survival according to the pathologic response of the primary tumor. —, No residual breast tumor; ---, residual breast tumor.

 


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  		Fig 4. Distant disease-free survival according to the status of both breast and axillary lymph nodes. —, Complete pathologic response; ---, residual disease in breast only; – – –, residual disease in axilla only; – ·· – ·· –, residual disease in breast and axilla.

 
In a multivariate Cox regression analysis, parameters associated with poor distant disease-free survival were age <= 40 years (P = .002), persistence of nodal involvement (P = .03), and S-phase fraction more than 4% (P = .02) (Table 4). Breast tumor pCR was not significantly associated with improved survival in the multivariate analysis.


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  		Table 4.  Cox Regression Analysis of Predictors of Distant Disease
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Assessment of residual disease after primary chemotherapy is important for selecting patients who may be candidates for further systemic therapy after surgery. Our study indicates that primary chemotherapy results in a complete axillary response in 23% of patients with cytologically proven node metastases at the time of diagnosis. The objective of this study was to determine the prognostic value of documented complete axillary downstaging after primary chemotherapy. Conversion of axillary lymph nodes from positive to negative pathologic status is a strong predictor of survival. On the other hand, in node-positive patients, pCR of breast tumor could be considered a marker of axillary conversion more than a predictor of survival. These results were expected because nodal status is strongly correlated with metastatic risk. In further studies, it will be interesting to correlate the prognostic significance of breast and axillary nodal status with the presence of bone marrow micrometastases, another independent marker of metastatic risk.17

The increased rates of negative nodes in patients treated with primary chemotherapy have been well documented. In National Surgical Adjuvant Breast and Bowel Project B-18, 36% of patients initially clinically node-positive were found to be pathologically node-negative after preoperative chemotherapy, compared with 14% of those in the postoperative group.6 Of the patients considered clinically node-negative, 67% in the preoperative group were found to be pathologically node-negative and 52% in the postoperative group were found to be pathologically node-negative. However, assessment of axillary lymph nodes by physical examination is well known to be highly inaccurate.1 Only studies in which nodal status is assessed by cytology provide accurate data on the conversion rate from positive to histologically negative axillary status after chemotherapy and on prognostic significance of axillary histologic clearance. In the study by McCready et al,18 25% of patients with stage III disease were found to have no metastatic axillary nodes after preoperative chemotherapy. This is twice the rate among patients treated with radical mastectomy without preoperative chemotherapy.19

The incidence of eradication of axillary lymph node metastases before surgery in breast cancer patients receiving primary chemotherapy has been reported only once in the literature.7 The rate of complete axillary downstaging in our study is similar to the one reported by those authors (23%). Our results were achieved in a study involving 152 women whose initial clinical and follow-up data were prospectively entered into a database. This large series of patients treated at a single institution and observed for a median of 75 months allows us to draw some conclusions regarding predictors of axillary downstaging and the effect of such downstaging on survival. However, this study has limitations. The heterogeneity of the primary chemotherapy regimens is the main limitation, although there was no statistical difference between the chemotherapy regimens used (data not shown). Further studies must assess whether more aggressive primary chemotherapy (e.g., combinations of doxorubicin and taxanes) is more effective in sterilizing axillary metastases.

The possibility of nonsurgical management of the axilla after primary chemotherapy has been suggested.7 But the conversion of axillary status is poorly evaluated by physical examination and ultrasonography (negative predictive values of 39% to 44% and 44% to 58%, respectively).20,21 Recently, Breslin et al22 demonstrated that sentinel lymph node biopsy is an effective means of determining axillary status after induction chemotherapy. However, other authors found sentinel lymph node biopsy inaccurate in this regard.23 Sentinel lymph node biopsy after primary chemotherapy requires validation, but identifying predictors of axillary downstaging could help clinicians select patients for sentinel lymph node biopsy or irradiation of the axilla. SBR grade 3 tumors were significantly associated with complete axillary histologic clearance (P = .04), whereas S-phase fraction was of borderline significance (P = .06). The correlation between proliferative indexes and chemosensitivity has been extensively demonstrated.24-26 Chang et al25 suggested that molecular markers, particularly Ki67 antigen, may be used to predict the likelihood of achieving good clinical response, which seems to be a valid marker for survival.12 In our study, determinants of lymph node downstaging and breast tumor response to primary chemotherapy were different: complete axillary downstaging seems to be related to aggressiveness indices (SBR grade, S-phase fraction, and estrogen receptor status), whereas breast tumor pCR is highly correlated with initial tumor size. Determining predictors of axillary and breast tumor response may be useful for identifying patients who will benefit from primary chemotherapy, either in terms of breast conservation or of improved prognosis through complete axillary downstaging.

