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Principal Investigator: Michael F. Berger
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2024
Award: $697,771
Funding agency: National Cancer Institute
PROJECT SUMMARY
The development of novel therapies is at the core of improving cancer outcomes worldwide. However, currently
used metrics to capture clinical benefit of these novel therapies may not always capture treatment success or
failure. The overarching goal of the proposed research is to increase precision by leveraging metrics that
integrate imaging with other measures of tumor response such as changes in plasma circulating tumor DNA
(ctDNA) in patients undergoing novel therapies. The proposed research builds on clinical proof-of-principle by
the investigative team using next-generation sequencing (NGS) of ctDNA that decreases in variant allele
frequency (VAF) of selected alterations can be observed prior to conventional radiologic response, and that
increases in VAF often occur several weeks to months before radiologic progression. Building on the foundation
of NGS, MSK-ACCESS, a highly sensitive deep sequencing liquid biopsy assay, was recently developed by the
investigative team based on its FDA-authorized counterpart MSK-IMPACT performed on tumor tissue, which
enables the identification of actionable genetic alterations that can be targeted with drugs. Additionally, the
research builds upon extensive experience of the investigative team with “basket trials” evaluating the activity of
precision genome-driven and immunomodulatory therapies, whereby the enrolling criterion is a putative
biomarker regardless of cancer type, which has put a premium on serially collecting co-clinical trial ctDNA
samples along with MSK-IMPACT testing on the tumor tissue, providing a baseline genomic profile to guide
ctDNA-based disease monitoring. The diverse and extensive collection of prospectively collected ctDNA samples
within these trials provides timepoints that can be compared to regulatory grade pre-treatment, on-treatment,
and post-progression imaging assessments via computed tomography (CT) and/or magnetic resonance imaging
(MRI), and positron emission tomography (PET). Specific Aim 1: To evaluate the correlation between early
changes in ctDNA variant allele frequencies (VAF) with best response to therapy via conventional and advanced
imaging assessments in early-phase targeted or immunomodulatory clinical trials. Specific Aim 2: To identify if
plasma ctDNA trends can more precisely predict longitudinal clinical benefit (measured by progression-free
survival) in patients who fall within the broad response category of stable disease via RECIST in early-phase
clinical trials. Specific Aim 3: To identify the median time prior to which rising ctDNA levels presages eventual
radiologic progression in patients who initially benefit from targeted or immunomodulatory therapy (i.e.,
complete/partial response or stable disease as best overall response) in early-phase clinical trials. Impact: The
insights from this study will lay the groundwork for integrating advanced imaging and ctDNA-based biomarkers
in the future that may be used by regulatory agencies around the globe for the purpose of assessing and
approving novel precision therapies and ultimately allow the possibility for personalized precision medicine.
Terms: <Allele Frequency><Area><Assay><Authorization><Authorization documentation><Bioassay><Biological Assay><Biological Markers><Blood Plasma><Blood Plasma Cell><CAT scan><CT X Ray><CT Xray><CT imaging><CT scan><Cancer Treatment><Cancers><Categories><Clinical><Clinical Trials><Collection><Complement><Complement Proteins><Computed Tomography><DNA seq><DNA sequencing><DNAseq><Data><Development><Disease><Disorder><Drugs><Enrollment><Failure><Foundations><Frequencies><Future><Gene Frequency><Gene variant><General Radiology><Genetic Alteration><Genetic Change><Genetic defect><Genome><Goals><Guidelines><Healthcare><Image><Immune Modulation Therapy><Immunomodulation><Liquid substance><MR Imaging><MR Tomography><MRI><MRIs><MSKCC><Magnetic Resonance Imaging><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Memorial Sloan-Kettering Cancer Center><Methods><Monitor><Mutation><NGS Method><NGS system><NMR Imaging><NMR Tomography><Nuclear Magnetic Resonance Imaging><Outcome><PET><PET Scan><PET imaging><PETSCAN><PETT><Patients><Permission><Pharmaceutical Preparations><Phase><Plasma><Plasma Cells><Plasma Serum><Plasmacytes><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Precision therapeutics><Prediction of Response to Therapy><Progression-Free Survivals><Progressive Disease><Rad.-PET><Radiology><Radiology Specialty><Research><Reticuloendothelial System, Serum, Plasma><Role><Sampling><Scientist><Services><Stable Disease><Testing><Time><Tomodensitometry><Treatment Side Effects><Treatment-related side effects><Tumor Burden><Tumor Load><Tumor Tissue><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><Zeugmatography><allele variant><allelic frequency><allelic variant><anti-cancer therapy><bio-markers><biologic marker><biomarker><cancer therapy><cancer type><cancer-directed therapy><catscan><cell free DNA><cell free circulating DNA><co-clinical trial><complementation><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><cone-beam CT><cone-beam computed tomography><customized therapy><customized treatment><cytotoxic><deep sequencing><developmental><drug development><drug/agent><early clinical trial><early phase clinical trial><enroll><experience><falls><fluid><genetic variant><genome mutation><genomic profiles><genomic variant><health care><image-based method><imaging><imaging method><imaging modality><imaging scientist><immune modulating therapies><immune modulation><immune modulatory therapies><immune regulation><immune-modulation treatment><immunologic reactivity control><immunomodulation therapy><immunomodulation treatment><immunomodulator therapies><immunomodulator treatment><immunomodulator-based therapies><immunomodulatory><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><immunoregulation><immunoregulatory><improved><improved outcome><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><insight><liquid><liquid biopsy><malignancy><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next gen sequencing><next generation sequencing><next generation therapeutics><nextgen sequencing><non-contrast CT><noncontrast CT><noncontrast computed tomography><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><partial response><patient specific therapies><patient specific treatment><plasmocyte><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><precision medicine><precision therapies><precision treatment><precision-based medicine><predict therapeutic response><predict therapy response><prospective><response><response to therapy><response to treatment><social role><success><tailored medical treatment><tailored therapy><tailored treatment><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapy prediction><therapy response><tool><treatment prediction><treatment response><treatment response prediction><treatment responsiveness><trend><tumor><tumor DNA><tumor cell DNA><tumor-specific DNA><unique treatment><volume CT><volume computed tomography><volumetric computed tomography>