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Background The aim of this study is to address the paucity of epidemiological data regarding the characteristics, treatment patterns and survival outcomes of Chinese glioblastoma patients. Methods This was a population-level study of Hong Kong adult (>18 years) Chinese patients with newly diagnosed histologically confirmed glioblastoma between 2006 and 2019. The age standardized incidence rate (ASIR), patient-, tumor- treatment-related characteristics, overall survival (OS) as well as its predictors were determined. Results One thousand and ten patients with a median follow-up of 10.0 months were reviewed. The ASIR of glioblastoma was 1.0 per 100 000 population with no significant change during the study period. The mean age was 57 + 14 years. The median OS was 10.6 months (IQR: 5.2–18.4). Independent predictors for survival were: Karnofsky performance score >80 (adjusted OR: 0.8; 95% CI: 0.6–0.9), IDH-1 mutant (aOR: 0.7; 95% CI: 0.5–0.9) or MGMT methylated (aOR: 0.7; 95% CI: 0.5–0.8) glioblastomas, gross total resection (aOR: 0.8; 95% CI: 0.5–0.8) and temozolomide chemoradiotherapy (aOR 0.4; 95% CI: 0.3–0.6). Despite the significant increased administration of temozolomide chemoradiotherapy from 39% (127/326) of patients in 2006–2010 to 63% (227/356) in 2015–2019 (P-value < .001), median OS did not improve (2006–2010: 10.3 months vs 2015–2019: 11.8 months) (OR: 1.1; 95% CI: 0.9–1.3). Conclusions The incidence of glioblastoma in the Chinese general population is low. We charted the development of neuro-oncological care of glioblastoma patients in Hong Kong during the temozolomide era. Although there was an increased adoption of temozolomide chemoradiotherapy, a corresponding improvement in survival was not observed.

Dietary factors show different effects on genetically diverse populations. Scientific research uses gene-environment interaction models to study the effects of dietary factors on genetically diverse populations for lung cancer risk. However, previous study designs have not investigated the degree of type I error inflation and, in some instances, have not corrected for multiple testing. Using a motivating investigation of diet-gene interaction and lung cancer risk, we propose a training and testing strategy and perform real-world simulations to select the appropriate statistical methods to reduce false-positive discoveries. The simulation results show that the unconstrained maximum likelihood (UML) method controls the type I error better than the constrained maximum likelihood (CML). The empirical Bayesian (EB) method can compete with the UML method in achieving statistical power and controlling type I error. We observed a significant interaction between SNP rs7175421 with dietary whole grain in lung cancer prevention, with an effect size (standard error) of -0.312 (0.112) for EB estimate. SNP rs7175421 may interact with dietary whole grains in modulating lung cancer risk. Evaluating statistical methods for gene-diet interaction analysis can help balance the statistical power and type I error.

Understanding the differences in outcomes based on study and patient characteristics can inform better research designs and improve the interpretation of translational glioblastoma studies. This study compared the clinical features and median overall survival (mOS) of 2,203 patients from two genomic cohorts (The Cancer Genome Atlas [TCGA] and the Chinese Glioma Genome Atlas [CGGA]) and two consecutive regional cohorts (Hong Kong [HK] and Southeast [SE] Scotland) with histologically confirmed glioblastoma. Differences in clinical characteristics reflected the distinct patient selection criteria for surgery. While the mOS were similar, the mOS of those who completed temozolomide chemoradiotherapy were 35.2 months in SE Scotland, 22.2 in HK, and 14.1 in the TCGA cohort. Survival functions were comparable in the multivariable survival analysis. Our findings highlight how a lack of clinical data impedes the translational value of research. Therefore, there is a need to develop common data elements to derive meaningful conclusions.

