Chee Lee

511PMOLECULAR SUBGROUPS FROM THE AGITG MAX TRIAL; RIGHT OR LEFT PRIMARY SITE OF COLORECTAL CANCER AND OUTCOMES FOR METASTATIC COLORECTAL CANCER (MCRC)

ABSTRACT Aim: Previous reports have described differences in biology and outcome based on whether the primary is right (R) or left (L) sided. Possible differences in response to biological agents have also been reported based on side of primary lesion.1,2 We have previously published molecular markers from the MAX trial and here we have assessed the panel of markers based on right or left primary site. Methods: We analysed the MAX trial of capecitabine v capecitabine/bevacizumab (+/-mitomycin C) for differences in patient characteristics, molecular profile and outcomes based on whether the primary was R (caecum to transverse colon) or L (descending colon to rectum) sided. Survival outcomes were analysed using Kaplan-Meier curves and proportional hazards regression modeling. Results: 440 patients had primary site documented and were analysed for baseline characteristics. 298 patients had molecular results. 28% had R sided primary. Major differences between R and L respectively are as follows; female 49% v 33% (p Conclusions: There are more negative prognostic factors in patients with R sided primary, in particular high BRAF MT, and these patients have inferior overall survival when compared to those with a L sided primary. There was no suggestion that site of primary had any impact on bevacizumab effect on PFS. 1SY Brule et al, J Clin Oncol 31, 2013 (supp #3528) 2MK Boisen et al, Ann Oncol 24, 2554-59 Disclosure: T.J. Price: Advisory board for Roche. All other authors have declared no conflicts of interest.

The prognostic impact of Consensus Molecular Subtypes (CMS) and its predictive effects for bevacizumab benefit in metastatic colorectal cancer: molecular analysis of the AGITG MAX clinical trial

Background The consensus molecular subtypes (CMS) is a transcriptome-based classification of colorectal cancer (CRC) initially described in early-stage cohorts, but the associations of CMS with treatment outcomes in the metastatic setting are yet to be established. This study aimed to evaluate the prognostic impact of CMS classification and its predictive effects for bevacizumab benefit in metastatic CRC by correlative analysis of the AGITG MAX trial. Patients and methods The MAX trial previously reported improved progression-free survival (PFS) for the addition of bevacizumab (B) to chemotherapy [capecitabine (C)±mitomycin (M)]. Archival primary tumours from 237 patients (50% of trial population) underwent gene expression profiling and classification into CMS groups. CMS groups were correlated to PFS and overall survival (OS). The interaction of CMS with treatment was assessed by proportional hazards model. Results The distribution of CMS in MAX were CMS1 18%, CMS2 47%, CMS3 12%, CMS4 23%. CMS1 was the predominant subtype in right-sided primary tumours, while CMS2 was the predominant subtype in left-sided. CMS was prognostic of OS (P = 0.008), with CMS2 associated with the best outcome and CMS1 the worst. CMS remained an independent prognostic factor in a multivariate analysis. There was a significant interaction between CMS and treatment (P-interaction = 0.03), for PFS, with hazard ratios (95% CI) for CB+CBM versus C arms in CMS1, 2, 3 and 4: 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25), respectively. Conclusions This exploratory study found that CMS stratified OS outcomes in metastatic CRC regardless of first-line treatment, with prognostic effects of CMS groups distinct from those previously reported in early-stage cohorts. In CMS associations with treatment, CMS2 and possibly CMS3 tumours may preferentially benefit from the addition of bevacizumab to first-line capecitabine-based chemotherapy, compared with other CMS groups. Validation of these findings in additional cohorts is warranted. Clinical trial number This is a molecular sub-study of MAX clinical trial (NCT00294359).

