This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nieto, Y. Articles by Bearman, S. I. Search for Related Content PubMed PubMed Citation Articles by Nieto, Y. Articles by Bearman, S. I. Social Bookmarking                            What's this?

Prognostic Model for Relapse After High-Dose Chemotherapy With Autologous Stem-Cell Transplantation for Stage IV Oligometastatic Breast Cancer

From the University of Colorado Bone Marrow Transplant Program and Departments of Pathology and Biostatistics, University of Colorado, Denver, CO.

Address reprint requests to Yago Nieto, MD, University of Colorado Health Sciences Center, 4200 E 9th Ave, B-190, Denver, CO 80262; email: yago.nieto{at}uchsc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To study prognostic factors after high-dose chemotherapy (HDC) for patients with stage IV oligometastatic breast cancer.

PATIENTS AND METHODS: Sixty patients with minimal metastatic disease amenable to local therapy enrolled onto a prospective HDC trial were analyzed for potential prognostic factors. Tumor blocks were retrospectively collected from referring institutions.

RESULTS: Median follow-up was 62 months (range, 4 to 120 months). Median relapse-free survival (RFS) and overall survival (OS) times were 52 and 80 months, respectively. Five-year RFS and OS rates were 52% (95% confidence interval [CI], 39% to 64%) and 62% (95% CI, 49% to 74%), respectively. HER-2 expression, number of tumor sites, primary axillary nodal ratio (number of positive nodes divided by number of sampled nodes), number of positive axillary nodes, and delivery or omission of radiotherapy to metastases correlated with RFS. HER-2 overexpression and more than one site were independent adverse risk factors for RFS. HER-2 and the axillary nodal ratio were independent predictors of OS. The following prognostic categories for RFS were established (RFS rate, median RFS): good risk, no factors (77%, 80 months); intermediate risk, one factor (41%, 28 months); and poor risk, both factors (10%, 10 months).

CONCLUSION: Long-term results in patients with oligometastatic breast cancer are encouraging but need validation in prospective randomized studies. HER-2 expression, number of sites, and primary nodal ratio are independent outcome predictors. Confirmation of these observations in this selected population would imply the need for reevaluation of the current tenet that early detection of metastatic breast cancer recurrence is of no benefit.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IT IS WIDELY ACCEPTED that the majority of patients with metastatic breast cancer (MBC) are not cured with conventional-dose chemotherapy.¹ In a large series of patients with MBC treated at the M.D. Anderson Cancer Center with doxorubicin-containing chemotherapy, only 1.7% of 1,581 patients remained alive in complete remission after long-term follow-up.²

Ten percent to 20% of chemosensitive patients with MBC treated in phase II studies of high-dose chemotherapy (HDC) with an autologous stem-cell transplant remain relapse free for the long term.^3-5 Those results could be due, at least in part, to patient selection or to biases in staging.⁶ Results of several relatively small randomized phase III studies that tested HDC in MBC have been reported. Trials that compared HDC with conventional chemotherapy in chemosensitive patients have either shown no superiority for HDC⁷ or have indicated a significant advantage in terms of progression-free survival but with no overall survival (OS) benefit.^8,9 Three other, larger randomized trials testing high-dose consolidation in responding patients with MBC are currently under way in Europe. Other small randomized trials have compared the immediate versus delayed use of HDC in patients with MBC in complete remission after chemotherapy¹⁰ or in hormone-refractory bone-only MBC.¹¹ In these two trials, statistically significant benefits in relapse-free survival (RFS) or progression-free survival were noted in favor of immediate transplantation, but with no significant impacts on OS.

These randomized studies have targeted chemosensitive patients for HDC evaluation. A different stage IV population that might potentially benefit from HDC is one that consists of patients with oligometastatic disease. These patients are characterized by small tumor burden and by amenability to local therapies capable of controlling the detectable tumor sites. Low metastatic tumor burden has been retrospectively identified as a favorable prognostic factor for outcome, independent of chemosensitivity, after both conventional-dose chemotherapy^2,12 and HDC.^3,13-15

In patients with oligometastases, the nondetectable micrometastatic systemic component of the disease seems ultimately responsible for its progression in most patients, which suggests a role for systemic therapies. We prospectively evaluated the use of HDC combined with local therapy in stage IV oligometastatic breast cancer. Local treatments that target tumors involving a specific organ, instead of the whole body, included the following: surgical excision of all visible disease, resulting in no evidence of disease (NED); single-field radiotherapy (RT) at curative doses; and in vitro stem-cell purging by use of CD34 selection, which seems capable of eradicating low-burden tumor contamination of stem-cell products in patients with minimal bone marrow (BM) involvement. The CD34 antigen is expressed on early hematopoietic progenitors, but not on breast cancer cells.¹⁶ CD34-positive cells, isolated by a biotin-avidin immunoadsorption device, are capable of reconstituting hematopoiesis and immune function in patients with breast cancer receiving HDC.^17,18 This procedure achieves a median 2-log (range, 1 to > 4 log) tumor-cell depletion in the stem-cell product.¹⁷ Therefore, patients with limited BM involvement can potentially be reinfused a tumor-free CD34-selected stem-cell product after myeloablation.

Thus, in this study, we considered CD34 selection a local treatment for limited BM metastases. Because involvement of the BM by breast cancer is patchy and focal by nature, sampling is a major factor determining its detection by histology. In view of this important caveat, we selected 5% as the maximum degree of BM involvement in bilateral biopsies for the purpose of this trial. We present here an update of patients enrolled onto this study after a median follow-up of 5 years and an analysis of potential prognostic factors.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
Details of inclusion criteria were based on organ function, pretransplantation evaluation, supportive care measures, and HDC with cyclophosphamide, cisplatin, and carmustine, were detailed in our preliminary analysis.¹⁹ The CD34-selection process has been described before.¹⁷ Enrolled patients had histologically proven MBC and met one or more of the following criteria: metastatic lesion that could either be surgically excised en bloc before HDC; metastatic disease that could be encompassed within a single RT field with curative intent, either before or after transplantation; and limited BM involvement, arbitrarily defined as less than 5% tumor by microscopic examination of bilateral biopsies, with either no other known metastases or metastases meeting the first two criteria. Specific exclusion criteria were liver or brain metastases, relapse within a prior RT field, and prior chemotherapy for metastatic disease. The study protocol and the informed consent form were approved by the University of Colorado Cancer Center Protocol Review Committee and the institutional review board. Written informed consent was obtained from all patients.

