TIMP-1 and responsiveness to gemcitabine in advanced breast cancer; results from a randomized phase III trial from the Danish breast cancer cooperative group.

BACKGROUND: Tissue inhibitor of metalloproteinases-1 (TIMP-1) has anti-apoptotic functions, which may protect TIMP-1 positive cancer cells from the effects of chemotherapy such as docetaxel and gemcitabine. The purpose of the present study was to evaluate TIMP-1 immunoreactivity as a prognostic and predictive marker in advanced breast cancer patients receiving docetaxel (D) or gemcitabine plus docetaxel (GD). METHODS: Patients with locally advanced or metastatic breast cancer who were assigned to D or GD by participation in a randomized phase III trial were included in the study. Assessment of TIMP-1 status was performed retrospectively on primary tumor whole-tissue sections by immunohistochemistry and tumor samples were considered positive if epithelial breast cancer cells were stained by the anti-TIMP-1 monoclonal antibody VT7. Time to progression (TTP) was the primary endpoint. Overall survival (OS) and response rate (RR) were secondary endpoints. Associations between TIMP-1 status and outcome after chemotherapy were analyzed by Kaplan-Meier estimates and Cox proportional hazards regression models. RESULTS: TIMP-1 status was available from 264 of 337 patients and 210 (80%) of the tumors were classified as cancer cell TIMP-1 positive. No significant difference for TTP between TIMP-1 positive versus TIMP-1 negative patients was observed in multivariate analysis, and RR did not differ according to TIMP-1 status. However, patients with TIMP-1 positive tumors had a significant reduction in OS events (hazard ratio = 0.71, 95% confidence interval (CI) = 0.52-0.98, P = 0.03). Additionally, a borderline significant interaction for OS was observed between TIMP-1 status and benefit from GD compared to D (Pinteraction = 0.06) such that median OS increased by nine months for TIMP-1 negative patients receiving GD. CONCLUSIONS: TIMP-1 status was an independent prognostic factor for OS but not TTP in patients with advanced breast cancer receiving either D or GD. There was no statistically significant interaction between TIMP-1 status and treatment, but a trend towards an incremental OS from the addition of gemcitabine to docetaxel in patients with TIMP-1 negative tumors suggests further investigation.

PAM50 breast cancer intrinsic subtypes and effect of gemcitabine in advanced breast cancer patients.

BACKGROUND: In vitro studies suggest basal breast cancers are more sensitive to gemcitabine relative to other intrinsic subtypes. The main objective of this study was to use specimens from a randomized clinical trial to evaluate whether the basal-like subtype identifies patients with advanced breast cancer who benefit from gemcitabine plus docetaxel (GD) compared to single agent docetaxel (D). MATERIAL AND METHODS: From patients randomly assigned to GD or D, RNA was isolated from archival formalin-fixed, paraffin-embedded primary breast tumor tissue and used for PAM50 intrinsic subtyping by NanoString nCounter. Statistical analyses were prespecified as a formal prospective-retrospective clinical trial correlative study. Using time to progression (TTP) as primary endpoint, overall survival (OS) and response rate as secondary endpoints, relationships between subtypes and outcome after chemotherapy were analyzed by the Kaplan-Meier method, and Cox proportional hazards regression models. Data analysis was performed independently by the Danish Breast Cancer Cooperative Group (DBCG) statistical core and all statistical tests were two-sided. RESULTS: RNA from 270 patients was evaluable; 84 patients (31%) were classified as luminal A, 97 (36%) luminal B, 43 (16%) basal-like, and 46 (17%) as HER2-enriched. PAM50 intrinsic subtype was a significant independent prognostic factor for both TTP (p=0.014) and OS (p=0.0003). Response rate was not different by subtype, and PAM50 was not a predictor of TTP by treatment arm. PAM50 was however a highly significant predictor of OS following GD compared to D (pinteraction=0.0016). Patients with a basal-like subtype had a significant reduction in OS events [hazard ratio (HR)=0.29, 95% confidence interval (CI)=0.15-0.57; pinteraction=0.0006]. CONCLUSION: A significantly improved and clinically important prolongation of survival was seen from the addition of gemcitabine to docetaxel in advanced basal-like breast cancer patients.

Gene aberrations of RRM1 and RRM2B and outcome of advanced breast cancer after treatment with docetaxel with or without gemcitabine.

