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Prospective Feasibility Study for Using Cell-Free Circulating Tumor DNA-Guided Therapy in Refractory Metastatic Solid Cancers: An Interim Analysis.

ABSTRACT: Purpose:Retrospective studies have demonstrated that cell-free circulating tumor DNA (ctDNA) hotspot testing predicts matched therapy response to first- and second-line therapies in patients with advanced non-small-cell lung cancer (NSCLC). However, no prospective outcomes studies have evaluated ctDNA-guided matched therapy decision making on the basis of comprehensive plasma genomic testing including all four major classes of alterations. Here, we report the clinical utility of this approach in advanced solid tumor cancers. Patients and Methods:We conducted a multiple parallel cohort, open-label, clinical trial using ctDNA-guided matched therapy when tissue was insufficient or unobtainable for next-generation sequencing. Plasma-based digital sequencing identified point mutations in 70 genes and indels, fusions, and copy number amplifications in selected genes. Patients with prespecified targetable alterations in metastatic NSCLC, gastric cancer (GC), and other cancers were matched to several independent targeted agent trials at a tertiary academic center. Results:Somatic alterations were detected in 59 patients with GC (78%), and 25 patients (33%) had targetable alterations (ERBB2, n = 11; MET, n = 5; FGFR2, n = 3; PIK3CA, n = 6). In NSCLC, 62 patients (85%) had somatic alterations, and 34 (47%) had targetable alterations (EGFR, n = 29; ALK, n = 2; RET, n = 1; ERBB2, n = 2). After confirmation of ctDNA findings on tissue (to meet trial eligibility criteria), 10 patients with GC and 17 patients with NSCLC received molecularly matched therapy. Response rate and disease control rate were 67% and 100%, respectively, in GC and 87% and 100%, respectively, in NSCLC. Response was independent of targeted alteration variant allele fraction in NSCLC (P = .63). Conclusion:To our knowledge, this is the first prospective feasibility study of comprehensive ctDNA-guided treatment in advanced GC and lung cancers. Response rates in this interim analysis are similar to those in tissue-based targeted therapy studies.

SUBMITTER: Kim ST

PROVIDER: S-EPMC7446388 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Prospective Feasibility Study for Using Cell-Free Circulating Tumor DNA-Guided Therapy in Refractory Metastatic Solid Cancers: An Interim Analysis.

Kim Seung Tae ST Banks Kimberly C KC Lee Se-Hoon SH Kim Kyung K Park Joon Oh JO Park Se Hoon SH Park Young Suk YS Lim Ho Yeong HY Kang Won Ki WK Lanman Richard B RB Talasaz AmirAli A Park Keunchil K Lee Jeeyun J

JCO precision oncology 20170626

<h4>Purpose</h4>Retrospective studies have demonstrated that cell-free circulating tumor DNA (ctDNA) hotspot testing predicts matched therapy response to first- and second-line therapies in patients with advanced non-small-cell lung cancer (NSCLC). However, no prospective outcomes studies have evaluated ctDNA-guided matched therapy decision making on the basis of comprehensive plasma genomic testing including all four major classes of alterations. Here, we report the clinical utility of this app ...[more]

