Celecoxib With Neoadjuvant Chemotherapy for Breast Cancer Might Worsen Outcomes Differentially by COX-2 Expression and ER Status: Exploratory Analysis of the REMAGUS02 Trial.
ABSTRACT: PURPOSE:The overexpression of cyclooxygenase 2 (COX-2) gene, also known as prostaglandin-endoperoxide synthase 2 ( PTGS2), occurs in breast cancer, but whether it affects response to anticox drugs remains unclear. We investigated the relationships between PTGS2 expression, celecoxib use during neoadjuvant chemotherapy (NAC), and both event-free survival (EFS) and overall survival (OS). MATERIALS AND METHODS:We analyzed a cohort of 156 patients with human epidermal growth factor receptor 2 -negative breast cancer from the REMAGUS02 (ISRCTN Registry No. 10059974) trial with pretreatment PTGS2 expression data. Patients were treated by sequential NAC (epirubicin plus cyclophosphamide followed by docetaxel with or without celecoxib). Experimental validation was performed on breast cancer cell lines. The Cancer and Leukemia Group B (CALGB) 30801 ( ClinicalTrials.gov identifier: NCT01041781) trial that tested chemotherapy with or without celecoxib in patients with lung cancer served as an independent validation cohort. RESULTS:After 94.5 months of follow-up, EFS was significantly lower in the celecoxib group (hazard ratio [HR], 1.7; 95% CI, 1 to 2.88; P = .046). A significant interaction between PTGS2 expression and celecoxib use was detected ( Pinteraction = .01). In the PTGS2-low group (n = 100), EFS was lower in the celecoxib arm (HR, 3.01; 95% CI, 1.45 to 6.24; P = .002) than in the standard treatment arm. Celecoxib use was an independent predictor of poor EFS, distant relapse-free survival, and OS. Celecoxib in addition to docetaxel enhanced cell viability in PTGS2-low cell lines but not in PTGS2-high cell lines. In CALGB 30801, a trend toward poorer progression-free survival was observed in the patients with low urinary metabolite of prostaglandin E2 who received celecoxib (HR = 1.57; 95% CI, 0.87 to 2.84; P = .13). CONCLUSION:Celecoxib use during chemotherapy adversely affected survival in patients with breast cancer, and the effect was more marked in PTGS2-low and/or estrogen receptor-negative tumors. COX-2 inhibitors should preferably be avoided during docetaxel use in patients with breast cancer who are undergoing NAC.
Project description:Background:Celecoxib and low-dose aspirin might decrease risk of breast cancer recurrence. Methods:In the Canadian Cancer Trials Group MA.27, postmenopausal hormone receptor-positive breast cancer patients were randomly assigned (2?×?2) to adjuvant exemestane or anastrozole, and celecoxib or placebo. Low-dose aspirin of 81 mg or less was a stratification factor. Due to concerns about cardiac toxicity, celecoxib use was stopped in December 2004, while stratification by aspirin use was removed through protocol amendment. We examined the effects of celecoxib and low-dose aspirin on event-free survival (EFS), defined as time from random assignment to time of locoregional or distant disease recurrence, new primary breast cancer, or death from any cause; distant disease-free survival (DDFS); and overall survival (OS). All statistical tests were two-sided. Results:Random assignment to celecoxib (n = 811, 50.0%) or placebo (n = 811, 50.0%) was discontinued after 18 months (n = 1622). At a median of 4.1 years' follow-up, among 1622 patients, 186 (11.5%) patients had an EFS event: 80 (4.9%) had distant relapse, and 125 (7.7%) died from any cause. Celecoxib did not statistically significantly impact EFS, DDFS, or OS in univariate analysis (respectively, P = .92, P = .55, and P = .56) or multivariable analysis (respectively, P = .74, P = .60, and P = .76). Low-dose aspirin use (aspirin users n = 476, 21.5%; non-aspirin users n = 1733, 78.5%) was associated in univariate analyses with worse EFS (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.12 to 1.96, P = 0.006) and worse OS (HR = 1.87, 95% CI = 1.35 to 2.61, P < .001). After adjusting for baseline characteristics and treatment arm, aspirin use showed no statistical association with EFS (P = .08) and DDFS (P = .82), but was associated with statistically worse OS (HR = 1.67, 95% CI = 1.13 to 2.49, P = .01). Conclusion:Random assignment to short-term (?18 months) celecoxib as well as use of low-dose aspirin showed no effect on DDFS and EFS in multivariable analysis. Low-dose aspirin increased "all-cause" mortality, presumably because of higher preexisting cardiovascular risks.
