Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer who are at high risk of disease recurrence (D-CARE): An international, randomized, double-blind, placebo-controlled phase III clinical trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS670-TPS670
Author(s):  
Paul Edward Goss ◽  
Carlos H. Barrios ◽  
Richard Bell ◽  
Dianne M Finkelstein ◽  
Hiroji Iwata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Early Stage ◽  
Human Monoclonal Antibody ◽  
Disease Free Survival ◽  
Early Stage Breast Cancer ◽  
Phase Iii ◽  
Free Survival ◽  
Oral Bisphosphonate ◽  
Her 2

TPS670 Background: Bone is a common site of distant recurrence in women with early-stage breast cancer, and represents approximately 40% of all first recurrences. Tumor cells in bone release growth factors and cytokines that stimulate osteoclast-mediated bone resorption through the RANK ligand (RANKL) pathway. In preclinical studies, RANKL inhibition significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab is a fully human monoclonal antibody that binds to RANKL with high affinity and specificity. It is approved for the prevention of skeletal-related events in patients with established bone metastases from a variety of solid tumors. The purpose of the D-CARE trial is to evaluate the ability of denosumab to prolong bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. Methods: Approximately 4,500 women with stage II or III breast cancer, at high risk for recurrence and with known hormone and HER-2 receptor status, are eligible. Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination must be planned. Exclusion criteria include: a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization or any intravenous BP use. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. All patients receive vitamin D (≥ 400 IU) and calcium (≥ 500 mg) supplements. Primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Safety, quality of life assessments, breast density, and biomarkers are additional endpoints. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and is expected to complete in October 2016. Paul Goss and Dianne Finkelstein supported in part by the Avon Foundation New York.

scholarly journals SWOG S0221: A Phase III Trial Comparing Chemotherapy Schedules in High-Risk Early-Stage Breast Cancer

2015 ◽  
Vol 33 (1) ◽  
pp. 58-64 ◽  
Author(s):  
George T. Budd ◽  
William E. Barlow ◽  
Halle C.F. Moore ◽  
Timothy J. Hobday ◽  
James A. Stewart ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Hormone Receptor ◽  
Early Stage ◽  
Disease Free Survival ◽  
Early Stage Breast Cancer ◽  
Phase Iii ◽  
Secondary Outcome ◽  
Original Design ◽  
Significant Difference

Purpose To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer. Patients and Methods A 2 × 2 factorial design was used to test two hypotheses: (1) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome. Results Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor–negative/human epidermal growth factor receptor 2 (HER2) –negative tumors (P = .067), with no differences seen with hormone receptor–positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40). Conclusion Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor–negative/HER2-negative tumors.

Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer at high risk of disease recurrence (D-CARE): An international, placebo-controlled, randomized, double-blind phase III clinical trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS662-TPS662
Author(s):  
Paul E. Goss ◽  
Carlos H. Barrios ◽  
Arlene Chan ◽  
Dianne M. Finkelstein ◽  
Hiroji Iwata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
High Risk ◽  
Bone Metastasis ◽  
Early Stage ◽  
Early Stage Breast Cancer ◽  
Phase Iii ◽  
Double Blind ◽  
Free Survival ◽  
Patient Reported

TPS662 Background: In women with early-stage breast cancer, bone is a common site of distant recurrence and represents approximately 40% of all first recurrences. Preclinical studies demonstrated that inhibition of RANKL significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab is approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors. The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. The primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Additional endpoints include safety, breast density, time to first on-study SRE (following the development of bone metastasis), patient reported outcomes, and biomarkers. Methods: In this international, randomized, double-blind, and placebo-controlled phase 3 trial, 4509 women with stage II or III breast cancer at high risk for recurrence and with known hormone and HERE2 receptor status were randomized. High risk was defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size > 5 cm (T3), or locally advanced disease (T4). Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination, must be planned. Patients with a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, were not eligible. Patients were randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) were required. The trial, sponsored by Amgen Inc., began enrolling patients in June 2010 and completed enrollment in late 2012. Clinical trial information: NCT01077154.

