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To investigate long-term results of patients with hormonal receptor-positive breast cancer treated with breast-conserving surgery (BCS) and consecutive endocrine therapy (ET) with or without whole breast irradiation (WBI).Within the 8 A trial of the Austrian Breast and Colorectal Cancer Study Group, a total of 869 patients received ET after BCS which was randomly followed by WBI (n = 439, group 1) or observation (n = 430, group 2). WBI was applied up to a mean total dosage of 50 Gy (+/- 10 Gy boost) in conventional fractionation.After a median follow-up of 9.89 years, 10 in-breast recurrences (IBRs) were observed in group 1 and 31 in group 2, resulting in a 10-year local recurrence-free survival (LRFS) of 97.5% and 92.4%, respectively (p = 0.004). This translated into significantly higher rates for disease-free survival (DFS): 94.5% group 1 vs 88.4% group 2, p = 0.0156. For distant metastases-free survival (DMFS) and overall survival (OS), respective 10-year rates amounted 96.7% and 86.6% for group 1 versus 96.4% and 87.6%, for group 2 (ns). WBI (hazard ratio [HR]: 0.27, p 0.01) and tumour grading (HR: 3.76, p = 0.03) were found as significant predictors for IBR in multiple cox regression analysis.After a median follow-up of 10 years, WBI resulted in a better local control and DFS compared with ET alone. The omission of WBI and tumour grading, respectively, were the only negative predictors for LRFS.

Purpose: To assess the predictive value of molecular breast cancer subtypes in premenopausal patients with hormone receptor–positive early breast cancer who received adjuvant endocrine treatment or chemotherapy. Experimental Design: Molecular breast cancer subtypes were centrally assessed on whole tumor sections by IHC in patients of the Austrian Breast and Colorectal Cancer Study Group Trial 5 who had received either 5 years of tamoxifen/3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 Results: 185 (38%), 244 (50%), and 59 (12%) of 488 tumors were classified as luminal A, luminal B/HER2-negative and luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with luminal B tumors had a significantly shorter RFS [adjusted HR for recurrence: 2.22; 95% confidence interval (CI), 1.41–3.49; P = 0.001] and OS (adjusted HR for death: 3.51; 95% CI, 1.80–6.87; P < 0.001). No interaction between molecular subtypes and treatment was observed (test for interaction: P = 0.84 for RFS; P = 0.69 for OS). Conclusions: Determination of molecular subtypes by IHC is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor–positive breast cancer but is not predictive for outcome of adjuvant treatment with tamoxifen/goserelin or CMF. See related commentary by Hunter et al., p. 5543

Background Elevated levels of intratumoral uPA and PAI-1 in ELISA-based measurements are associated with a high recurrence risk and allow to identify patients who might particularly benefit from adjuvant chemotherapy. The clinical utility of ELISA-based protein analysis is, however, greatly limited by the requirement of fresh tumor tisssue. We have therefore evaluated in a large clinical trial patient cohort with long-follow-up whether immunohistochemical detection of uPA and PAI-1 in FFPE archived tumor samples is also able to identify women with poor prognosis. Patients and Methods 547 postmenopausal women with hormone receptor–positive, early breast cancer who had received at least 5 years of endocrine therapy in the prospectively designed ABCSG-06 trial, and in whom FFPE tumor tissue was available, were included in this analysis. uPA and PAI-1 protein expression was evaluated by immunohistochemistry, and correlated with distant-disease free (DDFS) and overall survival (OS). Results Stromal co-expression of uPA and PAI-1 was detected in 166 of 276 (60%) evaluable tumor samples and was weakly associated with tumor size (p=0.012, Chi Square test) but not with age, nodal status, grading, or receptor status. Women with intratumoral uPA/PAI-1 expression were more likely to have a shorter DDFS in multivariate analysis (HR for relapse p=1.870; 95% CI 1.184-2.955; p=0.007 Cox regression analysis) and and OS (adjusted HR for death p=1.291; 95% CI 0.928-1.795; p=0.129) than women without. After a median follow-up of 10 years, women with uPA/PAI-1-positive tumors experienced a significantly shorter DDFS (p Conclusions Stromal co-expression of uPA and PAI-1 in breast cancer samples predicts poor DDFS and OS in postmenopausal women with hormone-receptor positive early-stage breast cancer who receive endocrine therapy. Citation Format: Singer CF, Filipits M, Jahn S, Abete L, Jakesz R, Greil R, Bauernhofer T, Kwasny W, Seifert M, Fitzal F, Schmitt M, Moinfar F, Gnant M. Stromal co-expression of urokinase-type plasminogen activator (uPA) and plasminogen activator Inhibitor (PAI-1) protein by IHC predicts poor disease outcome in endocrine-treated postmenopausal patients with receptor-positive early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-21.

Introduction: Invasive lobular cancer (ILC) is the second most common histological type of breast cancer, appearing to have a biology distinct from ductal cancer (IDC). In the first 5 years, the prognosis of ILC seems to be more favourable compared to IDC. The aim of this study was to investigate the differences in benefit from adjuvant Tamoxifen (Tam) and Anastrozol (Ana) for these histologic subtypes. Patients and Methods: The ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) study was a randomized phase III clinical trial (n=3.714) in hormone receptor-positive cancer addressing a sequence strategy with 3 years of Ana after 2 years of Tam in comparison with 5 years of Tam in a low- to intermediate-risk group (Grade 1/2) of postmenopausal patients not receiving adjuvant chemotherapy. Univariate and multivariate comparisons for overall (OS) and disease-free survival (DFS) between endocrine treatments were conducted per subgroup with respect to histology (ductal or lobular). Multivariate Cox analysis included endocrine treatment, histology and their interaction ± additional covariates (age, T-stage, N-stage, grade, ER, PR). For the time-to-event analyses, starting point for all patients was two years after randomization, i.e. when treatment changed from Tamoxifen to Anastrozole on the experimental arm. To avoid crossover effects for post-study treatment, the total time for this analysis is 3 years. Results: The 3-year OS hazard ratio (HR) for Anastrozol versus Tamoxifen in ILC (n=694) was 0.24 (0.08-0.70) vs. IDC (n=2.739) HR 1.08 (0.75-1.58). In multivariate analysis, HR for ILC was 0.23 (0.08-0.68) vs. 1.02 (0.70-1.49) for IDC. The test for interaction of treatment and histology was significant (p=0.01). In ILC, no other clinico-pathologic factor was significantly associated with survival differences compared to IDC, where age, T- and N-stage maintained significance. In the models for DFS, our preliminary analysis after 3-year follow-up did not show significant variations in treatment effect according to histology. Discussion: The magnitude of survival benefit from adjuvant Anastrozol vs. Tamoxifen varies by histology in this large phase III randomized trial. A significant reduction in risk of death occurs only in patients with lobular cancer compared to ductal cancer after only 3 years of follow-up. An updated analysis with additional follow-up will be available at presentation. Citation Format: Michael Knauer, Christine Gruber, Otto Dietze, Richard Greil, Herbert Stöger, Margaretha Rudas, Zsuzsanna Bago-Horvath, Brigitte Mlineritsch, Werner Kwasny, Christian Singer, Peter Dubsky, Raimund Jakesz, Florian Fitzal, Günther Steger, Rupert Bartsch, Martin Filipits, Christian Fesl, Michael Gnant. Survival advantage of anastrozol compared to tamoxifen for lobular breast cancer in the ABCSG-8 study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-06.

