High-risk Primary Breast Cancer Research Articles

Delivery of adjuvant sequential dose-dense FEC–Doc to patients with breast cancer is feasible, but dose reductions and toxicity are dependent on treatment sequence

This study prospectively investigates the impact of dose densification and altering sequence of fluorouracil, epirubicin and cyclophosphamide [FEC(100)] and docetaxel [Doc] on dose delivery and tolerability of adjuvant chemotherapy in breast cancer patients. 117 patients with high-risk primary operable breast cancer were randomized (1:1:2:2) to conventional (three cycles of 3-weekly FEC(100) then three cycles of 3-weekly Doc 100 mg/m(2) or reverse sequence) or dose-dense (dd) treatment (four 10- to 11-day cycles of FEC(75) then four 2-weekly cycles of Doc 75 mg/m(2), or the reverse). In the dd arms, pegfilgrastim was given on day 2 of each cycle, but only as secondary prophylaxis in conventional arms. The primary endpoint was the proportion of patients completing intended cycles at relative dose intensity >or=85% and this was achieved by 95% of patients in each group except for the ddDoc-->FEC group (90%). Dose intensity in the dd arms increased by 48% for FEC and 11% for docetaxel, compared with the conventional arms (both P < 0.001). Doc dose reductions were more frequent with dd treatment and when Doc was given after FEC. Grade 3-4 neutropenia was significantly more frequent with conventional treatment, while fatigue and hand-foot syndrome were numerically more common with dd treatment, particularly when Doc was given after FEC. Discussion Delivery of adjuvant sequential ddFEC and Doc is feasible with growth factor support, and chemotherapy sequence appeared to affect delivery of target doses and toxicity.

Detection of metastases in breast cancer patients

Distant metastases at primary diagnosis are a prognostic key factor in breast cancer patients and play a central role in therapeutic decisions. To detect them, chest X-ray, abdominal ultrasound, and bone scintigraphy are performed as standard of care in Germany and many centers world-wide. Although FDG PET detects metastatic disease with high accuracy, its diagnostic value in breast cancer still needs to be defined. The aim of this study was to compare the diagnostic performance of FDG PET with conventional imaging. A retrospective analysis of 119 breast cancer patients who presented for staging was performed. Whole-body FDG-PET (n = 119) was compared with chest X-ray (n = 106) and bone scintigraphy (n = 95). Each imaging modality was independently assessed and classified for metastasis (negative, equivocal and positive. The results of abdominal ultrasound (n = 100) were classified as negative and positive according to written reports. Imaging results were compared with clinical follow-up including follow-up imaging procedures and histopathology. FDG-PET detected distant metastases with a sensitivity of 87.3% and a specificity of 83.3%. In contrast, the sensitivity and specificity of combined conventional imaging procedures was 43.1% and 98.5%, respectively. Regarding so-called equivocal and positive results as positive, the sensitivity and specificity of FDG-PET was 93.1% and 76.6%, respectively, compared to 61.2% and 86.6% for conventional imaging. Regarding different locations of metastases the sensitivity of FDG PET was superior in the detection of pulmonary metastases and lymph node metastases of the mediastinum in comparison to chest x-ray, whereas the sensitivity of FDG PET in the detection of bone and liver metastases was comparable with bone scintigraphy and ultrasound of the abdomen. FDG-PET is more sensitive than conventional imaging procedures for detection of distant breast cancer metastases and should be considered for additional staging especially in patients with high risk primary breast cancer.

