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Related Concept Videos

Treatment Resistant Cancers02:56

Treatment Resistant Cancers

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Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
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Related Experiment Video

Updated: Sep 11, 2025

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
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Longitudinal Circulating Tumor DNA-Guided Resistance Analysis During Second-Line Osimertinib Treatment.

J W Tijmen van der Wel1, Merel Jebbink1, Vincent van der Noort2

  • 1Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

JTO Clinical and Research Reports
|August 12, 2025
PubMed
Summary

Early detection of resistance mechanisms in circulating tumor DNA (ctDNA) in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients treated with osimertinib can precede disease progression by weeks, offering opportunities for treatment adjustment.

Keywords:
EGFRNSCLCOsimertinibResistancectDNA

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Area of Science:

  • Oncology
  • Molecular Diagnostics
  • Genomics

Background:

  • Acquired resistance to osimertinib is common in EGFR mutation-positive non-small cell lung cancer (NSCLC).
  • Early identification of resistance mechanisms (RMs) via circulating tumor DNA (ctDNA) may enable timely therapeutic adjustments.
  • This study investigated the utility of plasma ctDNA for detecting RMs before radiologic progression.

Purpose of the Study:

  • To evaluate the detection rate and timing of RM emergence in plasma ctDNA in osimertinib-treated EGFRm-positive NSCLC patients.
  • To assess the interval between RM detection in ctDNA and radiologic progression.

Main Methods:

  • Prospective multicenter study involving 21 EGFRm-positive NSCLC patients treated with second- or third-line osimertinib.
  • Serial plasma ctDNA analysis (Roche AVENIO expanded panel) and computed tomography scans every 8 weeks.
  • Tumor biopsy after progression for correlation with ctDNA findings.

Main Results:

  • 18 out of 21 patients had detectable ctDNA at baseline.
  • In 33% of patients, an increase in EGFR mutation variant allele frequency preceded radiologic progression by a median of 9 weeks.
  • Resistance mechanisms were detected in ctDNA in 33% of patients, a median of 14 weeks before progression.
  • Plasma RMs were confirmed in 5 biopsies, with 5 additional RMs identified in biopsies.

Conclusions:

  • Plasma ctDNA can detect resistance mechanisms in a significant proportion of osimertinib-treated NSCLC patients before radiologic progression.
  • The median 14-week interval between RM detection and progression suggests a window for early intervention.
  • Monitoring ctDNA for RMs may facilitate personalized treatment strategies to potentially extend tyrosine kinase inhibitor efficacy.