Noninvasive monitoring of the genetic evolution of EGFR-mutant non-small-cell lung cancer by analyzing circulating tumor DNA during combination chemotherapy with gefitinib and pemetrexed or S-1.
BACKGROUND
Repetitive genotyping is useful to assess the genetic evolution of non-small-cell lung cancer (NSCLC) during treatment, but the need for sampling by biopsy is a major obstacle. Digital polymerase chain reaction (PCR) is a promising procedure for the detection of mutant alleles in plasma of cancer patients.


METHODS
This prospective study enrolled patients with NSCLC and known epidermal growth factor receptor (EGFR) mutations and who had experienced disease progression during ongoing EGFR-tyrosine kinase inhibitor (TKI) therapy. Eligible patients received daily gefitinib and either pemetrexed or S-1 every 3 weeks until disease progression or the development of unacceptable toxicity. Peripheral blood was collected before and after the combination therapy for digital PCR and hepatocyte growth factor measurement.


RESULTS
From May 2012 to January 2014, nine patients with a median age of 67 (range 52-80) years were enrolled. Patterns of disease progression during adjacent EGFR-TKI therapy were acquired resistance, observed in seven patients, and primary resistance, observed in two patients. Known EGFR mutations were detected in plasma samples of six (67%) patients at study enrollment. Of these, T790M mutation was concurrently detected in three (50%) patients. Four patients underwent gefitinib plus pemetrexed therapy, and five patients underwent gefitinib and S-1 therapy. The median number of cycles delivered was five, and the median progression-free survival was 5.7 months. Efficacy outcomes did not differ between treatments. After the combination therapy, plasma T790M status changed to positive in two patients. Hepatocyte growth factor level did not significantly change through the combination therapy.


CONCLUSIONS
The usefulness of monitoring the genetic evolution of EGFR-driven tumors using noninvasive procedures was demonstrated. Since continuation of EGFR-TKI therapy with cytotoxic agents has an acceptable tolerability and a possibility of inducing T790M mutation, the combination therapy may be useful for EGFR-mutant NSCLC resistant to EGFR-TKI therapy without T790M mutation.
Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo; Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara.
Yoshiro
Y
Nakahara
Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo; Oncology Scientific Affairs, Merck Sharp & Dohme Corp.
Yusuke
Y
Takagi
Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo.
Yukio
Y
Hosomi
GeneticLab Co., Ltd., Sapporo.
Akiko
A
Kagei
GeneticLab Co., Ltd., Sapporo.
Tomohiro
T
Yamamoto
Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo.
Takeshi
T
Sawada
Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo.
Makiko
M
Yomota
Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo.
Yusuke
Y
Okuma
Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo; Department of Respiratory Medicine, Fujieda Municipal General Hospital, Fujieda, Japan.
Shinichiro
S
Mikura
Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo.
Tatsuru
T
Okamura
S-1; circulating tumor DNA; epidermal growth factor receptor; gefitinib; pemetrexed