The synergy between locoregional therapies and immune checkpoint inhibitors has not been investigated as conversion therapy for unresectable hepatocellular carcinoma. We aimed to investigate the activity of sequential transarterial chemoembolisation (TACE) and stereotactic body radiotherapy followed by avelumab (an anti-PD-L1 drug) for locally advanced, unresectable hepatocellular carcinoma.START-FIT was a single-arm, phase 2 trial in patients with locally advanced hepatocellular carcinoma who were not suitable for curative treatment, conducted in two hospitals in Hong Kong and one in Shenzhen, China. Eligible patients were those aged 18 years or older with an Eastern Cooperative Oncology Group performance status 0-1, Child-Pugh liver function score A5 to B7, tumour size of at least 5 cm, a maximum of three tumour lesions, and adequate hepatic, renal, and bone marrow function. Participants received TACE on day 1, followed by stereotactic body radiotherapy (27·5-40·0 Gy in five fractions) at day 28. Avelumab (10 mg/kg) was administered 14 days following stereotactic body radiotherapy and every 2 weeks thereafter. The primary endpoint was the proportion of patients deemed amenable to curative treatment, defined as those who had a sustained complete or partial treatment response for at least 2 months and if curative treatment could be performed (ie, resection, radiofrequency ablation, or transplantation), analysed by intention to treat. Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03817736) and has been completed.Between March 18, 2019, and Jan 27, 2021, 33 patients (32 [97%] men and one [3%] woman) were enrolled. The median sum of the largest diameters of lesions was 15·1 cm (IQR 8·3-14·9). 21 (64%) patients had macrovascular invasion (hepatic vein [n=13], branched portal vein [n=3], or both [n=5]). Median follow-up was 17·2 months (IQR 7·8-25·8). 18 (55%) patients were deemed amenable to curative treatment: four (12%) of 33 patients had curative treatment (resection [n=2] or radiofrequency ablation [n=2]), and 14 (42%) had a radiological complete response and opted for close surveillance. 11 (33%) of 33 patients had treatment-related adverse events that were grade 3 or worse. The most common treatment-related grade 3 or worse adverse event was transient increase in alanine aminotransferase or aspartate aminotransferase (five [15%]) after TACE. Five (15%) patients developed immune-related adverse events of grade 3 or worse (three had hepatitis, two had dermatitis).To our knowledge, this is the first prospective trial using the combination of immunotherapy and locoregional treatment as conversion therapy for locally advanced unresectable hepatocellular carcinoma, with promising results. Future randomised trials with larger cohorts of patients are warranted.Merck.

An increasing number of breast cancer survivors (BCS) use traditional Chinese medicine (TCM) throughout their cancer journey. There is emerging evidence that TCM is effective in the reducing side effects of chemotherapy. However, qualitative patient-centric and culturally relevant research into TCM use is scant. This qualitative study aimed to explore the use and perceptions of Chinese Hong Kong BCS using TCM.Participants were recruited from a university hospital and three breast cancer patient groups in Hong Kong. Questionnaires regarding the use of TCM were given to all participants, followed by individual semi-structured interviews on selected BCS to comprehensively understand TCM's use and perceptions. A greater emphasis was placed on the qualitative data.About half of the participants (n = 67, 48.9%) used TCM during their cancer treatment journey, among which almost all (n = 64, 95.5%) had improved symptoms. Sleeping disturbances (n = 58, 86.6%) and fatigue (n = 53, 79.1%) were the two most common symptoms that improved after TCM. Interview data revealed that participants used TCM to satisfy unmet needs that mainstream conventional Western medicine could not fulfil. They wished for a sense of control and better well-being. They expressed improvements in physical and psychological well-being after the use of TCM. Despite existing barriers, including high cost, long duration of treatment, and disapproval from oncologists, most would still recommend TCM to fellow survivors.Chinese Hong Kong BCS who used TCM reported positive experiences. Understanding how BCS perceive and use TCM is important to integrating TCM into survivorship care in this population.

Background We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide. Methods We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours. Results Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10–300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1–2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3–18) weeks. Four of 18 evaluable patients (22%) had stable disease. Conclusions Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers.

