Early noninvasive detection of response to targeted therapy in non–small cell lung cancer

Jillian Phallen, Alessandro Leal, Brian D. Woodward, Patrick Forde, Jarushka Naidoo, Kristen Marrone, Julie Brahmer, Jacob Fiksel, Jamie E. Medina, Stephen Cristiano, Doreen N. Palsgrove, Christopher Gocke, Daniel C. Bruhm, Parissa Keshavarzian, Vilmos Adleff, Elizabeth Weihe, Valsamo Anagnostou, Robert B Scharpf, Victor E Velculescu, Hatim Husain

Research output: Contribution to journalArticle

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 ¼ 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.

Original languageEnglish (US)
Pages (from-to)1204-1213
Number of pages10
JournalCancer Research
Volume79
Issue number6
DOIs
StatePublished - Jan 1 2019

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phallen, J., Leal, A., Woodward, B. D., Forde, P., Naidoo, J., Marrone, K., Brahmer, J., Fiksel, J., Medina, J. E., Cristiano, S., Palsgrove, D. N., Gocke, C., Bruhm, D. C., Keshavarzian, P., Adleff, V., Weihe, E., Anagnostou, V., Scharpf, R. B., Velculescu, V. E., & Husain, H. (2019). Early noninvasive detection of response to targeted therapy in non–small cell lung cancer. Cancer Research, 79(6), 1204-1213. https://doi.org/10.1158/0008-5472.CAN-18-1082