Cerebrospinal fluid ctDNA clarifies clonal divergence: leptomeningeal flare of -mutant disease after switch to selpercatinib for acquired fusion.
1/5 보강
PICO 자동 추출 (휴리스틱, conf 2/4)
유사 논문P · Population 대상 환자/모집단
추출되지 않음
I · Intervention 중재 / 시술
afatinib followed by long-term osimertinib
C · Comparison 대조 / 비교
추출되지 않음
O · Outcome 결과 / 결론
CSF liquid biopsy provided actionable, compartment-specific genotyping that outperformed cytology and guided effective retreatment. Incorporating CSF ctDNA into routine evaluation may improve therapeutic alignment across sanctuary sites; when feasible, maintaining EGFR blockade should be considered when CNS involvement is suspected in -mutated NSCLC in routine practice.
Liquid biopsy can expose spatially segregated resistance biology that is invisible to single-site tissue testing, particularly across the blood-brain barrier.
APA
Kunimasa K, Tamiya M, et al. (2025). Cerebrospinal fluid ctDNA clarifies clonal divergence: leptomeningeal flare of -mutant disease after switch to selpercatinib for acquired fusion.. The journal of liquid biopsy, 10, 100450. https://doi.org/10.1016/j.jlb.2025.100450
MLA
Kunimasa K, et al.. "Cerebrospinal fluid ctDNA clarifies clonal divergence: leptomeningeal flare of -mutant disease after switch to selpercatinib for acquired fusion.." The journal of liquid biopsy, vol. 10, 2025, pp. 100450.
PMID
41446706 ↗
Abstract 한글 요약
Liquid biopsy can expose spatially segregated resistance biology that is invisible to single-site tissue testing, particularly across the blood-brain barrier. We report how cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) clarified therapeutic direction in -mutated non-small-cell lung cancer (NSCLC) with leptomeningeal involvement. A 67-year-old woman with exon 19-deleted adenocarcinoma received afatinib followed by long-term osimertinib. After three years, progression of the primary lesion prompted rebiopsy, which revealed a fusion with strong RET immunoreactivity. Selpercatinib monotherapy yielded minor thoracic shrinkage at 1 month but was followed by dizziness and MRI evidence of leptomeningeal enhancement at 3 months. CSF analysis showed pleocytosis without malignant cells. Critically, CSF ctDNA demonstrated the E746_A750 deletion at 29.2 % variant allele frequency by amplicon sequencing, whereas the fusion was undetectable by targeted sequencing and highly sensitive single-plex qPCR using junction-specific primers. Re-challenging with osimertinib rapidly improved symptoms and led to resolution of leptomeningeal enhancement. These data indicate clonal divergence at acquired resistance: a -fusion clone dominated the thoracic compartment while -addicted clones predominated in the leptomeninges. The leptomeningeal flare after discontinuing EGFR inhibition highlights the risk of switching to RET inhibitor monotherapy when CNS disease is driven by the original mutant clone. CSF liquid biopsy provided actionable, compartment-specific genotyping that outperformed cytology and guided effective retreatment. Incorporating CSF ctDNA into routine evaluation may improve therapeutic alignment across sanctuary sites; when feasible, maintaining EGFR blockade should be considered when CNS involvement is suspected in -mutated NSCLC in routine practice.
🏷️ 키워드 / MeSH 📖 같은 키워드 OA만
📖 전문 본문 읽기 PMC JATS · ~27 KB · 영문
Introduction
1
Introduction
Osimertinib, a third-generation irreversible oral epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) [1], was developed as a selective inhibitor of both EGFR-TKI-sensitizing and resistant EGFR T790M mutations [2,3]. Clinical trials have demonstrated the efficacy of osimertinib against brain metastases in patients with EGFR-mutated non-small cell lung cancer (NSCLC) who have experienced disease progression with first- and second-generation EGFR-TKIs [4,5]. Although initially developed to overcome the EGFR T790M resistant mutation, osimertinib is now used as a primary treatment because of its superior blood-brain barrier penetration, as evidenced by the results of the phase III FLAURA trial [3], which compared the effects of first-line osimertinib with those of other EGFR-TKIs in patients with EGFR-mutated NSCLC. Consequently, osimertinib has become the mainstay first-line treatment for patients with EGFR-mutated NSCLC, and overcoming this resistance remains a significant clinical challenge.