BACKGROUND: The purpose of the present study was to retrospectively evaluate whether copy number changes of the genes encoding the ribonucleotide reductase subunit M1 (RRM1) and/or subunit M2B (RRM2B) predict sensitivity to gemcitabine administered in combination with docetaxel compared to single agent docetaxel in advanced breast cancer patients. METHODS: Primary tumor samples from patients randomly assigned to gemcitabine plus docetaxel or docetaxel alone were analyzed for RRM1 and RRM2B copy number changes using Fluorescence In Situ Hybridization (FISH) technology with probes covering respectively RRM1 at 11p15.5 and a reference probe covering the centromere of chromosome 11 (CEN-11), and RRM2B at 8q22.3 and a reference probe covering the centromere of chromosome 8 (CEN-8). The assays were validated in a material of 60 normal breast samples. Time to progression (TTP) was the primary endpoint. Overall survival (OS) and response rate (RR) were secondary endpoints. Associations between RRM1/CEN-11 and/or RRM2B/CEN-8 ratios and time-to-event endpoints were analyzed by unadjusted and adjusted Cox proportional hazards regression models. Heterogeneity of treatment effects on TTP and OS according to gene status were investigated by subgroup analyses, and the Wald test was applied. All statistical tests were two-sided. RESULTS: FISH analysis for both RRM1 and RRM2B was successful in 251 patients. RRM1 and RRM2B aberrations (deletions and amplifications) were observed in 15.9% and 13.6% of patients, respectively. RRM1 aberrations were associated with a decreased OS in the time interval 1.5-7.4 years (hazard ratio = 1.72, 95% confidence interval = 1.05-2.79, P = 0.03). RRM2B aberrations alone or in combination with RRM1 aberrations had no prognostic impact in terms of TTP or OS. RR was not different by gene status. No significant differences were detected in TTP or OS within subgroups according to gene status and chemotherapy regimen. CONCLUSIONS: This study demonstrated the presence of RRM1 and RRM2B copy number changes in primary breast tumor specimens. Nevertheless, we found no support of the hypothesis that aberrations of RRM1 or RRM2B, neither individually nor in combination, are associated with an altered clinical outcome following chemotherapy with gemcitabine in combination with docetaxel compared to docetaxel alone in advanced breast cancer patients.

Improvement of prognosis in breast cancer in Denmark 1977-2006, based on the nationwide reporting to the DBCG Registry.

INTRODUCTION: Since 30 years DBCG (Danish Breast Cancer Coperative Group) has maintained, on a nation-wide basis, a clinical database of diagnostic procedures, therapeutic interventions, and clinical outcome in patients with primary breast cancer. The present analysis was undertaken to evaluate the development of the prognosis since 1977, and to analyse factors potentially contributing to the change of the prognosis. MATERIAL AND METHODS: All cases of invasive breast cancer reported to DBCG during the period 1977-2006 were included in the present analysis. RESULTS: A total of close to 80 000 patients were registered in the DBCG Database. Since 1977 the prognosis has improved significantly, thus 5 year survival for the total population of patients with primary breast cancer has increased from 65 to 81%. DISCUSSION: According to the present analysis diagnosis at an earlier stage in the natural course of the disease and especially the development of more active systemic treatment modalities have contributed to the improved prognosis.

Classical pathological variables recorded in the Danish Breast Cancer Cooperative Group's register 1978-2006.

The Danish Breast Cancer Cooperative Group's register containing data from about 75 000 patients undergoing surgery for primary invasive breast cancer from 1978-2006 has been examined for classical pathological variables. During that period the diagnostic approach of malignant breast tumours experienced a major shift from invasive surgical procedures to non invasive procedures with an increase of the proportion of both fine needle aspiration biopsy and core needle biopsy. According to variation in tumour size there has been a slight increase in tumours <10 mm and a significant decrease in tumours >50mm from 7 to 4%. The distribution of the histological subtypes of malignant breast tumours has been almost unchanged. We found however a significant increase in the number of high grade tumours. A large increase in the number of removed axillary lymph nodes from 1989-2001 is related to improved surgical procedure. The subsequent decline from 2002-2006 is the result of the introduction of the sentinel node technique. In the five-year period 2002-2006 following the introduction of sentinel node technique, the frequency of patients having at least one lymph node metastases (48.7%) was higher than in the preceding five-year period 1997-2001 (44.4%, p=0.0087).