Any localized nodal region involved with tumor and meeting the criteria for surgery or RT described above was considered a single site of disease, regardless of the actual number of individual nodes involved within that nodal site.

Potential Prognostic Variables
A potential association with RFS and OS was studied for the following variables: HER-2 overexpression, age, initial tumor size, primary axillary nodal status (assessed as either the nodal ratio or the absolute number of involved nodes), tumor grade, presence of hormone receptors, prior adjuvant therapy, prior exposure to doxorubicin, length of prior disease-free interval (DFI), number of tumor sites, locoregional versus distant relapse, amenability of metastatic lesions to surgical resection before HDC, delivery or omission of RT, BM involvement, and pharmacokinetics of high-dose cyclophosphamide, cisplatin, and carmustine.

Axillary nodal ratio was defined as the number of involved nodes divided by the number of dissected nodes at the time of initial breast surgery, as we previously described.²⁰ Histologic grade was determined by means of the system of Elston and Ellis.²¹ The combined hormone receptor status was considered negative if both estrogen receptors (ER) and progesterone receptors (PR) were negative, and positive if either one or both were positive. Delivery or omission of RT was only evaluated in patients who presented lesions amenable to irradiation, thus excluding patients with only BM disease.

HER-2 Immunohistochemical Analysis
Paraffin-embedded tumor blocks were obtained from the pathology departments of the referring hospitals. Histologic sections were processed routinely, sectioned at a thickness of 4 µm, and stained with hematoxylin and eosin. Immunostaining was performed on diagnostic sections with the mouse monoclonal antibody CB 11 (Ventana Medical Systems, Tucson, AZ), which has been indicated to present 100% specificity.²²

Freshly cut sections were mounted on positively charged slides (Fisher Scientific, Pittsburgh, PA) and dried overnight at 60°C; paraffin was removed with xylene, and the sections were rehydrated through decreasing concentrations of ethanol to distilled water. Epitope retrieval was accomplished by simmering at 100% power in a 800-W microwave oven with 20 nmol/L citrate buffer for p53, or BioGenex buffer 10x for HER-2 at pH 6.0 for 30 minutes after coming to a full boil (7.5 minutes). Slides were cooled at room temperature for 30 minutes in the citrate buffer before proceeding. Slides were then microwaved in 0.01 M citrate buffer, pH 6.0, by use of a standard technique. Immunohistochemical staining was performed by an indirect biotin-avidin method on a Ventana 320ES automated immunostainer. The stained sections were lightly counterstained with hematoxylin. Negative control reactions were performed by omitting the primary antibody and included in each run. Two positive controls were included in each staining run. One was provided by Dako Corp (Carpinteria, CA) containing three pelleted formalin-fixed, paraffin-embedded human breast cancer lines with staining intensity of 0, 1+, 2+, and 3+, as explained below. The other positive control was breast cancer tissue from a known HER-2 positive-staining fresh surgical specimen that was fixed, processed, and embedded in the same way as the study samples.

A semiquantitated scoring system was used according to the estimated fraction of positively stained cells. These scoring criteria were as follows: 0% stained cells = 0; 1% to 33% = 1+; 34% to 66% = 2+; and 67% to 100% = 3+. Because of the high specificity of CB-11 monoclonal antibody,²² tumors with 2+ staining, as well as those 3+, were considered to overexpress HER-2. All immunostained slides were reviewed by an experienced pathologist (S.N.) who remained blinded to patient outcome.

Pharmacokinetic Studies
Samples from patients underwent pharmacokinetic analysis of the three drugs included in the HDC regimen. Blood sampling, assay methodology, and analysis were performed as previously described.²³

Statistical Methods
Correlations between categorical variables were assessed by the ² test, or if this test was not appropriate, Fisher’s exact test. RFS was defined as the time from study entry to a documented relapse or death without relapse. OS was defined as the time from study entry to death from any cause. Both survival times were analyzed by the Kaplan-Meier method.²⁴ The log-rank test was used to study the correlation of the potential prognostic variables with survival times.²⁵ The median values for the continuous variables were chosen as their cutoffs. The nonparametric Wilcoxon two-sample test was used to evaluate pharmacodynamic associations of cyclophosphamide, cisplatin, and carmustine with clinical end points. The engraftment times in patients who received CD34-selected grafts or unmanipulated grafts were compared by Student’s t test.

A multivariable stepwise proportional hazard analysis for RFS was performed by using the patient- or tumor-related variables with significance at the P < .05 level in the univariate analyses.²⁶ The significance of the overall model was evaluated with the likelihood ratio test. Individual coefficients were tested by the Wald test. The proportionality assumption for all variables was assessed with Kaplan-Meier curves.

All P values are two-tailed. Statistical calculations were performed by the Statistica software package (StatSoft Inc, Tulsa, OK).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Enrollment
Sixty consecutive eligible patients with oligometastatic disease were prospectively enrolled and treated onto this study from 1991 to 1998. Patient demographics are listed in Table 1. These patients were classified in the following subgroups: (1) isolated locoregional recurrence (n = 18), and recurrence involving the chest wall (CW) (n = 7), axillary nodes (n = 5), CW plus axillary nodes (n = 1), or supraclavicular nodes (n = 5); (2) limited distant recurrence (n = 17); (3) combined locoregional and limited distant recurrence (n = 8); (4) limited distant disease at presentation (n = 13); and (5) ipsilateral supraclavicular involvement at presentation (n = 4).

Treatment Administered
Local treatment is summarized in Table 2. At the time of study entry, surgery was performed in 49 of 60 patients, 32 of whom were rendered NED by excision of all of their lesions. Surgical sites included breast plus axilla (n = 9), breast plus axilla plus supraclavicular nodes (n = 5), breast plus axilla plus cervical nodes (n = 3), axillary nodes (n = 6), cervical nodes (n = 2), CW (n = 9), CW plus axillary nodes (n = 1), CW plus cervical nodes (n = 1), CW plus supraclavicular nodes (n = 1), supraclavicular nodes (n = 8), bowel (n = 1), scalp (n = 1), scalp plus axillary nodes (n = 1), and vertebra (n = 1). All patients underwent mastectomy or lumpectomy, either at the time of their primary treatment in patients with recurrent tumors, or as part of the pretransplantation surgery in patients with limited distant disease at presentation.

Source of stem cells was BM (n = 13), peripheral blood (n = 45), or both (n = 2). Ten patients with BM involvement underwent CD34-positive selection of peripheral-blood progenitor cells (n = 6), BM (n = 2), or both (n = 2). The unmanipulated (n = 50) or CD34-selected (n = 10) stem-cell grafts were cryopreserved and subsequently used to reconstitute hematopoiesis after HDC.