The mechanisms of acquired resistance to EGFR-TKIs in EGFR-mutated NSCLC are diverse, including genomic mechanisms such as point mutations, amplifications, and oncogenic fusions [6,7]. Resistance mechanisms to osimertinib can be broadly divided into EGFR-dependent and EGFR-independent [6,7]. The most frequent EGFR-dependent mechanism, reported to occur in 7–10 % of cases, is the C797S mutation at the ATP-binding site to which osimertinib binds [8]. Other EGFR mutations associated with resistance include those at G724 and L718 [9,10]. The most frequent EGFR-independent mechanism is MET (mesenchymal–epithelial transition factor) amplification, reported to occur in 7–15 % of cases [6,7]. However, other targetable driver alterations have been detected, albeit rarely. Additional targetable driver mutations, such as BRAF (B-Raf proto-oncogene, serine/threonine kinase) V600E, RET (rearranged during transfection proto-oncogene), NTRK (neurotrophic tyrosine receptor kinase), and ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) fusions, have been identified [6,7,11]. Combination therapies with a molecularly targeted agent corresponding to resistant alterations with EGFR-TKIs are expected to overcome resistance. However, these combination therapies are still undergoing clinical trials and are challenging to apply in clinical practice.
We present a case in which a CCDC6 (coiled-coil domain containing 6)-RET fusion (CCDC6 [1]RET [11] fusion) was detected as an osimertinib-resistant mutation, and a patient was switched from osimertinib to selpercatinib monotherapy, resulting in a rapid onset of carcinomatous meningitis. Analysis using cell-free DNA from the cerebrospinal fluid suggested that EGFR-mutant clones were the primary cause of carcinomatous meningitis.
Introduction
Osimertinib, a third-generation irreversible oral epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) [1], was developed as a selective inhibitor of both EGFR-TKI-sensitizing and resistant EGFR T790M mutations [2,3]. Clinical trials have demonstrated the efficacy of osimertinib against brain metastases in patients with EGFR-mutated non-small cell lung cancer (NSCLC) who have experienced disease progression with first- and second-generation EGFR-TKIs [4,5]. Although initially developed to overcome the EGFR T790M resistant mutation, osimertinib is now used as a primary treatment because of its superior blood-brain barrier penetration, as evidenced by the results of the phase III FLAURA trial [3], which compared the effects of first-line osimertinib with those of other EGFR-TKIs in patients with EGFR-mutated NSCLC. Consequently, osimertinib has become the mainstay first-line treatment for patients with EGFR-mutated NSCLC, and overcoming this resistance remains a significant clinical challenge.
The mechanisms of acquired resistance to EGFR-TKIs in EGFR-mutated NSCLC are diverse, including genomic mechanisms such as point mutations, amplifications, and oncogenic fusions [6,7]. Resistance mechanisms to osimertinib can be broadly divided into EGFR-dependent and EGFR-independent [6,7]. The most frequent EGFR-dependent mechanism, reported to occur in 7–10 % of cases, is the C797S mutation at the ATP-binding site to which osimertinib binds [8]. Other EGFR mutations associated with resistance include those at G724 and L718 [9,10]. The most frequent EGFR-independent mechanism is MET (mesenchymal–epithelial transition factor) amplification, reported to occur in 7–15 % of cases [6,7]. However, other targetable driver alterations have been detected, albeit rarely. Additional targetable driver mutations, such as BRAF (B-Raf proto-oncogene, serine/threonine kinase) V600E, RET (rearranged during transfection proto-oncogene), NTRK (neurotrophic tyrosine receptor kinase), and ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) fusions, have been identified [6,7,11]. Combination therapies with a molecularly targeted agent corresponding to resistant alterations with EGFR-TKIs are expected to overcome resistance. However, these combination therapies are still undergoing clinical trials and are challenging to apply in clinical practice.