scholarly journals The role of functional polymorphisms in oxidative stress-related genes on early-stage breast cancer survival

2021 ◽  
pp. 172460082110111
Author(s):  
Erika Korobeinikova ◽  
Rasa Ugenskiene ◽  
Ruta Insodaite ◽  
Viktoras Rudzianskas ◽  
Jurgita Gudaitiene ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Single Nucleotide Polymorphisms ◽  
Early Stage ◽  
Disease Free Survival ◽  
Early Stage Breast Cancer ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Free Survival ◽  
Disease Free

Background: Genetic variations in oxidative stress-related genes may alter the coded protein level and impact the pathogenesis of breast cancer. Methods: The current study investigated the associations of functional single nucleotide polymorphisms in the NFE2L2, HMOX1, P21, TXNRD2, and ATF3 genes with the early-stage breast cancer clinicopathological characteristics and disease-free survival, metastasis-free survival, and overall survival. A total of 202 Eastern European (Lithuanian) women with primary I–II stage breast cancer were involved. Genotyping of the single nucleotide polymorphisms was performed using TaqMan single nucleotide polymorphisms genotyping assays. Results: The CA+AA genotypes of P21 rs1801270 were significantly less frequent in patients with lymph node metastasis and larger tumor size ( P=0.041 and P=0.022, respectively). The TT genotype in ATF3 rs3125289 had significantly lower risk of estrogen receptor (ER), progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2) positive status ( P=0.023, P=0.046, and P=0.040, respectively). In both, univariate and multivariate Cox analysis, TXNRD2 rs1139793 GG genotype vs. GA+AA was a negative prognostic factor for disease-free survival (multivariate hazard ratio (HR) 2.248; P=0.025) and overall survival (multivariate HR 2.248; P=0.029). The ATF3 rs11119982 CC genotype in the genotype model was a negative prognostic factor for disease-free survival (multivariate HR 5.878; P=0.006), metastasis-free survival (multivariate HR 4.759; P=0.018), and overall survival (multivariate HR 3.280; P=0.048). Conclusion: Our findings suggest that P21 rs1801270 is associated with lymph node metastasis and larger tumor size, and ATF3 rs3125289 is associated with ER, PR, and HER2 status. Two potential, novel, early-stage breast cancer survival biomarkers, TXNRD2 rs1139793 and ATF3 rs11119982, were detected. Further investigations are needed to confirm the results of the current study.

Outcomes after Surgery for Early Stage Breast Cancer in Women Staged With Preoperative Breast Magnetic Resonance Imaging According to Breast Tissue Density

2019 ◽  
Vol 1 (2) ◽  
pp. 115-121
Author(s):  
Renata Faermann ◽  
Jonathan Weidenfeld ◽  
Leonid Chepelev ◽  
Wayne Kendal ◽  
Raman Verma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Tissue ◽  
Early Stage ◽  
Disease Free Survival ◽  
Breast Mri ◽  
Early Stage Breast Cancer ◽  
Free Survival ◽  
Tissue Density ◽  
Breast Tissue Density ◽  
Preoperative Breast Mri

Abstract Purpose To determine surgical outcomes and breast cancer disease-free survival outcomes of women with early stage breast cancer with and without use of preoperative breast MRI according to breast tissue density. Methods Women with early stage breast cancer diagnosed from 2004 to 2009 were classified into 2 groups: 1) those with dense and heterogeneously dense breasts (DB); 2) those with nondense breasts (NDB) (scattered fibroglandular and fatty replaced tissue). The 2 groups were reviewed to determine who underwent preoperative MRI. Breast tissue density was determined with mammography according to ACR BI-RADS. Patients were compared according to tumor size, grade, stage, and treatment. Survival analysis was performed using Kaplan-Meier estimates. Results In total, 261 patients with mean follow-up of 85 months (25–133) were included: 156 DB and 105 NDB. Disease-free survival outcomes were better in the DB group in patients with MRI than in those without MRI: patients with MRI had significantly fewer local recurrences (P < 0.016) and metachronous contralateral breast cancers (P < 0.001), but this was not the case in the NDB group. Mastectomies were higher in the DB group with preoperative MRI than in those without MRI (P < 0.01), as it was in the NDB group (P > 0.05). Conclusions Preoperative breast MRI was associated with reduced local recurrence and metachronous contralateral cancers in the DB group, but not in the NDB group; however, the DB patients with MRI had higher mastectomy rates.