The clinical database and the treatment guidelines of the Danish Breast Cancer Cooperative Group (DBCG); its 30-years experience and future promise.

Introduction. Since 30 years, DBCG (Danish Breast Cancer Cooperative Group) has maintained a clinical database allowing the conduct of quality control studies, of randomised trials, examination of the epidemiology of breast cancer and of prognostic and predictive factors. Material and methods. The original database included patients with invasive breast cancer, but has later been expanded to patients with in situ breast cancer and hereditary breast and ovarian cancer families. Results. The multidisciplinary cooperative group has provided successive treatment guidelines and 70% of the 77284 registered patients have been enrolled and received treatment according to these guidelines. The standard treatments and the randomised trials included in the DBCG programmes are all briefly described. Among high-risk patients 48% have participated in randomised trials, and the results of these trials have largely been implemented in the next generation of treatment guidelines. Records within the clinical database of archival tumour tissue have established a basis for translational research and epidemiologic research has been enabled through linkage to other healthcare registries. Discussion. The joint conception of the multidisciplinary breast cancer group and a clinical database has provided improvements in the management of breast cancer patients and has enabled recruitment of patients onto randomised trials.

Breast cancer survival and season of surgery: an ecological open cohort study.

Background Vitamin D has been suggested to influence the incidence and prognosis of breast cancer, and studies have found better overall survival (OS) after diagnosis for breast cancer in summer-autumn, where the vitamin D level are expected to be highest. Objective To compare the prognostic outcome for early breast cancer patients operated at different seasons of the year. Design Open population-based cohort study. Setting Danish women operated 1978-2010. Cases 79 658 adjusted for age at surgery, period of surgery, tumour size, axillary lymph node status and hormone receptor status. Statistical analysis The association between OS and season of surgery was analysed by Cox proportional hazards regression models, at survival periods 0-1, 0-2, 0-5 and 0-10 years after surgery. A two-sided p value <0.05 was considered statistical significant. Results Only after adjustment for prognostic factors that may be influenced by vitamin D, 1-year survival was close to significantly associated season of surgery. 2, 5 and 10 years after surgery, the association between OS and season of surgery was not significant. Limitations Season is a surrogate measure of vitamin D. Conclusions The authors found no evidence of a seasonal variation in the survival after surgery for early breast cancer. Lack of seasonal variation in this study does not necessarily mean that vitamin D is of no importance for the outcome for breast cancer patients.

Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group.

PURPOSE: The objective of this phase III study was to compare the efficacy of gemcitabine plus docetaxel (GD) versus docetaxel in patients with advanced breast cancer. PATIENTS AND METHODS: Predominantly human epidermal growth factor receptor 2 (HER2) -negative patients were randomly assigned to gemcitabine (1,000 mg/m(2)) on days 1 and 8 plus docetaxel (75 mg/m(2)) on day 8 or to docetaxel (100 mg/m(2)) on day 1, every 21 days. Patients were untreated or had prior (neo)adjuvant chemotherapy or a single anthracycline-based chemotherapy regimen for metastatic breast cancer. The primary end point was time to progression (TTP), and secondary end points were overall survival (OS), response rate (RR), and toxicity. RESULTS: A total of 170 patients were allocated to GD, and 167 were allocated to docetaxel. Median TTP on GD was 10.3 months versus 8.3 months on docetaxel (hazard ratio [HR], 0.77; 95% CI, 0.59 to 1.01; log-rank P = .06). The adjusted Cox proportional model for TTP showed a significant difference favoring the combination (HR, 0.68; 95% CI, 0.51 to 0.90; P = .007). However, RR was similar (GD, 36%; docetaxel, 34%), and OS was not different (P = .57). Grades 3 to 4 neutropenia was common (GD, 75%; docetaxel, 69%); infection was reported in 26% and 21% of patients in the GD and docetaxel groups, respectively. Grades 3 to 4 thrombocytopenia was more frequent with GD (GD, 16%; docetaxel, 0.6%), and peripheral neuropathy was higher with docetaxel (GD, 5%; docetaxel, 16%). CONCLUSION: GD compared with docetaxel demonstrated increased TTP in metastatic breast cancer. However, RR and OS were similar. Thus, the addition of gemcitabine failed to demonstrate any clinically meaningful benefit when combined with docetaxel.