J K Mooi1, P Wirapati2, R Asher3, C K Lee3, P Savas4, T J Price5, A Townsend5, J Hardingham6, D Buchanan7, D Williams8, S Tejpar9, J M Mariadason10, N C Tebbutt11. 1. Olivia Newton-John Cancer Research Institute, Heidelberg; Department of Medicine, University of Melbourne, Melbourne, Australia. 2. Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland. 3. NHMRC Clinical Trials Centre, University of Sydney, Sydney. 4. Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne. 5. Medical Oncology, The Queen Elizabeth Hospital, Woodville; School of Medicine, University of Adelaide, Adelaide. 6. School of Medicine, University of Adelaide, Adelaide; The Basil Hetzel Institute, The Queen Elizabeth Hospital, Woodville. 7. Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Melbourne; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville; Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville. 8. Olivia Newton-John Cancer Research Institute, Heidelberg; Department of Pathology, Austin Health, Heidelberg; Department of Pathology, University of Melbourne, Melbourne, Australia. 9. Oncology, University Hospital Leuven, Leuven, Belgium. 10. Olivia Newton-John Cancer Research Institute, Heidelberg; School of Cancer Medicine, La Trobe University, Melbourne. 11. Medical Oncology, Austin Health, Heidelberg, Australia. Electronic address: niall.tebbutt@onjcri.org.au.
Abstract
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).
RCT Entities:
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).
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