After stem-cell collection, all 60 patients received HDC with cyclophosphamide, cisplatin, and carmustine.¹⁹ Single-field RT was administered before (n = 4) or after transplantation (n = 42) to sites of macroscopic disease, including single bony site (n = 11), CW (n = 8), and nodal regions (n = 27). One additional patient with a single vertebral metastatic lesion, who was to receive RT after transplantation, died as a result of HDC-related complications.

Five patients with ER/PR-positive tumors not previously treated with hormonal therapy received tamoxifen for 5 years after transplantation. Bisphosphonates were not administered after HDC because patients with widespread bone disease were not eligible. Trastuzumab was not available for this trial.

HDC-Related Toxicity
Four patients died as a result of treatment-related complications before day +100. They were included in the analysis of RFS and OS in the whole trial but were not evaluated for prognostic factors because their short survival precludes any meaningful prognostic analysis of breast cancer relapse. Cause of death was multiorgan failure resulting from sepsis (n = 3) or capillary leak syndrome (n = 1). One additional patient died as a result of complications of treatment for secondary acute myelogenous leukemia (AML) 21 months after HDC. No evidence of residual breast cancer cells in any organ was found in the postmortem examination. Although data from this patient was considered an event in the overall evaluation of RFS and OS, data from this patient were censored as nonrelapsed at the time of her death for purpose of the prognostic analyses.

Thirty-three patients had grade 3 nonhematologic toxicities that required treatment and resolved: interstitial pneumonitis (n = 31), cardiomyopathy (n = 3), and optic neuritis (n = 1). The incidences of pneumonitis (52%) and cardiomyopathy (5%) in this study are within the range we previously observed after cyclophosphamide, cisplatin, and carmustine.^27,28

Engraftment
In the whole group, the median times to neutrophil and platelet engraftment were 9 days (range, 7 to 26 days) and 10 days (range, 7 to 42 days), respectively. There were no cases of engraftment failure. There were no significant differences between patients who received a CD34-selected graft and an unselected graft, with respect to engraftment of neutrophils (8 and 9 days, respectively) and platelets (11 and 10 days, respectively).

Survival and Relapse
At a median follow-up from study entry of 62 months (range, 4 to 108 months), 25 patients experienced relapse. Posttransplantation relapses were systemic in 22 patients and locoregional in three patients (two patients with previous supraclavicular and axillary recurrences, respectively, that had been excised but not irradiated, and one patient with a previous CW treated with both surgery and RT). In an intent-to-treat analysis, 31 (51.6%) of 60 patients (95% confidence interval [CI], 39% to 64%) remained alive and free of disease. Thirty-seven patients (61.6%; 95% CI, 49% to 74%) were alive. Median RFS and OS times were 52 and 80 months, respectively (Fig 1).

View larger version (15K): [in this window] [in a new window]   Fig 1. RFS and OS Kaplan-Meier curves of the entire study population.

Association Between HER-2 Overexpression and Patient and Tumor Characteristics
Tumor blocks for HER-2 evaluation were obtained on all 56 patients who survived transplantation and were assessable for prognostic analysis. Twenty-two patients (39%) presented 2+ or 3+ HER-2 immunostaining. No cases of 1+ immunostaining were detected.

The incidence of HER-2 overexpression was significantly associated with hormone receptor–negative tumors (67% and 27% in ER/PR-negative and -positive tumors, respectively) (P = .003) and directly associated with the size of the primary tumor (27%, 38%, 27%, and 100% in T1, T2, T3, and T4 tumors, respectively) (P = .01).

The incidence of HER-2 overexpression in correlation with the following variables did not reach statistical significance: nodal ratio (26% and 52% in patients with ratio < 0.3 and 0.3, respectively) (P = .1), tumor grade (37.5%, 33%, and 42% in patients with grade 1, grade 2, and grade 3 tumors, respectively) (P = .8), number of positive nodes (33% and 46% in patients with one to three and four or more positive nodes, respectively) (P = .26), and age (median, 47 years and 46 years for patients with HER-2–positive and HER-2–negative tumors, respectively) (P = .95).

Predictive Factors for RFS and OS
By univariate analyses (Table 3), RFS was found to be superior in patients with HER-2–negative tumors (P = .0003) (Fig 2), original axillary nodal ratio less than 0.3 (P = .0008) (Fig 3), primary number of positive axillary nodes fewer than four (P = .01), delivery of RT to metastatic sites (P = .01), hormone receptor–positive tumors (P = .02), a single site of disease (P = .03) (Fig 4), and primary tumor size (P = .03).

View larger version (14K): [in this window] [in a new window]   Fig 2. Freedom from relapse according to HER-2 expression status (P = .0004). These curves, as well as those in Figs 3 through 6, do not include data from the four patients who experienced early treatment-related death.

View larger version (15K): [in this window] [in a new window]   Fig 3. Freedom from relapse according to the primary axillary nodal ratio (number of positive nodes divided by the number of dissected nodes) (P = .0008). Cutoff ratio is 0.3.

View larger version (15K): [in this window] [in a new window]   Fig 4. Freedom from relapse according to the number of sites (P = .03).

None of the following variables had a significant impact on RFS or OS: age, prior adjuvant chemotherapy, prior exposure to doxorubicin, length of the prior DFI, tumor grade, locoregional versus distant disease, BM involvement, resectability of lesions, administration of pretransplantation induction chemotherapy, and pharmacokinetic parameters of HDC. Likewise, the specific organ involved did not have prognostic impact in this trial that specifically excluded patients with brain or liver disease.

We subsequently performed an analysis of the significant variables within each patient subgroup. Because of small patient numbers, limited distant recurrence (former group 2) and combined locoregional and limited distant recurrence (former group 3) were grouped together. Likewise, limited distant disease at presentation (former group 4) and ipsilateral supraclavicular involvement at presentation (former group 5), were combined. The resulting subgroups were group 1, isolated locoregional relapse (n = 13); group 2, limited distant recurrence (with or without locoregional recurrence) (n = 30); and group 3, metastases at presentation (n = 17). In group 1, nodal ratio (75% v 25% RFS rates for ratios < 0.3 and 0.3, respectively) (P = .03) seemed to be the only predictor, in contrast to the absolute number of positive nodes (80% v 33% for one to three and four or more, respectively) (P = .06), and HER-2 expression (70% v 43% for HER-2–negative and HER-2–positive patients, respectively) (P = .21). Number of sites and delivery of RT were not applicable within group 1. Within group 2, HER-2 overexpression seemed a potent predictor (80% v 0% for HER-2–negative and HER-2–positive patients, respectively) (P = .00007). The rest of the results for group 2 were as follows: number of sites (69% v 17% for one v more than one, respectively) (P = .01), nodal ratio (87% v 33% for < 0.3 and 0.3, respectively) (P = .02), RT (60% v 0% for yes v no, respectively) (P = .07), and number of involved nodes (67% v 29% for one to three and four or more, respectively) (P = .14). No significant differences emerged for any variable within group 3: nodal ratio (100% v 36%) (P = .08), absolute number of positive nodes (100% v 42%) (P = .13), HER-2 overexpression (60% v 43%) (P = .44), and number of sites (53% v 50%) (P = .87). Although these subgroup analyses provide with some information on the differential impact of each variable on each subgroup, their results are clearly limited by small patient numbers.