BackgroundWe conducted this study to evaluate if a reduced cumulative dose of induction and concurrent cisplatin conferred similar favorable outcomes when compared to trial NPC-0501.MethodsNewly diagnosed nasopharyngeal carcinoma (NPC) with stage III-IVA were prospectively recruited from January 2015 to September 2019. Induction chemotherapy (IC) consisted of cisplatin 80mg/m2 on day 1 and capecitabine 1000mg/m2 twice daily from day 1 to 14 every 3 weeks for 3 cycles followed by concurrent chemoradiotherapy (CCRT) with 2 cycles of cisplatin 100mg/m2 given every 3 weeks. Tumor response was evaluated according to RECIST v1.1. Acute and late adverse events (AEs) were graded with CTCAE v4.0 and Late Radiation Morbidity Scoring of the RTOG, respectively.Results135 patients were recruited. At 16 weeks after CCRT, all 130 patients who completed the entire course of radiotherapy (RT) had a complete response upon final assessment. With a median follow-up of 36.2 months, 22 treatment failures and 8 deaths were observed. The 3-year progression-free survival, overall survival, locoregional recurrence-free survival, and distant recurrence-free survival were 83.7%, 94.1%, 94.1%, and 85.9%, respectively. Our survival data outcomes were similar to those reported in the cisplatin and capecitabine (PX) induction arm of the 0501 trial. 103 patients (76.3%) reported acute grade 3-4 AEs. Two patients (1.5%) had late grade 3-4 complications, numerically fewer than those reported in the NPC-0501 trial.ConclusionsInduction PX and concurrent cisplatin with a reduced cumulative cisplatin dose yield survival outcomes comparable to those reported in the NPC-0501 trial with excellent tolerability. Therefore, a reduced cumulative dose of cisplatin is a promising treatment scheme for nasopharyngeal carcinoma.

BackgroundThe efficacy of anti-angiogenic agents (AAAs) in epithelial ovarian cancer (EOC) remains unclear. Therefore, we conducted a systematic review and network meta-analysis (NMA) to synthesize evidence of their comparative effectiveness for improving overall survival (OS) among EOC patients. MethodsWe searched six databases for randomized controlled trials (RCTs) from their inception to February 2021. We performed a NMA with hazard ratios (HRs) and 95% confidence intervals (CIs) to evaluate comparative effectiveness among different AAAs in two disease settings, chemotherapy naïve, and recurrent EOC. P-score was used to provide an effectiveness hierarchy ranking. Sensitivity NMA was carried out by focusing on studies that reported high-risk disease chemotherapy-naïve, platinum-resistant, and platinum-sensitive EOC. The primary outcome was OS.FindingsWe identified 23 RCTs (n=11,560) which assessed effectiveness of eight different AAAs. NMA results showed no significant OS difference among anti-angiogenic agents in chemotherapy-naïve. In recurrent EOC, concurrent use of trebananib (10mg/kg) and chemotherapy was likely to be the best option (P-score: 0.88, NMA estimate versus chemotherapy: HR= 1.67, 95% CI: 0.94; 2.94). The sensitivity NMA indicated that bevacizumab plus chemotherapy with maintenance treatment (P-score: 0.99) and pazopanib plus chemotherapy (P-score: 0.79) had the highest probability of being the best intervention for improving OS in high-risk chemotherapy-naïve and platinum-resistant setting, respectively. InterpretationAAAs may not play a significant clinical role in chemotherapy-naïve and platinum-sensitive EOC. Conversely, the concurrent use of trebananib with chemotherapy was likely to be the best intervention in recurrent EOC.

We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide.We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours.Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10-300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1-2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3-18) weeks. Four of 18 evaluable patients (22%) had stable disease.Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers.

Non-epithelial cancers arising from the ovary are uncommon malignancies. Germ cell tumors of the ovary arise from primordial germ cells, and sex cord-stromal tumors of the ovary represent a cluster of tumors arising from the sex cord and stromal compartment. Most patients diagnosed with germ cell tumors are young adults and adolescent females. In contrast, ovarian sex cord-stromal tumors more commonly occur in a mature age group. Advances in the adjuvant management of non-epithelial ovarian cancer following optimal surgical and pathological staging have improved patient survival outcomes. In addition, active surveillance is preferentially assigned to patients diagnosed with stage I germ cell tumor, stage 1A grade 1 immature teratoma, stage 1A yolk sac tumor, and stage 1AI sex cord-stromal tumors. This article discusses the importance of selecting the adjuvant treatment approach most suitable to the patients' surgical and pathological stages, thereby safeguarding patient outcomes.