scholarly journals Neoadjuvant radiotherapy of early-stage breast cancer and long-term disease-free survival

2017 ◽  
Vol 19 (1) ◽  
Author(s):  
Jan Poleszczuk ◽  
Kimberly Luddy ◽  
Lu Chen ◽  
Jae K. Lee ◽  
Louis B. Harrison ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Disease Free Survival ◽  
Early Stage Breast Cancer ◽  
Neoadjuvant Radiotherapy ◽  
Free Survival ◽  
Disease Free

Phase III Trial of Concurrent or Sequential Adjuvant Chemoradiotherapy After Conservative Surgery for Early-Stage Breast Cancer: Final Results of the ARCOSEIN Trial

2007 ◽  
Vol 25 (4) ◽  
pp. 405-410 ◽  
Author(s):  
Alain Toledano ◽  
David Azria ◽  
Pascal Garaud ◽  
Alain Fourquet ◽  
Daniel Serin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Locoregional Recurrence ◽  
Early Stage ◽  
Treatment Protocol ◽  
Disease Free Survival ◽  
New Drugs ◽  
Phase Iii ◽  
Adjuvant Chemoradiotherapy ◽  
Free Survival ◽  
Significant Difference

Purpose In 1996, we initiated the French multicenter phase III randomized trial to compare the effect on disease-free survival (DFS) of concurrent versus sequential chemotherapy (CT) and radiotherapy (RT) after breast-conserving surgery for stages I and II breast cancer. This report presents the clinical results with a median follow-up of 60 months. Patients and Methods Between February 1996 and April 2000, 716 patients were entered onto this trial. Adjuvant treatment began within 6 weeks after surgery. Sequential treatment of CT administered first followed by RT was compared with concurrent treatment of CT administered with RT. The CT regimen consisted of mitoxantrone (12 mg/m2), fluorouracil (500 mg/m2), and cyclophosphamide (500 mg/m2) on day 1, and it was repeated every 21 days for six courses. RT was delivered to the breast and, when indicated, to the regional lymphatics. Results There was no statistically significant difference in treatment in the 5-year DFS (80% in both groups; P = .83), locoregional recurrence-free survival (LRFS; 92% in sequential v 95% in concurrent; P = .76), metastasis-free survival (87% in sequential v 84% in concurrent; P = .55), or overall survival (90% in sequential v 91% in concurrent; P = .76). Nevertheless, in the node-positive subgroup, the 5-year LRFS was statistically better in the concurrent arm (97% in concurrent v 91% in sequential; P = .02), corresponding to a risk of locoregional recurrence decreased by 39% (hazard ratio, 0.61; 95% CI, 0.38 to 0.93). Conclusion This treatment protocol remains an appealing clinical option for many women with operable breast cancer at a high risk of recurrence. Combination treatments with new drugs for breast cancer are warranted.

scholarly journals Pre-treatment Haemoglobin Concentration is a Prognostic Factor in Patients with Early-stage Breast Cancer

2005 ◽  
Vol 33 (3) ◽  
pp. 319-328 ◽  
Author(s):  
EG Kandemir ◽  
A Mayadagli ◽  
O Turken ◽  
M Yaylaci ◽  
A Ozturk
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Prognostic Factor ◽  
Early Stage ◽  
Haemoglobin Concentration ◽  
Disease Free Survival ◽  
Early Stage Breast Cancer ◽  
Free Survival ◽  
Pre Treatment ◽  
Disease Free

