Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study

Abstract

PurposeAnthracyclines remain a cornerstone in the treatment of primary and advanced breast cancer (BC). This study has evaluated the predictive value of a multigene mRNA-based drug response predictor (DRP) in the treatment of advanced BC with epirubicin. The DRP is a mathematical method combining in vitro sensitivity and gene expression with clinical genetic information from > 3000 clinical tumor samples.MethodsFrom a DBCG cohort, 140 consecutive patients were treated with epirubicin between May 1997 and November 2016. After patient informed consent, mRNA was isolated from archival formalin-fixed paraffin-embedded primary breast tumor tissue and analyzed using Affymetrix arrays. Using time to progression (TTP) as primary endpoint, the efficacy of epirubicin was analyzed according to DRP combined with clinicopathological data collected retrospectively from patients’ medical records. Statistical analysis was done using Cox proportional hazards model stratified by treatment line.ResultsMedian TTP was 9.3 months. The DRP was significantly associated to TTP (P = 0.03). The hazard ratio for DRP scores differing by 50 percentage points was 0.55 (95% CI –0.93, one-sided). A 75% DRP was associated with a median TTP of 13 months compared to 7 months following a 25% DRP. Multivariate analysis showed that DRP was independent of age and number of metastases.ConclusionThe current study prospectively validates the predictive capability of DRP regarding epirubicin previously shown retrospectively allowing the patients predicted to be poor responders to choose more effective alternatives. Randomized prospective studies are needed to demonstrate if such an approach will lead to increased overall survival.

Preparation, Biocompatibility and Antitumor Activity of Nanodelivery System Targeting Breast Cancer Base on a Silica Nanoparticle

“…As a cell cycle nonspecific drug, it is effective in many types of transplanted tumors. 35 In order to determine whether growth inhibition of MCF-7 cells is related to cell cycle and apoptosis, we evaluated the effects of CNPs on cell cycle and apoptosis after exposure of MCF-7 cells to CNPs ( Figure 8 ). The G0/G1 phase cell percentages in NC, PC, CNPs, EPI@NPs and Cur@NPs were 68.7%, 55.9%, 75.9%, 82.1% and 79.8%, respectively.…”

First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor

“…While the number of samples used for testing the novel 2X-121 DRP biomarker is very limited, this drug-specific biomarker approach has previously been applied to other chemotherapies, and has demonstrated its predictive value. 21 , 22 Moreover, additional studies, including two ongoing phase 2 clinical trials (NCT03878849 and NCT03562832), wherein the 2X-121 DRP biomarker will be employed prospectively, will be used to further validate these results.…”

“…Tumour biomarker analysis A novel, tumour-agnostic, molecular biomarker, 2X-121 DRP, was developed to identify responders and non-responders using 61 cell lines as previously described. 21,22 In these tumour cell lines, 414 genes were found to predict response to E7449: 172 genes were found to be positively correlated with sensitivity to E7449, and 242 genes were negatively correlated. Among these 414 genes predictive of the response to E7449, 111 were found to be associated in the literature with DNA damage response or Wnt/βcatenin pathways (Supplementary Table 2).…”

“…Matching baseline transcriptome and growth inhibition data were available for 61 of the 74 cell lines, and were used to develop a DRP as previously described. 21 , 22 Briefly, IC 50 values in the 61 cell lines were correlated to gene-expression levels in the same cell lines; 172 genes with a Pearson correlation above 0.25 were retained as potential markers of sensitivity, while 242 genes with a Pearson correlation below −0.25 were retained as potential markers of resistance. The 414 genes were searched in PubMed for known associations to DNA damage response or Wnt/β-catenin pathways.…”

“…Matching baseline transcriptome and growth inhibition data were available for 61 of the 74 cell lines, and were used to develop a DRP as previously described. 21,22 Briefly, IC 50 values in the 61 cell lines were correlated to gene-expression levels in the same cell lines;…”