The potential risk of neoadjuvant chemotherapy in breast cancer patients—results from a prospective randomized trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-07)

To evaluate the impact that pre- and postoperatively administered chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF) and postoperative chemotherapy vs. postoperative chemotherapy alone have on long-term prognosis. The ABCSG conducted a nationwide randomized phase III trial in high-risk endocrine non-responsive breast cancer patients comparing pre- and postoperative chemotherapy containing CMF as preoperative treatment vs. postoperative chemotherapy alone between 1991 and 1999. From 1996 the ABCSG-07 protocol was amended to also allow randomization of high-risk endocrine-responsive patients. Of 423 eligible patients with high-risk primary breast cancer, 203 patients were randomly assigned to preoperatively receive three cycles of CMF (cyclophosphamide, methotrexate, fluorouracil; 600/40/600 mg/m(2)) intravenously on day 1 and 8, while 195 patients received postoperative chemotherapy alone. In both groups, three cycles of CMF were given initially, and another three cycles of CMF were administered in node-negative patients, whereas node-positive patients received three cycles of EC (epirubicin, cyclophosphamide; 70/600 mg/m(2)). Overall response rate to preoperative chemotherapy with three cycles of CMF was 56.2%; complete pathological response was achieved in 12 patients (5.9%). Recurrence-free survival was significantly better in patients receiving chemotherapy postoperatively (HR 0.7, 0.515-0.955; P = 0.024). No survival difference was observed between the two therapy groups (HR 0.800, 0.563-1.136; P = 0.213). Preoperative chemotherapy with CMF has to be considered as insufficient in high-risk breast cancer patients. Delayed surgery and anthracycline-based chemotherapy result in shorter recurrence-free survival but not overall survival.

Quality of life and quality-adjusted survival (Q-TWiST) in patients receiving dose-intensive or standard dose chemotherapy for high-risk primary breast cancer

Quality of life (QL) is an important consideration when comparing adjuvant therapies for early breast cancer, especially if they differ substantially in toxicity. We evaluated QL and Q-TWiST among patients randomised to adjuvant dose-intensive epirubicin and cyclophosphamide administered with filgrastim and progenitor cell support (DI-EC) or standard-dose anthracycline-based chemotherapy (SD-CT). We estimated the duration of chemotherapy toxicity (TOX), time without disease symptoms and toxicity (TWiST), and time following relapse (REL). Patients scored QL indicators. Mean durations for the three transition times were weighted with patient reported utilities to obtain mean Q-TWiST. Patients receiving DI-EC reported worse QL during TOX, especially treatment burden (month 3: P<0.01), but a faster recovery 3 months following chemotherapy than patients receiving SD-CT, for example, less coping effort (P<0.01). Average Q-TWiST was 1.8 months longer for patients receiving DI-EC (95% CI, −2.5 to 6.1). Q-TWiST favoured DI-EC for most values of utilities attached to TOX and REL. Despite greater initial toxicity, quality-adjusted survival was similar or better with dose-intensive treatment as compared to standard treatment. Thus, QL considerations should not be prohibitive if future intensive therapies show superior efficacy.

Prognostic significance of overexpression and phosphorylation of epidermal growth factor receptor (EGFR) and the presence of truncated EGFRvIII in locoregionally advanced breast cancer.

The prognostic value of the epidermal growth factor receptor (EGFR) in breast cancer and more specifically, in patients with locoregionally advanced disease, is still undefined. We hypothesized that EGFR status plays a major prognostic role in this setting, through expression, activation, or the presence of its mutated variant EGFRvIII. We reviewed tumor samples of 225 patients treated uniformly in prospective trials of high-dose chemotherapy for four to nine positive axillary nodes, > or = 10 positive nodes, or inflammatory carcinoma, and observed for a median of 9 years (range, 3 to 13 years). We analyzed the effect on outcome of expression of EGFR, phosphorylated EGFR (phospho-EGFR), and EGFRvIII, as studied by immunohistochemistry. EGFR expression, phospho-EGFR, and mutated EGFRvIII were detected in 43%, 54%, and 4% of the patients, respectively. EGFR expression correlated with negative hormone receptor status, and was associated with significantly worse relapse-free survival (59% v 79%; P < .001) and overall survival (61% v 81%; P = .001) than no expression. There was no association of phospho-EGFR or EGFRvIII with outcome. Multivariate models confirmed the prognostic effect of EGFR independent of other known prognostic variables in this population. The prognostic value of EGFR was most prominent in the human epidermal growth factor receptor 2 (HER-2) -positive and the estrogen receptor/progesterone receptor-negative subgroups. EGFR expression, but not phospho-EGFR or EGFRvIII expression, is an independent adverse prognostic factor in patients with high-risk primary breast cancer, particularly when it is coexpressed with HER-2. Our results suggest the potential benefit of dual EGFR/HER-2 receptor targeting in this setting.

