Axillary Node-positive Breast Cancer Research Articles

Extracapsular Extension Is Associated with Increased Ratio of Metastatic to Examined Lymph Nodes in Axillary Node-Positive Breast Cancer

Background Extracapsular extension of nodal tumor cells, although it is not a parameter of staging, has recently been shown to be correlated with the high number of metastatic lymph nodes in patients with axillary-positive breast cancer. It is suggested that the use of involved/examined lymph node ratio instead of the number of metastatic lymph nodes in axillary evaluation would obtain standardized prognostic data for patient management. This study investigated the association of the extracapsular extension with the lymph node ratio in a node-positive group of patients. Patients and Methods Medical records of 170 patients with positive axillary status were retrospectively reviewed. Of these, 54 were extracapsular extension positive, and the remaining were extracapsular extension negative. A comparison was made between extracapsular extension– positive and extracapsular extension–negative groups with respect to some potential prognostic indicators. Results Number of metastatic lymph nodes, number of examined lymph nodes, and involved/examined lymph node ratio were found to be significantly higher in patients with a presence of extracapsular extension. Conclusion The results suggest that the presence of extracapsular extension might force physicians to perform more aggressive adjuvant therapies and that the extracapsular extension could be a valuable parameter in the management of breast cancer because it has a strong relationship with the proven prognostic factors.

Estrogen receptor expression and efficacy of docetaxel in early breast cancer: A pooled analysis of 3,490 patients included in two randomized trials

537 Background: It has been suggested that estrogen receptor (ER) expression is associated with relative resistance to adjuvant chemotherapy. The efficacy of adjuvant chemotherapy is still matter of controversy in this subset of patients. The aim of the present study was to assess the efficacy of docetaxel according to ER expression in adjuvant treatment trials. Patients and Methods: The efficacy of docetaxel according to ER expression was assessed in a pooled analysis of two randomized studies (BCIRG001 and PACS01) that included overall 3,490 patients with axillary node positive breast cancer. These studies compared either 3 (PACS01) or 6 (BCIRG001) cycles of a docetaxel-containing regimen, to a chemotherapy that did not contain docetaxel. Hazard ratios (HR) for death were determined by a Cox model adjusted for clinical characteristics (age, T size and number of lymph node involved). Interaction between docetaxel efficacy and ER expression was tested. Results: ER status was assessable in 3,329 patients (95%). The median age was 49 years old (range, 23–70). ER was expressed in 2,493 tumors (74%). In patients with assessable ER status (n=3329), docetaxel was associated with a significant reduction in the risk of death (HR=0.69; 95%CI: 0.51–0.92, p=0.01). Docetaxel therapy was associated with a 30% reduction in the risk of death in ER-positive disease (HR=0.70; 95%CI: 0.54–0.91) and a 31% reduction in the risk of death in ER-negative disease (HR=0.69; 95% CI: 0.52–0.94). Test for interaction did not detect any statistically significant difference in the relative effect of docetaxel according to ER status (HR for interaction=1.03; p=0.87). Conclusion: In this pooled analysis of two randomized trials, the relative effect of docetaxel on overall survival in adjuvant setting was not different between ER-positive and ER-negative disease. Docetaxel was associated with a significant risk reduction of death in patients with ER-positive disease. No significant financial relationships to disclose.

A phase III adjuvant trial of sequenced EC + filgrastim + epoetin-alpha followed by paclitaxel compared to sequenced AC followed by paclitaxel compared to CEF in women with node-positive or high-risk node-negative breast cancer (NCIC CTG MA.21)