Project description:BACKGROUND:Prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase-2, COX-2)-prostaglandin E2 (PGE2) pathway promotes tumour progression. Considering evidence suggesting increased PGE2 synthesis by BRAF mutation in tumour cells, we hypothesised that the association of tumour PTGS2 (COX-2) expression with colorectal cancer mortality might be stronger in BRAF-mutated tumours than in BRAF-wild-type tumours. METHODS:Using 1708 patients, including 1200 stage I-IV colorectal carcinoma cases in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) and 508 stage III colon cancer cases in a National Cancer Institute-sponsored randomised controlled trial of adjuvant therapy (CALGB/Alliance 89803), we evaluated tumour PTGS2 (COX-2) expression status using immunohistochemistry. We examined the prognostic association of PTGS2 (COX-2) expression in strata of BRAF mutation status by multivariable Cox proportional hazards regression models to adjust for potential confounders, including disease stage, tumour differentiation, microsatellite instability status and KRAS and PIK3CA mutations. RESULTS:In NHS and HPFS, the association of PTGS2 (COX-2) expression with colorectal cancer-specific survival differed by BRAF mutation status (Pinteraction = 0.0005); compared with PTGS2 (COX-2)-negative/low carcinomas, the multivariable-adjusted hazard ratios for PTGS2 (COX-2)-high carcinomas were 2.44 (95% confidence interval, 1.39-4.28) in BRAF-mutated cases and 0.82 (95% confidence interval, 0.65-1.04) in BRAF-wild-type cases. Differential prognostic associations of PTGS2 (COX-2) expression in strata of BRAF mutation status were similarly observed in CALGB/Alliance 89803 trial (Pinteraction = 0.03). CONCLUSIONS:The association of tumour PTGS2 (COX-2) expression with colorectal cancer mortality is stronger in BRAF-mutated tumours than in BRAF-wild-type tumours, supporting interactive roles of PTGS2 (COX-2) expression and BRAF mutation statuses in prognostication of patients with colorectal cancer; ClinicalTrials.gov Identifier, NCT00003835.
Project description:Background: Epirubicin combined with docetaxel is the cornerstone of neoadjuvant chemotherapy (NAC) for breast cancer. The efficacy of NAC for luminal A breast cancer patients is very limited, and single nucleotide polymorphism is one of the most important factors that influences the efficacy. Our study is aimed to explore genetic markers for the efficacy of epirubicin combined with docetaxel for NAC in patients with luminal A breast cancer. Methods: A total of 421 patients with two stages of luminal A breast cancer were enrolled in this study from 2 centers. Among them 231 patients were included in the discovery cohort and 190 patients are in the replication cohort. All patients received epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1, in a 21-day cycle, a cycle for 2-6 cycles. Before treatment, 2 ml of peripheral blood was collected from each patient to isolate genomic DNA. Fourteen functional variants potentially regulating epirubicin/docetaxel response genes were prioritized by CellMiner and bioinformatics approaches. Moreover, biological assays were performed to determine the effect of genetic variations on response to chemotherapy. Results: The patients carrying rs6484711 variant A allele suffered a poor response to epirubicin and docetaxel for NAC (OR = 0.37, 95% CI: 0.18-0.74, P = 0.005) in combined stage. Moreover, expression quantitative trait loci (eQTL) analyses and luciferase reporter assays revealed that rs6484711 A allele significantly increased the expression of ABTB2. Subsequent biological assays illustrated that upregulation of ABTB2 significantly reduced the apoptosis rate of breast cancer cells and enhanced the chemo-resistance to epirubicin. Conclusions: Our study demonstrated rs6484711 polymorphism regulating ABTB2 expression might predict efficacy to epirubicin based NAC in luminal A breast cancer patients. These results provided valuable information about potential role of genetic variations in individualized chemotherapy.
Project description:Purpose:The current multicenter phase II study was conducted to evaluate the efficacy and safety of the combination of docetaxel and gemcitabine as neoadjuvant chemotherapy (NAC) for locally advanced breast cancer. Methods:A total of 98 patients with stage II-III breast cancer were enrolled. The primary endpoint was pathological complete response (pCR) rate of invasive cancer after the completion of the fourth cycle of NAC. The secondary endpoints included response rate (RR), rate of breast-conserving surgery, toxicity, and disease-free survival (DFS). This study is registered with ClinicalTrials.gov (NCT01352494). Results:pCR in the breast and the axillary lymph node was observed in seven of the 98 enrolled patients (7.1%). The overall clinical RR, including partial responses, was 65.3%. Breast-conserving surgery was performed in 75 of the 98 assessable patients (76.5%). Neutropenia was frequent and was observed in 92 of the 98 patients (93.9%), including grade 3 and 4 in 24 patients (24.5%) and 63 patients (64.3%), respectively. Dose reductions were required for 30 of the 92 patients (32.6%). After a median follow-up of 24 months, the overall DFS of the group was 86.7%. Conclusion:The combination of docetaxel and gemcitabine did not improve pCR. However, this regimen has shown potential as a NAC by producing a reasonable rate of breast-conserving surgery and favorable responses in patients with locally advanced breast cancer. The therapeutic efficacy of this regimen will be determined in additional trials to overcome the limitations of the current study.