e12527 Background: RIB + aromatase inhibitor (AI) is approved as 1L treatment (tx) for HR+, HER2− MBC. Real-world data on efficacy and safety of RIB+AI are limited. REACHAUT, a prospective, noninterventional trial assessed the safety of RIB+AI in 1L setting in postmenopausal patients (pts) with HR+, HER2− MBC in a real-world setting. First interim analysis results about safety are presented. Methods: 75 postmenopausal pts with HR+, HER2− MBC, QTc < 450 msec, and no prior ET for advanced disease were enrolled at 13 sites. 1L chemotherapy (CT) was allowed. Results: At data cutoff (25-Jan-2019), 61 pts were evaluable for safety (ongoing, n = 44; discontinued, n = 17). Median duration of follow-up was 29 d. Median age at baseline was 65 y ( < 65 y, n = 28; ≥65 y, n = 33); ECOG performance status was 0 (n = 39) and 1 (n = 12). 42.6% had visceral (lung, liver) metastases (mets), while 34.4% had bone only mets. Most common prior tx included CT (29.5% in neoadjuvant/adjuvant/metastatic setting) and ET (41%). Pts received RIB in 1L (93.4%) and second-line (6.6%) setting. In 80.3% pts receiving RIB, the ET partner included letrozole (57.4%), exemestane (11.5%), anastrozole (9.8%). Median duration of RIB exposure was 100 d. Median time to first AE was 14 d. 83.6% pts experienced AEs with mild (63.9%) to moderate (50.8%) severity. Serious AEs were noted in 6.6% pts. Most common AEs were neutropenia (42.6%) and QTc prolongation (24.6%). 4.9% pts had hepatobiliary AEs. Due to AEs, dose adjustments (4.9%) and dose interruptions (19.8%) were needed. No deaths were reported; median PFS was not reached. Subgroup analysis by age ( < 65 y vs ≥65 y) showed that the incidence of AEs was 55.9% vs 44.1%. Neutropenia was reported in 46.4% pts aged < 65 y vs 39.3% pts aged ≥65 y; QT prolongation events were noted in 21.4% pts aged < 65 y vs 27.2% pts aged ≥65 y. Dose adjustments and dose interruptions were needed in 14.3% and 46.4% pts aged < 65 y vs 15.2% and 45.5% pts aged ≥65 y. Conclusions: Overall safety of RIB+AI in routine clinical practice in REACHAUT was consistent with that reported in the MONALEESA-2 study. In real-world setting, pt age ( < 65 y vs ≥65 y) had minimal impact on AEs. Clinical trial information: NIS006622.

Background: We investigated whether body mass index (BMI) can be used as a predictive parameter indicating patients who benefit from extended aromatase inhibitor (AI) treatment. Methods: The ABCSG-6a trial re-randomised event-free postmenopausal hormone receptor-positive patients from the ABCSG-6 trial to receive either 3 additional years of endocrine therapy using anastrozole vs nil. In this retrospective analysis, we investigated the prognostic and predictive impact of BMI on disease outcome and safety. Results: In all, 634 patients (177 normal weight, 307 overweight, and 150 obese) patients were included in this analysis. Normal weight patients with additional 3 years of anastrozole halved their risk of disease recurrence (disease-free survival (DFS) HR 0.48; P=0.02) and death (HR 0.45; P=0.06) and had only a fifth of the risk of distant metastases (HR 0.22; P=0.05) compared with normal weight patients without any further treatment. In contrast, overweight+obese patients derived no benefit from additional 3 years of anastrozole (DFS HR 0.93; P=0.68; distant recurrence-free survival HR 0.91; P=0.78; and OS HR 0.9; P=0.68). The possible predictive impact of BMI on extended endocrine treatment could be strengthened by a Cox regression interaction model between BMI and treatment (P=0.07). Conclusion: Body mass index may be used to predict outcome benefit of extended AI treatment in patients with receptor-positive breast cancer.

Background: There exists evidence that body mass index (BMI) impacts on the efficacy of aromatase inhibitors in patients with breast cancer. The relationship between BMI and the efficacy of tamoxifen is conflicting. We investigated the impact of BMI on the efficacy of single tamoxifen and tamoxifen plus an aromatase inhibitor in the well-defined prospective study population of the ABCSG-06 trial. Methods: ABCSG-06 investigated the efficacy of tamoxifen vs tamoxifen plus aminoglutethimide in postmenopausal women with hormone receptor-positive breast cancer. Taking BMI at baseline, patients were classified as normal weight (BMI=18.5–24.9 kg m−2), overweight (BMI=25–29.9 kg m−2), and obese (30 kg m−2) according to WHO criteria. Results: Overweight+obese patients had an increased risk for distant recurrences (hazard ratio (HR): 1.51; Cox P=0·018) and a worse overall survival (OS; HR: 1·49; Cox P=0·052) compared with normal weight patients. Analysing patients treated with single tamoxifen only, no difference between overweight+obese patients and normal weight patients regarding distant recurrence-free survival (HR: 1.35; Cox P=0·24) and OS (HR: 0.99; Cox P=0·97) could be observed. In contrast, in the group of patients treated with the combination of tamoxifen plus aminoglutethimide, overweight+obese patients had an increased risk for distant recurrences (1.67; Cox P=0·03) and a worse OS (1.47; Cox P=0·11) compared with normal weight patients. Conclusion: BMI impacts on the efficacy of aromatase inhibitor-based treatment but not single tamoxifen.

Purpose Anastrozole (ANA) alone delivers significant disease-free survival benefits over tamoxifen (TAM) monotherapy in postmenopausal women with early estrogen receptor–positive breast cancer. The ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) study is a large phase III clinical trial addressing the sequence strategy containing ANA in comparison with 5 years of TAM in a low- to intermediate-risk group of postmenopausal patients. Patients and Methods Endocrine receptor–positive patients with G1 or G2 tumors were eligible. After surgery, patients were randomly assigned to 5 years of TAM or 2 years of TAM followed by 3 years of ANA. Adjuvant chemotherapy and G3 and T4 tumors were exclusion criteria. Intention-to-treat and censored analyses of on-treatment recurrence-free survival (RFS) were performed, and exploratory survival end points and toxicity were investigated. Results Information from 3,714 patients, including 17,563 woman-years, with a median of 60 months of follow-up was available for this analysis. Median age was 63.8 years, 75% were node negative, and 75% had T1 tumors. Sequencing of ANA after identical 2-year treatment with TAM in both arms did not result in a statistically significant improvement of RFS (hazard ratio [HR], 0.80; 95% CI, 0.63 to 1.01; P = .06). Exploratory analyses of distant relapse-free survival indicated a 22% improvement (HR, 0.78; 95% CI, 0.60 to 1.00). On-treatment adverse events and serious adverse events were consistent with known toxicity profiles of ANA and TAM treatment. Conclusion Despite a low overall rate of recurrence in a population with breast cancer at limited risk of relapse, the a priori sequence strategy of 2 years of TAM followed by 3 years of ANA led to small outcome and toxicity benefits.

The number of removed axillary lymph nodes and the ratio of involved to removed lymph nodes are described as independent prognostic factors beside the absolute number of involved lymph nodes in breast cancer patients. The correlation between these factors and prognosis were investigated in trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG).This retrospective analysis is based on the data of 7052 patients with endocrine-responsive breast cancer who were randomized in four trials of the ABCSG in the years 1990-2006 and underwent axillary lymph node dissection. The prognostic value of number of removed nodes (NRN), number of involved nodes (NIN), and ratio of involved to removed nodes (lymph node ratio, LNR) concerning recurrence-free survival and overall survival was analyzed.A total of 2718 patients had node-positive disease. No correlation was found between NRN and prognosis. Increasing NIN and LNR were significantly associated with worse recurrence-free survival and overall survival in univariate and multivariate analyses (P.001). Only in the subgroup of patients with one to three positive lymph nodes and treated with mastectomy (n = 728) was LNR an additional prognostic factor in univariate and multivariate analyses.For breast cancer patients stringently medicated in the framework of prospective adjuvant clinical trials and requiring a mandatory minimum of removed nodes, NRN does not influence prognosis, and LNR is not superior to NIN as prognostic factor. In patients with one to three positive lymph nodes and mastectomy, LNR could play a role as an additional prognostic factor.

Purpose: To determine the effects of anemia on local relapse-free, relapse-free, and overall survival (LRFS, RFS, and OS, respectively) in premenopausal, primary breast cancer patients receiving adjuvant polychemotherapy, and to determine which conventional prognostic factors affected these outcomes. Experimental Design: Four hundred twenty-four premenopausal patients with early-stage primary breast cancer and hormone receptor–expressing tumors were treated with i.v. cyclophosphamide/methotrexate/5-fluorouracil (CMF) polychemotherapy as part of an adjuvant phase III trial (Austrian Breast and Colorectal Cancer Study Group Trial 5). The influence of anemia (hemoglobin Results: Of 424 patients, 77 (18.2%) developed anemia on CMF chemotherapy. After a median follow-up time of 5 years, 8.9% of nonanemic patients had local relapse compared with 19.6% of anemic patients (P = 0.0006). Although mastectomy was associated with anemia (26% versus 13.7% in breast conserving surgery; P = 0.002), multivariate analysis did not show mastectomy per se to be a significant risk factor for LRFS. Age, lymph node status, and hemoglobin had an independent significant influence on LRFS (P < 0.005). Anemic patients had a relative risk of 2.96 (95% confidence interval, 1.41-6.23) for developing local relapse in comparison with nonanemic patients. Conclusion: Premenopausal breast cancer patients who developed anemia during the CMF regimen had significantly worse LRFS. In Austrian Breast and Colorectal Cancer Study Group Trial 5, anemia may have contributed to an almost doubled incidence of local recurrence in the chemotherapy arm. Molecular targets associated with tumor hypoxia and distinct from erythropoiesis should receive further attention in experimental and clinical settings.