550 Background: CEF and AC followed by paclitaxel (AC/T) are commonly used adjuvant regimens in women with early breast cancer. In a trial conducted by the EORTC, NCIC CTG, and SAKK three months of dose-dense EC was equivalent to six months of CEF in women with locally advanced breast cancer. We hypothesized that three months of a taxane following dose-dense EC would be superior to CEF alone or AC/T. The results of a planned interim analysis were presented in San Antonio 2006 (Abstract #53). We now present more detailed results on efficacy and toxicity. Methods: Women 60 years of age or younger, with axillary node positive or high risk node negative breast cancer were randomized to CEF, EC/T or AC/T for six months. Results: Between December 2000 and April 2005, 2104 patients were enrolled. The median follow-up is 30.4 months. Hazard ratios for recurrence are: AC/T vs. CEF, 1.49 (95% CI, 1.12–1.99), p=0.005; AC/T vs. EC/T, 1.68 (95% CI, 1.25–2.27), p=0.0006; and EC/T vs. CEF, 0.89 (95% CI, 0.64–1.22), p=0.46. Three year recurrence-free survival rates for CEF, EC/T, and AC/T are 90.1, 89.5 and 85.0%, respectively. There was no significant interaction between ER status and treatment. Multivariate analysis of predictive factors will be presented. The numbers of deaths are 50 (CEF), 47 (EC/T) and 65 (AC/T). There was more toxicity in CEF and EC/T compared to AC/T. Conclusion: AC/T given every three weeks, although less toxic is significantly inferior to CEF or EC/T in terms of relapse-free survival. It is too early to detect any difference between CEF and dose-dense EC/T. Our results indicate that there is still room to explore anthracycline and taxane adjuvant chemotherapy regimens. Supported by: NCI Canada and Canadian Cancer Society, Pfizer, Bristol-Myers Squibb, Amgen, Janssen Ortho, Ortho Biotech, and NCI US. [Table: see text] No significant financial relationships to disclose.

Sentinel node identification rate, but not accuracy, is significantly decreased after pre-operative chemotherapy in axillary node-positive breast cancer patients

The aim was to prove the low identification rate of sentinel lymph node biopsy (SNB) and to determine the feasibility of replacing axillary lymph node dissection (AND) in axillary lymph node positive patients after chemotherapy. From October 2001 to July 2005, 875 consecutive patients with primary operable breast cancer underwent SNB and AND. Among them, 238 received pre-operative chemotherapy. We compared the identification rate, false negative rate (FNR), negative predictive value (NPV), and accuracy of SNB in clinically node-positive patients with or without chemotherapy. The identification rate was significantly lower in patients received chemotherapy (77.6%) than in those not received it (97.0%) (P<0.001). In those received the therapy, the FNR was 5.6%, the NPV was 86.8%, and the accuracy was 95.9%. In those not received therapy, the FNR was 7.4% and the accuracy was 92.6% (differences not statistically significant). The identification rate in confirmed axillary lymph node-positive patients was significantly lower in patients received pre-operative chemotherapy, but accuracy did not differ significantly between the two groups. Thus, for patients who achieve complete axillary clearance by chemotherapy, SNB could replace AND.

Prognostic significance of urokinase plasminogen activator and plasminogen activator inhibitor-1 mRNA expression in lymph node- and hormone receptor-positive breast cancer.

BackgroundOne of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system that comprises of, among others, the urokinase Plasminogen Activator (uPA) and its main inhibitor, the Plasminogen Activator Inhibitor-1 (PAI-1). In this study, we investigated the prognostic value of uPA and PAI-1 at the mRNA level in lymph node- and hormone receptor-positive breast cancer.MethodsThe study included a retrospective series of 87 patients with hormone-receptor positive and axillary lymph node-positive breast cancer. All patients received radiotherapy, adjuvant anthracycline-based chemotherapy and five years of tamoxifen treatment. The median patient age was 54 and the median follow-up time was 79 months. Distant relapse occurred in 30 patients and 22 patients died from breast cancer during follow-up. We investigated the prognostic value of uPA and PAI-1 at the mRNA level as measured by real-time quantitative RT-PCR.ResultsuPA and PAI-1 gene expression was not found to be correlated with any of the established clinical and pathological factors. Metastasis-free Survival (MFS) and Breast Cancer specific Survival (BCS) were significantly shorter in patients expressing high levels of PAI-1 mRNA (p < 0.0001; p < 0.0001; respectively). In Cox multivariate analysis, the level of PAI-1 mRNA appeared to be the strongest prognostic factor for MFS (Hazard Ratio (HR) = 10.12; p = 0.0002) and for BCS (HR = 13.17; p = 0.0003). Furthermore, uPA gene expression was not significantly associated neither with MFS (p = 0.41) nor with BCS (p = 0.19). In a Cox-multivariate regression analysis, uPA expression did not demonstrate significant independent prognostic value.ConclusionThese findings indicate that high PAI-1 mRNA expression represents a strong and independent unfavorable prognostic factor for the development of metastases and for breast cancer specific survival in a population of hormone receptor- and lymph node-positive breast cancer patients.

