Serial ctDNA Analysis for Monitoring Molecular Response and Acquired Resistance in Metastatic NSCLC and HR+/HER2‐Negative Breast Cancer: A Real‐World Study
4 affiliations
- 1Molecular Oncology Center Hospital Sírio‐Libanês São Paulo Brazil
- 2Oncology Center Hospital Sírio‐Libanês São Paulo Brazil
- 3Bioinformatics Team, Centre for Evolution and Cancer The Institute of Cancer Research London UK
- 4Translational Oncogenomics Lab The Institute of Cancer Research London UK
Abstract
Circulating tumor DNA (ctDNA) is a promising biomarker for disease monitoring, yet evidence of its clinical utility in routine care remains limited. We evaluated the utility of serial ctDNA monitoring using digital PCR (ddPCR) for detecting acquired resistance (AR) and monitoring response in metastatic non‐small cell lung cancer (NSCLC) and breast cancer (MBC). This real‐world, longitudinal study included 48 metastatic patients (42 with EGFR‐mutant NSCLC; 6 with HR+/HER2‐negative MBC) treated at a Brazilian oncology reference center. Serial plasma samples were analyzed by ddPCR for activating and resistance mutations at specific time points. In the NSCLC cohort, EGFR T790M was detected in 48.4% of patients who progressed on 1st/2nd‐generation TKIs. For patients on 3rd‐generation TKIs, EGFR C797S was the main AR mechanism (47%), followed by PIK3CA, BRAF mutations, and ERBB2/EGFR amplifications. Longitudinal analysis anticipated radiological progression by approximately 5 months. Early molecular response, characterized by mutation clearance, preceded radiological response. In the MBC cohort, hotspot ESR1 mutations (D538G, L536R, Y537S) were identified in 50% of patients. Variations in ctDNA fractional abundance predicted disease progression up to 9 months before radiological confirmation. This study provides real‐world evidence that ddPCR‐based ctDNA monitoring enables early detection of resistance and predicts disease progression significantly earlier than standard imaging in both NSCLC and MBC. Despite the limited sample size, particularly in the MBC cohort, these real‐world findings support liquid biopsy as a minimally invasive tool with the potential to guide therapeutic decisions and inform personalized management in precision oncology. Larger prospective studies are needed to confirm these observations.
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BibTeX
@article{knebel2026serial,
title = {{Serial ctDNA Analysis for Monitoring Molecular Response and Acquired Resistance in Metastatic NSCLC and HR+/HER2‐Negative Breast Cancer: A Real‐World Study}},
author = {Franciele Hinterholz Knebel and Maurício Fernando Silva Almeida Ribeiro and Rudinei Diogo Marques Linck and Isabela Flauzino Ferreira and Cibele Masotti and Rodrigo Saddi and Karina Perez Sacardo and Felipe Sales Nogueira Amorim Canedo and Leandro Jonata Carvalho Oliveira and Daniele Coelho Duarte and Paula Fontes Asprino and Ernande Xavier dosSantos and Elisângela Monteiro Coser and Dimitrios Kleftogiannis and Louise J. Barber and Marco Gerlinger and João Victor Machado Alessi and Andrea Kazumi Shimada and Fernando Costa Santini and Ciro Eduardo deSouza and Olavo Feher and Gilberto de Castro Junior and Frederico Perego Costa and Max Senna Mano and Artur Katz and Anamaria Aranha Camargo and Fabiana Bettoni},
journal = {Cancer Medicine},
year = {2026},
month = oct,
doi = {10.1002/cam4.72208},
url = {https://doi.org/10.1002/cam4.72208},
note = {CC BY},
}
RIS
TY - JOUR
TI - Serial ctDNA Analysis for Monitoring Molecular Response and Acquired Resistance in Metastatic NSCLC and HR+/HER2‐Negative Breast Cancer: A Real‐World Study
AU - Franciele Hinterholz Knebel
AU - Maurício Fernando Silva Almeida Ribeiro
AU - Rudinei Diogo Marques Linck
AU - Isabela Flauzino Ferreira
AU - Cibele Masotti
AU - Rodrigo Saddi
AU - Karina Perez Sacardo
AU - Felipe Sales Nogueira Amorim Canedo
AU - Leandro Jonata Carvalho Oliveira
AU - Daniele Coelho Duarte
AU - Paula Fontes Asprino
AU - Ernande Xavier dosSantos
AU - Elisângela Monteiro Coser
AU - Dimitrios Kleftogiannis
AU - Louise J. Barber
AU - Marco Gerlinger
AU - João Victor Machado Alessi
AU - Andrea Kazumi Shimada
AU - Fernando Costa Santini
AU - Ciro Eduardo deSouza
AU - Olavo Feher
AU - Gilberto de Castro Junior
AU - Frederico Perego Costa
AU - Max Senna Mano
AU - Artur Katz
AU - Anamaria Aranha Camargo
AU - Fabiana Bettoni
PY - 2026
DA - 2026/10/24
JO - Cancer Medicine
DO - 10.1002/cam4.72208
UR - https://doi.org/10.1002/cam4.72208
AB - Circulating tumor DNA (ctDNA) is a promising biomarker for disease monitoring, yet evidence of its clinical utility in routine care remains limited. We evaluated the utility of serial ctDNA monitoring using digital PCR (ddPCR) for detecting acquired resistance (AR) and monitoring response in metastatic non‐small cell lung cancer (NSCLC) and breast cancer (MBC). This real‐world, longitudinal study included 48 metastatic patients (42 with EGFR‐mutant NSCLC; 6 with HR+/HER2‐negative MBC) treated at a Brazilian oncology reference center. Serial plasma samples were analyzed by ddPCR for activating and resistance mutations at specific time points. In the NSCLC cohort, EGFR T790M was detected in 48.4% of patients who progressed on 1st/2nd‐generation TKIs. For patients on 3rd‐generation TKIs, EGFR C797S was the main AR mechanism (47%), followed by PIK3CA, BRAF mutations, and ERBB2/EGFR amplifications. Longitudinal analysis anticipated radiological progression by approximately 5 months. Early molecular response, characterized by mutation clearance, preceded radiological response. In the MBC cohort, hotspot ESR1 mutations (D538G, L536R, Y537S) were identified in 50% of patients. Variations in ctDNA fractional abundance predicted disease progression up to 9 months before radiological confirmation. This study provides real‐world evidence that ddPCR‐based ctDNA monitoring enables early detection of resistance and predicts disease progression significantly earlier than standard imaging in both NSCLC and MBC. Despite the limited sample size, particularly in the MBC cohort, these real‐world findings support liquid biopsy as a minimally invasive tool with the potential to guide therapeutic decisions and inform personalized management in precision oncology. Larger prospective studies are needed to confirm these observations.
SN - 2045-7634
ER -