e18029 Background: Patients with recurrent or metastatic nasopharyngeal cancer (R/M NPC) who failed platinum-based chemotherapy have poor prognoses. We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor (TGF)-βRII receptor fused to a human IgG1 antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated R/M NPC. Tumor and plasma-based biomarkers were investigated in an exploratory analysis. Methods: Eligible patients had histologically confirmed NPC that had recurred at distant sites and were not amenable to curative treatment. All patients received at least one prior line of platinum-based chemotherapy for recurrent disease. Patients were treated with bintrafusp alfa (1200mg every 2 weeks) until disease progression. The sample size was estimated to assume a 40% objective response rate (ORR) to bintrafusp alfa compared with 20% for checkpoint inhibitors. Modified Simon two-stage optimal design was used (power, 80%; a = 0.05; P0 = 0.20; P1 = 0.40; n1 = 18; n = 33 with an additional five patients to allow for ineligibility or other reasons). The primary endpoint was ORR and secondary endpoints included survival and toxicity. Expression of PD-L1 in archived tumors, plasma clearance of Epstein-Barr virus (EBV) DNA, plasma clearance of TGF-β, and exosomal PD-L1 were assessed for a potential correlation with ORR. (NCT 04396886). Results: Out of 43 patients screened, 38 patients were enrolled. After a median follow-up of 14.9 months (range: 1.6-23.3 months), the confirmed ORR was 23.7% (95% CI: 12.4-38.8%) (complete response, n = 1; partial response, n = 8). The median treatment duration was 1.8 months (range: 0.5-14.3 months). 8 patients (21.1%) and 2 patients (5.3%) received bintrafusp alfa for > 6 months and > 12 months respectively. The 1-year overall survival (OS) rate was 57.5% (95% CI, 40.2% to 71.5%) and 1-year progression-free survival rate was 23% (95% CI, 10.1% to 39.4%). ORR was higher in patients with a decreasing trend in EBV-DNA at week 4 (40% vs. 6.3%, p = 0.02), whereas high exosomal PD-L1 levels at week 4 were predictive of worse ORR (5.3% vs. 41.7%, p = 0.012). There were no associations between clinical outcome and tissue PD-L1 expression (p = 0.952) or plasma TGF-β clearance (p = 0.28). 16 patients (42.4%) experienced ≥ grade 3 treatment-related adverse events, most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). Conclusions: Bintrafusp alfa has promising activity in heavily pretreated R/M NPC and a favorable 1-year OS rate, though the observed activity was not as high as the study initially aimed. The biomarker results warrant validation in larger cohorts. Clinical trial information: NCT04396886.

SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials.

Introduction: 40-45% of patients with High Grade Serous Ovarian Cancer (HGSOC) will eventually relapse with platinum resistant disease. Tothill et al and TCGA are two independent gene expression datasets which have demonstrated the presence of a mesenchymal molecular subgroup, characterised by upregulation of angiogenesis regulating genes. Angiogenesis is known to be an integral pathological feature of HGSOC and anti-angiogenics have dominated the field of drug development in EOC. However, despite this, anti-angiogenic agents have failed to demonstrate a significant impact on overall survival (OS) benefit. In this study, we asked if platinum resistance could be associated with an improved response to anti-angiogenic agents and what the underlying biological rationale for this could be. Methods: A meta-analysis of 14 phase II and III clinical trials in EOC were used to investigate the association between platinum resistance and response to anti-angiogenic agents. In addition, we analysed gene expression in 12 matched pre- and post-chemotherapy EOC samples. Novel isogenic cisplatin-resistant HGSOC cell lines were established to study the development of an angiogenic phenotype. Further studies were performed in novel ascites-derived primary cell lines from HGSOC patients with known outcomes following platinum-based chemotherapy. Result: In the clinical trial meta-analysis, an OS benefit for antiangiogenics was observed in platinum-resistant disease (p=0.029), whilst platinum-sensitive EOC only derived progression free survival (PFS) (p= Discussion: We have demonstrated that previous platinum therapy for EOC is associated with an increase in tumor PDGFα and VEGF-A expression, correlating with a response to anti-angiogenic therapies. This data suggests that platinum therapy resistance may inform the selection of EOC patients for novel antiangiogenic therapies in future clinical trials. Citation Format: Aya El Helali, Nuala McCabe, Christopher Steele, Lara Dura Perez, Christina L. O'Neill, Naomi Dickson, Niamh McGivern, Caolan Harkin, Andrena McCavigan, Reinhold J. Medina, Laura A. Knight, Stephen McQuaid, Jacqueline A. James, Caroline O. Michie, Charlie Gourley, W Glenn McCluggage, Denis P. Harkin, Richard H. Wilson, Alan W. Stitt, Richard D. Kennedy. Platinum resistance in epithelial ovarian cancer is dependent on a PDGFR alpha-VEGF-A signalling mechanism that activates downstream angiogenesis pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 7.