Low local recurrence rate without postmastectomy radiation in node-negative breast cancer patients with tumors 5 cm and larger

To assess the need for adjuvant radiotherapy following mastectomy for patients with node-negative breast tumors 5 cm or larger. Between 1981 and 2002, a total of 70 patients with node-negative breast cancer and tumors 5 cm or larger were treated with mastectomy and adjuvant systemic therapies but without radiotherapy at three institutions. We retrospectively assessed rates and risk factors for locoregional failure (LRF), overall survival (OS), and disease-free survival (DFS) in these patients. With a median follow-up of 85 months, the 5-year actuarial LRF rate was 7.6% (95% confidence interval, 3%-16%). LRF was primarily in the chest wall (4/5 local failures), and lymphatic-vascular invasion (LVI) was statistically significantly associated with LRF risk by the log-rank test (p=0.017) and in Cox proportional hazards analysis (p=0.038). The 5-year OS and DFS rates were 83% and 86% respectively. LVI was also significantly associated with OS and DFS in both univariate and multivariate analysis. This series demonstrates a low LRF rate of 7.6% among breast cancer patients with node-negative tumors 5 cm and larger after mastectomy and adjuvant systemic therapy. Our data indicate that further adjuvant radiation therapy to increase local control may not be indicated by tumor size alone in the absence of positive lymph nodes. LVI was significantly associated with LRF in our series, indicating that patients with this risk factor require careful consideration with regard to further local therapy.

Cardiac and pulmonary complication probabilities for breast cancer patients after routine end-inspiration gated radiotherapy

Purpose Substantial reductions of radiation doses to heart and lung can be achieved using breathing adaptation of adjuvant radiotherapy following conservative surgery for breast cancer. The purpose of this study was to estimate the radiobiological implications after routine use of an end-inspiration gated treatment, and to compare the results with predictions based on pre-clinical CT-studies. Patients and methods Nineteen consecutive patients with axillary lymph node-positive left-sided breast cancer were referred for adjuvant radiotherapy after breast conserving surgery. Treatment was performed with gating in the end-inspiration phase of audio-coached enhanced free breathing. The target intended to encompass the remaining breast, ipsilateral internal mammary and periclavicular nodes, and the prescription dose was 48 Gy in 24 fractions. A three-field mono-isocentric conformal technique using deep tangentials and a supraclavicular field was employed. NTCPs were calculated using the relative seriality model for the heart, and the model proposed by Burman et al. for the lung. The observed values were compared to those predicted from two previous CT-studies for a deep inspiration breath-hold technique and an uncoached end-inspiration gating technique. Results The ipsilateral lung V 50 (relative volume receiving more than 50% of the prescription dose) had a median value of 23.7% (range 10.8–35.1%) over the patient population. The corresponding median lung pneumonitis probability was 1.1% (range 0–14%). The median heart V 50 was 0.8% (range 0–19.1%) with a corresponding median cardiac mortality NTCP of 0.1% (range 0–5.7%). These results compare well with the predictions of our previous CT-studies. There is a significant reduction in dose to the left anterior descending coronary artery for the enhanced end-inspiration gating technique compared to the uncoached end-inspiration technique employed in the CT-studies. Conclusions In a routine clinical practice involving adjuvant breast radiotherapy gated in an enhanced end-inspiration phase, remarkably low doses to organs at risk are observed. The corresponding cardiac and pulmonary complication risks are of the order of 1% and smaller.

Toll like receptor 3 expression and efficacy of adjuvant treatment with polyadenylic-polyuridylic acid in patients with axillary node positive breast cancer: Results from two randomized trials