In women with favorable early breast cancer treated by lumpectomy plus tamoxifen or anastrazole, it remains unclear whether whole breast radiotherapy is beneficial.Between January 1996 and June 2004, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) randomly assigned 869 women to receive breast radiotherapy +/- boost (n = 414) or not (n = 417) after breast-conserving surgery (ABCSG Study 8A). Favorable early breast cancer was specified as tumor size3 cm, Grading 1 or 2, negative lymph nodes, positive estrogen and/or progesterone receptor status, and manageable by breast-conserving surgery. Breast radiotherapy was performed after lumpectomy with 2 tangential opposed breast fields with mean 50 Gy, plus boost in 71% of patients with mean 10 Gy, in a median of 6 weeks. The primary endpoint was local relapse-free survival; further endpoints were contralateral breast cancer, distant metastases, and disease-free and overall survival. The median follow-up was 53.8 months.The mean age was 66 years. Overall, there were 21 local relapses, with 2 relapses in the radiotherapy group (5-y rate 0.4%) vs. 19 in the no-radiotherapy group (5.1%), respectively (p = 0.0001, hazard ratio 10.2). Overall relapses occurred in 30 patients, with 7 events in the radiotherapy group (5-y rate 2.1%) vs. 23 events in the no-radiotherapy group (6.1%) (p = 0.002, hazard ratio 3.5). No significant differences were found for distant metastases and overall survival.Breast radiotherapy +/- boost in women with favorable early breast cancer after lumpectomy combined with tamoxifen/anastrazole leads to a significant reduction in local and overall relapse.

Scientifically, it has been well established that breast-conserving treatment (BCT) in patients with breast cancer does not impair overall prognosis as compared to mastectomy. Several randomized clinical trials in the past two decades have shown that survival rates in breast cancer are stage-dependent, but independent of the extent of surgical breast tissue removal, as long as the resection margins are free of tumor infiltration. The particular importance the breast shows for female psychology and social interaction and the potential for feelings of mutilation and impaired physical integrity are another argument for carefully considering the implications connected with ablative surgical procedures. As a rational and informed basis for the shift in paradigms of invasiveness, the scientific community has felt the need to evidence the concept that local procedures have no detrimental impact on survival in such patients. Proof has been elaborated repeatedly by many investigators from different areas of the world. 1–3 The extent of tissue removed in breast cancer surgery, however, can be a predictor for local failure rate. Local relapse following mastectomy depends on tumor stage, nodal stage, and the biologic aggressiveness of the tumor and usually is an indicator of poor prognosis. By contrast, local recurrence after BCT does not necessarily have an impact on survival. In any case, the psychological and subjective burden of local failure following such interventions must never be underestimated. Therefore, BCT in general calls for adjuvant radiotherapy, although it has been shown that in a highly selected group of patients at very low risk for locoregional relapse, radiotherapy may indeed not be required. 4 This issue is under investigation in a number of prospective clinical trials. By accepted academic standards, BCT combined with adjuvant radiotherapy should be regarded as the surgical treatment of choice in patients with stage I and II breast cancer, as stated by the Consensus Development Conference as early as 1990. 5 Yet in contrast to these well-established standards, for various reasons BCT has not been fully accepted in general practice. This unfortunate discrepancy is linked to specific factors with regard to both patients and physicians. BCT rates are at considerable variance between different countries, but also within highly industrialized nations. For example, differences are reported to be marked between states in the United States. 6,7 In addition to geographic factors, the treatment level of a given hospital department is a key issue for the degree to which BCT is accepted. Women treated at university or teaching hospitals had doubled chances to have their breast preserved, while women over 70 and patients from rural areas were less likely candidates for BCT. 8 The most important factor influencing a patient’s decision on the surgical procedure to be used has proven to be the treating physician’s recommendation, which is rarely questioned in routine practice. 9 Thus, surgeons play the key role in patients’ decision-making processes. Surgeons participating in clinical trials should be particularly well educated and trained at the highest level of medical knowledge. After all, one chief argument for performing clinical trials is that quality control is given considerable attention under such circumstances. This refers to primary trial endpoints as much as general medical care for patients, including quality control measurements applied to surgical techniques and the standards of histopathology. Since 1984, the Austrian Breast & Colorectal Cancer Study Group (ABCSG) has been conducting nationwide, multicenter clinical trials in patients with stage I and II breast cancer. This framework has provided the opportunity, over one and a half decades, to investigate BCT rates in women participating in these investigations throughout Austria. To minimize potential selection bias, we selected subjects with identical basic prognostic characteristics (tumor and nodal stage, receptor status, and age) for the present analysis.

There is no established second-line treatment for advanced pancreatic cancer after gemcitabine failure. In view of the urgent need for such therapy, and since preclinical and phase I clinical data suggest an encouraging, potentially synergistic activity between raltitrexed and irinotecan, the present randomised phase II study was initiated. A total of 38 patients with metastatic pancreatic adenocarcinoma, who progressed while receiving or within 6 months after discontinuation of palliative first-line chemotherapy with gemcitabine, were enrolled in this study. They were randomised to 3-weekly courses of raltitrexed 3 mg x m(-2) on day 1 (arm A) or irinotecan 200 mg x m(-2) on day 1 plus raltitrexed 3 mg x m(-2) on day 2 (arm B). The primary study end point was objective response, secondary end points included progression-free survival (PFS) and overall survival (OS), as well as clinical benefit response in symptomatic patients (n=28). In the combination arm, the IRC-confirmed objective response rate was 16% (three out of 19 patients had a partial remission; 95% CI, 3-40%), which was clearly superior to that in the comparator/control arm with raltitrexed alone, in which no response was obtained. Therefore, the trial was already stopped at the first stage of accrual. Also, the secondary study end points, median PFS (2.5 vs 4.0 months), OS (4.3 vs 6.5 months), and clinical benefit response (8 vs 29%) were superior in the combination arm. The objective and subjective benefits of raltitrexed+irinotecan were not negated by severe, clinically relevant treatment-related toxicities: gastrointestinal symptoms (42 vs 68%), partial alopecia (0 vs 42%), and cholinergic syndrome (0 vs 21%) were more commonly noted in arm B; however, grade 3 adverse events occurred in only three patients in both treatment groups. Our data indicate that combined raltitrexed+irinotecan seems to be an effective salvage regimen in patients with gemcitabine-pretreated pancreatic cancer. The superior response activity, PFS and OS (when compared to raltitrexed), as well as its tolerability and ease of administration suggest that future trials with this combination are warranted.

Purpose: To determine whether the addition of aminoglutethimide to tamoxifen is able to improve the outcome in postmenopausal patients with hormone receptor–positive, early-stage breast cancer. Patients and Methods: A total of 2,021 postmenopausal women were randomly assigned to receive either tamoxifen for 5 years alone or tamoxifen in combination with aminoglutethimide (500 mg/d) for the first 2 years of treatment. Tamoxifen was administered at 40 mg/d for the first 2 years and at 20 mg/d for 3 years. Results: All randomized and eligible patients were included in the analysis according to the intention-to-treat principle. After a median follow-up of 5.3 years, the 5-year disease-free survival in the aminoglutethimide plus tamoxifen group was 83.6% versus 83.7% in the monotherapy group (P = .89). The corresponding data for overall survival at 5 years were 91.4% and 91.2%, respectively (P = .74). More patients failed to complete combination treatment (13.7%) because of side effects as compared to tamoxifen alone (5.2%; P = .0001). Conclusion: Aminoglutethimide given for 2 years in addition to tamoxifen for 5 years does not improve the prognosis of postmenopausal patients with receptor-positive, lymph node-negative or lymph node-positive breast cancer.

PURPOSE: Effective adjuvant treatment modalities in premenopausal breast cancer patients today include chemotherapy, ovariectomy, and tamoxifen administration. The purpose of Austrian Breast and Colorectal Cancer Study Group Trial 5 was to compare the efficacy of a combination endocrine treatment with standard chemotherapy. PATIENTS AND METHODS: Assessable trial subjects (N = 1,034) presenting with hormone-responsive disease were randomized to receive either 3 years of goserelin plus 5 years of tamoxifen or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Stratification criteria included tumor stage and grade, number of involved nodes, type of surgery, and steroid hormone receptor content. Relapse-free survival (RFS) was defined as time from randomization to first relapse, local recurrence, or contralateral incidence, and overall survival (OS) as time to date of death. RESULTS: With a 60-month median follow-up, 17.2% of patients in the endocrine group and 20.8% undergoing chemotherapy developed relapses. Local recurrences emerged in 4.7% and 8.0%, respectively. RFS and local recurrence-free survival differed significantly in favor of endocrine therapy (P = .037 and P = .015), with a similar trend observed in OS (P = .195). CONCLUSION: Overall, our data suggest that the goserelin-tamoxifen combination is significantly more effective than CMF in the adjuvant treatment of premenopausal patients with stage I and II breast cancer.