Multivariable analyses for RFS and OS were performed in the whole patient group. We excluded the variable "delivery or omission of RT" from the multivariable models because it does not relate to tumor or patient characteristics. The multivariable analysis for RFS included HER-2 overexpression, number of sites, and axillary nodal ratio. To avoid multicollinearity between the variables "axillary nodal ratio" and "absolute number of involved nodes," only the ratio, which seemed more potent in the univariate analyses, was included. Likewise, the variables "hormone receptor status" and "primary tumor size" were omitted because they both indicate a high correlation with HER-2 expression. The resulting model (Table 4) accounted well for the observed outcomes (P = .0002). HER-2 expression, with a hazard ratio of 4.74 (95% CI, 2.05 to 11) (P = .0003), and number of tumor sites, with a hazard ratio of 2.26 (1.01 to 5.2) (P = .04), were independent predictors of RFS (Figs 2 to 4).

View larger version (24K): [in this window] [in a new window]   Fig 5. Prognostic categories (freedom from relapse). (A) Four groups (P = .00009). Group A: HER-2–negative, 1 site. Group B (dashed line): HER-2–positive, 1 site. Group C: HER-2–negative, >1 site. Group D: HER-2–positive, >1 site. (B) Final model (P = .00003).

This model is also applicable to OS (P = .001): it discriminates between patients at good risk (83% OS rate, median OS not reached), intermediate risk (53% OS, median OS 76 months), and poor risk (30% OS, median OS 36 months) (Fig 6).

View larger version (17K): [in this window] [in a new window]   Fig 6. Overall survival of the final model based on HER-2 expression status and number of sites (P = .001). These curves exclude data from the four patients who experienced early treatment-related death.

The AUC of cisplatin was significantly higher in the patients who had a toxic death than in those who survived HDC: 1,020 and 510 µg/mL/min, respectively (P = .03). Those groups had AUCs of carmustine of 700 and 510 µg/mL/min, respectively (P = .52), and of cyclophosphamide of 71,200 and 84,000 µg/mL/min, respectively (P = .14).

There were no statistically significant differences in the AUCs of cyclophosphamide, cisplatin, or carmustine between patients who experienced and did not experience grade 3 or greater nonhematologic toxicities. Likewise, the AUC of carmustine did not differ significantly between patients who presented interstitial pneumonitis and those who did not.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Stage IV oligometastatic breast cancer is characterized by small-volume disease amenable to effective local control. It seems to constitute a different population than those patients with MBC in complete remission after chemotherapy, who are primarily defined by their chemosensitivity and not necessarily by a low tumor burden at the time of their metastatic recurrence. In virtually all patients with oligometastatic disease who are treated with local therapy alone, the inability to control micrometastatic spread ultimately causes disease progression and death. This underscores the need for evaluation of effective systemic treatments for this population.

At median follow-up of 5 years, the RFS and OS rates of oligometastatic patients enrolled onto this HDC study are 51.6% and 62.6%, respectively. Median RFS and OS times are 52 months and 80 months, respectively. These results seem superior to those reported using HDC for other metastatic populations, including patients with chemosensitive disease, after similar pretransplantation staging. Local therapy, capable of controlling sites of detectable tumor, seems a major contributor to this multimodal approach.

Abraham et al²⁹ retrospectively evaluated 20 patients with isolated supraclavicular lymph node metastases treated with induction standard chemotherapy, followed by HDC that used mitoxantrone, cyclophosphamide, and carboplatin and RT. With shorter follow-up (median, 28 months), the observed 55% RFS rate in their study was similar to that in ours.

A few prospective phase II studies have formally evaluated the use of conventional-dose chemotherapy combined with local treatments in this population (Table 6).^30-32 Most patients included in these trials had isolated soft-tissue relapses after extensive staging work-up and were subsequently rendered NED by surgery, RT, or both. The reported long-term RFS rates in those studies ranged from 34% to 55%. Brito et al³³ from the M.D. Anderson Cancer Center reported the long-term outcome of 70 patients with isolated ipsilateral supraclavicular metastatic recurrence included in three consecutive prospective trials of combined-modality therapy for locally advanced breast cancer. Treatment consisted of pre- and postoperative conventional doxorubicin-based chemotherapy, surgery, and RT to the supraclavicular lesion. At 5- and 10-year follow-up, the RFS rates were 34% and 32%, respectively, and the OS rates were 41% and 31%, respectively. Median duration of survival was 3.5 years.

Locoregional relapses after mastectomy virtually always represent a component of widespread disease, eventually causing the patient’s death.^37,38 Similar to our trial, these patients have been considered as stage IV in numerous studies for MBC, such as the aforementioned randomized phase III HDC trials and phase II studies of conventional chemotherapy in oligometastastatic disease. The value of systemic therapy for patients with isolated locoregional relapses remains unsettled. Retrospective analyses evaluating the addition of conventional chemotherapy to RT have not consistently indicated an improvement in outcome.^39-42 Borner et al⁴³ prospectively randomized 167 minimally pretreated patients with good-risk locoregional relapses (ER positivity, long DFI, or small-volume disease) with local therapy, then either tamoxifen therapy or observation. At 5 years, significant differences in RFS (59% v 36%), but not in OS, were observed in favor of the tamoxifen group.