10563 Background: Toll like receptor 3 (TLR3) are transmembrane receptors involved in the cellular response to danger signal and specifically activated by double stranded RNA. Based on these data, we hypothesized that the TLR3 expression by tumor cells is associated with the efficacy of a treatment with double stranded RNA in cancer patients. Patients and Methods: TLR3 expression was assessed by immunohistochemistry in 336 patients with axillary node positive breast cancer. These patients were selected to have been included in two randomized trials that compared a post-operative administration of polyadenylic-polyuridylic acid (polyAU) to either no treatment (n = 174, trial I) or an adjuvant chemotherapy by CMF regimen (n = 162, trial II). In the trial II, locoregional and pelvic radiotherapy were given in the polyAU arm. Results: TLR3 was found to be overexpressed in 45 tumors (13%). Median follow-up were 23 and 17 years for living patients included in the trials I and II respectively. When the analysis focused on the first trial, the 20 year overall survival rates were 87% (95% CI: 53–97%) and 32% (95% CI: 12–63%) for patients with TLR3-overexpressing tumour treated (n = 8) or not (n = 11) with polyAU (p = 0.03). In the same trial, the 20 year overall survival rates were 43% (95% CI: 33–54%) and 35% (95% CI: 25–46%) for patients with TLR3-negative tumor treated (n = 81) or not (n = 74) with polyAU (p = 0.32). When the analysis focused on the Trial II, the 15 year overall survival were 62% (95% CI: 45%-91%) and 21% (95% CI: 8%-47%) for patients with TLR3-overexpressing tumors treated (n = 12) or not (n = 14) with polyAU (p = 0.005). In the same trial, 15 year overall survival rates were 31% (95% CI: 21%-42%) and 39% (95% CI: 28%-51%) for patients with TLR3-negative tumors treated (n = 66) or not (n = 70) with polyAU (p = 0.39). Conclusion: This study suggests that the post-operative administration of polyadenylic-polyuridylic acid improves outcome of patient with TLR3-overexpressing, node-positive breast cancer. [Table: see text]

Expression of chemokine receptors predicts the site of metastatic relapse in patients with axillary node positive primary breast cancer

BackgroundRecent studies have suggested that chemokine receptors are involved in development of organ-specific pattern of metastases. In the present study, we evaluated the association between the chemokine receptors expressed in primary tumor cells and the site of metastatic relapse in patients with breast cancer. MethodsPrimary tumors were obtained from 142 patients with axillary node–positive breast cancer and stained for CX3CR1, CXCR4, CCR6, and CCR7 expression. All statistical analyses were adjusted for systemic post-operative treatment. ResultsAfter a median follow-up of 13 years, none of the chemokine receptors was associated with overall survival or disease free survival. However, expression of chemokine receptors was found to be associated with increased risk of relapse in certain organs. By estimating the Mantel-Haenszel odds ratios (OR), CXCR4 was associated with increased risk of metastasis to the liver (OR = 3.71, P = 0.005), CX3CR1 was associated with metastasis to the brain (OR = 13.18, P = 0.01). Patients with CCR6 positivity were more likely to develop a first metastasis in the pleura (OR = 2.82, P = 0.06). In addition, CCR7 expression was associated with the occurrence of skin metastases (11% versus 0%, P = 0.017). InterpretationExpression of chemokine receptors in the primary tumor predicts the site of metastatic relapse in patients with axillary node positive breast cancer. This study, in concordance with the data obtained in animal models, suggests that the chemokine receptors family could be the biological support of the ‘seed and soil’ theory.

Factorial design for randomized clinical trials

Factorial design for randomized clinical trials

Adjuvant docetaxel plus doxorubicin and cyclophosphamide increases survival compared with fluorouracil plus doxorubicin and cyclophosphamide in women with operable node-positive breast cancer

Combination chemotherapy with fluorouracil plus doxorubicin and cyclophosphamide is an accepted adjuvant treatment for early breast cancer. It is uncertain whether adjuvant chemotherapy with docetaxel plus doxorubicin and cyclophosphamide can increase survival compared with fluorouracil plus doxorubicin and cyclophosphamide in women with operable axillary node-positive breast cancer.

Prediction of prognosis in axillary lymph node positive breast cancer patients: a statistical study.

This work has identified variables of importance to short- and long-term prognosis in 97 node positive breast cancer patients followed for a minimum of 98 months. The diameter of the primary tumour (less than or equal to 3 cm/greater than 3 cm) is shown to be an important prognostic variable. Its addition to the presence/absence of tumour cells in the efferent nodal vessels and the mean nuclear area of the tumour cells gave correct prediction of the disease outcome, 60 and 98 months after the operation, in 83 and 80 per cent of the patients respectively. Although the number of tumour-bearing nodes is shown to be a strong variable, more information was gained from the tumour diameter. Histological grade was only of value for 5-year prognosis. Factors that did not add information of prognostic value in these circumstances were identified. The proposed models demonstrate the great heterogeneity within this group of patients.