Inflammatory Markers Have a Role in Renal Cell Carcinoma Prognosis

The cause is unclear for most renal cell cancers (RCCs), although inactivation of the von Hippel-Lindau tumorsuppressor gene plays a key role for some clear-cell variants. The resulting elevation of hypoxia-inducible factor and subsequent dysregulation of cell growth is well documented. The role of inflammation as a cause or promoter of cancer cell growth has been appreciated better in the laboratory than in the clinic, but in recent years the spotlight has turned to inflammation, fueled primarily by two observations: (1) recognition of the neutrophil/lymphocyte ratio (NLR) as a marker of inflammation for many cancers, including renal cancer [1,2]; and (2) the extraordinarily rapid development of PD1/L1 inhibitors [3–5], which has highlighted the importance of immune function in some cancers. The biological mechanisms for the interplay between inflammation and immune function are still unclear, but there is increasing evidence that perturbations to many parts of the immune and inflammation signaling pathways aid in the promotion of angiogenesis and immune surveillance tolerance. In the clinic, evaluation of systemic inflammation is difficult and there is no gold standard test. Elevated C-reactive protein (CRP), elevated erythrocyte sedimentation rate, hypoalbuminemia, thrombocytosis, and leukocytosis are clues to a systemic inflammatory response. Others are combinations of clinical factors, including NLR, and clinical scores such as the modified Glasgow Prognostic score are perhaps more sensitive tests of clinical information. For RCC, it has been shown that all of these measurements are statistically significant prognostic factors in settings such as the preoperative scenario [6–9] and metastatic RCC [10–12]. Because NLR is cheap to measure and readily available, much evidence has emerged in the literature to support the hypothesis that inflammation is a

Abstract A75: The IMPaCT trial: Individualised Molecular Pancreatic Cancer Therapy. A pilot, randomized, open label Phase II trial assessing first line treatment with gemcitabine or personalized treatment based on tumour molecular signature in patients with metastatic pancreatic cancer.

Background: Less than 5% of patients with metastatic pancreatic cancer survive to 5 years and there have been no major improvements in outcomes over the last 20 years. The use of treatments targeted according to the molecular phenotype of individual tumours may result in improved response and survival compared to standard therapy. Methods: The IMPaCT trial is a multidisciplinary collaboration between the AGITG, NHMRC Clinical Trials Centre, Sydney Catalyst, and the Kinghorn Cancer Centre at Garvan Institute of Medical Research, which houses the Australian Pancreatic Cancer Genome Initiative (APGI). Patients who have available sequence data will be screened for actionable molecular phenotypes and randomized 1:1 to receive standard therapy (gemcitabine) or personalized treatment. Recruitment to the IMPaCT trial is based on the following defined molecular phenotypes: HER2/neu overexpression: personalized treatment with gemcitabine + trastuzumab; BRCA1, BRCA2, and PALB2 mutations: personalized treatment with 5-FU and mitomycin C; Kras wildtype: personalized treatment with gemcitabine + erlotinib. The study will be conducted in two parts: an initial 20 patient pilot trial across 4 Australian sites assessing feasibility, followed by an additional 70 patients to assess progression (90 patients in total). The pilot study is now open and active. Results: The novel trial design involves personalized treatment, where therapies are assigned based on a defined molecular phenotype, in a standard care setting. Stratifying randomization for individual molecular signatures will provide evidence, albeit in small numbers, for confirmation in a larger Phase III trial and broader clinical applicability. Additionally, the study offers the opportunity to explore a number of unique tertiary/correlative objectives, including the planned examination of circulating DNA as a surrogate of survival. Conclusion: The IMPaCT trial exemplifies a strong collaboration between basic scientists, clinicians and clinical trial investigators to illustrate the promises and challenges facing the development and successful testing of personalized therapeutic strategies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A75. Citation Format: Lorraine Chantrill, Amber Johns, Adnan Nagrial, Venessa Chin, Angela Chou, Mark Pinese, Scott Mead, Val Gebski, Katrin Sjoquist, Chee Lee, Sonia Yip, Danielle Miller, Lucille Sebastian, Ray Asghari, Sandra Harvey, Nick Pavlakis, Sanjay Mukhedkar, Peter Grimison, David Miller, John Pearson, Nicola Waddell, Sean Grimmond, John Simes, Andrew Biankin. The IMPaCT trial: Individualised Molecular Pancreatic Cancer Therapy. A pilot, randomized, open label Phase II trial assessing first line treatment with gemcitabine or personalized treatment based on tumour molecular signature in patients with metastatic pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A75.