We present a case in which a CCDC6 (coiled-coil domain containing 6)-RET fusion (CCDC6 [1]RET [11] fusion) was detected as an osimertinib-resistant mutation, and a patient was switched from osimertinib to selpercatinib monotherapy, resulting in a rapid onset of carcinomatous meningitis. Analysis using cell-free DNA from the cerebrospinal fluid suggested that EGFR-mutant clones were the primary cause of carcinomatous meningitis.
Case presentation
2
Case presentation
A 67-year-old woman with back pain and lower-extremity weakness presented to our hospital. Computed tomography revealed a 25-mm mass in the left lower lobe (Fig. 1A) and multiple masses in the thoracic vertebrae. Histopathologic analysis of the lung mass biopsy specimen revealed adenocarcinoma. Genetic profiling of the tumor revealed an EGFR exon 19 p. E746_A750del mutation; therefore, she was treated with afatinib as first-line chemotherapy. After approximately 1 month of afatinib treatment, the patient developed severe diarrhea and was switched to osimertinib due to intolerable toxicities. Switching to osimertinib improved the diarrhea, and treatment with osimertinib was continued with mild adverse skin events (Fig. 1B). After approximately 3 years of treatment, the primary left lower lobe lesion gradually increased in size (Fig. 1C) and was re-biopsied. Genetic analysis of the specimen revealed a CCDC6-RET fusion (CCDC6-intron1-RET-intron11; chr10:61639130-chr10:43611591 (hg19 genome)) in addition to the EGFR exon 19 p. E746_A750del. No fusion was detected in the specimens collected before EGFR-TKI administration. When the patient was switched from osimertinib to selpercatinib monotherapy, the primary lesion slightly reduced 1 month after treatment (Fig. 1D) but tended to increase again 3 months later (Fig. 1E), accompanied by severe light-headedness and dizziness. Immunostaining using an anti-RET antibody (#ab134100) showed strong staining only in the rebiopsied sample (Fig. 1F and G). Brain-enhanced magnetic resonance imaging (MRI) revealed new metastatic brain lesions suggestive of carcinomatous meningitis. Cerebrospinal fluid examination revealed an elevated number of cells; however, no malignant cells were detected. When the treatment was switched back to osimertinib, the patient's clinical symptoms improved rapidly, and head contrast-enhanced MRI showed a trend toward resolution of the brain metastases (Fig. 2).
To study the clonality of tumor cells in central lesions, cell-free DNA was extracted from the spinal fluid (Fig. 3A), and amplicon target sequencing was performed on EGFR Ex.19 deletions, which revealed an E746_A750 deletion at a variant allele frequency of 29.2 % (Fig. 3B). The same cell-free DNA was used to search for the CCDC6-RET fusion but was not detected. To increase detection sensitivity, singleplex quantitative polymerase chain reaction (qPCR) was performed on the fusion gene using PCR primers specific for the border region between the CCDC6 and RET genes (Fig. 3C); however, no amplification was observed in cell-free DNA from the spinal fluid. The same experiment was performed using a resistant lung tumor specimen as a positive control, and amplification of the boundary region was observed (Fig. 3D).
Case presentation
A 67-year-old woman with back pain and lower-extremity weakness presented to our hospital. Computed tomography revealed a 25-mm mass in the left lower lobe (Fig. 1A) and multiple masses in the thoracic vertebrae. Histopathologic analysis of the lung mass biopsy specimen revealed adenocarcinoma. Genetic profiling of the tumor revealed an EGFR exon 19 p. E746_A750del mutation; therefore, she was treated with afatinib as first-line chemotherapy. After approximately 1 month of afatinib treatment, the patient developed severe diarrhea and was switched to osimertinib due to intolerable toxicities. Switching to osimertinib improved the diarrhea, and treatment with osimertinib was continued with mild adverse skin events (Fig. 1B). After approximately 3 years of treatment, the primary left lower lobe lesion gradually increased in size (Fig. 1C) and was re-biopsied. Genetic analysis of the specimen revealed a CCDC6-RET fusion (CCDC6-intron1-RET-intron11; chr10:61639130-chr10:43611591 (hg19 genome)) in addition to the EGFR exon 19 p. E746_A750del. No fusion was detected in the specimens collected before EGFR-TKI administration. When the patient was switched from osimertinib to selpercatinib monotherapy, the primary lesion slightly reduced 1 month after treatment (Fig. 1D) but tended to increase again 3 months later (Fig. 1E), accompanied by severe light-headedness and dizziness. Immunostaining using an anti-RET antibody (#ab134100) showed strong staining only in the rebiopsied sample (Fig. 1F and G). Brain-enhanced magnetic resonance imaging (MRI) revealed new metastatic brain lesions suggestive of carcinomatous meningitis. Cerebrospinal fluid examination revealed an elevated number of cells; however, no malignant cells were detected. When the treatment was switched back to osimertinib, the patient's clinical symptoms improved rapidly, and head contrast-enhanced MRI showed a trend toward resolution of the brain metastases (Fig. 2).