PURPOSE: A multicenter phase II trial was performed to investigate the efficacy and tolerance of docetaxel, vinorelbine with or without recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer. PATIENTS AND METHODS: Between February 1998 and March 1999, 57 patients participated in this trial. Forty-two patients received this combination as first-line and 15 patients as second-line chemotherapy, including 10 patients who had failed anthracyclines. Therapy consisted of vinorelbine 30 mg/m2 on days 1 and 15 and docetaxel 30 mg/m2 on days 1, 8, and 15 every 4 weeks. Depending on the absolute neutrophil counts on the day of scheduled chemotherapeutic drug administration, a 5-day course of G-CSF 5 μg/kg/d was given. RESULTS: The overall response rate was 64.3% (95% confidence interval, 48.1% to 78.4%) in patients receiving docetaxel plus vinorelbine as first-line chemotherapy, including eight complete (19%) and 19 partial remissions (45.3%); 11 patients (26.2%) had disease stabilization, and only four (9.5%) progressed. Second-line treatment with this regimen resulted in eight (53.3%) of 15 objective responses, four had stable disease, and three had progressive disease. The median time to progression was 12 months in the first-line and 9.8 months in the second-line setting, respectively. After a median follow-up time of 18 months, 38 patients (65%) were still alive with metastatic disease. Myelosuppression was commonly observed; World Health Organization grade 3 or 4 neutropenia both occurred in 18 patients (32%) and was complicated by septicemia in four cases; grade 3 or 4 thrombocytopenia was seen in two patients (4%), and grade 3 anemia was seen in only one patient (2%). Severe (grade 3) nonhematologic toxicity, except for alopecia, was rarely observed and included nausea/vomiting in two patients (4%), and stomatitis, peripheral neuropathy, and skin toxicity each in one patient. CONCLUSION: Our data suggest that docetaxel and vinorelbine with or without G-CSF is an effective and fairly well tolerated regimen for the treatment of advanced breast cancer. It might be particularly useful in patients previously exposed to adjuvant or palliative anthracyclines and/or alkylating agents.

A phase II study was performed to investigate the efficacy and tolerance of alternating docetaxel and epirubicin/cyclophosphamide plus recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with advanced breast cancer who failed previous non-anthracycline/taxane-containing palliative chemotherapy.Between November 96 and June 98, a total of 45 patients participated in this trial. Chemotherapy consisted of docetaxel 100 mg/m2 given as a 1-h infusion on day 1, and epirubicin 100 mg/m2 plus cyclophosphamide 800 mg/m2 both administered on day 21. G-CSF 5 microg/kg/day was given subcutaneously from days 22-28 during each cycle. Treatment courses were repeated every 42 days for a total of three courses unless prior evidence of progressive disease.The overall response rate was 57.8% (95% confidence interval, 42.1-72.3%), including seven complete (15.5%) and 19 partial remissions (42.3%); nine patients (20%) had stabilization of disease and 10 (22.3%) progressed. The median time to treatment failure was 7.0 months (range 1.5-26.0), and the median overall survival time 15.0 months (range 2.0-37.0+) with 12 patients (27%) currently still alive with metastatic disease. Myelosuppression was commonly observed with WHO grade 3/4 neutropenia in 20 patients (44%) complicated by septicemia in five (11%). Severe nonhematologic toxicity included stomatitis in five patients (11%), skin and peripheral neurotoxicity each in one patient; alopecia was seen in all 45 patients with complete hair loss in 26 (58%).Our data suggest that alternating docetaxel and epirubicin/cyclo-phosphamide plus G-CSF is an effective and tolerable second-line combination regimen for the treatment of advanced breast cancer.

BACKGROUND Although the novel cytidine analog gemcitabine has shown superior antitumor activity compared with weekly bolus 5-fluorouracil in patients with advanced pancreatic carcinoma, further improvements of therapeutic results are warranted. The current Phase II study was initiated to investigate whether this might be achieved by dose intensification. METHODS Between August 1997 and September 1998, 43 consecutive patients with metastatic pancreatic adenocarcinoma were enrolled in this multicenter Phase II trial. Patients received 4 weekly courses of gemcitabine 2200 mg/m2 given as intravenous infusion during 30 minutes on Days 1 and 15 for a duration of 6 months unless there was prior evidence of progressive disease. The efficacy of treatment was assessed according to standard criteria, i.e., objective response, progression free survival, and overall survival, as well as by analysis of clinical benefit response (defined as ≥ 50% reduction in pain intensity, ≥ 50% reduction in daily analgesic consumption, and/or ≥ 20 point improvement in Karnofsky performance status that was sustained for ≥ 4 consecutive weeks). RESULTS Of 43 patients evaluable for objective response, 1 achieved complete and 8 partial remissions, for an overall response rate of 21% (95% confidence interval, 10–36%); 18 additional patients (42%) had stable and 16 (37%) progressive disease. The median time to progression was 5.3 months. Median survival was 8.8 months, and the probability of surviving beyond 12 months was 26.3%. Of 36 patients with tumor-related symptoms who were considered evaluable for clinical benefit response, 16 (44%) experienced significant palliation. The median time to achieve a clinical benefit response was 6 weeks, and its median duration was 27 weeks. Chemotherapy was well tolerated, with leukopenia/granulocytopenia representing the most common side effect. Gastrointestinal and other subjective toxicities were infrequent and generally mild. CONCLUSIONS Biweekly high dose gemcitabine seems to represent a safe, tolerable, and effective regimen for the palliative treatment of patients with advanced pancreatic carcinoma. Cancer 2000;88:2505–11. © 2000 American Cancer Society.

The aim of the study was to evaluate the effectiveness and safety of a combined treatment modality including systemic chemotherapy with 5-fluorouracil (FU), leucovorin, cisplatin and external beam radiotherapy in patients with locally advanced pancreatic cancer. Systemic chemotherapy consisted of FU 400 mg m−2and leucovorin 20 mgm−2both given as intravenous bolus injection on days 1–4, plus cisplatin 20 mgm−2administered as 90-min infusion on days 1–4. Treatment courses were repeated every 4 weeks × 6 unless prior evidence of progressive disease. Radiation therapy using megavolt irradiation of ≥ 6 MV photons with a 3- or 4-field technique was delivered during the second and third chemotherapy course, that was reduced in dose by 25%. Between October 1994 and July 1996, a total of 38 patients were entered onto this trial, all of whom were assessable for toxicity and survival. Eighteen of these (47%) had objective remissions to combined radiochemotherapy, including four CR (11%), 13 (34%) had stable disease and seven patients (18%) showed tumour progression during treatment. The median progression-free interval of the entire study population was 10 months (range 3–32), and median overall survival was 14.0 months (range 3–45+ months); 53% of all patients were alive at 12 months, and 18% of patients were alive at 24 months respectively. Severe haematological side-effects comprised neutropenia in 18%, thrombocytopenia in 8% and anaemia in 11%. The most frequent non-haematological side-effects were nausea/vomiting (WHO grade 3: 18%), and diarrhoea (grade 3: 13%). This combined radiochemotherapy regimen was tolerable and effective in patients with locally advanced pancreatic cancer. Since therapeutic results, in fact, compare favourably with other series, including surgical treatment of potentially resectable tumours, further evaluation of combined treatment modalities in the neoadjuvant setting seems warranted. © 2000 Cancer Research Campaign