There were four treatment-related deaths before day +100 in our study. They all occurred before 1993. Two of those patients received BM grafts, which have been associated with a higher mortality than peripheral-blood progenitor cells.^44,45 These facts may reflect the improvement in supportive care of patients receiving HDC, particularly in large-volume referral centers. One patient died as a result of secondary AML 21 months after HDC. An incidence of secondary AML–myelodysplastic syndrome of 0.58% was observed among 864 patients with breast cancer who received HDC with cyclophosphamide, cisplatin, and carmustine.⁴⁶

It is necessary to acknowledge an important caveat to the results of our multivariable analyses, which is the instability conferred by the small number of events (23 relapses and 18 deaths caused by relapse). In addition, our observation of a lack of negative effect resulting from BM involvement is clearly limited by the small number of patients with positive BM.

In our series, overexpression of HER-2, number of metastatic sites, the initial axillary status, and delivery or omission of RT to metastases were significantly associated with RFS in univariate analyses. In particular, HER-2 status had a dramatic impact on relapse and survival after transplantation (Fig 2). The resulting prognostic model, which is based on HER-2 expression and number of sites, which indicated independent value in multivariate analyses for RFS, identifies groups with 5-year-RFS probabilities of 77% (zero risk factors), 41% (either factor), and 10% (both factors) after HDC. Importantly, this simple model can prospectively identify risk groups after HDC for this selected population.

We and others have identified a major prognostic role of HER-2 expression in patients with breast cancer who receive a variety of HDC regimens, both for high-risk stage II/III^47,48 and stage IV disease.^15,49,50 Likewise, other authors have previously described a single metastatic site and incorporation of RT as favorable prognostic factors for patients with MBC treated with HDC.^3,13-15,51

It has been previously reported that in patients treated with conventional therapy, the original axillary status, expressed as the absolute number of positive nodes, remains a major prognostic factor even after subsequent metastatic recurrence, independent of the length of the DFI.^31,52,53 These observations and ours suggest that the axillary nodal status reflects the biology of breast cancer, not merely its chronology. Furthermore, we noted a superior predictive capacity in our study for the nodal ratio over the absolute number of nodes. This is consistent with our previous observation in HDC-treated stage II/III patients,²⁰ later confirmed by others.^54,55 Nodal ratio, as defined here, is a novel but important predictive factor in breast cancer. Fisher and Slack⁵⁶ and Fisher et al⁵⁷ reported that the number of involved nodes, but not the number of sampled nodes, predicted relapse in node-negative and node-positive patients included in early trials of the National Surgical Adjuvant Breast and Bowel Project, in which single-agent thiotepa or fluorouracil, oophorectomy, or no adjuvant therapy (for most patients) were evaluated. Their observations imply that the nodal ratio is a less valuable predictor of relapse risk than the absolute number of involved nodes. In contrast, more recent analyses suggest a value for the number of dissected nodes.^58,59 Studies are under way comparing the relative prognostic values of the nodal ratio and the absolute number of nodes in large series of patients receiving modern adjuvant conventional-dose chemotherapy.

Taken together, the results from prospective conventional-chemotherapy studies, summarized in Table 6, and our own HDC trial strongly suggest that a significant fraction of oligometastatic patients may achieve survival benefit from systemic treatment. If this promising conclusion is validated in prospective randomized trials, a compelling case could be made for closer follow-up of selected patients with primary breast cancer after mastectomy and adjuvant treatment than the postmastectomy breast cancer surveillance guidelines of the American Society of Clinical Oncology.⁶⁰ Early detection of recurrences may allow salvage systemic therapy to be delivered at a time when the probability of cure might exceed the outcome of patients with more widespread metastatic disease.

In conclusion, the results of our study evaluating HDC in stage IV oligometastatic patients seem encouraging. HER-2 expression is a powerful predictor of outcome in these patients. A prognostic model based on HER-2 expression and number of tumor sites can identify patients with high, intermediate, and low risk of relapse after transplantation.

APPENDIX
The appendix is available online at www.jco.org.

The following pathology departments submitted tumor block samples from patients enrolled onto this study:Aurora Regional Medical Center, Denver, CO; Boca Raton Community Hospital, Boca Raton, FL; Clinical Laboratories Cheyenne, Cheyenne, WY; Fort Collins Consultants in Pathology, Fort Collins, CO; The Hospital for Special Surgery, New York, NY; Lenox Hill Hospital, New York, NY; Lutheran Medical Center, Wheat Ridge, CO; Mayo Clinic, Rochester, MN; Memorial Sloan-Kettering Cancer Center, New York, NY; North Colorado Medical Center, Greeley CO; Porter Memorial Hospital, Denver, CO; Providence Medical Center, Portland, OR; Rose Medical Center, Denver, CO; Sinai Hospital, Detroit, MI; St Anthony’s Hospital, Denver, CO; St Joseph Hospital, Denver, CO; St Mary Corwin Hospital, Pueblo, CO; Sterling Regional Medical Center, Sterling, CO; Swedish Medical Center, Englewood, CO; The New York Hospital, New York, NY; Valley View Hospital, Glenwood Springs, CO; Winthrop University Hospital, Mineola, NY.

	ACKNOWLEDGMENTS

 
Supported by National Institutes of Health grant no. RO-1 CA61532 (R.B.J.). S.I.B. is a recipient of an NCI Midcareer Investigator Award in Patient-Oriented Research (grant no. 1K24 CA81408-01A1A).

We thank the nurses, nurse practitioners, and house staff of the Bone Marrow Transplant Unit for outstanding patient care, the referring physicians who entrusted us with their patients, and our patients. We thank Anthony Elias, MD, for his comments on the manuscript.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Harris J, Morrow M, Norton L: Malignant tumors of the breast, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott-Raven, 1997, pp 1602-1603

2. Greenberg PAC, Hortobagyi GN, Smith TL, et al: Long-term follow-up of patients with CR following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14: 2197-2205, 1996[Abstract]

3. Rizzieri DA, Vredenburgh JJ, Jones R, et al: Prognostic and predictive factors for patients with metastatic breast cancer undergoing aggressive induction therapy followed by high-dose chemotherapy with autologous stem-cell support. J Clin Oncol 17: 3064-3074, 1999[Abstract/Free Full Text]

4. Antman K, Ayash L, Elias A, et al: A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous bone marrow support in women with measurable advanced breast cancer responding to standard-dose therapy. J Clin Oncol 10: 102-110, 1992[Abstract]

5. Laport GF, Grad G, Grinblatt DL, et al: High-dose chemotherapy consolidation with autologous stem cell rescue in metastatic breast cancer: A 10-year experience. Bone Marrow Transplant 21: 127-132, 1998[CrossRef][Medline]

6. Rahman ZU, Frye DK, Buzdar AU, et al: Impact of selection process on response rate and long-term survival of potential high-dose chemotherapy candidates treated with standard-dose doxorubicin-containing chemotherapy in patients with metastatic breast cancer. J Clin Oncol 15: 3171-3177, 1997[Abstract]