In the study by Kuerer et al,7 patients with complete axillary conversion had smaller tumors than did patients with incomplete axillary conversion. However, only patients with tumors >= 4 cm were included in the study. In our study, 71 patients had T1 or T2 tumors that were less than 4 cm, along with cytologically documented axillary lymph node metastases. The effect of chemotherapy on axillary lymph node metastases had never been clearly evaluated in patients with small tumors. In the current study, there was no significant difference in complete axillary downstaging rates between patients with small tumors and those with large tumors, whereas pCR in the breast was significantly more frequent among patients with small tumors. Our data are concordant with those of all trials comparing adjuvant and primary chemotherapy: none of those trials found primary chemotherapy to be more effective in small breast tumors, even when the primary tumor pCR rates were higher than those among patients with large breast tumors.6,27 Randomized studies comparing primary and adjuvant chemotherapy did not show any differences in terms of disease-free survival and overall survival, but they did show that primary chemotherapy allowed more frequent breast-conserving surgery.28-32 In patients with small tumors, avoiding mastectomy is not the concern, and Thames et al.33 has suggested that if surgery is delayed, there is an appreciable risk of new distant disease. Chemotherapy may modify tumor growth kinetics and seeding frequency, but the current study demonstrates that involvement of axillary nodes is persistent in 76% of patients (48 of 63) with breast tumors <= 3 cm and in 78% of patients (69 of 89) with tumors larger than 3 cm. These similar rates of residual nodal disease may bring into question the administration of primary chemotherapy to patients with tumors <= 3 cm.

Our results confirm that axillary status and the number of involved axillary nodes are better prognostic factors than response of the primary tumor to primary chemotherapy. We did not find a higher complete axillary downstaging rate in patients with breast tumors <= 3 cm compared with patients with larger breast tumors. Therefore, delaying surgery may have no advantage in patients with small primary tumors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Recht A, Houlihan MJ: Axillary lymph nodes and breast cancer. Cancer 76: 1491-1512, 1995[CrossRef][Medline]

2. Pierga JY, Mouret E, Dieras V, et al: Prognostic value of persistent node involvement after neoadjuvant chemotherapy in patients with operable breast cancer. Br J Cancer 83: 1480-1487, 2000[CrossRef][Medline]

3. Hortobagyi GN: Treatment of breast cancer. N Engl J Med 339: 974-984, 1998[Free Full Text]

4. Fisher B, Wolmark N, Bauer M, et al: The accuracy of clinical nodal staging and of limited axillary dissection as a determinant of histologic nodal status in carcinoma of the breast. Surg Gynecol Obstet 152: 765-772, 1981[Medline]

5. Ptaszynski A, Van den Bogaert W, Van Glabbeke M, et al: Patient population analysis in EORTC trial 22881/10882 on the role of a booster dose in breast-conserving therapy. Eur J Cancer 30A: 2073-2081, 1994[CrossRef]

6. Fisher B, Brown A, Mamounas E, et al: Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15: 2483-2493, 1997[Abstract/Free Full Text]

7. Kuerer HM, Sahin AA, Hunt KK, et al: Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg 230: 72-78, 1999[CrossRef][Medline]

8. Zajdela A, Zillhart P, Voillemot N: Cytological diagnosis by fine needle sampling without aspiration. Cancer 59: 1201-1205, 1987[CrossRef][Medline]

9. Bloom HJG, Richardson WW: Histological grading and prognosis in breast cancer. Br J Cancer 11: 359-377, 1957[Medline]

10. Vielh P, Magdelenat H, Mosseri V, et al: Immunocytochemical determination of estrogen and progesterone receptors on 50 fine needle samples of breast cancer: A prospective study including biochemical correlation and DNA flow cytometric analysis. Am J Clin Pathol 97: 254-261, 1992[Medline]

11. Remvikos Y, Vielh P, Padoy E, et al: Breast cancer proliferation measured on cytological samples: A study by flow cytometry of S-phase fractions and BrdU incorporation. Br J Cancer 64: 501-507, 1991[Medline]

12. 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 31A: 1969-1975, 1995[CrossRef]

13. Vincent-Salomon A, Carton M, Freneaux P, et al: ERBB2 overexpression in breast carcinomas: No positive correlation with complete pathological response to preoperative high-dose anthracycline-based chemotherapy. Eur J Cancer 36: 586-591, 2000

14. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef]

15. Mantel N, Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22: 719-748, 1959

16. Cox DR: Regression models and life tables. J R Stat Soc B 34: 187-202, 1972

17. Braun S, Pantel K, Müller P, et al: Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II or III breast cancer. N Engl J Med 342: 525-533, 2000[Abstract/Free Full Text]

18. 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 124: 21-25, 1989[Abstract/Free Full Text]

19. Fracchia AA, Evans JF, Eisenberg BL: Stage III carcinoma of the breast: A detailed analysis. Ann Surg 192: 705-710, 1980[Medline]

20. Kuerer HM, Newman LA, Fornage BD, et al: Role of axillary lymph node dissection after tumor downstaging with induction chemotherapy for locally advanced breast cancer. Ann Surg Oncol 5: 673-680, 1998[Abstract]

21. Herrada J, Iyer RB, Atkinson EN, et al: Relative value of physical examination, mammography, and breast sonography in evaluating the size of the primary tumor and regional lymph node metastases in women receiving neoadjuvant chemotherapy for locally advanced breast carcinoma. Clin Cancer Res 3: 1565-1569, 1997[Abstract]