To study the clonality of tumor cells in central lesions, cell-free DNA was extracted from the spinal fluid (Fig. 3A), and amplicon target sequencing was performed on EGFR Ex.19 deletions, which revealed an E746_A750 deletion at a variant allele frequency of 29.2 % (Fig. 3B). The same cell-free DNA was used to search for the CCDC6-RET fusion but was not detected. To increase detection sensitivity, singleplex quantitative polymerase chain reaction (qPCR) was performed on the fusion gene using PCR primers specific for the border region between the CCDC6 and RET genes (Fig. 3C); however, no amplification was observed in cell-free DNA from the spinal fluid. The same experiment was performed using a resistant lung tumor specimen as a positive control, and amplification of the boundary region was observed (Fig. 3D).
Discussion
3
Discussion
Osimertinib is currently one of the most effective drugs available against EGFR major activating mutations, such as Ex.19 del and L858R, and overcoming this resistance is a critical issue. Drug concentration in the central nervous system (CNS) is lower than in the bloodstream due to the blood-brain barrier, making it harder to control and more prone to recurrence than in the rest of the body [12,13]. In the present case, when the treatment was switched to selpercatinib monotherapy for RET fusion, the patient developed a disease flare due to carcinomatous meningitis. Analysis of cell-free DNA from the spinal fluid implied that the primary seeding lesions of the meninges could have been EGFR exon 19 p. E746_A750del clones. Although direct examination of meningeal dissemination was not feasible, the appearance of CCDC6 [1]RET [11] fusion may be a localized phenomenon in the resistant area of the primary pulmonary lesion.
Despite their low incidence, oncogenic fusion genes have also been implicated in osimertinib resistance mechanisms [11], including CCDC6 [1]RET [11] fusion. In both mouse models and clinical case reports, additional targetable driver alterations were often ineffective when treated with the corresponding molecularly targeted agents as switching monotherapies [14]. Therefore, combination therapy with EGFR-TKIs has been demonstrated to be more effective [14]. A biomarker-directed phase II platform study is currently underway to assess the efficacy of combinational molecular targeted therapies based on osimertinib resistance mechanisms; the results should lead to the establishment of new molecular targeted therapies after osimertinib resistance acquisition [15]. There is also a recent report confirming the efficacy and safety of the combination of selpercatinib and osimertinib in the treatment of acquired resistant RET fusion [16]. Currently, combination therapy with osimertinib and molecularly targeted agents based on resistance mechanisms is not feasible in practice, and only switching to molecularly targeted agents based on resistance mechanisms, as in this case, can be attempted.
Selpercatinib is a potent and selective RET inhibitor with high CNS penetration and high control of brain metastases [17,18]. The patient developed cancerous meningitis 3 months after starting selpercatinib treatment, although no obvious brain metastases were detected on head-contrast MRI at the start of selpercatinib treatment. After discontinuing osimertinib and switching to selpercatinib, rapid onset of cancerous meningitis was observed, and the lack of amplification of the CCDC6 [1]RET [11] fusion boundary by qRT-PCR (quantitative reverse-transcription polymerase chain reaction) using spinal fluid-derived cell-free DNA suggested that the brain metastases were likely predominant EGFR exon 19 p. E746_A750del mutated clones. The clinical course seems to support this hypothesis, as osimertinib rechallenge rapidly improved the cancerous meningitis. Administration of molecularly targeted agents may increase heterogeneity within the tumor, forming a branched evolutionary pattern due to selective pressure [19]. In the present case, the CCDC6 [1]RET [11] fusion clone might have developed osimertinib resistance only in the primary tumor.
