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PURPOSE: Anthracyclines 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.METHODS: From 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.RESULTS: Median 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.CONCLUSION: The 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.

e13077Background: In an ongoing, open-label Phase 2 study liposomal cisplatin (LiPlaCis) was evaluated in metastatic breast cancer (mBC) patients selected by a cisplatin-specific mRNA-based drug re...

1071 Background: Epirubicin remains a cornerstone in the treatment of primary and advanced breast cancer. This study evaluated the predictive effect of a multigene mRNA-based Drug Response Predictor (DRP) in the treatment of advanced breast cancer (ABC). We applied a mathematical method combining in vitro sensitivity with gene expression patterns in tumors. Previously the DRP has been broadly validated1, 2 including retrospective validation of epirubicin3. Methods: Among 838 consecutive patients from a DBCG cohort 137 patients were treated with epirubicin between May 1997 and November 2016 at one of the participating sites. Patients were examined every 9 to 12 weeks by CT scan and clinical evaluation. After patient informed consent, mRNA was isolated from formalin fixed paraffin embedded tumor tissue from diagnostic biopsies and analyzed using Affymetrix arrays. Blinded predictions of epirubicin efficacy were compared to clinical data collected retrospectively from patients’ medical records. Statistical analysis was done using Cox proportional hazards model adjusted for treatment line. Primary endpoint was progression free survival (PFS). Results: Median time to progression was 9.3 months (95% CI: 7.2-13.2). Of the 137 patients, four received epirubicin more than once. Scoring the DRP as a continuous covariate demonstrated that the DRP was significantly associated to PFS (p = 0.02). The estimated hazard ratio was 0.56 (90% CI: 0.35-0.89) comparing two patients with DRP score differing by 50 percentage points. The estimated median time to progression for a patient with a DRP value of 25% was 7 months versus 13 months for a patient with a DRP value of 75%. No interaction with previous adjuvant chemotherapy was observed (p = 0.98). Conclusions: The current study demonstrates a potential clinical value by being able to select patients that benefit from epirubicin against patients predicted not to benefit sparing the last patients unnecessary toxicity. Studies evaluating the predictor in an adjuvant setting will follow. 1 Knudsen et al PLoS ONE 9(2): e87415; 2 Buhl et al PLoS ONE 11(5): e0155123; 3 Wang et al JNCI 105(17): 1284-91

e12056Background: Fulvestrant is a highly selective estrogen receptor (ER) antagonist used in the treatment of postmenopausal patients with ER-positive advanced breast cancer. To identify patients ...

Purpose: To determine the safety, dose-limiting toxicity, maximum tolerated dose, and pharmacokinetic and pharmacodynamic profiles of the novel hydroxamate histone deacetylase inhibitor belinostat (previously named PXD101) in patients with advanced refractory solid tumors. Experimental Design: Sequential dose-escalating cohorts of three to six patients received belinostat administered as a 30-min i.v. infusion on days 1 to 5 of a 21-day cycle. Pharmacokinetic variables were evaluated at all dose levels. Pharmacodynamic measurements included acetylation of histones extracted from peripheral blood mononuclear cells, caspase-dependent cleavage of cytokeratin-18, and interleukin-6 levels. Results: Forty-six patients received belinostat at one of six dose levels (150-1,200 mg/m2/d). Dose-limiting toxicities were grade 3 fatigue (one patient at 600 mg/m2; one patient at 1,200 mg/m2), grade 3 diarrhea combined with fatigue (one patient at 1,200 mg/m2), grade 3 atrial fibrillation (one patient at 1,200 mg/m2; one patient at 1,000 mg/m2), and grade 2 nausea/vomiting leading to inability to complete a full 5-day cycle (two patients at 1,000 mg/m2). The maximum tolerated dose was 1,000 mg/m2/d. I.v. belinostat displayed linear pharmacokinetics with respect to Cmax and AUC. The intermediate elimination half-life was 0.3 to 1.3 h and was independent of dose. Histone H4 hyperacetylation was observed after each infusion and was sustained for 4 to 24 h in a dose-dependent manner. Increases in interleukin-6 levels were detected following belinostat treatment. Stable disease was observed in a total of 18 (39%) patients, including 15 treated for ≥4 cycles, and this was associated with caspase-dependent cleavage of cytokeratin-18. Of the 24 patients treated at the maximum tolerated dose (1,000 mg/m2/d), 50% achieved stable disease. Conclusions: I.v. belinostat is well tolerated, exhibits dose-dependent pharmacodynamic effects, and has promising antitumor activity.

Irofulven, a DNA damaging semi -synthetic analog of Illudin S (phytotoxin from Omphalotus illudins, jack-o'-lantern mushroom) which in the body is activated by prostaglandin reductase, has shown promising clinical activity in a range of cancer forms but the objective response rates were too low to justify further clinical development. Of particular interest is that irofulven may not be a substrate of the mdr-1 drug efflux pump and thereby potentially active in prostate cancer patients with acquired resistance to docetaxel. We have now developed an irofulven responsive predictor which is based on gene expression data by comparing associations between gene expression profiles and growth inhibition in a panel of cell lines treated with irofulven. A second step has included filtering the identified gene expression profile against mRNA expression from a collection of 3200 human tumors. Only genes being differentially expressed in the clinical tumor material were retained in the model. A total of 205 mRNA's were selected for the final irofulven responsive profile. The profile can be converted to a single score of predicted irofulven responsiveness. We are now initiating a prospective clinical trial (Simon's two stage design) in selected patients with castration - and docetaxel resistant prostate cancer and with a favorable irofulven responsive profile. We are screening 600 prostate cancer samples (FFPE tissue) in order to select the 10% of patients with the highest likelihood of benefit from irofulven treatment. Primary end-points are objective response rate and changes in serum PSA. Citation Format: Steen Knudsen, Thomas Jensen, Anker Hansen, Ulla Buhl, Annie Rasmussen, Bruce Pratt, Arun Asaithambi, Nils Brünner, Peter Buhl Jensen. A two stage prospective clinical trial with irofulven treatment targeting a selected subgroup of castration- and docetaxel resistant prostate cancer patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C168.

3035 BackgroundPXD101 is a novel HDAC inhibitor with potent antiproliferative activity in vitro. PXD101 inhibits tumour growth in vivo in pre-clinical models. We present a phase 1 trial of PXD101 i...