7. Stadtmauer EA, O’Neill A, Goldstein LJ, et al: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med 342: 1069-1076, 2000[Abstract/Free Full Text]

8. Lotz J-P, Curé H, Janvier M, et al: High-dose chemotherapy (HD-CT) with hematopoietic stem cells transplantation (HSCT) for metastatic breast cancer (MBC): Results of the French Protocol PEGASE 04. Proc Am Soc Clin Oncol 18: 43a, 1999 (abstr 161)

9. Crump M, Gluck S, Stewart D, et al: A randomized trial of high-dose chemotherapy (HDC) with autologous peripheral blood stem cells support (ASCT) compared to standard chemotherapy in women with metastatic breast cancer: A National Cancer Institute of Canada (NCIC) Clinical Trials Group study. Proc Am Soc Clin Oncol 20: 21a, 2001 (abstr 82)

10. Peters WP, Jones RB, Vredenburgh J, et al: A large, prospective, randomized trial of high-dose combination alkylating agents (CPB) with autologous cellular support (ABMS) as consolidation for patients with metastatic breast cancer achieving CR after intensive doxorubicin-based induction therapy (AFM). Proc Am Soc Clin Oncol 15: 121a, 1996 (abstr 149)

11. Madan B, Broadwater G, Rubin P, et al: Improved survival with consolidation high-dose cyclophosphamide, cisplatin and BCNU (HD-CPB) compared with observation in women with metastatic breast cancer (MBC) and only bone metastases treated with induction Adriamycin, 5-fluorouracil and methotrexate (AFM): A phase III prospective randomized comparative trial. Proc Am Soc Clin Oncol 19: 48a, 2000 (abstr 184)

12. Swenerton KD, Legha SS, Smith T, et al: Prognostic factors in metastatic breast cancer treated with combination chemotherapy. Cancer Res 39: 1552-1562, 1979[Abstract/Free Full Text]

13. Dunphy FR, Spitzer G, Rossiter Fornoff JE, et al: Factors predicting long-term survival for metastatic breast cancer patients treated with high-dose chemotherapy and bone marrow support. Cancer 73: 2157-2167, 1994[CrossRef][Medline]

14. Ayash LJ, Wheeler C, Fairclough D, et al: Prognostic factors for prolonged progression-free survival with high-dose chemotherapy with autologous stem-cell support for advanced breast cancer. J Clin Oncol 13: 2043-2049, 1995[Abstract/Free Full Text]

15. Doroshow JH, Somlo G, Ahn C, et al: Prognostic factors predicting progression-free and overall survival in patients with responsive metastatic breast cancer treated with high-dose chemotherapy and bone marrow stem cell reinfusion. Proc Am Soc Clin Oncol 14: 319a, 1995 (abstr 942)

16. Krause DS, Fackler MJ, Civin CI, et al: CD34: Structure, biology, and clinical utility. Blood 87: 1-13, 1996[Free Full Text]

17. Shpall EJ, Jones RB, Bearman SI, et al: Transplantation of enriched CD34-positive autologous marrow into breast cancer patients following high-dose chemotherapy: Influence of CD34-positive peripheral-blood progenitors and growth factors on engraftment. J Clin Oncol 12: 28-36, 1994[Abstract]

18. Shpall EJ, LeMaistre CF, Holland K, et al: A prospective randomized trial of buffy coat versus CD34-selected autologous bone marrow support in high-risk breast cancer patients receiving high-dose chemotherapy. Blood 90: 4313-4320, 1997[Abstract/Free Full Text]

19. Nieto Y, Cagnoni PJ, Shpall EJ, et al: Phase II trial of high-dose chemotherapy with autologous stem cell transplant for stage IV breast cancer with minimal metastatic disease. Clin Cancer Res 5: 1731-1737, 1999[Abstract/Free Full Text]

20. Nieto Y, Cagnoni PJ, Shpall EJ, et al: A predictive model for relapse in high-risk primary breast cancer patients treated with high-dose chemotherapy and autologous stem-cell transplant. Clin Cancer Res 5: 3425-3431, 1999[Abstract/Free Full Text]

21. Elston CW, Ellis IO: Pathological prognostic factors in breast cancer I: The value of histological grade in breast cancer—Experience from a large study with long-term follow-up. Histopathology 19: 403-410, 1991[Medline]

22. Press MF, Hung G, Godolphin W, et al: Sensitivity of HER-2 antibodies in archival tissue samples: Potential source of error in immunohistochemical studies of oncogene expression. Cancer Res 54: 2771-2777, 1994[Abstract/Free Full Text]

23. Jones RB, Matthes S, Dufton C, et al: Pharmacokinetic/pharmacodynamic interactions of intensive cyclophosphamide, cisplatin and BCNU in patients with breast cancer. Breast Cancer Res Treat 26: S11-S17, 1993

24. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. JAMA 53: 457-481, 1958

25. Peto R, Peto J: Asymptomatically efficient rank invariant test procedures. J R Stat Soc A 135: 185-198, 1971

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

27. Jones RB, Matthes S, Shpall EJ, et al: Acute lung injury following treatment with high-dose cyclophosphamide, cisplatin and carmustine: Pharmacodynamic evaluation of carmustine. J Natl Cancer Inst 85: 640-647, 1993[Abstract/Free Full Text]

28. Nieto Y, Cagnoni PJ, Bearman SI, et al: Cardiac toxicity following high-dose cyclophosphamide, cisplatin, and BCNU (STAMP-I) for breast cancer. Biol Blood Marrow Transplant 6: 198-203, 2000[CrossRef][Medline]

29. Abraham R, Nagy T, Goss PE, et al: High dose chemotherapy and autologous blood stem cell support in women with breast carcinoma and isolated supraclavicular lymph node metastases. Cancer 88: 790-795, 2000[CrossRef][Medline]

30. Buzdar AU, Blumenschein GR, Montague ED, et al: Combined modality approach in breast cancer with isolated or multiple metastases. Am J Clin Oncol 6: 45-50, 1983[Medline]

31. Holmes FA, Buzdar AU, Kau S-W, et al: Combined-modality approach for patients with isolated recurrences of breast cancer (IV-NED): The M.D. Anderson experience. Breast Dis 7: 7-20, 1994

32. Blumenschein GR, DiStefano A, Caderao J, et al: Multimodality therapy for locally advanced and limited stage IV breast cancer: The impact of effective non–cross-resistant late-consolidation chemotherapy. Clin Cancer Res 3: 2633-2637, 1997[Abstract/Free Full Text]