This study has several limitations. A more detailed analysis of the clonality of tumor cells in central lesions would have been possible if tissue samples from the metastatic brain had been examined. However, the patient's load in clinical practice renders biopsies of central lesions impracticable owing to the high encumbrance of the patient. For the examination of cell-free DNA from the spinal fluid, cell-free RNA would have been more desirable for scrutinizing fusion genes. However, in the present study, the quantity of spinal fluid collected was insufficient and analysis with cell-free RNA was unattainable.
In the present study, we detected the CCDC6 [1]RET [11] fusion as an osimertinib resistance mutation and switched the patient to selpercatinib monotherapy. However, the patient developed an acute exacerbation of cancerous meningitis, and analysis using cell-free DNA from the spinal fluid suggested meningeal dissemination mainly caused by EGFR exon 19 p. E746_A750del mutant clones, which might have contributed to the worsening of the cancerous meningitis on selpercatinib treatment. In the future, combination therapy with molecularly targeted agents and EGFR-TKIs may be desirable for additional targetable driver alterations after EGFR-TKI therapy.
Discussion
Osimertinib is currently one of the most effective drugs available against EGFR major activating mutations, such as Ex.19 del and L858R, and overcoming this resistance is a critical issue. Drug concentration in the central nervous system (CNS) is lower than in the bloodstream due to the blood-brain barrier, making it harder to control and more prone to recurrence than in the rest of the body [12,13]. In the present case, when the treatment was switched to selpercatinib monotherapy for RET fusion, the patient developed a disease flare due to carcinomatous meningitis. Analysis of cell-free DNA from the spinal fluid implied that the primary seeding lesions of the meninges could have been EGFR exon 19 p. E746_A750del clones. Although direct examination of meningeal dissemination was not feasible, the appearance of CCDC6 [1]RET [11] fusion may be a localized phenomenon in the resistant area of the primary pulmonary lesion.
Despite their low incidence, oncogenic fusion genes have also been implicated in osimertinib resistance mechanisms [11], including CCDC6 [1]RET [11] fusion. In both mouse models and clinical case reports, additional targetable driver alterations were often ineffective when treated with the corresponding molecularly targeted agents as switching monotherapies [14]. Therefore, combination therapy with EGFR-TKIs has been demonstrated to be more effective [14]. A biomarker-directed phase II platform study is currently underway to assess the efficacy of combinational molecular targeted therapies based on osimertinib resistance mechanisms; the results should lead to the establishment of new molecular targeted therapies after osimertinib resistance acquisition [15]. There is also a recent report confirming the efficacy and safety of the combination of selpercatinib and osimertinib in the treatment of acquired resistant RET fusion [16]. Currently, combination therapy with osimertinib and molecularly targeted agents based on resistance mechanisms is not feasible in practice, and only switching to molecularly targeted agents based on resistance mechanisms, as in this case, can be attempted.
Selpercatinib is a potent and selective RET inhibitor with high CNS penetration and high control of brain metastases [17,18]. The patient developed cancerous meningitis 3 months after starting selpercatinib treatment, although no obvious brain metastases were detected on head-contrast MRI at the start of selpercatinib treatment. After discontinuing osimertinib and switching to selpercatinib, rapid onset of cancerous meningitis was observed, and the lack of amplification of the CCDC6 [1]RET [11] fusion boundary by qRT-PCR (quantitative reverse-transcription polymerase chain reaction) using spinal fluid-derived cell-free DNA suggested that the brain metastases were likely predominant EGFR exon 19 p. E746_A750del mutated clones. The clinical course seems to support this hypothesis, as osimertinib rechallenge rapidly improved the cancerous meningitis. Administration of molecularly targeted agents may increase heterogeneity within the tumor, forming a branched evolutionary pattern due to selective pressure [19]. In the present case, the CCDC6 [1]RET [11] fusion clone might have developed osimertinib resistance only in the primary tumor.
