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Background Even with positive oestrogen receptor (ER+) status some advanced breast cancer (ABC) patients fail to benefit from endocrine therapy (ET). A method that previously predicted other drugs in various cancers was evaluated. Here multigene markers based on aromatase inhibitor (AI) effect in vitro were used for prediction of AI benefit in ER+ ABC patients. Simultaneously effects of long-term ET on predictive efficacy was evaluated. Methods The Drug Response Predictors (DRPs) are based on correlations between baseline gene expression and growth inhibition patterns of exemestane, anastrozole and letrozole, respectively, in the National Cancer Institute 60 cell lines. The genes were controlled for expression in 3,500 tumours. In a Danish Breast Cancer Cooperative Group cohort of 695 ABC patients with complete gene expression and time-to-progression (TTP) data, 414 received an AI as monotherapy. Hereof, 57 received anastrozole, 166 received exemestane, and 327 received letrozole. mRNA was isolated from archival formalin-fixed paraffin embedded tumour tissue and run on microarray and 60% of the tumours were from time of primary diagnosis. Medical records of the patients were assessed for TTP for all treatments given for ABC. Results The DRPs were tested in subsets 1) with no adjuvant ET and 2) with adjuvant ET. In 1) the anastrozole DRP predicted benefit of anastrozole (hazard ratio (HR) was 0.21 upper 95%-confidence interval limit (CI) 0.76, p=0.023) but not in 2). Dichotomised by a DRP of 50, the anastrozole DRP did predict benefit (HR=0.16, upper 95%-CI 0.75, p=0.026). Only in 1) the exemestane DRP predicted benefit of exemestane (HR=0.57, upper 95%-CI 1.00, p=0.0497). The letrozole DRP had no predictive value. Additionally, we tested each DRPs ability to predict other AIs. Only the anastrozole DRP predicted benefit of overall AI treatment, in 1) with an HR of 0.76 (upper 95%-CI 0.99, p=0.044) and in 2) with an HR of 0.71 (upper 95%-CI 0.92, p=0.015). The anastrozole DRP did though not predict benefit of letrozole. All tests are one-sided, alpha=5%. Conclusions Among the DRPs for AIs, the anastrozole DRP was strongest with clinically relevant prediction of TTP in AI treated ER+ ABC patients. Trial registration: ClinicalTrials.gov NCT01861496.

IntroductionEffective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts are presented.MethodsThe profiles are correlations between in vitro sensitivity to cisplatin and vinorelbine and baseline mRNA expression of the 60 cell lines in the National Cancer Institute panel. An applied clinical samples filter focused the profiles to clinically relevant genes. The profiles were tested on 1) snap-frozen tumors from 133 patients with completely resected stage 1B-2 NSCLC randomized to adjuvant cisplatin and vinorelbine (ACV, n = 71) or no adjuvant treatment (OBS, n = 62) and 2) formalin-fixed paraffin-embedded (FFPE) tumors from 95 patients with completely resected stage 1A-3B NSCLC receiving adjuvant cisplatin and vinorelbine.ResultsThe combined cisplatin and vinorelbine profiles showed: 1) univariate Hazard Ratio (HR) for sensitive versus resistant of 0.265 (95% CI:0.079–0.889, p = 0.032) in the ACV cohort and a HR of 0.28 in a multivariate model (95% CI:0.08–1.04, p = 0.0573); 2) significant prediction at 3 year survival from surgery in univariate (HR = 0.138 (95% CI:0.035–0.537), p = 0.004) and multivariate analysis (HR = 0.14 (95% CI:0.030–0.6), p = 0.0081). No discrimination was found in the OBS cohort (HR = 1.328, p = 0.60). The cisplatin predictor alone had similar figures with 1) univariate HR of 0.37 (95% CI:0.12–1.15, p = 0.09) in the ACV cohort and 2) univariate HR of 0.14 (95% CI:0.03–0.59, p = 0.0076) to three years. Functional analysis on the cisplatin profile revealed a group of upregulated genes related to RNA splicing as a part of DNA damage repair and apoptosis.ConclusionsProfiles derived from snap-frozen and FFPE NSCLC tissue were prognostic and predictive in the patients that received cisplatin and vinorelbine but not in the cohort that did not receive adjuvant treatment.