33. Brito RA, Valero V, Buzdar AU, et al: Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 19: 628-633, 2001[Abstract/Free Full Text]

34. Falkson G, Gelman R, Falkson CI, et al: Factors predicting for response, time to treatment failure, and survival in women with metastatic breast cancer treated with DAVTH: A prospective Eastern Cooperative Oncology Group study. J Clin Oncol 9: 2153-2161, 1991[Abstract]

35. Buzdar AU, Legha SS, Hortobagyi GN, et al: Management of breast cancer patients failing adjuvant chemotherapy with Adriamycin-containing regimens. Cancer 47: 2798-2802, 1981[CrossRef][Medline]

36. Hortobagyi GN, Smith TL, Legha SS, et al: Multivariate analysis of prognostic factors in metastatic breast cancer. J Clin Oncol 1: 776-786, 1983[Abstract]

37. Kennedy MJ, Abeloff MD: Management of locally recurrent breast cancer. Cancer 71: 2395-2409, 1993[CrossRef][Medline]

38. Recht A, Hayes DF, Eberlein TJ, et al: Local-regional recurrence after mastectomy or breast-conserving therapy, in Harris JR, Lippman ME, Morrow M, et al (eds): Diseases of the Breast. Philadelphia, PA, Lippincott-Raven, 1996, pp 649-667

39. Janjan NA, McNeese MD, Buzdar AU, et al: Management of locoregional recurrent breast cancer. Cancer 58: 1552-1556, 1986[CrossRef][Medline]

40. Halverson KJ, Perez CA, Kuske RR, et al: Locoregional recurrence of breast cancer: A retrospective comparison of irradiation alone versus irradiation and systemic therapy. Am J Clin Oncol 15: 93-101, 1992[Medline]

41. Beck TM, Hart NE, Woodard DA, et al: Local or regionally recurrent carcinoma of the breast: Results of therapy in 121 patients. J Clin Oncol 1: 400-405, 1983[Abstract]

42. Toonkel M, Fix I, Jacobsen LH, et al: The significance of local recurrence of carcinoma of the breast. Int J Radiat Oncol Biol Phys 9: 33-39, 1983[Medline]

43. Borner M, Bacchi M, Goldhirsch A, et al: First isolated locoregional recurrence following mastectomy for breast cancer: Results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. J Clin Oncol 12: 2071-2077, 1994[Abstract/Free Full Text]

44. Kritz A, Crown J, Motzer RJ, et al: Beneficial impact of peripheral blood progenitor cells in patients with metastatic breast cancer treated with high-dose chemotherapy plus granulocyte-macrophage colony-stimulating factor. Cancer 71: 2515-2521, 1993[CrossRef][Medline]

45. Chao NJ, Schriber JR, Grimes K, et al: Granulocyte colony-stimulating factor "mobilized" peripheral blood progenitor cells accelerate granulocyte and platelet recovery after high-dose chemotherapy. Blood 81: 2031-2035, 1993[Abstract/Free Full Text]

46. Laughlin MJ, McGaughey DS, Crews JR, et al: Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant. J Clin Oncol 16: 1008-1012, 1998[Abstract]

47. Bitran JD, Samuels B, Trujillo Y, et al: HER-2/neu overexpression is associated with treatment failure in women with high-risk stage II and stage IIIA breast cancer (>10 involved lymph nodes) treated with high-dose chemotherapy and autologous hematopoietic progenitor cell support following standard-dose adjuvant chemotherapy. Clin Cancer Res 2: 1509-1513, 1996[Abstract]

48. Nieto Y, Cagnoni PJ, Nawaz S, et al: Evaluation of the predictive value of HER-2 overexpression and p53 mutations in high-risk primary breast cancer patients treated with high-dose chemotherapy and autologous stem-cell transplantation. J Clin Oncol 18: 2070-2080, 2000[Abstract/Free Full Text]

49. Bewick M, Chadderton T, Conlon M, et al: Expression of C-erbB-2/HER-2 in patients with metastatic breast cancer undergoing high-dose chemotherapy and autologous blood stem cell support. Bone Marrow Transplant 24: 377-384, 1999[CrossRef][Medline]

50. Bewick M, Conlon M, Gerard S, et al: HER-2 expression is a prognostic factor in patients with metastatic breast cancer treated with a combination of high-dose cyclophosphamide, mitoxantrone, paclitaxel and autologous blood stem cell support. Bone Marrow Transplant 27: 847-853, 2001[CrossRef][Medline]

51. Carter DL, Marks LB, Bean JM, et al: Impact of consolidation RT in patients with advanced breast cancer treated with high-dose chemotherapy and autologous bone marrow rescue. J Clin Oncol 17: 887-893, 1999[Abstract/Free Full Text]

52. Jatoi I, Hilsenbeck SG, Clark GM, et al: Significance of axillary lymph node metastasis in primary breast cancer. J Clin Oncol 17: 2334-2340, 1999[Abstract/Free Full Text]

53. Juan O, Lluch A, de Paz L, et al: Prognostic factors in patients with isolated recurrences of breast cancer (stage IV-NED). Breast Cancer Res Treat 53: 105-112, 1999[CrossRef][Medline]

54. Bolwell B, Andresen S, Pohlman BL, et al: Prognostic importance of the axillary lymph node ratio in autologous transplantation for high-risk stage II–III breast cancer. Bone Marrow Transplant 27: 843-846, 2001[CrossRef][Medline]

55. Prósper F, Sola C, Hornedo J, et al: Prognostic factors for relapse after high-dose chemotherapy (HDC) and stem cell transplant (SCT) in patients with high risk breast cancer (HRBC). Proc Am Soc Clin Oncol 19: 147a, 2000 (abstr 581)

56. Fisher B, Slack NH: Number of lymph nodes examined and the prognosis of breast carcinoma. Surg Gynecol Obstet 131: 79-88, 1970[Medline]

57. 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]

58. Recht A, Gray R, Davidson NE, et al: Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol 17: 1689-1700, 1999[Abstract/Free Full Text]

59. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative RT in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337: 949-955, 1997[Abstract/Free Full Text]

60. Smith TJ, Davidson NE, Schapira DV, et al: American Society of Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines. J Clin Oncol 17: 1080-1082, 1999[Abstract/Free Full Text]