We investigated the prevalence of anaemia (haemoglobin concentration < 12 g/dl) in 336 women with early-stage breast cancer and its association with other known prognostic factors. The median follow-up period was 60.5 months (range 9-123 months). Seventy-nine women (23.5%) had a low pre-treatment haemoglobin concentration, but anaemia was not correlated with age, tumour size, nodal status, histological grade or hormone receptor status. Univariate analysis revealed that disease-free survival and overall survival were shorter in patients with anaemia at the time of diagnosis than in patients with normal haemoglobin concentrations. Anaemia remained a significant prognostic factor for disease-free survival and overall survival in the multivariate analysis (relative risk, 1.884 and 1.785, respectively). These results suggest that pre-treatment haemoglobin concentration is an independent prognostic factor in patients with early-stage breast cancer.

A randomised phase III trial comparing two dose-dense, dose-intensified approaches (EPC and PM(Cb)) for neoadjuvant treatment of patients with high-risk early breast cancer (GeparOcto).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 518-518 ◽  
Author(s):  
Andreas Schneeweiss ◽  
Volker Moebus ◽  
Hans Tesch ◽  
Claus Hanusch ◽  
Carsten Denkert ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Early Stage ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Primary Objective ◽  
Early Stage Breast Cancer ◽  
Phase Iii ◽  
Luminal B

518 Background: The sequential use of intense does-dense (idd) epirubicin, paclitaxel, cyclophosphamide (EPC) and weekly paclitaxel/liposomal doxorubicin (+/- carboplatin (Cb) in triple negative breast cancer (TNBC) (PM(Cb)) are considered highly efficient regimens for high-risk early stage breast cancer (BC). Methods: GeparOcto (NCT02125344) patients (pts) received 18 weeks (wks) either EPC (3x E 150mg/m² q2w followed by 3x P225 mg/m² q2w followed by 3x C 2000mg/m² q2) or PM(Cb) (12x P 80mg/m² plus M 20 mg/m² q1w, plus Cb AUC 1.5 q1w in TNBC). For HER2+ BC trastuzumab 6 (8) mg/kg q3w and pertuzumab 420 (840) mg q3w cycles were given concomitantly with P and C. Pts with histologically confirmed, cT1c - cT4a-d BC and central receptor assessment were included. Pts with HER2+ or TNBC were eligible irrespective of nodal status, luminal B-like tumours only if pN+. Primary objective compared pathologic complete response (pCR) rates (ypT0/is ypN0). Sample size calculations assumed a pCR rate of 50% for EPC and 60% for PM(Cb), requiring 950 pts to show superiority of PM(Cb). Secondary objectives compared pCR rates within the stratified subgroups (BC subtype, HER2+ vs HER2- HR+ vs HER2- HR-), amongst others. Results: 961 pts were recruited between 12/2014 and 05/2016, 945 started treatment. Median age was 48 years, 4% T3, 2% T4d, 46% N+, 82% ductal invasive, 66% G3 tumors; 40% were HER2+, 43% TNBC. 347 pts reported SAEs (176 EPC/171 PM(Cb)) and 2 pts died. 35 pneumonias (2 EPC vs 33 PM(Cb)) and 18 pneumonitis (3 EPC vs 15 PM(Cb)) were reported. 16.4% pts with EPC and 33.8% with PM(Cb) discontinued treatment (p<0.001), mainly due to AEs (47 EPC vs 113 PM(Cb)). Mean treatment duration was 17 wks with EPC and 16 wks with PM(Cb). pCR rate was 48.3% with EPC and 47.6% with PM(Cb)(OR 0.97 (95%CI 0.75-1.25), p=0.876). pCR rate in TNBC was 48.5% with EPC and 51.7% with PM(Cb); in HER2+ 62.0% vs 57.4% and in Luminal B 14.1% vs 14.6%. Conclusions: In high-risk early stage breast cancer pts pCR rates of idd EPC compared to weekly PM(Cb) were not significantly different. PM(Cb) appeared to be less feasible. Clinical trial information: NCT02125344.

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