Background No biomarkers predict efficacy of 5-FU for metastatic colorectal cancer (mCRC). A gene expression based drug response predictor (DRP) had been shown to predict benefit of 5-FU in the PETACC-3 cohort [1]. The current study aimed to validate the biomarker in a cohort of mCRC patients. Methods 100 mCRC patients treated with 5-FU and leucovorin (FLV) at Sahlgrenska University Hospital from 1996-2013 had mRNA isolated from pretreatment formalin-fixed paraffin embedded tumor tissue and run on Affymetrix HG-133_Plus_2 microarray. The DRP is based on correlations of in-vitro cytotoxicity to 5-FU and consequently correlations to mRNA expression of 3.500 tumors and evaluated blinded to outcome. Primary outcome was progression-free-survival (PFS) at 3 years after treatment with FLV. In addition to variables in the table, right vs left colon cancer vs rectal cancer, age, gender and surgery elective or acute were assessed in the multivariate model. Treatments in the metastatic setting included oxaliplatin and irinotecan from year 2000. To correct for possible selection bias for FLV-treatment, we corrected for treatment year 2000 in the analysis plan. Results The DRP was able to predict benefit of FLV in patients treated after 2000 (n = 73) with a univariate hazard ratio (HR) of 0.60 (95% confidence interval (CI) 0.38-0.93, p = 0.023) for a 50% difference of the DRP. For patients treated before 2000 results were not statistically significant. In the Cox model including all variables, a DRP score of 90 corresponds to a 50% likelihood of 9 months PFS and a score of 32 corresponds to a PFS of 6 months. Table . 644P Multivariate analysis of PFS Variable Level HR 95%-CI P-value DRP, difference of 50 Treatment before 2000 1.24 0.52-3.03 0.63 Treatment after 2000 0.47 0.28-0.78 0.004 Grade of differentiation Medium + high vs low 0.48 0.29-0.80 0.005 Mucinous vs low 0.32 0.13-0.83 0.019 Performance status 2 vs 0-1 2.65 1.41-4.97 0.002 Conclusions In patients treated with 5-FU after 2000 the DRP appears to predict benefit. There are no obvious reasons for the lack of prediction before 2000 but options include mRNA degradation, change in handling of samples, or the selection of older patients after 2000. [1] PLOS ONE; 11(5): e0155123. Legal entity responsible for the study Oncology Venture. Funding Oncology Venture. Disclosure I.K. Buhl: Full / Part-time employment, Shareholder (immediate family): Oncology Venture. B. Gustavsson: Shareholder / Stockholder / Stock options: Isofol. I.J. Christensen: Advisory / Consultancy, Shareholder / Stockholder / Stock options: Oncology Venture. A. Hansen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Oncology Venture. S. Knudsen: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Oncology Venture. P.B. Jensen: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Oncology Venture. All other authors have declared no conflicts of interest.

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...

e20007Background: This study evaluated the predictive effect of a mRNA-based Drug Response Predictor DRP in the adjuvant setting of non-small cell lung cancer (NSCLC). We apply a mathematical metho...

Purpose This study evaluates whether gene signatures for chemosensitivity for irinotecan and 5-fluorouracil (5-FU) derived from in vitro grown cancer cell lines can predict clinical sensitivity to these drugs. Methods To test if an irinotecan signature and a SN-38 signature could identify patients who benefitted from the addition of irinotecan to 5-FU, we used gene expression profiles based on cell lines and clinical tumor material. These profiles were applied to expression data obtained from pretreatment formalin fixed paraffin embedded (FFPE) tumor tissue from 636 stage III colon cancer patients enrolled in the PETACC-3 prospective randomized clinical trial. A 5-FU profile developed similarly was assessed by comparing the PETACC-3 cohort with a cohort of 359 stage II colon cancer patients who underwent surgery but received no adjuvant therapy. Results There was no statistically significant association between the irinotecan or SN-38 profiles and benefit from irinotecan. The 5-FU sensitivity profile showed a statistically significant association with relapse free survival (RFS) (hazard ratio (HR) = 0.54 (0.41–0.71), p

e18502 Background: There are no established biomarkers for prediction of clinical platinum sensitivity. A new platinum response prediction method using multigene expression is reported. Methods: We...

Aim: There is a clinical need for biomarkers of response to adjuvant 5-fluorouracil (5-FU) in colon cancer (CC). The current project seeks to validate a predictive 5-FU gene expression profile. A similar model has recently been validated with MD Anderson in three different clinical settings [1] and with researchers from AstraZeneca with fulvestrant [2]. Methods: The 5-FU profile consisted of in total 205 positively and negatively correlated genes mapped to 669 probe sets (on the ALMAC Colon DSA). This profile was tested using expression data obtained from a Colon DSA gene expression array from ALMAC applied on the PETACC-3 CC population [3] with formalin fixed paraffin embedded (FFPE) tissue from 636 stage III CC patients treated adjuvantly with 5-FU with or without irinotecan. It was also tested on ALMAC Colon DSA data obtained from FFPE tissue from 359 stage II CC patients who did not receive adjuvant treatment [4]. The analyses were performed using Cox proportional hazards (CPH) regression models and Kaplan-Meier curves. The logrank test was used to compare the survival distributions. Results: In the PETACC-3 cohort the 5-FU predictive profile showed a statistically significant association with overall survival (OS) (hazard ratio (HR) = 0.47 (0.34, 0.63), P = 7.4e - 07; binary scores). In the untreated cohort no differences were observed in OS (HR = 0.96 (0.67, 1.4), P = 0.849; binary scores). The statistical significance of the effect of the profile score (as continuous variable) adjusted for several relevant clinicopathological parameters including microsatellite instability (MSI) vs stability (MSS) and KRAS mutation status was confirmed in a multivariable CPH model on the PETACC-3 data (Table). PETACC-3, HR estimates, variables with P HR CI 5FU predict 1 unit = 1 iqr 0.69 0.58, 0.82 T stage T4 vs T3 2.03 1.4, 2.95 N stage N2 vs N1 2.01 1.45, 2.79 grade G34 vs G12 1.81 1.07, 3.07 KRAS mut vs wt 1.89 1.34, 2.67 MSI, MSI vs MSS 0.42 0.21, 0.81 Conclusions: Our data could suggest that the present 5-FU signature provides independent predictive information regarding benefit from adjuvant 5-FU in CC patients. [1] JNCI 2013;105:1284-1291 [2] PLoS One 2014;9:e87415 [3] JCO 2009;27:3117-3125 [4] JCO 2011;29:4620-4626. Disclosure: I.K. Buhl: is affilated, but has no employment nor stock ownership in Medical Prognosis Institute (MPI). T. Jensen: P.B. Jensen, A. Hansen and S. Knudsen: has employment and stock ownership in Medical Prognosis Institute (MPI). All other authors have declared no conflicts of interest.

TPS1139 Background: Cisplatin has shown activity in BRCA associated breast cancer patients but generally the use of cisplatin in breast cancer has been hampered by high toxicity and low response ra...