Giant Magnetoresistive Nanosensor Analysis of Circulating Tumor DNA Epidermal Growth Factor Receptor Mutations for Diagnosis and Therapy Response Monitoring

• Published in: Clinical chemistry (Baltimore, Md.) Vol. 67; no. 3; pp. 534 - 542
• Main Authors: Nesvet, Jared C, Antilla, Katie A, Pancirer, Danielle S, Lozano, Alexander X, Preiss, Jordan S, Ma, Weijie, Fu, Aihua, Park, Seung-Min, Gambhir, Sanjiv S, Fan, Alice C, Neal, Joel W, Padda, Sukhmani K, Das, Millie, Li, Tianhong, Wakelee, Heather A, Wang, Shan X
• Format: Journal Article
• Language: English
• Published: England American Association for Clinical Chemistry, Inc 01-03-2021; Oxford University Press
• Subjects: Acrylamides - therapeutic use; Aged; Analysis; Aniline Compounds - therapeutic use; Assaying; Biopsy; Biosensing Techniques; Biosensors; Cancer patients; Carcinoma, Non-Small-Cell Lung - diagnosis; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Circulating Tumor DNA - genetics; Cost analysis; Deoxyribonucleic acid; Diagnosis; DNA; DNA Mutational Analysis - methods; Drug Monitoring - methods; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; Female; Genetic aspects; Growth factors; Humans; Identification and classification; Liquid Biopsy; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - diagnosis; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Magnetoresistivity; Male; Medical diagnosis; Methods; Middle Aged; Monitoring; Mutants; Mutation; Nanosensors; Non-small cell lung carcinoma; Nucleic acids; Oligonucleotide Array Sequence Analysis; Patients; Precision medicine; Predictions; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Receptors; Sensitivity analysis; Small cell lung carcinoma; Telemedicine; Therapy; Tumors; United States
• ISSN: 0009-9147; 1530-8561
• DOI: 10.1093/clinchem/hvaa307

Liquid biopsy circulating tumor DNA (ctDNA) mutational analysis holds great promises for precision medicine targeted therapy and more effective cancer management. However, its wide adoption is hampered by high cost and long turnaround time of sequencing assays, or by inadequate analytical sensitivity of existing portable nucleic acid tests to mutant allelic fraction in ctDNA.
We developed a ctDNA Epidermal Growth Factor Receptor (EGFR) mutational assay using giant magnetoresistive (GMR) nanosensors. This assay was validated in 36 plasma samples of non-small cell lung cancer patients with known EGFR mutations. We assessed therapy response through follow-up blood draws, determined concordance between the GMR assay and radiographic response, and ascertained progression-free survival of patients.
The GMR assay achieved analytical sensitivities of 0.01% mutant allelic fraction. In clinical samples, the assay had 87.5% sensitivity (95% CI = 64.0-97.8%) for Exon19 deletion and 90% sensitivity (95% CI = 69.9-98.2%) for L858R mutation with 100% specificity; our assay detected T790M resistance with 96.3% specificity (95% CI = 81.7-99.8%) with 100% sensitivity. After 2 weeks of therapy, 10 patients showed disappearance of ctDNA by GMR (predicted responders), whereas 3 patients did not (predicted nonresponders). These predictions were 100% concordant with radiographic response. Kaplan-Meier analysis showed responders had significantly (P < 0.0001) longer PFS compared to nonresponders (N/A vs. 12 weeks, respectively).
The GMR assay has high diagnostic sensitivity and specificity and is well suited for detecting EGFR mutations at diagnosis and noninvasively monitoring treatment response at the point-of-care.