This study has several limitations. A more detailed analysis of the clonality of tumor cells in central lesions would have been possible if tissue samples from the metastatic brain had been examined. However, the patient's load in clinical practice renders biopsies of central lesions impracticable owing to the high encumbrance of the patient. For the examination of cell-free DNA from the spinal fluid, cell-free RNA would have been more desirable for scrutinizing fusion genes. However, in the present study, the quantity of spinal fluid collected was insufficient and analysis with cell-free RNA was unattainable.
In the present study, we detected the CCDC6 [1]RET [11] fusion as an osimertinib resistance mutation and switched the patient to selpercatinib monotherapy. However, the patient developed an acute exacerbation of cancerous meningitis, and analysis using cell-free DNA from the spinal fluid suggested meningeal dissemination mainly caused by EGFR exon 19 p. E746_A750del mutant clones, which might have contributed to the worsening of the cancerous meningitis on selpercatinib treatment. In the future, combination therapy with molecularly targeted agents and EGFR-TKIs may be desirable for additional targetable driver alterations after EGFR-TKI therapy.
Availability of data and materials
Availability of data and materials
The data that support the findings of this study are not publicly available because they contain information that could compromise the privacy of the research participants, but are available from the corresponding author (Kei Kunimasa, kei.kunimasa@oici.jp) upon reasonable request. Further inquiries can be directed to the corresponding authors.
The data that support the findings of this study are not publicly available because they contain information that could compromise the privacy of the research participants, but are available from the corresponding author (Kei Kunimasa, kei.kunimasa@oici.jp) upon reasonable request. Further inquiries can be directed to the corresponding authors.
CRediT authorship contribution statement
CRediT authorship contribution statement
Kei Kunimasa: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Writing – original draft. Shun Futamura: Formal analysis, Investigation, Resources. Aki Kubota: Data curation, Formal analysis, Investigation, Methodology, Software and Writing – original draft. Kiyohide Komuta: Formal analysis, Investigation, Resources. Tsunehiro Tanaka: Formal analysis, Investigation, Resources. Takahisa Kawamura: Formal analysis, Investigation, Resources. Nobuaki Mamesaya: Formal analysis, Investigation, Resources. Takako Inoue: Formal analysis, Investigation, Resources. Motohiro Tamiya: Formal analysis, Investigation, Resources. Kazumi Nishino: Formal analysis, Investigation, Resources, Writing – review & editing.
Kei Kunimasa: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Writing – original draft. Shun Futamura: Formal analysis, Investigation, Resources. Aki Kubota: Data curation, Formal analysis, Investigation, Methodology, Software and Writing – original draft. Kiyohide Komuta: Formal analysis, Investigation, Resources. Tsunehiro Tanaka: Formal analysis, Investigation, Resources. Takahisa Kawamura: Formal analysis, Investigation, Resources. Nobuaki Mamesaya: Formal analysis, Investigation, Resources. Takako Inoue: Formal analysis, Investigation, Resources. Motohiro Tamiya: Formal analysis, Investigation, Resources. Kazumi Nishino: Formal analysis, Investigation, Resources, Writing – review & editing.
Ethical approval
Ethical approval
The present study was approved by the ethics committee in our institute (#20136–3 and #22129). In addition, written informed consent was obtained from the patient for participation in this study and for publication of anonymized clinical information, images, and genetic findings.
The present study was approved by the ethics committee in our institute (#20136–3 and #22129). In addition, written informed consent was obtained from the patient for participation in this study and for publication of anonymized clinical information, images, and genetic findings.
Declaration of generative AI in scientific writing
Declaration of generative AI in scientific writing
During the preparation of this manuscript, the authors used ChatGPT (OpenAI) solely to improve the readability and English phrasing of the text (e.g., polishing sentences and figure legends). ChatGPT was not used to generate, analyze, or interpret any data or scientific content. All AI-assisted text was reviewed and edited by the authors, who take full responsibility for the content of the published article.
During the preparation of this manuscript, the authors used ChatGPT (OpenAI) solely to improve the readability and English phrasing of the text (e.g., polishing sentences and figure legends). ChatGPT was not used to generate, analyze, or interpret any data or scientific content. All AI-assisted text was reviewed and edited by the authors, who take full responsibility for the content of the published article.
Funding sources
Funding sources
This work was supported by the 10.13039/501100001691Japan Society for the Promotion of Science (10.13039/501100001691JSPS) 10.13039/501100001691KAKENHI (Grant Number 22K16208).