5578Background: Patients with High Grade Serous Ovarian Cancer (HGSOC) initially respond to SOC platinum based treatment but most will eventually relapse with platinum resistant disease. Angiogenes...

12111Background: Unsupervised hierarchical clustering of gene expression data from 265 high grade serous ovarian cancer (HGSOC) patients identified 3 major molecular subgroups. One subgroup is driv...

Introduction: Platinum resistant High Grade Serous Ovarian Cancer (HGSOC) has a poor outcome with limited treatment options. Angiogenesis is a key pathological feature of ovarian cancer and anti-angiogenics have dominated the field of drug development in EOC, particularly in the second-line setting (Marachini et al 2013). In this study we asked if platinum resistance could be associated with an improved response to anti-angiogenic agents. Method: A review of phase III anti-angiogenic clinical trials was used to investigate the association between platinum resistance and response to anti-angiogenic agents. To investigate the effect of chemotherapy on predefined ovarian cancer molecular subgroups (Gourley, et al. J Clin Oncol 32:5s, 2014), we analysed 35 matched pre- and post-chemotherapy samples by gene expression. Novel isogenic cisplatin-resistant HGSOC cell lines were established to study the mechanisms of cisplatin section pressure and shift to an angiogenic phenotype. This was further validated in novel ascites-derived primary cell lines from HGSOC patients with known outcomes following platinum-based chemotherapy. Results: Critical review of 22 phase III anti-angiogenic trials suggested that there was a better response to anti-angiogenics following previous platinum-based chemotherapy. Our analysis demonstrated that 67% of treatment naïve tumours that were initially classified as non-angiogenic shifted to an angiogenic biology, which was associated with platinum resistance. Additionally we found that cisplatin resistant cancer cell lines demonstrated hallmarks of vascular mimicry and an associated increase in vessel density using an angiogenesis Matrigel plug assay in Athymic nude mice (p-value= Conclusion: We have demonstrated that platinum-resistance in HGSOC is associated with angiogenic biology supporting the use of anti-angiogenic agents in this setting. Citation Format: Aya El Helali, Nuala McCabe, Naomi Dickson, Lara Dura Perez, Denis P Harkin, Richard Wilson, Richard Kennedy. Acquired platinum resistance enhances tumour angiogenesis through activation of vascular mimicry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 776. doi:10.1158/1538-7445.AM2017-776