Project description:Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ~30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy.
Project description:Pathological complete response (pCR) following chemotherapy is strongly associated with both breast cancer subtype and long-term survival. Within a phase III neoadjuvant chemotherapy trial, we sought to determine whether the prognostic implications of pCR, TP53 status and treatment arm (taxane versus non-taxane) differed between intrinsic subtypes.Patients were randomized to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET). pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in primary tumour and lymph nodes. We used a simplified intrinsic subtypes classification, as suggested by the 2011 St Gallen consensus. Interactions between pCR, TP53 status, treatment arm and intrinsic subtype on event-free survival (EFS), distant metastasis-free survival (DMFS) and overall survival (OS) were studied using a landmark and a two-step approach multivariate analyses.Sufficient data for pCR analyses were available in 1212 (65%) of 1856 patients randomized. pCR occurred in 222 of 1212 (18%) patients: 37 of 496 (7.5%) luminal A, 22 of 147 (15%) luminal B/HER2 negative, 51 of 230 (22%) luminal B/HER2 positive, 43 of 118 (36%) HER2 positive/non-luminal, 69 of 221(31%) triple negative (TN). The prognostic effect of pCR on EFS did not differ between subtypes and was an independent predictor for better EFS [hazard ratio (HR) = 0.40, P < 0.001 in favour of pCR], DMFS (HR = 0.32, P < 0.001) and OS (HR = 0.32, P < 0.001). Chemotherapy arm was an independent predictor only for EFS (HR = 0.73, P = 0.004 in favour of T-ET). The interaction between TP53, intrinsic subtypes and survival outcomes only approached statistical significance for EFS (P = 0.1).pCR is an independent predictor of favourable clinical outcomes in all molecular subtypes in a two-step multivariate analysis.EORTC 10994/BIG 1-00 Trial registration number NCT00017095.
Project description:INTRODUCTION:MicroRNAs (miRNAs) are small non-coding RNA that plays a vital role in cancer progression. Neo-adjuvant chemotherapy (NAC) has become the standard of care for locally advanced breast cancer. The aim of this study was to evaluate miRNA alterations during NAC using multiple samples of tissue and serum to correlate miRNA expression with clinico-pathological features and patient outcomes. METHODS:Tissue and serum samples were collected from patients with locally advanced breast cancer undergoing NAC at four time points: time of diagnosis, after the first and fourth cycle of doxorubicin/cyclophosphamide treatment, and after the fourth cycle of docetaxel administration. First, we evaluated the miRNA expression profiles in tissue and correlated expression with clinico-pathological features. Then, a panel of four miRNAs (miR-451, miR-3200, miR-21, and miR-205) in serum samples was further validated using quantitative reverse-transcription polymerase chain reaction (RT-qPCR). The alterations in serum levels of miRNA, associations with clinical and pathological responses, correlation with clinico-pathological features, and survival outcomes were studied using Friedman, Mann-Whitney U, and Spearman, Wilcoxon signed-ranks tests. P?0.05 was considered statistically significant. RESULTS:We analyzed 72 tissue samples and 108 serum samples from 9 patients and 27 patients, respectively. MicroRNA expression profiling of tumor versus normal tissue revealed more than 100 differentially expressed miRNAs. Serum miR-451 levels were significantly decreased during treatment, and higher serum levels were associated with improved clinical and pathological responses and disease-free survival. This is one of the early reports on miR-3200 in response to treatment in breast cancer, as serum levels of miR-3200 found to decline during NAC, and higher serum levels were associated with lower residual breast cancer burden and relapse rates at time of diagnosis. CONCLUSION:Variations in serum miRNA levels during NAC treatment may be therapeutically significant for predicting response and survival outcomes.