Submitted March 16, 2001; accepted September 6, 2001.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				W. J. Gradishar, J. R. Bellon, M. A. Gadd, H. A. D'Alessandro, and K. Braaten Case 30-2008 -- A 47-Year-Old Woman with a Mass in the Breast and a Solitary Lesion in the Spine N. Engl. J. Med., September 25, 2008; 359(13): 1382 - 1391. [Full Text] [PDF]

				R. Sposto, W. B. London, and T. A. Alonzo Criteria for Optimizing Prognostic Risk Groups in Pediatric Cancer: Analysis of Data From the Children's Oncology Group J. Clin. Oncol., May 20, 2007; 25(15): 2070 - 2077. [Abstract] [Full Text] [PDF]

				D. Rades, T. Veninga, L. J.A. Stalpers, H. Basic, V. Rudat, J. H. Karstens, J. Dunst, and S. E. Schild Outcome After Radiotherapy Alone for Metastatic Spinal Cord Compression in Patients With Oligometastases J. Clin. Oncol., January 1, 2007; 25(1): 50 - 56. [Abstract] [Full Text] [PDF]

				N. Kroger, M. Frick, O. Gluz, S. Mohrmann, B. Metzner, C. Jackisch, Y. Ko, H.-W. Lindemann, C. R. Meier, H. P. Lohrmann, et al. Randomized Trial of Single Compared With Tandem High-Dose Chemotherapy Followed by Autologous Stem-Cell Transplantation in Patients With Chemotherapy-Sensitive Metastatic Breast Cancer J. Clin. Oncol., August 20, 2006; 24(24): 3919 - 3926. [Abstract] [Full Text] [PDF]

				W. A. Woodward, V. Vinh-Hung, N. T. Ueno, Y. C. Cheng, M. Royce, P. Tai, G. Vlastos, A. M. Wallace, G. N. Hortobagyi, and Y. Nieto Prognostic Value of Nodal Ratios in Node-Positive Breast Cancer J. Clin. Oncol., June 20, 2006; 24(18): 2910 - 2916. [Abstract] [Full Text] [PDF]

				M. Morrow and L. Goldstein Surgery of the Primary Tumor in Metastatic Breast Cancer: Closing the Barn Door After the Horse Has Bolted? J. Clin. Oncol., June 20, 2006; 24(18): 2694 - 2696. [Full Text] [PDF]

				S. Rodenhuis, M. Bontenbal, Q. G. C. M. van Hoesel, W. M. Smit, M. A. Nooij, E. E. Voest, E. van der Wall, P. Hupperets, H. van Tinteren, J. L. Peterse, et al. Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer Ann. Onc., April 1, 2006; 17(4): 588 - 596. [Abstract] [Full Text] [PDF]

				Y. Nieto, J. J. Vredenburgh, E. J. Shpall, S. I. Bearman, P. A. McSweeney, N. Chao, D. Rizzieri, C. Gasparetto, S. Matthes, A. E. Baron, et al. Phase II Feasibility and Pharmacokinetic Study of Concurrent Administration of Trastuzumab and High-Dose Chemotherapy in Advanced HER2+ Breast Cancer Clin. Cancer Res., November 1, 2004; 10(21): 7136 - 7143. [Abstract] [Full Text] [PDF]

				C. Bernard-Marty, F. Cardoso, and M. J. Piccart Facts and Controversies in Systemic Treatment of Metastatic Breast Cancer Oncologist, November 1, 2004; 9(6): 617 - 632. [Abstract] [Full Text] [PDF]

				V. J. Assikis, K.-A. Do, S. Wen, X. Wang, J. H. Cho-Vega, S. Brisbay, R. Lopez, C. J. Logothetis, P. Troncoso, C. N. Papandreou, et al. Clinical and Biomarker Correlates of Androgen-Independent, Locally Aggressive Prostate Cancer with Limited Metastatic Potential Clin. Cancer Res., October 15, 2004; 10(20): 6770 - 6778. [Abstract] [Full Text] [PDF]

				Y. Nieto, E. J. Shpall, I. K. McNiece, S. Nawaz, J. Beaudet, S. Rosinski, J. Pellom, V. Slat-Vasquez, P. A. McSweeney, S. I. Bearman, et al. Prognostic Analysis of Early Lymphocyte Recovery in Patients with Advanced Breast Cancer Receiving High-Dose Chemotherapy with an Autologous Hematopoietic Progenitor Cell Transplant Clin. Cancer Res., August 1, 2004; 10(15): 5076 - 5086. [Abstract] [Full Text] [PDF]

				Y. Nieto, S. Nawaz, E. J. Shpall, S. I. Bearman, J. Murphy, and R. B. Jones Long-Term Analysis and Prospective Validation of a Prognostic Model for Patients with High-Risk Primary Breast Cancer Receiving High-Dose Chemotherapy Clin. Cancer Res., April 15, 2004; 10(8): 2609 - 2617. [Abstract] [Full Text] [PDF]

				P. J. Wild, A. Reichle, R. Andreesen, G. Rockelein, W. Dietmaier, J. Ruschoff, H. Blaszyk, F. Hofstadter, and A. Hartmann Microsatellite Instability Predicts Poor Short-Term Survival in Patients with Advanced Breast Cancer after High-Dose Chemotherapy and Autologous Stem-Cell Transplantation Clin. Cancer Res., January 15, 2004; 10(2): 556 - 564. [Abstract] [Full Text] [PDF]

				S. Rodenhuis, M. Bontenbal, L. V.A.M. Beex, J. Wagstaff, D. J. Richel, M. A. Nooij, E. E. Voest, P. Hupperets, H. van Tinteren, H. L. Peterse, et al. High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for High-Risk Breast Cancer N. Engl. J. Med., July 3, 2003; 349(1): 7 - 16. [Abstract] [Full Text] [PDF]

				S. E. Singletary, G. Walsh, J.-N. Vauthey, S. Curley, R. Sawaya, K. L. Weber, F. Meric, and G. N. Hortobagyi A Role for Curative Surgery in the Treatment of Selected Patients with Metastatic Breast Cancer Oncologist, June 1, 2003; 8(3): 241 - 251. [Abstract] [Full Text] [PDF]

				L. Gianni High-dose chemotherapy for breast cancer: any use for it? Ann. Onc., May 1, 2002; 13(5): 650 - 652. [Full Text] [PDF]

				G. N. Hortobagyi Can We Cure Limited Metastatic Breast Cancer? J. Clin. Oncol., February 1, 2002; 20(3): 620 - 623. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nieto, Y. Articles by Bearman, S. I. Search for Related Content PubMed PubMed Citation Articles by Nieto, Y. Articles by Bearman, S. I. Social Bookmarking                            What's this?