Prognostic analysis of tumour angiogenesis, determined by microvessel density and expression of vascular endothelial growth factor, in high-risk primary breast cancer patients treated with high-dose chemotherapy

In contrast to early breast cancer, the prognostic effect of tumour angiogenesis in tumours with advanced axillary spread has been less studied. We retrospectively analysed the effect of microvessel density (MVD) and vascular endothelial growth factor (VEGF) by immunohistochemistry on the outcome of 215 patients treated uniformly within prospective trials of high-dose chemotherapy for 4–9 and ⩾10 positive nodes, and followed for a median of 9 (range 3–13) years. Microvessel density was associated with epidermal growth factor receptor (EGFR) expression (P<0.001) and tumour size (P=0.001). Vascular endothelial growth factor overexpression (51% of patients) was associated with overexpression of EGFR (P=0.01) and HER2 (P<0.05), but not with MVD (P=0.3). High MVD was associated with worse relapse-free survival (74 vs 44%, P<0.001) and overall survival (76 vs 44%, P<0.001). Vascular endothelial growth factor overexpression had no effect on outcome. Multivariate analyses showed a prognostic effect of MVD independently of other known prognostic factors in this patient population. In conclusion, tumour angiogenesis, expressed as MVD, is a major independent prognostic factor in breast cancer patients with extensive axillary involvement.

Influence of sequencing of chemotherapy and radiotherapy regarding adverse effects of the cytostatic treatment: Results of the ADEBAR trial

559 Background: The ADEBAR-trial was designed as a multicenter randomised phase III study for high risk primary breast cancer (BC) pts., i.e. with more than 3 axillary lymph node metastases. Primary objective of the trial was to evaluate the benefit of a sequential anthracycline-docetaxel regimen (E90C-D: 4 cycles epirubicin [E] 90 mg/m2 plus cyclophosphamide [C] 600 mg/m2 q21 days followed by 4 cycles docetaxel [D] 100mg/m2 q21 days) compared to dose-intensive anthracycline- containing polychemotherapy (FE120C: 6 cycles E 60 mg/m2 d 1+8, 5-FU 500mg/m2 d 1+8 and C 75 mg/m2 d 1–14, q4 weeks). Patients and Methods: The study started in 2001 and was closed in 2005. By this time 200 actively participating sites had recruited a total number of 1,502 patients. One of the stratification issues was the sequencing of chemotherapy and radiotherapy. All patients were required to receive adjuvant radiotherapy. However the timing of irradiation, either in a sandwich setting after the first half of chemotherapy cycles or after completion of the entire cytostatic treatment was at the discretion of the study sites. In a toxicity-analysis in December 2006, the influence of sequencing of chemotherapy and radiotherapy was analyzed in 980 patients. Results: In 223 pts. radiotherapy was performed midtime after the first half of chemotherapy cycles, 757 pts. received radiotherapy only after completing the entire cytostatic treatment and before starting endocrine treatment, if applicable. Hospitalisation occurred in 32.7 % (73 pts.) of the sandwich group and in 27.9% (211 pts.) of the sequential group (p-value = 0.160). Interval prolongation was necessary in 37.7% (84 pts.) versus 31.6% (239 pts.) in the sequential group, (p-value = 0.089). The target dose was reduced in 15.7% (35 pts.) in the sandwich group and in 20.2% (153 pts.) of the sequential group, (p-value = 0.132). SAEs occurred in 29.6% (66 pts.) in the sandwich group versus 23.1% (175 pts.), (p-value = 0.048). Conclusion: No consistent association between treatment toxicity and the timing of chemotherapy and radiotherapy was observed. Because in this high risk patient group, the prevention of systemic relapse is most important, chemotherapy should be completed before the start of radiotherapy. No significant financial relationships to disclose.

Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-γ after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer

High-risk primary breast cancer patients treated with high-dose chemotherapy (HDC) and stem cell support (SCS) have shown prolonged disease-free survival (DFS) in many studies; however, only one trial has demonstrated an overall survival benefit (OS). We hypothesize that the period following myeloablative therapy is ideal for immunologic manipulation and studied the effects of two different methods of immunotherapy following HDC with SCS aimed at the window of immune reconstitution. Seventy-two women with high-risk stage II or III breast cancer were randomized following HDC to receive either interleukin 2 (IL-2) at 1 million units/m(2) SQ daily for 28 days or combined cyclosporine A (CsA) at 1.25 mg/kg intravenously daily from day 0 to +28 and interferon gamma (IFN-gamma) 0.025 mg/m(2) SQ every 2 days from day +7 to +28. At a median follow-up of 67 months, no significant difference was observed in DFS or OS between the two treatment groups. The IL-2 arm had a 59% DFS (95% CI (0.45, 0.78)) and a 72% OS (95% CI (0.58, 0.88)) at 5 years. The CsA/INF-gamma arm had a similar outcome with a 55% DFS (95% CI (0.40, 0.76)) and a 78% OS (95% CI (0.65, 0.94)) at 5 years. Treatment was well tolerated, without increased toxicity.

Scandinavian Breast Group (SBG)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Scandinavian Breast Group (SBG). Clinical trials include: High-dose chemotherapy + autologous stem cell transplantation compared with dose escalating chemotherapy in breast cancer with poor prognosis ≥ 8 positive lymph nodes or ≥ 5 lymph nodes combined with R-combined with either G II–III or high S-phase. A randomized study. SBG 9401Standard CEF-60 versus tailored CEF in high-risk primary breast cancer. SBG CEF-60, SBG 2000-1HABITS – Hormonal replacement therapy after breast cancer diagnosis – is it safe? BIG 03-97A phase II study continuing into a randomized phase III study comparison of safety, feasibility and efficacy of: dose dense and tailored and dose escalated epirubicin + cyclophosphamide followed by docetaxel (dEC→T) or dose dense epirubicin + cyclophosphamide followed by docetaxel (EC→T) or docetaxel + doxorubicin + cyclophosphamide (TAC) in lymph node positive breast cancer patients. SBG 2004-1 STUDY

Advances in Targeting Human Epidermal Growth Factor Receptor-2 Signaling for Cancer Therapy

Human epidermal growth factor receptor (HER)-2 is a member of the HER tyrosine kinase family, which regulates cell growth and proliferation. HER-2 is overexpressed in 20% to 30% of breast cancers and has been associated with an aggressive phenotype and a poorer prognosis, making it an appealing therapeutic target. Since 1998, the anti-HER-2 antibody trastuzumab has been used for the treatment of women with HER-2-positive metastatic breast cancer. Results from large trials have established a role for trastuzumab in the adjuvant setting for the treatment of high-risk primary breast cancer as well. Tyrosine kinase inhibitors that target HER-2 are also very promising therapies and are likely to be incorporated into clinical practice in the near future. HER-2-targeted therapies represent a major step forward in achieving our goal of delivering individualized targeted therapy for breast cancer. However, there are many unanswered questions about the optimal use of these agents. Ongoing research will better elucidate the best combination therapies to overcome resistance to HER-2-targeted agents and will help identify patients at high enough risk to warrant their toxicity.