Project description:PURPOSE:Prognostic value of pathologic complete response (pCR) and extent of pathologic response attained with anthracycline-free platinum plus taxane neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) is unknown. We report recurrence-free survival (RFS) and overall survival (OS) according to degree of pathologic response in patients treated with carboplatin plus docetaxel NAC. PATIENTS AND METHODS:One-hundred and ninety patients with stage I-III TNBC were treated with neoadjuvant carboplatin (AUC6) plus docetaxel (75 mg/m2) every 21 days × 6 cycles. pCR (no evidence of invasive tumor in breast and axilla) and Residual cancer burden (RCB) were evaluated. Patients were followed for recurrence and survival. Extent of pathologic response was associated with RFS and OS using the Kaplan-Meier method. RESULTS:Median age was 51 years, and 52% were node-positive. pCR and RCB I rates were 55% and 13%, respectively. Five percent of pCR patients, 0% of RCB I patients, and 58% of RCB II/III patients received adjuvant anthracyclines. Three-year RFS and OS were 79% and 87%, respectively. Three-year RFS was 90% in patients with pCR and 66% in those without pCR [HR = 0.30; 95% confidence interval (CI), 0.14-0.62; P = 0.0001]. Three-year OS was 94% in patients with pCR and 79% in those without pCR (HR = 0.25; 95% CI, 0.10-0.63; P = 0.001). Patients with RCB I demonstrated 3-year RFS (93%) and OS (100%) similar to those with pCR. On multivariable analysis, higher tumor stage, node positivity, and RCB II/III were associated with worse RFS. CONCLUSIONS:Neoadjuvant carboplatin plus docetaxel yields encouraging efficacy in TNBC. Patients achieving pCR or RCB I with this regimen demonstrate excellent 3-year RFS and OS without adjuvant anthracycline.
Project description:Pathologic complete response (pCR) is a predictor for favorable outcome after neoadjuvant treatment in early breast cancer. Modulation of gene expression may also provide early readouts of biological activity and prognosis, offering the possibility for timely response-guided treatment adjustment. The role of early transcriptional changes in predicting response to neoadjuvant chemotherapy plus bevacizumab was investigated. One-hundred-and-fifty patients with large, operable and locally advanced HER2-negative breast cancer received epirubicin and docetaxel, with the addition of bevacizumab. Patients underwent tumor biopsies at baseline, after Cycle 2 and at the time of surgery. The primary end point, pCR, and its relation with the secondary endpoints event-free survival (EFS), overall survival (OS) and gene expression profiles, are reported. The pCR rate was 13% (95% CI 8.6-20.2), with significantly more pCRs among triple-negative [28% (95% CI 14.8-45.4)] than among hormone receptor positive (HR+) tumors [9% (95% CI 4.6-16.3); (OR?=?3.9 [CI?=?1.5-10.3])]. pCR rates were not associated with EFS or OS. PAM50 subtypes significantly changed after Cycle 2 (p?=?0.03) and an index of absolute changes in PAM50 correlations between these time-points was associated with EFS [HR?=?0.62 (CI?=?0.3-1.1)]. In univariable analyses, signatures for angiogenesis, proliferation, estrogen receptor signaling, invasion and metastasis, and immune response, measured after Cycle 2, were associated with pCR in HR+ tumors. Evaluation of changes in molecular subtypes and other signatures early in the course of neoadjuvant treatment may be predictive of pCR and EFS. These factors may help guide further treatment and should be considered when designing neoadjuvant trials.
Project description:Purpose Tumor overexpression of cyclooxygenase-2 (COX-2) has been associated with worse outcome in non-small-cell lung cancer (NSCLC). In Cancer and Leukemia Group B (CALGB) 30203, we found that the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved progression-free and overall survival in patients with moderate to high COX-2 expression by immunohistochemistry (IHC). CALGB 30801 (Alliance) was designed to prospectively confirm that finding. Patients and Methods Patients with NSCLC (stage IIIB with pleural effusion or stage IV according to American Joint Committee on Cancer [sixth edition] criteria) were preregistered, and biopsy specimens were analyzed for COX-2 by IHC. Patients with COX-2 expression ? 2, performance status of 0 to 2, and normal organ function were eligible. Chemotherapy was determined by histology: carboplatin plus pemetrexed for nonsquamous NSCLC and carboplatin plus gemcitabine for squamous histology. Patients were randomly assigned to celecoxib (400 mg twice per day; arm A) or placebo (arm B). The primary objective was to demonstrate improvement in progression-free survival in patients with COX-2 index ? 4 with hazard ratio of 0.645 with approximately 85% power at two-sided significance level of .05. Results The study was halted for futility after 312 of the planned 322 patients with COX-2 index ? 2 were randomly assigned. There were no significant differences between the groups (hazard ratio, 1.046 for COX-2 ? 4). Subset analyses evaluating histology, chemotherapy regimen, and incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition. Elevation of baseline urinary metabolite of prostaglandin E2, indicating activation of the COX-2 pathway, was a negative prognostic factor. Values above the third quartile may have been a predictive factor. Conclusion COX-2 expression by IHC failed to select patients who could benefit from selective COX-2 inhibition. Urinary metabolite of prostaglandin E2 may be able to identify patients who could benefit from COX-2 inhibition.