Niamh Coleman

CNS cancer immunity cycle and strategies to target this for glioblastoma

Immunotherapeutics have revolutionized the management of solid malignancies over the last few years. Nevertheless, despite relative successes of checkpoint inhibitors in numerous solid tumour types, success in tumours of the central nervous system (CNS) has been lacking. There are several possible reasons for the relative lack of success of immunotherapeutics in this setting, including the immune microenvironment of glioblastoma, lymphocyte tracking through the blood-brain barrier (BBB) into the central nervous system and impairment of drug delivery into the CNS through the BBB. This review utilizes the cancer-immunity cycle as a conceptual framework through which the specific challenges associated with the development of immunotherapeutics for CNS malignancies can be viewed.

Development of Molecularly Targeted Agents and Immunotherapies in Glioblastoma: A Personalized Approach:

Over the past decade, precision cancer medicine has driven major advances in the management of advanced solid tumours with the identification and targeting of putative driver aberrations transforming the clinical outcomes across multiple cancer types. Despite pivotal advances in the characterization of genomic landscape of glioblastoma, targeted agents have shown minimal efficacy in clinical trials to date, and patient survival remains poor. Immunotherapy strategies similarly have had limited success. Multiple deficiencies still exist in our knowledge of this complex disease, and further research is urgently required to overcome these critical issues. This review traces the path undertaken by the different therapeutics assessed in glioblastoma and the impact of precision medicine in this disease. We highlight challenges for precision medicine in glioblastoma, focusing on the issues of tumour heterogeneity, pharmacokinetic-pharmacodynamic optimization and outline the modern hypothesis-testing strategies being undertaken to address these key challenges.

MGMT promoter methylation status: time for a frank discussion

tumour cells, and which demonstrate the best associations with treatment outcome and patient survival. Various MGMT-MS techniques are currently in use, designed to detect methylated (or unmethylated) CpGs; this is under the assumption that methylation of these CpGs reflects protein expression and can thus be predictive of temozolamide response. The CpG island of MGMT includes 98 CpG sites [3] and patterns of methylation are heterogeneous. Typically, cut-off values for differentiating the MGMT-MS represent a technical cut-off, and are set as the nadir of the logarithmic distribution curve of quantitative methylation values taken from a large number of test results. MGMT-MS techniques in use include MSP, the MethyLight Assay, pyrosequencing, methylation-specific multiplex ligation-dependent probe amplification, and protein immunohistochemistry analysis on surgical pathology specimens. These assays were designed to detect completely methylated or unmethylated alleles, denying the reality of partial allelic methylation. In sensitive methods, methylated or unmethylated alleles are detected by designing primers overlapping multiple CpG dinucleotides. In quantitative methods, primers are designed to amplify both methylated and unmethylated alleles with equal efficiency, and the methylation level is analyzed. Sequence specificity of the primers and probes are not always perfect, and due to the incomplete elimination of residual amplification of unmethylated DNA, quantification of methylated DNA is not accurate, but approximate. Furthermore, MSP-based assays detect only methylation sites within the selected primer and probe regions, and cannot detect other sites excluded in the test design. To investigate the clinical implications of the inconsistency in MGMT-MS testing in clinical trials, and to determine if local testing within our service correlated with To the Editor,

Abstract CT067: 2-hydroxyoleic acid (2-OHOA), a novel activator of sphingomyelin synthase with antitumor activity in refractory glioblastoma: results of the first-in-human dose-escalation (DE) study in patients with advanced solid tumors (AST) and refractory gliomas/glioblastomas

Background: 2-OHOA, is a synthetic hydroxylated lipid that activates sphingomyelin synthase and regulates the lipid content of cell membranes resulting in translocation of Ras to the cytoplasm and inactivation of Ras/MAPK, PI3K/Akt and PKC/cyclin/CDK signaling pathways. 2-OHOA causes autophagic cell death of glioma cell lines in vitro, and reduces tumor growth in numerous xenograft mice models including glioblastoma (GBM), prostate, leukemia, breast and colon cancer. It also crosses the blood brain barrier. This first-in-human trial was designed to determine the safety, tolerability, and recommended phase 2 dose (RP2D), alongside the pharmacokinetic (PK), pharmacodynamic (PD) and anti-tumor profile of 2-OHOA. Methods: Eligible pts with AST or GIII/IV gliomas/glioblastomas received 2-OHOA as a daily PO suspension in 21 day cycles using a 3+3 DE design. Adverse events (AE) were assessed by CTCAEv4; Tumor response was assessed every 2 cycles using RECIST 1.1/RANO criteria. Results: 32 pts were enrolled on the DE stage. 28 pts were evaluable for safety (13 gliomas and 15 AST). Pts were treated with doses from 500mg-16g/day in 7 cohorts. Drug-related AEs >Grade 3 of nausea, vomiting and diarrhea (n = 6) were seen at high doses. DLTs were diarrhea (n = 3) and vomiting (n = 1) at 12 and 16g/day. Extent of exposure (AUC) was generally proportional to the dose. The PK profile showed dose accumulation from 8g/day. Average t1/2 ranged from 1-2h to 8-12h with longer half-lives seen at higher doses Steady state was reached with 12 and 16g/day. 4 pts had clinical benefit for >6mo, 25% of refractory GBM patients treated (3/12) had objective responses by RANO criteria : 1 partial response (PR) and 2 stable disease (SD). The GBM pt with confirmed PR was treated at 1g/daily for 41 cycles and continues on treatment; the other 2 GBM pts were treated at 12g/day and had SD for 9 cycles. Conclusions: The MTD and RP2D of 2-OHOA is 12g/daily. Clinical benefit was observed in 4 pts including durable responses in 25% of advanced treatment-refractory GBM pts treated. Recruitment is ongoing including an expansion cohort for advanced gliomas/glioblastomas. Clinical trial information: NCT01792310 Citation Format: Juanita S. Lopez, Mariane Fontes, Niamh Coleman, Analia Azaro, Yvette Drew, Pablo Escriba, Xavier Busquets, Gareth Veal, Vicenc Tur, Antoine Perier, Elisabet Sicart, Rhoda Molife, Ruth Plummer, Jordi Rodon. 2-hydroxyoleic acid (2-OHOA), a novel activator of sphingomyelin synthase with antitumor activity in refractory glioblastoma: results of the first-in-human dose-escalation (DE) study in patients with advanced solid tumors (AST) and refractory gliomas/glioblastomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT067.

