1. Early Noninvasive Detection of Response to Targeted Therapy in Non-Small Cell Lung Cancer
- Author
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Phallen, Jillian, Leal, Alessandro, Woodward, Brian D, Forde, Patrick M, Naidoo, Jarushka, Marrone, Kristen A, Brahmer, Julie R, Fiksel, Jacob, Medina, Jamie E, Cristiano, Stephen, Palsgrove, Doreen N, Gocke, Christopher D, Bruhm, Daniel C, Keshavarzian, Parissa, Adleff, Vilmos, Weihe, Elizabeth, Anagnostou, Valsamo, Scharpf, Robert B, Velculescu, Victor E, and Husain, Hatim
- Subjects
Biotechnology ,Cancer ,Lung ,Biomedical Imaging ,Lung Cancer ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,Good Health and Well Being ,Adenocarcinoma ,Aged ,Aged ,80 and over ,Biomarkers ,Tumor ,Carcinoma ,Non-Small-Cell Lung ,Carcinoma ,Squamous Cell ,Circulating Tumor DNA ,DNA ,Neoplasm ,Female ,Follow-Up Studies ,Gene Expression Regulation ,Neoplastic ,Humans ,Lung Neoplasms ,Male ,Middle Aged ,Molecular Targeted Therapy ,Mutation ,Prognosis ,Protein Kinase Inhibitors ,Survival Rate ,Tumor Burden ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
With the advent of precision oncology, there is an urgent need to develop improved methods for rapidly detecting responses to targeted therapies. Here, we have developed an ultrasensitive measure of cell-free tumor load using targeted and whole-genome sequencing approaches to assess responses to tyrosine kinase inhibitors in patients with advanced lung cancer. Analyses of 28 patients treated with anti-EGFR or HER2 therapies revealed a bimodal distribution of cell-free circulating tumor DNA (ctDNA) after therapy initiation, with molecular responders having nearly complete elimination of ctDNA (>98%). Molecular nonresponders displayed limited changes in ctDNA levels posttreatment and experienced significantly shorter progression-free survival (median 1.6 vs. 13.7 months, P < 0.0001; HR = 66.6; 95% confidence interval, 13.0-341.7), which was detected on average 4 weeks earlier than CT imaging. ctDNA analyses of patients with radiographic stable or nonmeasurable disease improved prediction of clinical outcome compared with CT imaging. These analyses provide a rapid approach for evaluating therapeutic response to targeted therapies and have important implications for the management of patients with cancer and the development of new therapeutics.Significance: Cell-free tumor load provides a novel approach for evaluating longitudinal changes in ctDNA during systemic treatment with tyrosine kinase inhibitors and serves an unmet clinical need for real-time, noninvasive detection of tumor response to targeted therapies before radiographic assessment.See related commentary by Zou and Meyerson, p. 1038.
- Published
- 2019