PMID: 32913970

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Project description:BackgroundCell-free DNA (cfDNA) profiling is increasingly used to guide cancer care, yet mutations are not always identified. The ability to detect somatic mutations in plasma depends on both assay sensitivity and the fraction of circulating DNA in plasma that is tumor-derived (i.e., cfDNA tumor fraction). We hypothesized that cfDNA tumor fraction could inform the interpretation of negative cfDNA results and guide the choice of subsequent assays of greater genomic breadth or depth.MethodsPlasma samples collected from 118 metastatic cancer patients were analyzed with cf-IMPACT, a modified version of the FDA-authorized MSK-IMPACT tumor test that can detect genomic alterations in 410 cancer-associated genes. Shallow whole genome sequencing (sWGS) was also performed in the same samples to estimate cfDNA tumor fraction based on genome-wide copy number alterations using z-score statistics. Plasma samples with no somatic alterations detected by cf-IMPACT were triaged based on sWGS-estimated tumor fraction for analysis with either a less comprehensive but more sensitive assay (MSK-ACCESS) or broader whole exome sequencing (WES).ResultscfDNA profiling using cf-IMPACT identified somatic mutations in 55/76 (72%) patients for whom MSK-IMPACT tumor profiling data were available. A significantly higher concordance of mutational profiles and tumor mutational burden (TMB) was observed between plasma and tumor profiling for plasma samples with a high tumor fraction (z-score≥5). In the 42 patients from whom tumor data was not available, cf-IMPACT identified mutations in 16/42 (38%). In total, cf-IMPACT analysis of plasma revealed mutations in 71/118 (60%) patients, with clinically actionable alterations identified in 30 (25%), including therapeutic targets of FDA-approved drugs. Of the 47 samples without alterations detected and low tumor fraction (z-score<5), 29 had sufficient material to be re-analyzed using a less comprehensive but more sensitive assay, MSK-ACCESS, which revealed somatic mutations in 14/29 (48%). Conversely, 5 patients without alterations detected by cf-IMPACT and with high tumor fraction (z-score≥5) were analyzed by WES, which identified mutational signatures and alterations in potential oncogenic drivers not covered by the cf-IMPACT panel. Overall, we identified mutations in 90/118 (76%) patients in the entire cohort using the three complementary plasma profiling approaches.ConclusionscfDNA tumor fraction can inform the interpretation of negative cfDNA results and guide the selection of subsequent sequencing platforms that are most likely to identify clinically-relevant genomic alterations.

Project description:Accurate tumor tracking remains a challenge in current radiation therapy. Many strategies including image guided radiation therapy alleviate the problem to certain extents. The authors propose a new modality called emission guided radiation therapy (EGRT) to accurately and directly track the tumor based on its biological signature. This work is to demonstrate the feasibility of EGRT under two clinical scenarios using a 4D digital patient model.EGRT uses lines of response (LOR's) from positron emission events to direct beamlets of therapeutic radiation through the emission sites inside a tumor. This is accomplished by a radiation delivery system consisting of a Linac and positron emission tomography (PET) detectors on a fast rotating closed-ring gantry. During the treatment of radiotracer-administrated cancer patients, PET detectors collect LOR's from tumor uptake sites and the Linac responds in nearly real-time with beamlets of radiation along the same LOR paths. Moving tumors are therefore treated with a high targeting accuracy. Based on the EGRT concept, the authors design a treatment method with additional modulation algorithms including attenuation correction and an integrated boost scheme. Performance is evaluated using simulations of a lung tumor case with 3D motion and a prostate tumor case with setup errors. The emission process is simulated by Geant4 Application for Tomographic Emission package (GATE) and Linac dose delivery is simulated using a voxel-based Monte Carlo algorithm (VMC++).In the lung case with attenuation correction, compared to a conventional helical treatment, EGRT achieves a 41% relative increase in dose to 95% of the gross tumor volume (GTV) and a 55% increase to 50% of the GTV. All dose distributions are normalized for the same dose to the lung. In the prostate case with the integrated boost and no setup error, EGRT yields a 19% and 55% relative dose increase to 95% and 50% of the GTV, respectively, when all methods are normalized for the same dose to the rectum. In the prostate case with integrated boost where setup error is present, EGRT contributes a 21% and 52% relative dose increase to 95% and 50% of the GTV, respectively.As a new radiation therapy modality with inherent tumor tracking, EGRT has the potential to substantially improve targeting in radiation therapy in the presence of intrafractional and interfractional motion.

Dataset Information

Prospective Feasibility Study for Using Cell-Free Circulating Tumor DNA-Guided Therapy in Refractory Metastatic Solid Cancers: An Interim Analysis.

Publications

Prospective Feasibility Study for Using Cell-Free Circulating Tumor DNA-Guided Therapy in Refractory Metastatic Solid Cancers: An Interim Analysis.

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