Randomized Trial Comparing Cyclophosphamide, Epirubicin, and Fluorouracil With Cyclophosphamide, Methotrexate, and Fluorouracil in Premenopausal Women With Node-Positive Breast Cancer: Update of National Cancer Institute of Canada Clinical Trials Group Trial MA5

Certain anthracycline-containing adjuvant chemotherapy regimens are associated with improved relapse-free survival (RFS) and overall survival (OS) compared with the classic regimen of cyclophosphamide, methotrexate, and fluorouracil in women with early-stage breast cancer. Between 1989 and 1993, 710 pre- and perimenopausal women with axillary node-positive breast cancer were randomly assigned to either cyclophosphamide 75 mg/m(2) orally days 1 through 14, epirubicin 60 mg/m(2) intravenously days 1 and 8, and fluorouracil 500 mg/m(2) intravenously days 1 and 8 (CEF) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14, methotrexate 40 mg/m(2) intravenously days 1 and 8, and fluorouracil 600 mg/m(2) intravenously days 1 and 8). On the basis of follow-up to May 1997 (median follow-up time, 59 months), there was a statistically significant improvement in RFS and OS for CEF compared with CMF. The trial results are now updated, with a median follow-up of 10 years for live patients. The 10-year RFS is 52% for patients who received CEF compared with 45% for CMF patients (hazard ratio [HR] for CMF v CEF = 1.31; stratified log-rank, P = .007). The 10-year OS for patients who received CEF and CMF are 62% and 58%, respectively (HR for CMF v CEF = 1.18; stratified log-rank, P = .085). The rates of acute leukemia have not changed since the original report, whereas the rates of congestive heart failure are slightly higher but acceptable (four patients [1.1%] in the CEF group v one patient [0.3%] in the CMF group). The previously demonstrated benefit of CEF compared with CMF adjuvant chemotherapy is maintained with longer follow-up in the MA5 trial.

The pattern of chemokine receptors expressed by tumor cells predicts the site of metastatic relapse in patients with axillary node positive breast cancer

9501 Background: Some types of tumors present an organ-specific pattern of metastases. Although studies performed in animal models present strong evidence for a role of chemokine receptors in this phenomenon, there is no clinical study that specifically correlates the pattern of chemokine receptor expression with the site of metastases. In the present study, we have looked at the correlation between the chemokine receptors expressed by primary tumor cells and the site of metastatic relapse in patients with T1–3N+M0 breast cancer. Methods: CX3CR1, CXCR4, CCR6 and CCR7 expressions were evaluated by immunohistochemistry on primary tumors obtained from 142 patients with T1–3N+M0 breast cancer. These patients were included in a prospective trial between 1972 and 1979. None of the patients received adjuvant chemotherapy. Results: CX3CR1, CXCR4, CCR6, CCR7 expressions were found in 59 (43%), 42 (31%), 45 (34%) and 93 (66%) patients respectively. The expression of chemokine receptors did not correlate with any clinical characteristics, except a higher rate of very young patients (<35 year) in the CXCR4+ subgroup (14% vs 4%, p=0.04). After a median follow-up of 25 years, 75 patients (53%) have presented a metastatic relapse. The expression of chemokine receptors did not predict the metastasis-free survival, nor the overall survival. On the other hand, the pattern of chemokine receptor expression predicted the site of metastatic relapse. CX3CR1 staining predicted the occurence of brain metastases (14% vs 1%, p=0.004). CXCR4 staining predicted the occurrence of liver metastases (38% vs 14%, p=0.001) and lung metastases (28% vs 16%, p=0.05). CCR7 predicted the occurrence of skin metastases (11% vs 0%, p=0.03) and CCR6 predicted the occurrence of malignant pleural effusion (24% vs 10%, p=0.04). Conclusion: The study shows that the pattern of chemokine receptors expressed by tumor cells predicts the site of metastatic relapse in patients with T1–3N+M0 breast cancer. This study, in line with data obtained in animal models, may suggest in a clinical model that the chemokine receptor family could be the biological support of the << seed and soil >> theory. No significant financial relationships to disclose.