22. Breslin TM, Cohen L, Sahin A, et al: Sentinel lymph node biopsy is accurate after neoadjuvant chemotherapy for breast cancer. J Clin Oncol 18: 3480-3486, 2000[Abstract/Free Full Text]

23. Nason KS, Anderson BO, Byrd DR, et al: Increased false negative sentinel node biopsy rates after preoperative chemotherapy for invasive breast carcinoma. Cancer 89: 2187-2194, 2000[CrossRef][Medline]

24. Remvikos Y, Beuzeboc P, Zajdela A, et al: Correlation of pretreatment proliferative activity of breast cancer with the response to cytotoxic chemotherapy. J Natl Cancer Inst 81: 1383-1387, 1989[Abstract/Free Full Text]

25. Chang J, Powles TJ, Allred DC, et al: Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. J Clin Oncol 17: 3058-3063, 1999[Abstract/Free Full Text]

26. Gardin G, Alama A, Rosso R, et al: Relationship of variations in tumor cell kinetics induced by primary chemotherapy to tumor regression and prognosis in locally advanced breast cancer. Breast Cancer Res Treat 32: 311-318, 1994[CrossRef][Medline]

27. Powles TJ, Hickish TF, Makris A, et al: Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 13: 547-552, 1995[Abstract/Free Full Text]

28. Mauriac L, MacGrogan G, Avril A, et al: Neoadjuvant chemotherapy for operable breast carcinoma larger than 3 cm: A unicentre randomized trial with a 124-month median follow-up. Institut Bergonie Bordeaux Groupe Sein (IBBGS). Ann Oncol 10: 47-52, 1999[Abstract/Free Full Text]

29. Broet P, Scholl SM, de la Rochefordiere A, et al: Short and long-term effects on survival in breast cancer patients treated by primary chemotherapy: An updated analysis of a randomized trial. Breast Cancer Res Treat 58: 151-156, 1999[CrossRef][Medline]

30. Danforth D, Jacobson J, O’Shaughnessy J, et al: Effect of preoperative chemotherapy on axillary lymph node metastases in stage II breast cancer: A prospective randomized trial. Proc Am Soc Clin Oncol 14: 128, 1995 (abstr 213)

31. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16: 2672-2685, 1998[Abstract]

32. Semiglazov ZF, Topuzov EE, Bavli JL, et al: Primary (neoadjuvant) chemotherapy and radiotherapy compared with radiotherapy alone in stage IIB-IIIA breast cancer. Ann Oncol 5: 591-595, 1994[Abstract/Free Full Text]

33. Thames HD, Buchloz TA, Smith CD: Frequency of first metastatic events in breast cancer: Implications for sequencing of systemic and local-regional treatment. J Clin Oncol 17: 2649-2658, 1999[Abstract/Free Full Text]

Submitted May 11, 2001; accepted November 6, 2001.


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Sequential Preoperative or Postoperative Docetaxel Added to Preoperative Doxorubicin Plus Cyclophosphamide for Operable Breast Cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27
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B. T. Hennessy, G. N. Hortobagyi, R. Rouzier, H. Kuerer, N. Sneige, A. U. Buzdar, S. W. Kau, B. Fornage, A. Sahin, K. Broglio, et al.
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M. L. Smidt, D. M. Kuster, G. J. van der Wilt, F. B. Thunnissen, K. J. Van Zee, and L. J. A. Strobbe
Can the Memorial Sloan-Kettering Cancer Center Nomogram Predict the Likelihood of Nonsentinel Lymph Node Metastases in Breast Cancer Patients in The Netherlands?
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M. S. Mano and A. Awada
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H. D. Bear, S. Anderson, A. Brown, R. Smith, E. P. Mamounas, B. Fisher, R. Margolese, H. Theoret, A. Soran, D. L. Wickerham, et al.
The Effect on Tumor Response of Adding Sequential Preoperative Docetaxel to Preoperative Doxorubicin and Cyclophosphamide: Preliminary Results From National Surgical Adjuvant Breast and Bowel Project Protocol B-27
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G. Ganem, M. Tubiana-Hulin, P. Fumoleau, M. Combe, J.-L. Misset, J.-M. Vannetzel, T. Bachelot, L. R. De Ybarlucea, V. Lotz, B. Bendahmane, et al.
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L. A. Newman, N. L. Pernick, V. Adsay, K. A. Carolin, P. I. Philip, S. Sipierski, D. L. Bouwman, M. A. Kosir, M. White, and D. W. Visscher
Histopathologic Evidence of Tumor Regression in the Axillary Lymph Nodes of Patients Treated With Preoperative Chemotherapy Correlates With Breast Cancer Outcome
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J. S. Fant, M. D. Grant, S. M. Knox, S. A. Livingston, K. Ridl, R. C. Jones, and J. A. Kuhn
Preliminary Outcome Analysis in Patients With Breast Cancer and a Positive Sentinel Lymph Node Who Declined Axillary Dissection
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G. Lawrence, J. Crawford, F. Sherman, J. A. van der Hage, and C. J.H. van de Velde
Evaluating Neoadjuvant Chemotherapy in Breast Cancer
J. Clin. Oncol., June 15, 2002; 20(12): 2905 - 2907.
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