Retrospective analysis of WSG AM01 tandem high dose chemotherapy trial in high risk primary breast cancer: A hypothesis generating study

665 Background: The WSG AM 01 trial is the first one to report superiority of HDC in terms of DFS and OS in patients with &gt;9 positive axillary lymph nodes. Retrospectively we tried to identify patient subgroups with maximum benefit from HDC. Methods: 403 patients were randomized to tandem HDC or to dose-dense conventional chemotherapy (DD). 236 tumors were available for central pathologic review (117/119). A panel of 34 markers were determined by IHC in TMA. Kaplan-Meier, Log rank and Cox proportional hazard models were used for uni- and multivariate analysis. We choose K-means clustering with K=5 and using Manhattan distance as similarity measure. Results: Pts: n=236 (HDC/DD): mean age 47.3/47.4 yrs, mean tumor sizes 3.5/3.4cm, mean positive lymph nodes 17.2/17.0, HR+ 55%/53%, G3 44%/35%. HDC was superior to DD (p=0.02). Multivariate analysis demonstrated a significant correlation for grading, tumor size, PR+. HR &gt; 2 were reported for the following markers: Her2neu+, p53+, bcl2−, Ck 5/6 and 17+, Ck8−, c-kit+, vimentin+, ETR 1/2, BCRP+. Triple negative tumors (TN) (31%) had a large benefit from HDC (HR DD vs. HD: 3.06, 95%CI:1.41–6.06). Groups identified by K-means clustering could be attributed to luminal-A-(31%), luminal-B-(27%), her2-(11%), basal like-(11%) type and a so far undefined proliferative group (20%) characterized mainly by the absence of specifying markers. Interestingly, the proportion of the above mentioned molecular subtypes within of high risk populations very similar to those reported for less selected populations. Her2, basal-like and the undefined proliferative group had significantly worse outcome when compared to luminal tumors (p&lt;0.01). Very poor prognosis if treated by conventional CT was observed in basal like (HR DD vs HD=2.66 95%CI: 0.9–7.9) und the undefined group (HR=1,72, 95%CI:0.92–3.21), where most of the TN tumors were found. Conclusions: Tandem HDC is superior to DD conventional CT for treatment of HRBC. The largest benefit from high dose chemotherapy was reported for younger patients with TN poor differentiated tumors, &gt;2cm. Negative hormone receptor status, p53+, bcl2−, MIB/p16+ and BCRP+ predicted benefit from dose intensification. Subgroups are small and may help to generate further hypothesises. No significant financial relationships to disclose.

Multicycle Dose-Intensive Chemotherapy for Women With High-Risk Primary Breast Cancer: Results of International Breast Cancer Study Group Trial 15-95

To compare adjuvant dose-intensive epirubicin and cyclophosphamide chemotherapy administered with filgrastim and progenitor cell support (DI-EC) with standard-dose anthracycline-based chemotherapy (SD-CT) for patients with early-stage breast cancer and a high risk of relapse, defined as stage II disease with 10 or more positive axillary nodes; or an estrogen receptor-negative or stage III tumor with five or more positive axillary nodes. Three hundred forty-four patients were randomized after surgery to receive seven cycles of SD-CT over 22 weeks, or three cycles of DI-EC (epirubicin 200 mg/m2 plus cyclophosphamide 4 gm/m2 with filgrastim and progenitor cell support) over 6 weeks. All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). After a median follow-up of 5.8 years (range, 3 to 8.4 years), 188 DFS events had occurred (DI-EC, 86 events; SD-CT, 102 events). The 5-year DFS was 52% for DI-EC and 43% for SD-CT, with hazard ratio of DI-EC compared with SD-CT of 0.77 (95% CI, 0.58 to 1.02; P = .07). The 5-year overall survival was 70% for DI-EC and 61% for SD-CT, with a hazard ratio of 0.79 (95% CI, 0.56 to 1.11; P = .17). There were eight cases (5%) of anthracycline-induced cardiomyopathy (two fatal) among those who received DI-EC. Women with hormone receptor-positive tumors benefited significantly from DI-EC. There was a trend in favor of DI-EC with respect to disease-free survival. A larger trial or meta-analysis will be required to reveal the true effect of dose-intensive therapy.

