Response After Neoadjuvant Chemoradiotherapy: A Systematic ...
Strategies For Meaningful Biomarkers in Neoadjuvant Trials...Strategies For Meaningful Biomarkers in...
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Strategies For Meaningful Biomarkers in Neoadjuvant
Trials
Federico Innocenti, MD, PhD University of North Carolina
Chapel Hill, NC, USA
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Clonal selection o Genomic heterogeneity within individual
tumors o Result of clonal evolution during progression
o Early aberrations appear in most cells o Later-occurring aberrations appear only in a
subpopulation o Facilitate sustainable phenotype escaping control
check points
Yates & Campbell, Nature Rev Genet, 2012
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Bain GH and Petty RD, The Oncologist 2010
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Poste G, Nature 2011
Biomarker discovery
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Potential of molecular biomarkers to predict histopathological response
Bain GH and Petty RD, The Oncologist 2010
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Different settings in GI
• GEJ
• Pancreas
• Colon
• Rectal
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Adjuvant therapy, clonal selection, and mCRC
• Adjuvant FOLFOX and improved OS in
FOLFIRI/bevacizumab
• CALGB 80405 (not on FOLFOX+targeted, Venook et al., ASCO 2014)
• TRIBE (not in FOLFOXIRI/bevacizumab) (Loupakis et al., NEJM 2014)
• FIRE-3 (Heinemann et al., ESMO 2014)
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Adjuvant therapy, clonal selection, and mCRC
Neo-
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Serial FDG-PET in GEJ adenocarcinoma
• During the course on neoadj
• Early metabolic response and correlation with – decrease in tumor size – higher rate of curative resections – histopathological regression – survival
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Serial FDG-PET in GEJ adenocarcinoma
• High NPV • Limited PPV
• Optimization of time and point repeat, plus standardization of protocols
• IMAGE trial
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Borderline resectable PDAC • Node involvement and marginal status predict
relapse
• Neoadj (CRT) – might improve R0 resection rates – select out patients
• Studies not adequately powered • Utility not fully established yet
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Mullard A, Nature Reviews Drug Discovery 13, 803 (2014) Published online 31 October 2014
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NCI Exceptional Responders Initiative
• To understand the molecular underpinnings of exceptional responses to chemotherapy
• Cancer Therapy Evaluation Program phase II trial database over a period of 10 years (2002-2012)
• 100 cases were identified
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Definitions of an “exceptional responder”
• Achieved either a complete response or a partial response for >6 months, as defined by RECIST
• Received a treatment in which <10% of patients had either a complete response or partial response for >6 months
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NCI Exceptional Responders Initiative
• DNA and RNA will be isolated from tissues submitted to the NCI
• Exome sequencing and/or mRNA sequencing from 100 cases (up to 300 possibly)
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Opportunities – neoadj in PDAC
• Ultrasound and FNAs for diagnosis – pre-sample unlikely to be available
• Use of circulating tumor cells • Stroma predominates in core biopsies
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• VDR activation reprograms reactive stroma and reduces inflammation
• Increased gemcitabine concentration
• Reduced tumor volume
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Opportunities – neoadj in PDAC • Rather than stromal ablation or inhibition
• Modality of reprogramming the stromal function
• Prospective testing
• Pre- and post-evaluations of molecular biomarkers
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Liquid biopsies
New York Times Sidestepping the Biopsy With New Tools to Spot Cancer, Pollack A, April 7th, 2014
Crowley E et al., Nat Rev Clin Oncol 2013
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