INTRODUCTION Unsupervised hierarchical clustering of gene expression data from 265 High Grade Serous Ovarian Cancer (HGSOC) patients identified 3 major molecular subgroups. One subgroup is driven by activation of the MAPK pathway and is associated with poor prognosis and resistance to platinum chemotherapy. The MAPK pathway is currently being targeted by novel therapeutics and hence an assay to detect activation of the pathway across cancers would be highly valuable as a clinical trial enrichment tool. Using internal and publicly available gene expression datasets we have demonstrated that the MAPK subgroup also exists in other cancer types and is associated with poor prognosis. The aim of this study was to develop a gene expression signature to predict the MAPK subgroup across multiple cancer types. METHODS Evaluation of gene expression data in a range of tumours (ovarian, colon, lung, melanoma and prostate) identified a common gene list (CGL) of 7802 genes showing high variability and high expression across diseases. The CGL was input to different machine learning algorithms developing signatures under 10x5-fold cross-validation (CV), trained against the MAPK HGSOC subgroup. Filter-Feature-Selection removed 10% of genes under CV based upon ranked correlation adjusted t-scores and the final model selected to satisfy a number of key criteria: AUC for predicting the endpoint; association with survival (C-Index); and functional relevance of signature content. RESULTS A 15 gene signature was selected, yielding an AUC=0.87 [95% CI:0.84-0.89] with respect to the MAPK subgroup. This model has validated as a poor prognostic marker in several other cancer types (Colorectal, Relapse free survival: HR=1.46 [95% CI:1.07-1.98]; Lung, Relapse free survival: HR=2.18 [95% CI:1.33-3.56]; Prostate cancer, Biochemical recurrence: HR 2.49 CI: 1.43-4.34), and is suppressed by MEK inhibition (p=0.0023) and elevated by KRAS, NRAS and MEK1 overexpression in cell line models (p=0.0443, CONCLUSION A 15 gene signature has been developed from formalin fixed paraffin embedded samples across multiple diseases to detect a molecular subgroup driven by MAPK signalling. This assay predicts sensitivity to MEK inhibitors in pre-clinical model systems and in primary cells derived from patients. Further work aims to validate the signature in clinical samples from patients treated with a MEK inhibitor. This assay may be helpful for clinical trial enrichment to select patients that are likely to benefit from MAPK targeted therapies. Citation Format: Laura A. Knight, Bethanie Price, Andrena McCavigan, Aya El-Helali, Charlie Gourley, Denis P. Harkin, Richard Kennedy, Nuala McCabe. Development of a pan-cancer 15 gene expression signature to detect a subgroup driven by MAPK signalling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1777. doi:10.1158/1538-7445.AM2017-1777

BACKGROUND: We previously defined 3 molecular subgroups of High Grade Serous Ovarian Cancer (HGSOC), using gene expression data from 265 FFPE samples obtained from treatment naive patients, who received platinum based treatment following surgical resection. The 3 molecular subgroups were Angio: characterised by upregulation of angiogenesis genes; Immune: characterised by upregulation of immune genes and AngioImmune: characterised by upregulation of angiogenesis and immune genes. Patients within these 3 subgroups respond differently to standard of care treatment The Immune subgroup have the best prognosis and the Angio and AngioImmune subgroups have similar worse prognosis. A weighted gene signature to identify each of the molecular subgroups was developed. This dataset was used as a reference to investigate the effect of chemotherapy on molecular subgroup designation. METHODS: To investigate the effect of chemotherapy on predefined molecular subgroups, we analysed 35 matched pre- and post- chemotherapy samples by gene expression. The molecular subgroup assignment for each of the paired samples was determined using the gene expression signatures for each subgroup. Novel cisplatin resistant HGSOC cell lines were generated to study the mechanisms of acquired cisplatin resistance. RESULTS: 40% of the treatment naive samples that were aligned with the AngioImmune subgroup and this increased to 67.5% post-chemotherapy. 10/15 (67%) treatment naïve tumours that were initially assigned to the good prognostic Immune molecular subgroup shifted to the bad prognostic AngioImmune molecular subgroup post chemotherapy. Hence platinum chemotherapy selects for the AngioImmune subgroup, suggesting that this subgroup represents tumours which are innately platinum resistant but also provides a mechanism of acquired resistance. Additionally we demonstrate that the AngioImmune subgroup is driven by activation of the MAPK pathway and shows that cisplatin resistant HGSOC cell lines are specifically sensitive to MEK inhibitors. CONCLUSIONS: The MAPK pathway is a mechanism of innate and acquired platinum resistance in HGSOC. Furthermore the data suggests that original pre-treatment surgical/biopsy samples may fall within a different molecular subgroup to samples taken post-platinum therapy. Citation Format: Aya El-Helali, Nuala McCabe, Charlie Gourley, Andrena McCavigan, Caroline O. Michie, Bethanie Price, Niamh McGivern, Michael Churchman, Aya El-Helai, Eamonn J. O'Brien, Laura Hill, Timothy S Davison, Alistair Williams, W Glenn McCluggage, Katherine E Keating, Denis P Harkin, and Richard Kennedy. IDENTIFICATION OF A MOLECULAR SUBTYPE OF HIGH GRADE SEROUS OVARIAN CANCER REPRESENTING MAPK PATHWAY ACTIVATION AND PLATINUM RESISTANCE [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-055.