A phase II trial was performed to evaluate the efficacy and tolerance of vinorelbine (VNB), mitomycin C (MMC), and recombinant human granulocyte colony-stimulating factor (G-CSF) in advanced breast cancer. Between October 1992 and July 1994, 55 patients entered this trial. Nine patients had locally advanced disease and 46 had distant metastases, including 14 who had received previous palliative chemotherapy with (n = 9) or without anthracyclines (n = 5). Therapy consisted of VNB 40-50 mg m(-2) diluted in 250 ml saline infused over 30 min every 3 weeks, and MMC 15 mg m(-2) administered by intravenous bolus injection every 6 weeks. G-CSF was given at 5 microg kg(-1) day(-1) subcutaneously from days 2 to 7 following each cytotoxic drug administration. Treatment was continued in case of response or stable disease for a total of six courses. The overall response rate was 73% for all 55 patients (95% confidence interval, 59-84%), including 12 (22%) complete response (CR) and 28 (51%) partial response (PR); 13 patients (24%) had stable disease (SD), and only two (4%) progressed. All nine patients with locally advanced disease were rated responsive (two pCR, seven PR) and underwent surgery with curative intent. Eight out of nine remain disease free after a median observation period of 18 months (range, 13.5-28 months). Among the 32 previously untreated patients with metastatic disease, nine (28%) achieved CR, 15 PR (47%), seven SD (22%) and one PD (3%). Second-line chemotherapy with this regimen resulted in 7/14 (50%) objective remissions (one CR, six PR), six had SD and one PD. The median time to progression was 12 months (range, 2-24+ months) in previously untreated patients with disseminated disease, and 6.0 months (range, 2-22 months) in those who had failed prior chemotherapy. After a median follow-up time of 20 months, 24 patients with distant metastases are still alive with disease; median survival has not been reached yet. The dose-limiting toxicity was myelosuppression: six (11%) and ten patients (18%) had World Health Organization grade 3, and eight (14%) and nine patients (16%) had grade 4 leucopenia and granulocytopenia respectively. Severe (WHO grade 3) non-haematological toxicities included nausea/vomiting in 7%, constipation in 9%, peripheral neuropathy in 5%, infectious episodes in 7%, phlebitis due to drug extravasation in 5%, alopecia in 9%, and acute reversible pulmonary toxicity in 11%. Our data suggest that vinorelbine, mitomycin C plus G-CSF has an excellent anti-tumour activity in advanced breast cancer, probably superior to most other available combination chemotherapy regimens. This combination does not seem to present significant cross-resistance with previous CMF or anthracycline regimens. Apart from reversible, acute pulmonary toxicity, a rare adverse reaction that had previously been described for VNB, as well as the combination of natural vinca alkaloids with mitomycin C, and few episodes of grade 3 neurotoxicity (all of which occurred at the initial 50 mg m(-2) VNB dose level), the tolerance of this regimen seems acceptable and justifies further evaluation in front-line and salvage therapy of advanced breast cancer.

Patients who underwent potential curative surgery for colonic adenocarcinoma were enrolled in a prospectively randomised, controlled clinical trial of combined intraperitoneal (i.p.) plus systemic intravenous (i.v.) chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV). We investigated whether this adjuvant treatment approach, specifically addressing the risk of peritoneal and hepatic recurrence, could improve disease-free and overall survival. Between May 1988 and December 1990, 121 patients with resected stage III or high-risk stage II (T4N0M0) colon cancer were randomly assigned for observation (which was considered standard care until the NIH consensus conference) or adjuvant chemotherapy with LV (200 mg/m2) plus 5-FU (350 mg/m2), both given i.v. (days 1–4) and i.p. (days 1 and 3) every 4 weeks for a total of six courses. After a median follow-up time of 4.6 years, a comparative analysis between the two groups of patients suggested both an improvement in disease-free survival (75% versus 58%; P = 0.06) and a survival advantage (78% versus 63%; P = 0.05) in favour of adjuvant chemotherapy. The sites of recurrence were also different, i.e. local regional and intrahepatic tumour recurrences were observed in only 6 58 (10%) and 5 58 (9%) adjuvant treated patients as compared to 11 60 (18%) and 10 60 (17%) observed patients. The overall benefit of adjuvant therapy appeared to be greatest in patients with stage III colon cancer. Treatment-associated toxicity was infrequent and generally mild with only 5% experiencing severe (WHO grade 3) adverse reactions. Interim results of this adjuvant trial suggest that combined i.p. plus systemic i.v. chemotherapy with 5-FU and LV represents a potentially effective adjuvant regimen in stage II/III colon cancer.

Summary Background Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months' follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival. We have now assessed long-term clinical efficacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid. Methods ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 premenopausal women with endocrine-receptor-positive early-stage (stage I–II) breast cancer receiving goserelin (3·6 mg every 28 days), comparing the efficacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defined as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing. Findings At a median follow-up of 62 months (range 0–114·4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0·68, 95% CI 0·51–0·91; p=0·009), although the difference was not significant in the tamoxifen (HR 0·67, 95% CI 0·44–1·03; p=0·067) and anastrozole arms (HR 0·68, 95% CI 0·45–1·02; p=0·061) assessed separately. Zoledronic acid did not significantly affect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0·67, 95% CI 0·41–1·07; p=0·09). There was no difference in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1·08, 95% CI 0·81–1·44; p=0·591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1·75, 95% CI 1·08–2·83; p=0·02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121). Interpretation Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no difference in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefits with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer. Funding AstraZeneca; Novartis.

The efficacy and toxicity of navelbine 30 mg/m2 administered intravenously (IV) over 30 minutes every 3 weeks, and mitomycin C 15 mg/m2 administered IV every 6 weeks was assessed in 34 patients with metastatic breast cancer refractory to first-line chemotherapy. An overall objective response rate of 35% was achieved (95% confidence interval, 20% to 53%), with an additional 47% of patients maintaining stable disease (SD). Four of 12 patients who responded had received previous anthracycline therapy. Median time to progression for responders and patients with SD was 6.3 months. The median survival of all patients was 8.8 months. Tolerance of this regimen was remarkable. WHO grade 3/4 side effects consisted of granulocytopenia in 12% and thrombocytopenia in 15%, and included only 1 patient each with grade 3 neurotoxicity and local toxicity due to extravasation. Delay of treatment was required for hematologic toxicity in 7 patients, and 5 required dose reductions. In conclusion, navelbine/mitomycin C is an active and well-tolerated regimen that may be considered for second-line treatment. If our results are confirmed by larger analyses of other patients studies, this combination might also warrant further exploration in combination with other active agents for front line chemotherapy of advanced breast cancer.

Purpose: Previously, we have shown that p27 may be a potential predictive biomarker for the selection of premenopausal women with early-stage hormone-responsive breast cancer for adjuvant endocrine therapy. The purpose of the present study was to assess the clinical relevance of p27 expression in postmenopausal hormone receptor–positive breast cancer patients who were treated with adjuvant tamoxifen therapy. Experimental Design: We determined the expression of p27 by immunohistochemistry in the surgical specimens of breast carcinoma patients who had been enrolled in Austrian Breast and Colorectal Cancer Study Group Trial 06 and received tamoxifen for 5 years. Early relapse and death within the first 5 years of follow-up were analyzed using Cox models adjusted for clinical and pathologic factors. Results: p27 expression was high (>70% p27-positive tumor cells) in 252 of 483 (52%) tumor specimens and was associated with favorable outcome of the patients. Women with high p27 expression had a significantly longer disease-free survival (adjusted hazard ratio for relapse, 0.22; 95% confidence interval, 0.11-0.42; P < 0.001) and overall survival (adjusted hazard ratio for death, 0.39; 95% confidence interval, 0.21-0.72; P = 0.002) as compared with women with low p27 expression. Conclusion: Low p27 expression independently predicts early relapse and death in postmenopausal women with early-stage, hormone receptor–positive breast cancer who received adjuvant tamoxifen for 5 years. (Clin Cancer Res 2009;15(18):5888–94)

The combination of ovarian suppression and tamoxifen is a standard adjuvant endocrine therapy in premenopausal women with endocrine-responsive breast cancer. Several reports have demonstrated that adjuvant endocrine therapy with aromatase inhibitors is superior to endocrine therapy with tamoxifen in postmenopausal women with endocrine-responsive breast cancer. The benefits of aromatase inhibitors, however, in premenopausal women are largely unknown. Previous studies showing that bisphosphonate therapy with zoledronic acid had antitumor and antimetastatic properties and prevented aromatase inhibitor-associated bone loss were the basis for the Austrian Breast and Colorectal Cancer Study Group trial 12. This randomized trial was part of the Austrian Breast and Colorectal Cancer Study Group trial 12 and investigated the possible benefits of adding zoledronic acid to adjuvant endocrine therapy with either Anastrozole or Tamoxifen in premenopausal women with endocrine-responsive early breast cancer. After primary surgery, 1803 patients were randomized to receive goserelin plus tamoxifen with (n = 449) or without (n = 451) zoledronic acid or goserelin plus anastrozole with (n = 450) or without (n = 453) zoledronic acid for 3 years. The primary end-point was disease-free survival, defined as the first occurrence of one or more of the following event(s): death from any cause, local or regional relapse, distant metastasis, contralateral breast cancer, and a second primary tumor. Secondary end points were recurrence-free survival and overall survival. At a median follow-up of 47.8 months, 137 events met the criteria for the primary end point. No significant difference in disease-free survival was found between the goserelin/anastrozole and goserelin/tamoxifen groups (92.0% vs. 92.8%, respectively); the hazard ratio (HR) for disease progression was 1.10, with a 95% confidence interval [CI] of 0.78―1.53; P = 0.59. Rates of recurrence-free survival and overall survival also did not differ among the 2 groups. The addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival at 47.8 months; 94.0% of patients receiving zoledronic acid were free of disease compared to 90.8% of those receiving adjuvant endocrine therapy alone (HR, 0.64; 95% CI, 0.46―0.91; P = 0.01). No significant reduction in the risk of death was associated by adding zoledronic acid to adjuvant endocrine treatment (HR, 0.60; 95% CI, 0.32―1.11; P = 0.11). Overall, adverse events were as expected and no increase in serious adverse events or treatment-related deaths occurred. These data show that addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in a population of premenopausal women with endocrine-responsive early breast cancer.