Q-TWiST Analysis of Cyclophosphamide, Epirubicin, Fluorouracil versus Cyclophosphamide, Methotrexate, Fluorouracil Treatment for Premenopausal Women with Node-Positive Breast Cancer

To estimate the Q-TWiST (Quality-Adjusted Time Without Symptoms and Toxicity) for premenopausal women with axillary node-positive breast cancer receiving either cyclophosphamide, epirubicin and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF), using data from a phase III clinical trial (National Cancer Institute of Canada Clinical Trials Group [NCIC-CGT.MA5]). Restricted mean times by treatment group were computed at 3, 4 and 5 years as the area under the Kaplan-Meier survival curves for the period of treatment-related symptomatic toxicities (TOX), disease-free survival (DFS) and overall survival (OS). Restricted REL (the period of relapse) and TWiST (the period of best possible QOL after breast cancer diagnosis) mean times were indirectly computed as OS minus DFS and DFS minus TOX, respectively. It was assumed that TWiST has a utility coefficient equal to 1. Patients' utility values were arbitrarily set to 0.5 for the toxicity and relapse health states. It was assumed that the utility scores were constant over time. A threshold utility sensitivity analysis was conducted allowing the trade-off between the two treatments to be assessed for the entire range of the utility coefficients. A bootstrap empirical test distribution of the Q-TWiST difference between CEF and CMF was constructed in order to test the statistical significance of the Q-TWiST difference point estimate. The Q-TWiST mean differences (CEF minus CMF) were -0.37, 1.20 and 2.62 months at 3, 4 and 5 years, respectively. Positive differences are in favour of the CEF arm but none of the above differences were statistically significant. The threshold-utility analysis confirmed the indifference of treatment choice with respect to the utility values, at least at 5 years. There were no combinations of TOX and REL utility values such that the Q-TWiST for the standard therapy (CMF) was greater than the Q-TWiST of the experimental treatment (CEF). The computed Q-TWiST difference of 2.62 months in favour of CEF (p = 0.492 vs CMF), while not statistically significant, is an indicator that CEF treatment could be a better choice from the patient's perspective than CMF after 5 years of treatment. These results should be considered within the context of the methodological limitations posed by the assumptions in the study.

Quality of adjuvant CMF chemotherapy for node-positive primary breast cancer: a population-based study.

Adjuvant 'classical' oral cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) has long been the mainstay of adjuvant chemotherapy for premenopausal breast cancer patients. The Comprehensive Cancer Center North Netherlands (CCCN) breast cancer working group performed a retrospective audit of treatment guideline adherence and quality of CMF in hospitals in the CCCN area. The CMF treatment data of 251 consecutive axillary lymph node-positive breast cancer patients <50 years old, diagnosed between 1993 and 1996, were analyzed. Ninety-four patients (42%) completed adjuvant CMF without dose adjustment or delay. Overall median relative dose intensity (RDI) was 92.6 (IQR 85.5-97.7). Sixty patients (24%) had an RDI <85, and 7% had an RDI <65. Myelotoxicity was the main reason for reductions and delays. Of 176 irradiated patients, 96% received radiotherapy simultaneously with CMF. Median CMF dose intensity nor median duration differed between patients who underwent mastectomy, mastectomy and radiotherapy, or breast-conserving therapy. Radiotherapy did not influence the median RDI (94 without versus 92 with radiotherapy). G-CSF, administered at least once to 76 patients, did not result in a higher median RDI. Median RDI was slightly higher when >3 patients/year (P=0.014) were treated by one specialist or >10 patients classified for adjuvant chemotherapy yearly in a hospital (P=0.037). The adherence to CMF treatment guidelines was generally good. Simultaneous radiotherapy did not affect the median RDI of CMF. G-CSF had no impact on the median RDI but patient volume did influence the RDI.

Long-term outcome of patients with complete eradication of cytologically proven axillary node metastases after primary chemotherapy: The University of Texas M. D. Anderson Cancer Center experience