Prognostic and Predictive Effects of Immunohistochemical Factors in High-Risk Primary Breast Cancer Patients

To analyze prognostic and predictive effects of immunohistochemical factors within a randomized study of high-dose versus standard-dose chemotherapy in high-risk breast cancer with >10 involved lymph nodes. Histopathologic specimens in 188 of 302 patients were analyzed for Ki-67, p16, maspin, Bcl-2, Her2/neu, and p53. In a univariate analysis after adjustment for therapy, tumor size, and estrogen receptor, Her2/neu positivity (P = 0.001) was a negative and Bcl2 positivity (P = 0.003) was a positive prognostic factor for event-free survival. In a multivariate analysis, Her2/neu positivity (hazard ratio, 3.68; 95% confidence interval, 2.01-6.73; P = 0.0001) had a negative influence on event-free survival, whereas p53 positivity (hazard ratio, 0.57; 95% confidence interval, 0.34-0.95; P = 0.03) and Bcl2 positivity (hazard ratio, 0.35; 95% confidence interval, 0.19-0.64; P = 0.0006) were associated with a better event-free survival. Analyzing the predictive effect of the immunohistochemical factors, an interaction between p53 and treatment could be shown (P = 0.005). The hazard ratio for high-dose chemotherapy versus standard chemotherapy is estimated as 2.3 (95% confidence interval, 0.67-7.92) in p53-negative patients and as 0.46 (95% confidence interval, 0.2-1.07) in p53-positive patients, which indicates a superiority of high-dose chemotherapy in p53-positive patients and an inferiority in p53-negative patients. No interactive effect could be shown for the other factors. Her2/neu and Bcl-2 are prognostic but not predictive factors in patients with high-risk primary breast cancer; p53-positive patients might benefit more from high-dose chemotherapy than from standard chemotherapy, and p53-negative patients might benefit more from standard chemotherapy than from high-dose therapy.

Postoperative serum proteomic profiles may predict metastatic relapse in high-risk primary breast cancer patients receiving adjuvant chemotherapy

A total of 30-50% of early breast cancer (EBC) patients considered as high risk using standard prognostic factors develop metastatic recurrence despite standard adjuvant systemic treatment. A means to better predict clinical outcome is needed to optimize and individualize therapeutic decisions. To identify a protein signature correlating with metastatic relapse, we performed surface-enhanced laser desorption/ionization-time of flight mass spectrometry profiling of early postoperative serum from 81 high-risk EBC patients. Denatured and fractionated serum samples were incubated with IMAC30 and CM10 ProteinChip arrays. Several protein peaks were differentially expressed according to clinical outcome. By combining partial least squares and logistic regression methods, we built a multiprotein model that correctly predicted outcome in 83% of patients. The 5-year metastasis-free survival in 'good prognosis' and 'poor prognosis' patients as defined using the multiprotein index were strikingly different (83 and 22%, respectively; P<0.0001, log-rank test). In a multivariate Cox regression including conventional pathological factors and multiprotein index, the latter retained the strongest independent prognostic significance for metastatic relapse. Major components of the multiprotein index included haptoglobin, C3a complement fraction, transferrin, apolipoprotein C1 and apolipoprotein A1. Therefore, postoperative serum protein pattern may have an important prognostic value in high-risk EBC.

Prognostic analysis of intratumor microvessel density (MVD) and vascular endothelial growth factor (VEGF) in high-risk primary breast cancer (HRPBC) patients (PTS) receiving high-dose chemotherapy (HDC)