Purpose: The objective of our study was to determine the clinical relevance of cyclin D1 expression in hormone receptor–positive breast cancer patients who were treated with tamoxifen-based therapy. Experimental Design: We assessed expression of cyclin D1 in surgical specimens of breast carcinoma by means of immunohistochemistry. Patients had been enrolled in either Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 05 or ABCSG Trial 06 and received tamoxifen as part of their adjuvant treatment. Overall survival and relapse-free survival were analyzed with Cox models adjusted for clinical and pathologic factors. Results: Cyclin D1 was expressed in 140 of 253 (55%) tumors of ABCSG Trial 05 and in 569 of 948 (60%) tumors of ABCSG Trial 06. Expression of cyclin D1 was associated with poor outcome in both cohorts. Overall survival was significantly shorter in patients with cyclin D1–positive tumors compared with patients with cyclin D1–negative tumors [adjusted hazard ratio (HR) for death (ABCSG Trial 05), 2.47; 95% confidence interval (95% CI), 1.08-5.63; P = 0.03; adjusted HR for death (ABCSG Trial 06), 1.78; 95% CI, 1.36-2.34; P < 0.0001]. Relapse-free survival was also shorter in patients with cyclin D1–positive tumors than in patients with cyclin D1–negative tumors [adjusted HR for relapse (ABCSG Trial 05), 2.73; 95% CI, 1.50-4.96; P = 0.001; adjusted HR for relapse (ABCSG Trial 06), 1.52; 95% CI, 1.14-2.04; P = 0.005]. Conclusion: Cyclin D1 expression is an independent poor prognostic factor in women with early-stage, hormone receptor–positive breast cancer who received adjuvant tamoxifen-based therapy.

Background Clinical trial data have shown that among breast cancer patients who were disease free after 5 years of adjuvant treatment with tamoxifen, further extended treatment with the nonsteroidal aromatase inhibitor letrozole reduces breast cancer recurrence. We examined the efficacy and tolerability of extended adjuvant therapy with another aromatase inhibitor, anastrozole, for 3 years among women who had completed 5 years of adjuvant therapy. Methods Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6a is an extension of ABCSG Trial 6, in which hormone receptor – positive postmenopausal patients received 5 years of adjuvant tamoxifen, with or without the aromatase inhibitor aminoglutethimide, for the first 2 years of therapy. For ABCSG Trial 6a, patients who were disease free at the end of Trial 6 were randomly assigned to receive either 3 years of anastrozole or no further treatment. Efficacy data were analyzed with the use of a Cox proportional hazards regression model with two-sided P values and Kaplan – Meier curves, and tolerability data were estimated using logistic regression analysis with odds ratios and 95% confidence intervals (CIs). Results ABCSG Trial 6a included 856 patients. At a median follow-up of 62.3 months, women who received anastrozole (n = 387) had a statistically significantly reduced risk of recurrence (locoregional recurrence, contralateral breast cancer, or distant metastasis) compared with women who received no further treatment (n = 469; hazard ratio = 0.62; 95% CI = 0.40 to 0.96, P = .031). Anastrozole was well tolerated, and no unexpected adverse events were reported. Conclusions These data confirm the benefit of extending adjuvant tamoxifen therapy beyond 5 years with anastrozole compared with no further treatment. Further research is required to define the optimum length of extended adjuvant therapy and to investigate the possibility of tailoring this period to suit different disease types. J Natl Cancer Inst 2007;99: 1845 – 53

Purpose 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. Patients and Methods 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/m2) 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/m2). Results 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). Discussion 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.

Purpose Preoperative (neoadjuvant) chemotherapy for operable breast cancer downstages tumors initially not suitable for breast-conserving surgery. A pathologic complete response (pCR) to neoadjuvant chemotherapy may be a surrogate for longer overall survival, but this beneficial effect remains to be established. This phase III trial evaluated whether doubling the number of cycles of neoadjuvant treatment increased the pCR rate. Patients and Methods Patients with biopsy-proven breast cancer (T1-4a-c, N±, M0; stage I to III) were eligible and randomly assigned to either three or six cycles of epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1 and granulocyte colony-stimulating factor on days 3 through 10 (ED+G), every 21 days. The primary end point was the pCR rate of the breast tumor. Secondary end points were pathologic nodal status after surgery and the rate of breast-conserving surgery. Results A total of 292 patients were accrued, and 288 patients were assessable for efficacy and safety. Groups were well balanced for known prognostic factors. Six cycles of ED+G, compared with three cycles, resulted in a significantly higher pCR rate (18.6% v 7.7%, respectively; P = .0045), a higher percentage of patients with negative axillary status (56.6% v 42.8%, respectively; P = .02), and a trend towards more breast-conserving surgery (75.9% v 66.9%, respectively; P = .10). Rates of adverse events were similar, and no patients died on treatment. Conclusion Doubling the number of neoadjuvant ED+G cycles from three to six results in higher rates of pCR and negative axillary nodal status with no excess of adverse effects. Thus, six cycles of ED+G should be the standard neoadjuvant treatment for operable breast cancer if this combination is chosen.

A phase II trial was performed to investigate the efficacy and tolerance of combined gemcitabine and liposomal doxorubicin +/- recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with chemotherapeutically pretreated metastatic breast cancer. Thirty-four patients were entered in this trial. Chemotherapy consisted of gemcitabine and liposomal doxorubicin +/- G-CSF. Twenty seven patients received this regimen as 2nd line therapy, five patients as 3rd line and two patients as 4th line therapy after having failed taxane- and/or anthracycline-based chemotherapy or other drug combinations. After a median of six courses, an overall response rate of 26% (9 PR in 34 enrolled patients) was observed; 14 patients had disease stabilization (41%), and eight (24%) progressed. Three patients were not evaluable for response due to anaphylaxis after the first course and protracted thrombocytopenia. The median TTP was 7.5 months, and median overall survival was 15 months. Myelosuppression was the most frequently observed toxicity. Non-haematological side effects were generally mild to moderate. Our data suggest that gemcitabine and liposomal doxorubicin +/- G-CSF is an effective and fairly well tolerated regimen for chemotherapeutically pretreated patients with advanced breast cancer.

551 Background: Elevated intratumoral levels of uPA and PAI-1 in ELISA-based measurements are associated with a high recurrence risk and allow to select patients who might particularly benefit from...

Summary Background Tamoxifen has been the standard adjuvant treatment for postmenopausal women with hormone-responsive early breast cancer for more than 20 years. However, the third-generation aromatase inhibitor anastrozole has proven efficacy and tolerability benefits compared with tamoxifen when used as initial adjuvant therapy. We investigate whether women who have received a period of adjuvant tamoxifen would benefit from being switched to anastrozole. Methods We present a combined analysis of data from two prospective, multicentre, randomised, open-label trials with nearly identical inclusion criteria. Postmenopausal women with hormone-sensitive early breast cancer who had completed 2 years' adjuvant oral tamoxifen (20 or 30 mg daily) were randomised to receive 1 mg oral anastrozole (n=1618) or 20 or 30 mg tamoxifen (n=1606) daily for the remainder of their adjuvant therapy. The primary endpoint was event-free survival, with an event defined as local or distant metastasis, or contralateral breast cancer. Analysis was by intention to treat. Findings 3224 patients were included in analyses. At a median follow-up of 28 months, we noted a 40% decrease in the risk for an event in the anastrozole group as compared with the tamoxifen group (67 events with anastrozole vs 110 with tamoxifen, hazard ratio 0·60, 95% CI 0·44–0·81, p=0·0009). Both study treatments were well tolerated. There were significantly more fractures (p=0·015) and significantly fewer thromboses (p=0·034) in patients treated with anastrozole than in those on tamoxifen. Interpretation These data lend support to a switch from tamoxifen to anastrozole in patients who have completed 2 years' adjuvant tamoxifen.