604 Background: Following primary chemotherapy (PCT) for cytologically confirmed axillary node-positive (LN+) breast cancer (BC), patients (pts) who undergo conversion to negative axillary lymph nodes (LN neg) on hematoxylin & eosin (H&E) examination subsequently have a 5-year disease-free survival (DFS) rate of 87% (median follow-up of 61 months), whereas those with residual nodal disease after PCT have a 5-year DFS rate of 51% (Kuerer et al, JCO 1999). We present the 10-year outcome of the 43 pts in this review who achieved a pathologically complete axillary response with PCT, as well as another 26 pts treated subsequent to the publication of this data who also achieved complete axillary conversion with primary chemotherapy. Methods: Pts with cytologically documented axillary lymph node metastases were treated in four prospective trials of doxorubicin- or taxane-based PCT and were identified following subsequent definitive surgery to have complete histologic eradication of lymph node disease by H&E. Survival was calculated by the Kaplan-Meier method. Results: Fifty-two percent (n=36) of the pts had N1 disease, and 46% (n=32) had N2 disease. The majority of tumors were ductal (97%). In 60 cases, the estrogen receptor (ER) status was known. Of these, 75% were ER negative. The median follow-up was 73 months (range, 18–169 months). The relapse-free survival (RFS) rate of the group was 89% at 5 and 10 years. Overall survival (OS) rate was 92% at 5 years and 84% at 10 years. Forty-two patients (61%) had histologic eradication of disease in the breast in addition to the axillary nodal basin. For this group, RFS was 90% at 5 and 10 years, and OS was 93% at 5 years and 85% at 10 years, very similar to the outcome of patients who had residual disease in the breast (but not axilla) after neoadjuvant treatment (RFS 89% at 5 and 10 years, and OS 90% at 5 years and 83% at 10 years). Conclusions: Patients with complete histologic eradication of axillary metastatic disease by PCT have an excellent long-term DFS and OS. No significant financial relationships to disclose.

Long-term outcome of patients with complete eradication of cytologically proven axillary node metastases after primary chemotherapy: The University of Texas M. D. Anderson Cancer Center experience

604 Background: Following primary chemotherapy (PCT) for cytologically confirmed axillary node-positive (LN+) breast cancer (BC), patients (pts) who undergo conversion to negative axillary lymph nodes (LN neg) on hematoxylin & eosin (H&E) examination subsequently have a 5-year disease-free survival (DFS) rate of 87% (median follow-up of 61 months), whereas those with residual nodal disease after PCT have a 5-year DFS rate of 51% (Kuerer et al, JCO 1999). We present the 10-year outcome of the 43 pts in this review who achieved a pathologically complete axillary response with PCT, as well as another 26 pts treated subsequent to the publication of this data who also achieved complete axillary conversion with primary chemotherapy. Methods: Pts with cytologically documented axillary lymph node metastases were treated in four prospective trials of doxorubicin- or taxane-based PCT and were identified following subsequent definitive surgery to have complete histologic eradication of lymph node disease by H&E. Survival was calculated by the Kaplan-Meier method. Results: Fifty-two percent (n=36) of the pts had N1 disease, and 46% (n=32) had N2 disease. The majority of tumors were ductal (97%). In 60 cases, the estrogen receptor (ER) status was known. Of these, 75% were ER negative. The median follow-up was 73 months (range, 18–169 months). The relapse-free survival (RFS) rate of the group was 89% at 5 and 10 years. Overall survival (OS) rate was 92% at 5 years and 84% at 10 years. Forty-two patients (61%) had histologic eradication of disease in the breast in addition to the axillary nodal basin. For this group, RFS was 90% at 5 and 10 years, and OS was 93% at 5 years and 85% at 10 years, very similar to the outcome of patients who had residual disease in the breast (but not axilla) after neoadjuvant treatment (RFS 89% at 5 and 10 years, and OS 90% at 5 years and 83% at 10 years). Conclusions: Patients with complete histologic eradication of axillary metastatic disease by PCT have an excellent long-term DFS and OS. No significant financial relationships to disclose.

Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741

Using a 2 x 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node-positive breast cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS); to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities. A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A x 4 (doses) --> T x 4 --> C x 4 with doses every 3 weeks, (II) sequential A x 4 --> T x 4 --> C x 4 every 2 weeks with filgrastim, (III) concurrent AC x 4 --> T x 4 every 3 weeks, or (IV) concurrent AC x 4 --> T x 4 every 2 weeks with filgrastim. A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced relapse or died, compared with 515 expected treatment failures. Dose-dense treatment improved the primary end point, DFS (risk ratio [RR] = 0.74; P =.010), and OS (RR = 0.69; P =.013). Four-year DFS was 82% for the dose-dense regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and sequential schedules. There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens. Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this time. Sequential chemotherapy is as effective as concurrent chemotherapy.

Doxorubicin and cyclophosphamide adjuvant chemotherapy is no more effective than cyclophosphamide, methotrexate, and 5-fluorouracil for premenopausal axillary lymph node positive breast cancer

Doxorubicin and cyclophosphamide adjuvant chemotherapy is no more effective than cyclophosphamide, methotrexate, and 5-fluorouracil for premenopausal axillary lymph node positive breast cancer