11616 Background: Epithelial–mesenchymal transition (EMT) is the conversion of epithelial cells to mesenchymal cells and involves loss of cell–cell adhesion and cell polarity and increased motility, invasiveness and metastases. The EMT process has therefore been under investigation as a new target for anticancer drug discovery. The aim of this work was to develop an EMT biomarker suitable for formalin-fixed paraffin embedded (FFPE) tissue that could be used for patient treatment selection. Methods: Unsupervised hierarchical clustering of ovarian cancer gene expression data (TCGA. 2011) previously identified an EMT subgroup. We confirmed this EMT subgroup in FFPE tissue using 265 high grade serous ovarian cancer (HGSOC) FFPE samples. The analysis was extended to show existence of an EMT subgroup across a range of solid tumours including colon, lung, melanoma and prostate cancer. Further to this, a common gene list was generated to include only transcripts with high variability and expression across diseases, and used as a starting list for development of a 15 transcript assay which can be used to prospectively identify the EMT subgroup from archived tissue. Results: The 15 gene expression assay was a poor prognostic marker in Colorectal, (Relapse free survival: HR = 1.46 [95% CI:1.07-1.98]); Lung, (Relapse free survival: HR = 2.18 [95% CI:1.33-3.56]); Prostate cancer, (Biochemical recurrence: HR 2.49 CI: 1.43-4.34) and was associated with activated MAPK (phospho-MAPK) in preclinical models and clinical samples (p < 0.05). The assay score was reduced by MEK inhibition (p < 0.05) and elevated by KRAS, NRAS and MEK1 overexpression (p < 0.05). The assay predicted response to the MEK inhibitors Trametinib and Selumetinib in cell line models (p < 0.001). Conclusions: A 15 gene expression assay has been developed from FFPE samples across multiple diseases to detect an EMT molecular subgroup associated with MAPK signalling. The assay predicted sensitivity to MEK inhibitors in pre-clinical model systems. Further work aims to validate the assay as a predictive biomarker in clinical samples from patients treated with EMT or MEK targeted therapies.

e16101 Background: Treatment with Abiraterone acetate (AA) combined with prednisolone has proven benefit in overall survival compared with prednisolone alone in men with metastatic castration resis...

Journal of Thoracic Oncology • Volume 7, Number 10, October 2012 A 65-year-old male patient with stage IIIB non–small-cell lung cancer (squamous cell carcinoma) treated with palliative chemotherapy (carboplatin area under the curve = 5 Day 1, gemcitabine 1250 mg/m Day 1, Day 8 every 21 days), presented on day 10 after cycle 3 of chemotherapy with progressive worsening, including shortness of breath, cough upon drinking fluids, and fever. His pretreatment staging computed tomography (CT) scan showed bulky subcarinal and mediastinal lymphadenopathy (Fig. 1A, white arrow). Upon presentation with the above symptoms, a computed tomography scan of the thorax showed the presence of a fistula (Fig. 1B, white arrow) between the esophagus (single asterisks) and left main bronchus (double asterisks) with evidence of aspiration pneumonia. Subsequently, a bronchial stent was placed in the left main bronchus (Fig. 1C, white arrows) with improvement of his symptoms. The patient did not receive any further systemic treatment because of worsening performance status. He was discharged to the community palliative care team for further management and died 3 months after his presentation and stent placement.