SummaryPlatelet count has been reported to have predictive value in various cancer entities. In the case of breast cancer, evidence about involvement of platelets is still incomplete. Our objective was to assess the influence of pretreatment thrombocytosis on survival and establish its prognostic relevance for breast cancer patients.We performed a retrospective, multivariate analysis of 4,300 patients with early-stage breast cancer. All subjects participated in one of five prospective, randomized, multicenter trials conducted by the Austrian Breast and Colorectal Cancer Study Group. Thrombocytosis was defined as a platelet count exceeding 400 G/L. Median follow-up was 52 months. Univariate and multiple Cox regression models were calculated for overall survival (OS), breast cancer-related survival and disease-free survival (DFS). Pretreatment thrombocytosis was observed in 161 patients (3.7%). Estimated median OS, breast cancer-related survival and DFS for patients with versus those without thrombocytosis was 71.0 versus 99.5, 72.0 versus 100.9, and 80.4 versus 88.4 months, respectively (p = 0.0054, p = 0.0095, p = 0.0199). A multiple Cox regression model including tumor and nodal status, grading, age, hormone receptor status and pretreatment thrombocytosis identified pretreatment thrombocytosis as an independent predictive factor for OS (p = 0.0064) and breast cancer-related survival (p = 0.0162). Multivariate analysis failed to identify pretreatment thrombocytosis as an independent risk factor for DFS (p = 0.1355).In our retrospective study, elevated platelet counts at time of diagnosis were associated with poor prognosis in breast cancer. We hypothesize that platelets may contribute to the patho-physiology of hematogenous metastasis.

Background Gemcitabine is an active antitumor agent in the treatment of advanced pancreatic cancer, and has shown potential synergistic activity with the oral fluoropyrimidine capecitabine in previous phase I/II trials. Based on this background and in order to define the therapeutic potential and tolerance of this combination more precisely, the present randomized multicenter phase II trial was initiated. Patients and methods We prospectively randomized 83 patients to treatment with biweekly gemcitabine 2200 mg/m2 given as a 30 min intravenous infusion on day 1, or the same treatment plus oral capecitabine2500 mg/m2 given from days 1 to 7. In both arms, chemotherapy was administered for a duration of 6 months unless there was prior evidence of progressive disease. The efficacy of the two treatment arms was evaluated according to standard criteria, i.e. objective response, progression-free survival (PFS) and overall survival (OS), as well as by analysis of clinical benefit response. Results The overall objective response rate among the 42 patients treated with gemcitabine alone was 14% compared with 7/41 (17%) among those treated with the combination arm. Similar to response rates, there was no apparent difference between the two groups in terms of median PFS (4.0 versus 5.1 months) and median OS (8.2 versus 9.5 months) in the gemcitabine and combination arm, respectively. Of 61 patients with tumor-related symptoms, who were considered evaluable for clinical benefit response, 10/30 (33%) and 15/31 (48.4%) experienced significant palliation in the gemcitabine and combination arm, respectively. Chemotherapy was well tolerated in both arms with only four versus six patients experiencing WHO grade 3 symptoms. Apart from the occurrence of hand–foot syndrome in 10 patients, no major increase in incidence and/or degree of adverse reactions was noted in the combination arm. Conclusions Results of this trial suggest a fairly good therapeutic index for the combination of biweekly high-dose gemcitabine and capecitabine for the treatment of advanced pancreatic cancer. Despite a somewhat superior clinical benefit response rate, no advantage over single-agent gemcitabine, however, was noted in terms of objective efficacy parameters.

Hypoxia-inducible factor (HIF)-1alpha is a transcription factor that supports the adaptation of human cancer cells to hypoxia and is involved in various pathways supporting tumor growth and progression. The aim of this study was to determine the prognostic influence of HIF-1alpha expression in patients with advanced-stage breast cancer, evident by positive lymph nodes.Expression of HIF-1alpha was determined immunohistochemically in 206 patients with lymph node-positive breast cancer. Furthermore, the interrelationship of HIF-1alpha with p53 and HER-2 protein expression, estrogen receptor density, and survival was analyzed. Colocalization of p53 and HIF-1alpha proteins was analyzed by confocal laser scanning microscopy.Strong nuclear expression of HIF-1alpha by invasive cancer cells was found in 48 patients (23.3%), moderate expression was found in 74 patients (35.9%), and weak expression was found in 35 patients (17%); no expression was observed in 49 patients (23.8%). HIF-1alpha protein overexpression was associated with significantly shorter overall and disease-free survival time (P = 0.003 and P = 0.001, respectively; Cox regression analysis). No correlation of HIF-1alpha and HER-2 expression or estrogen receptor density was observed.This study shows that HIF-1alpha is an independent prognostic factor for an unfavorable prognosis in patients with lymph node-positive breast cancer. Our results indicate that patients with advanced-stage breast cancers might profit from future therapies targeting HIF-1alpha.

A multicenter Phase II trial was performed to investigate the efficacy and tolerance of combined docetaxel and gemcitabine +/- recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer.Fifty-two patients participated in this trial, 51 of whom are evaluable for response. Thirty-eight patients received this combination as first-line chemotherapy, and 14 patients received this combination as second-line chemotherapy, including 10 patients who had failed anthracyclines. Therapy consisted of 1500 mg/m2 gemcitabine and 50 mg/m2 docetaxel, both administered on days 1 and 15 every 4 weeks. Depending on the absolute neutrophil counts on the day of scheduled chemotherapeutic drug administration, a 5-day course of 5 microg/kg G-CSF was given.The overall response rate was 60.5% (95% confidence interval, 43.4-75.9%) in patients receiving docetaxel plus gemcitabine as first-line chemotherapy, including 4 complete responses (10.5%) and 19 partial remissions (50%); 9 patients (24%) had disease stabilization, and only 5 (13%) progressed. Second-line treatment with this regimen resulted in 6 of 14 (43%) objective responses, 5 had stable disease, and 3 progressive disease. The median time to progression was 8.5 months in the first-line setting and 6.6 months in the second-line setting, respectively. After a median follow-up time of 15 months, 36 patients (69%) are still alive with metastatic disease. Myelosuppression was commonly observed; WHO grade 3 or 4 neutropenia, however, occurred in only 15 (29%) patients and was complicated by septicemia in 2 cases; grade 3 anemia was seen in 1 patient (2%). Severe (grade 3) nonhematological toxicity except for alopecia was rarely observed and included nausea/vomiting in 3 (6%), stomatitis in 2 (4%), anaphylaxis in 2, and peripheral neuropathy, skin toxicity, and increase of liver enzymes each in one patient.Our data suggest that docetaxel and gemcitabine with and without G-CSF is an effective and fairly well-tolerated regimen for the treatment of advanced breast cancer. It might be particularly useful in patients exposed previously to adjuvant or palliative anthracyclines and/or alkylating agents.

Histological grading is an important parameter for the risk assessment in patients with breast cancer. However, up to now differing grading methods are used which have not been compared with respect to their prognostic significance. In the present study the prognostic significance of three different methods of histological grading (Elston, Contesso, Helpap) was determined in a sample of 292 patients. Furthermore, results obtained in needle biopsies were compared with those obtained in surgical resection specimens in 31 cases. The mitotic counts and the Contesso method were performed on two microscopes with different field areas (0.238 mm 2 and 0.345 mm 2 ). Univariate and multivariate analysis revealed that all three histological grading methods had a high prognostic value concerning overall survival (OS) and disease-free survival (DFS). Using univariate and multivariate analysis the Elston method performed best to determine OS and DFS (p