Abstract P1-07-09: Retrospective cohort study of patients (pts) diagnosed with breast cancer (BC) <40 yrs: 2000 to 2015〈

Background Young women ( Methods YWBC were identified from pathology databases at 2 tertiary centers. Pts were divided into 2 cohorts: BC diagnoses from 2000-2007 (G1) and 2008-2015 (G2). ClinPath and Rx data were retrieved from clinical, radiology and histology databases. Statistical analysis was performed using SPSS. Results We identified 347 pts. Tumor features are shown in Table I. Median age is 36 (23-39). By histology, 90.8% (n=315) had invasive ductal carcinoma, 53.1% (n=181) had Grade III BC and 56.3% (n=171) had lymphovascular invasion. Pregnancy-associated BC occurred in 10.7% (n=34). Mastectomy (MX) was performed in 53% (n=176) and axillary lymph node clearance (ALNC) in 63.8% (n=192 [G1: 84.3% vs. G2: 48.6%, p Rx characteristics are shown in Table 2. 85 pts received neo-adjuvant therapy (NAT); 48.3% (n=41) ER+/HER2-, 27% (n=23) HER2+ and 24.7% (n=21) TNBC. Pts receiving NAT in G2 trended towards improved pCR rate (G2: 24.6% vs G1: 8.3%, p=0.057). Endocrine Rx alone was received by 9.8% (n=22); 13.6% (n=18) in G2 vs 4.3% (n=4) in G1. OncotypeDx(ODx) was used in 23 pts (14.9%) (median score 17), 1 had a DR (ODx Score = 18). DR occurred in 50 pts (16%), including 13 (20.3%) HER2+ pts. Of note, 92.3% (n=12) of these were in G1. Relapse rates (RR) in TN and ER+/HER- pts were 19.6% (n=11) and 13.7% (n=26) respectively. There was a higher RR in G1 (34.8% vs 11.4%, p Conclusion In line with existing data, locally advanced dx is more prevalent in YWBC. MX and ALNC rates were high and most received multimodal Rx. The extent of axillary surgery declined. Pts in G2 had lower volume BC at diagnosis suggesting increasing awareness. TN and HER2+ subtypes accounted for a slightly higher proportion of BC cases. Pts with PCR had better outcomes. Only 16% relapsed with metastatic dx. The impact of HER2 Rx is highlighted by reduced RR in HER2+ G2 pts. Outcomes were unchanged in pts with ER+/HER2- and TNBC. These remain a priority for future research. Citation Format: Greally M, Kielty J, Das G, Malouf C, O9Riordan L, Coleman N, Quinn C, McDermott E, Gullo G, Kelly C, Crown J, Prichard R, Walshe J. Retrospective cohort study of patients (pts) diagnosed with breast cancer (BC)

Does interval from histologic diagnosis (Dx) to start of chemotherapy (Ctx) impact survival in metastatic colorectal cancer (MCRC)

615 Background: Optimal timing from colorectal surgery to initiation of adjuvant chemotherapy is between 4 to 6 weeks based on recent data. In MCRC, therapeutic benefits of ctx are frequently calculated from start of treatment. We investigated whether the interval between dx and commencement of ctx influences overall survival (OS) in patients (pts) with MCRC. Methods: Pts with CRC were identified from the institutional database. Inclusion criteria were MCRC and receipt of ctx. Clinicopathologic details were collected. Intervals from histologic dx to ctx were calculated. Analyses were based on receipt of ctx within 4 weeks (w), 5-8w and > 8w of dx. Survival was compared between groups. OS was presented as hazard ratio (HR) with associated p value. Results: Between 2003 and 2013, 123 pts were identified, where 58 pts receive ctx within 4w, 38 within 5-8w and 27 > 8w. Median OS (mOS) was 8.7, 15.7 and 13.7 months (mths) respectively. Improvement in OS was noted in pts treated 5-8w and >8w compared to within ...