597 Background: The prognostic value of tumor angiogenesis in N- and early N+ disease is well known. Its effect in advanced HRPBC is less clear. Methods: We analyzed MVD and VEGF by immunohistochemistry of paraffin-embedded tumor blocks from 210 pts enrolled in trials for 4–9+ (N=73), >=10+ nodes (N=89), or inflammatory carcinoma (IBC) (N=48), at long-term follow-up (F-U). All pts received adriamycin-based chemotherapy, uniform HDC (cyclophosphamide/cisplatin/BCNU), radiotherapy, and tamoxifen if hormone receptor (ER/PR)+. Anti-CD31 and anti-VEGF monoclonal antibodies (Santa Cruz, CA) were used. The MVD assay involved separate counting of CD31-stained microvessels by two pathologists in a hot neovascularization spot on the peripheral tumor margins on a 400x power field. VEGF was scored semiquantitatively, with any staining considered +. Results: Median microvessel count was 7 (0–27). VEGF expression was seen in 51% pts (1+: 29 pts, 2+: 44, 3+: 36). No correlation was seen between VEGF and MVD (p=0.3). MVD correlated directly with EGFR+ (p<0.0005) and larger tumors (p=0.01). VEGF+ prevalence was higher among pts with IBC (p<0.005), EGFR+ (p=0.01), or HER2+ (p<0.05) tumors. No correlations were seen between VEGF or MVD and ER/PR or nodal status. At median F-U of 7.5 (2–12) years, relapse-free (RFS) and overall survival (OS) rates of the entire group were 66% and 70%, respectively. A prognostic cut-off count of 14 microvessels was identified. High MVD (>14) was associated with worse RFS [74% (67–80%) vs. 44% (36–51%), p<0.005] and OS [76% (69%–82%) vs. 44% (36–51%), p<0.001] than low MVD (<=14). No differences in RFS (p=0.8) or OS (p=0.4) per VEGF were observed. Multivariate analyses of MVD with other known prognostic factors (HER2, nodal status, ER/PR and tumor size) showed an independent effect on RFS and OS. Conclusions: MVD has independent prognostic value in HRPBC pts receiving HDC. VEGF lacked prognostic value in this population with advanced disease, in contrast to prior observations in earlier tumors. No significant financial relationships to disclose.

Twelve-year follow-up of a randomized trial of high-dose chemotherapy (HDC) and autologous hematopoietic stem cell support (ASCS) for high-risk primary breast carcinoma

663 Background: We previously reported on the results of a randomized trial of standard-dose chemotherapy with 5-fluorouracil, Adriamycin and cyclophosphamide (FAC) versus FAC followed by HDC and ASCS for high-risk primary breast cancer (J Natl Cancer Inst. 2000;92[3]:225–33). At a median follow-up of 6.5 years, no relapse-free (RFS) or overall survival (OS) advantage was seen between the two arms. Morbidity was increased with HDC. This report updates the survival analysis. Methods: Patients with ≥ 10 positive axillary nodes after primary surgery or ≥ 4 positive nodes at surgery following primary chemotherapy were eligible. All patients were to receive 8 cycles of FAC. Patients were stratified by stage, and randomly assigned to receive no further chemotherapy or 2 cycles of high-dose cyclophosphamide, etoposide, and cisplatin with ASCS. Primary endpoints were RFS and OS. Survival was calculated by the Kaplan-Meier method. The log-rank statistic was used to compare survival between treatment arms. Results: From 1990 to 1997, 78 patients were registered: 48 after primary surgery and 30 after primary chemotherapy. 39 patients were randomly assigned to FAC alone, and 39 to FAC followed by HDC. The median follow-up of live patients is 143 months (range 45 to 169 months). Detailed outcomes are shown in the table below. In intention-to-treat analysis, there was no significant difference in RFS (p = 0.114) or OS (p = 0.136) between the two groups by log-rank test. There have been no late toxicities since the last report. Conclusions: With 12 years of follow-up, this study continues to show no RFS or OS advantage associated with the use of HDC for high-risk primary breast carcinoma. No significant financial relationships to disclose.

Prognostic studies in patients with high-risk primary breast cancer (HRPBC) receiving high-dose chemotherapy (HDC)

After standard-dose chemotherapy (SDC), more than 50% of patients with HRPBC (defined as extensive axillary node involvement or inflammatory disease) experience relapse. Controversy has surrounded the use of HDC for HRPBC for over a decade. Current results from at least 15 randomized trials comparing diverse forms of HDC and SDC for HRPBC appear contradictory at this point [1]. In addition, some studies suggest that younger women might benefit selectively from HDC. An NCI-sponsored meta-analysis is in progress. Regardless of this unsettled issue, it is clear that a substantial percentage of HRPBC patients still relapse after HDC. Extensive prognostic studies are required to improve their outcome. Such investigations may allow us to identify adequate patient subsets and new therapeutic targets for trials of developmental therapeutics. Combinations of HDC, capable of ample cytoreduction, with novel agents that target specific tumor features responsible for post-transplant relapse may hold promise.