BACKGROUND Oxaliplatin and raltitrexed both are active anticancer agents in the treatment of patients with advanced colorectal carcinoma: They have different mechanisms of action and toxicity profiles and have shown at least additive effects in experimental and preliminary clinical studies. The aim of this disease oriented Phase I–II study was to determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLT), and the objective response rate of this combination in patients with advanced colorectal carcinoma. METHODS Between April 1998 and March 1999, 69 patients with measurable metastatic colorectal carcinoma who previously were unexposed to palliative chemotherapy were enrolled. In the Phase I part of the study, 27 patients were treated with 3-weekly courses of a fixed dose of raltitrexed (3 mg/m2 given as a 15-minute intravenous infusion) followed by a 2-hour infusion of oxaliplatin, which was escalated in consecutive cohorts of three to six patients from 85 mg/m2 to 100 mg/m2, 120 mg/m2, 130 mg/m2, and 140 mg/m2. After having defined the toxic dose, 42 additional patients were entered at one dose level below to define the therapeutic index of this combination more precisely. RESULTS In the Phase I part of the study, during the first three dose levels, only one patient each experienced DLT (Grade 3 increase in transaminases, diarrhea, and stomatitis); at level 4, two of the first six patients entered had Grade 3 neutropenic infection or peripheral neurotoxicity, whereas dose level 5 (oxaliplatin 140 mg/m2) constituted the toxic dose with three of three patients experiencing DLT (Grade 3 asthenia, transient amaurosis, and diarrhea with Grade 4 neutropenia). Externally reviewed objective responses were noted in 9 of these 27 patients (33%), and stable disease occurred in 12 patients (44.4%). Among the 42 patients who were treated subsequently at the MTD level (Phase II portion), 20 patients (47.6%) responded (95% confidence interval, 32–62.6%), and 21 patients (50%) had stable disease. Their median progression free survival was 9.0 months, and the median overall survival, with 42 patients (67%) currently alive, is > 14.5 months. Treatment tolerance at the MTD was acceptable, with only 9 of 42 patients (21%) experiencing Grade 3–4 neutropenia; Grade 3 nonhematologic adverse reactions included increase in serum transaminases in 6 patients, peripheral neuropathy in 3 patients, diarrhea in 3 patients, and both stomatitis and emesis in only 1 patient each. CONCLUSIONS The described objective response and toxicity data, which are in agreement with preliminary results of other Phase I–II studies, support the promising therapeutic potential of this combination in the treatment of patients with advanced colorectal carcinoma. Due to its substantial antitumor activity, tolerance (at the recommended MTD level), and convenient 3-weekly outpatient administration schedule, further evaluation of this regimen seems warranted. Cancer 2001;91:1264–71. © 2001 American Cancer Society.

Background. To determine the maximum tolerated dose of epirubicin for use in combination with 5-fluorouracil (5-FU) and low-dose leucovorin (LV), a Phase I–II trial was conducted in 37 patients with advanced gastric carcinoma. Methods. The doses of 5-FU (425 mg/m2) and LV (20 mg/m2), both given intravenously on days 1–5, were held constant while the dose of epirubicin was escalated in cohorts of patients (beginning dose, 50 mg/m2 on day 1). Cycles were repeated every 4 weeks. Results. Significant gastrointestinal symptoms and myelosuppression were observed infrequently at the initial dose level. At a dose of 60 mg/m2 of epirubicin on day 1, however, five of eight patients had significant mucosal toxic effects during the first cycle of therapy. In addition, two patients treated at this dose level had Grade 4 granulocytopenia with insufficient recovery to permit a second course by day 28, and one patient each had severe diarrhea and nausea and vomiting. Among 37 patients with assessable disease, there were 3 complete and 11 partial responses (response rate, 38%). Conclusions. LV modulation of 5-FU can be incorporated safely into combination chemotherapy with epirubicin and provides a relatively active regimen for treatment of disseminated gastric cancer.

534 Background: Anastrozole (ANA) alone delivers significant DFS benefits over tamoxifen (TAM) therapy in postmenopausal women with early ER+ breast cancer. Limited data have been published concern...

Abstract #14 Background: Historically, standard endocrine treatment for postmenopausal women with hormone-sensitive early breast cancer (EBC) was 5 years' tamoxifen. However, the inclusion of an aromatase inhibitor (AI) is now considered standard practice. There is increasing evidence that whether as initial adjuvant treatment or as a switch treatment following 2-3 years of tamoxifen therapy, Ais improve patients' outcomes compared with 5 years' tamoxifen monotherapy. To date, there is limited evidence comparing a prospective sequencing strategy of 2 years of tamoxifen followed by 3 years of an AI compared with 5 years' tamoxifen. Previously presented data from ABCSG Trial 8 (SABCS 2005), at a median follow-up of 55 months, revealed a 24% reduction in the risk of recurrence in favor of a sequencing strategy compared with 5 years' tamoxifen (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.56-1.02), although the difference was not statistically significant (p=0.07). Here we present updated data from ABCSG Trial 8. Methods: Postmenopausal women with histologically verified G1 or G2, locally radically treated invasive or minimally invasive hormone receptor-positive breast cancer were eligible for inclusion. Newly diagnosed patients were randomized to receive 5 years' tamoxifen therapy or 2 years' tamoxifen followed by anastrozole for 3 years. The primary endpoint was event-free survival, including locoregional and distant metastatic recurrences and new contralateral breast cancers. Results: This final analysis will report the data cut-off point, the number of eligible patients, and the median follow-up period of the trial, which will exceed 5 years. The incidence of first events, local recurrences, distant metastases, and contralateral breast cancers for the two treatment arms of the study will be presented. The effect of treatment on the trial endpoint will be analyzed using a Cox proportional hazards model and data will be presented as estimated HRs with two-sided 95% CIs and p-values. Conclusions: The updated analyses of ABCSG Trial 8 will provide evidence regarding 2 years' treatment with tamoxifen followed by 3 years' anastrozole in comparison to 5 years' tamoxifen for postmenopausal women with newly diagnosed hormone-sensitive EBC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 14.

527 Background: ABCSG Trial 6 demonstrated that postmenopausal women with pT1–3a, any N, M0 hormone receptor-positive early stage breast cancer (EBC) randomized to 2 years tamoxifen (TAM) in combination with aminoglutethimide (AG) 500 mg, followed by 3 years TAM (n=996), did not have an improved prognosis, when compared with patients treated with 5 years TAM (n=990). We present results from ABCSG-6a, an extended adjuvant trial of ABCSG-6, which investigates whether continuing treatment with anastrozole (‘Arimidex’) [ANA] will improve overall prognosis. Methods: Postmenopausal women who had received TAM in combination with AG (n=406), or TAM alone (n=450), were re-randomized to switch to ANA 1 mg/day or no treatment (NT) for a further 3 years. The primary endpoint was event-free survival. Local or regional relapse was confirmed histologically where possible. Differences between the treatment groups were assessed by log-rank test. Results: Tumors 2cm in diameter were found in 135, 402 and ...

696 Background: To evaluate the safety and efficacy of gemcitabine in combination with lioposomal doxorubicin in pretreated patients with ABC. Methods: Thirty-four patients (pts) with ABC were entered in this multicenter phase II trial in order to investigate the efficacy and tolerance of a combination regimen consisting of gemcitabine (800 mg/m2, days 1 + 8) and liposomal doxorubicin (24 mg/m2 day 1) ± granulocyte colony-stimulating factor (GCSF; 5mcg/kg/d x 5 s.c.), depending on ANCs on the days of scheduled drug administration. Treatment courses were repeated every 3 weeks. Thirty-one pts (91%) are presently evaluable for response and all pts for toxicity assessment. Seven pts were pre- and 27 pts post-menopausal. Their median age was 64 (37–80) years, and the median WHO performance status 1(0–2). Predominant tumor sites were visceral in 26 pts, bone in 6 pts, and soft-tissue in 2 pts, respectively. Twenty-six patients (76%) had 2 or multiple tumor sites. Twenty-seven pts received this regimen as 2nd l...

PURPOSE: To evaluate the efficacy and tolerance of combined irinotecan and oxaliplatin in patients with advanced colorectal cancer pretreated with leucovorin-modulated fluoropyrimidines. PATIENTS AND METHODS: Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin, were enrolled onto this study. Treatment consisted of oxaliplatin 85 mg/m2 on days 1 + 15 and irinotecan 80 mg/m2 on days 1 + 8 + 15 every 4 weeks. Depending on the absolute neutrophil counts (ANC) on the day of scheduled chemotherapeutic drug administration, a 5-day course of granulocyte colony-stimulating factor (G-CSF) 5 μg/kg/d was given. RESULTS: The overall response rate was 42% for all 36 assessable patients (95% confidence interval, 26% to 59%), including two complete remissions (6%). Thirteen additional patients (36%) had stable disease, and only eight (22%) progressed. The median time to treatment failure was 7.5 months (range, 1 to 13.5+ months). After a median follow-up time of 14 months, 19 patients (53%) are still alive. Hematologic toxicity was commonly observed, although according to the ANC-adapted use of G-CSF (in 31 patients during 81 of 174 courses), it was generally mild: grade 3 and 4 granulocytopenia occurred in only five and two cases, respectively. The most frequent nonhematologic adverse reactions were nausea/emesis and diarrhea, which were rated severe in 17% and 19%, respectively. CONCLUSION: Our data suggest that the combination of irinotecan and oxaliplatin with or without G-CSF has substantial antitumor activity in patients with progressive fluoropyrimidine/leucovorin-pretreated colorectal cancer. Overall toxicity was modest, with gastrointestinal symptoms constituting the dose-limiting side effects. Further evaluation of this regimen seems warranted.