Long-term Analysis and Prospective Validation of a Prognostic Model for Patients With High-Risk Primary Breast Cancer Receiving High-Dose Chemotherapy

Long-term Analysis and Prospective Validation of a Prognostic Model for Patients With High-Risk Primary Breast Cancer Receiving High-Dose Chemotherapy

Prospective, Randomized Comparison of High-Dose Chemotherapy With Stem-Cell Support Versus Intermediate-Dose Chemotherapy After Surgery and Adjuvant Chemotherapy in Women With High-Risk Primary Breast Cancer: A Report of CALGB 9082, SWOG 9114, and NCIC MA-13

The prognosis for women with primary breast cancer involving multiple axillary nodes remains poor. High-dose chemotherapy with stem-cell support produced promising results in initial clinical trials conducted at single institutions. Seven hundred eighty-five women aged 22 to 66 years with stage IIA, IIB, or IIIA breast cancer involving 10 or more axillary lymph nodes were randomized after surgery and standard adjuvant chemotherapy to either high-dose cyclophosphamide, cisplatin, and carmustine (HD-CPB) with stem-cell support or intermediate-dose cyclophosphamide, cisplatin, and carmustine (ID-CPB) with G-CSF support but without stem cells. Planned treatment for all patients included locoregional radiation therapy. Hormone-receptor-positive patients were to receive 5 years of tamoxifen. Event-free survival (EFS) was the primary end point. Median follow-up was 7.3 years. Event-free survival was not significantly different between the two treatment groups (P = .24). The probability of being free of an event at 5 years with HD-CPB was 61% (95% CI, 56% to 65%), and was 58% (95% CI, 53% to 63%) for ID-CPB. Thirty-three patients died of causes attributed to HD-CPB, compared with no therapy-related deaths among women treated with ID-CPB. Overall survival for the two arms was identical at 71% at 5 years (P = .75). HD-CPB with stem-cell support was not superior to ID-CPB for event-free or overall survival among all randomized women with high-risk primary breast cancer.

High-Dose Chemotherapy of Cyclophosphamide, Thiotepa and Carboplatin (CTCb) followed by Autologous Stem-Cell Transplantation as a Consolidation for Breast Cancer Patients with 10 or more Positive Lymph Nodes: a 5-Year follow-Up Results

The benefit of consolidation high-dose chemotherapy (HDC) for high-risk primary breast cancer is controversial. We evaluated the efficacy and safety of consolidation HDC with cyclophosphamide, thiotepa and carboplatin (CTCb) followed by autologous stem-cell transplantation (ASCT) in resected breast cancer patients with 10 or more positive lymph nodes. Between December 1994 and April 2000, 22 patients were enrolled. All patients received 2 to 6 cycles of adjuvant chemotherapy after surgery for breast cancer. The HDC regimen consisted of cyclophosphamide 1,500 mg/m(2)/day, thiotepa 125 mg/m(2)/day and carboplatin 200 mg/m(2)/day intravenous for 4 consecutive days. With a median follow-up of 58 months, 11 patients recurred and died. The median disease-free survival (DFS) and median overall survival (OS) were 49 and 69 months, respectively. The 5-year DFS and OS rates were 50% and 58%, respectively. The 12 patients with 10 to 18 involved nodes had better 5-year DFS (67%) and OS (75%) than 10 patients with more than 18 involved nodes (30% and 38%, respectively). The most common grade 3 or 4 nonhematologic toxicity was diarrhea, which occurred in 5 patients (23%). No treatment-related death was observed. Consolidation HDC with CTCb followed by ASCT for resected breast cancer with more than 10 positive nodes had an acceptable toxicity but does not show promising survival.