This work was supported by the 10.13039/501100001691Japan Society for the Promotion of Science (10.13039/501100001691JSPS) 10.13039/501100001691KAKENHI (Grant Number 22K16208).
Declaration of competing interest
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kei Kunimasa reports financial support was provided by Japan Society for the Promotion of Science. Kei Kunimasa reports a relationship with Amgen Inc that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with AstraZeneca Pharmaceuticals LP that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with DAIICHI SANKYO COMPANY, LIMITED that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Eli Lilly Japan KK that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Janssen Pharmaceutical KK that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Merck & Co Inc that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with MSD that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Novartis Pharmaceuticals Corporation that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Ono Pharmaceutical Co Ltd that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Pfizer Inc that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Chugai Pharmaceutical Co Ltd that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Pfizer Inc that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with MSD that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Chugai Pharmaceutical Co Ltd that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Bristol Myers Squibb that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Johnson and Johnson KK that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Eli Lilly that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with AstraZeneca that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Ono Pharmaceutical Co Ltd that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Boehringer Ingelheim Ltd that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Takako Inoue reports a relationship with AstraZeneca that includes: speaking and lecture fees. Takako Inoue reports a relationship with Chugai Pharmaceutical Co Ltd that includes: speaking and lecture fees. Takako Inoue reports a relationship with Bristol Myers Squibb that includes: speaking and lecture fees. Takako Inoue reports a relationship with Ono Pharmaceutical Co Ltd that includes: speaking and lecture fees. Takako Inoue reports a relationship with MSD that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Ono Pharmaceutical Co Ltd that includes: funding grants. Kazumi Nishino reports a relationship with Taiho Pharmaceutical Co Ltd that includes: funding grants and paid expert testimony. Kazumi Nishino reports a relationship with Eli Lilly Japan KK that includes: funding grants. Kazumi Nishino reports a relationship with AbbVie Inc that includes: funding grants. Kazumi Nishino reports a relationship with DAIICHI SANKYO COMPANY, LIMITED that includes: funding grants. Kazumi Nishino reports a relationship with Amgen Inc that includes: funding grants and speaking and lecture fees. Kazumi Nishino reports a relationship with Eisai that includes: funding grants. Kazumi Nishino reports a relationship with Sanofi that includes: funding grants. Kazumi Nishino reports a relationship with Janssen Pharmaceuticals Inc that includes: funding grants and speaking and lecture fees. Kazumi Nishino reports a relationship with Novartis that includes: funding grants. Kazumi Nishino reports a relationship with Pfizer that includes: funding grants. Kazumi Nishino reports a relationship with Merck & Co Inc that includes: funding grants. Kazumi Nishino reports a relationship with Takeda Pharmaceutical Company Limited that includes: funding grants. Kazumi Nishino reports a relationship with AstraZeneca that includes: funding grants and speaking and lecture fees. Kazumi Nishino reports a relationship with Merus NV that includes: funding grants. Kazumi Nishino reports a relationship with MSD that includes: funding grants and speaking and lecture fees. Kazumi Nishino reports a relationship with Bayer Corporation that includes: funding grants. Kazumi Nishino reports a relationship with Delta-Fly Pharma, Inc. That includes: funding grants. Kazumi Nishino reports a relationship with IQVIA Holdings Inc that includes: funding grants. Kazumi Nishino reports a relationship with Nippon Boehringer Ingelheim Co Ltd that includes: funding grants. Kazumi Nishino reports a relationship with Parexel International (MA) Corporation that includes: funding grants. Kazumi Nishino reports a relationship with Asahi Kasei Pharma Corporation that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with DAIICHI SANKYO COMPANY, LIMITED that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Eli Lilly Japan KK that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Kyorin Pharmaceutical Co Ltd that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Kyowa Kirin Co., Ltd that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Merck Biopharma Co., Ltd. That includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Mochida Pharmaceutical Co Ltd that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Nippon Boehringer Ingelheim Co Ltd that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Nippon Kayaku Co Ltd that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kei Kunimasa reports financial support was provided by Japan Society for the Promotion of Science. Kei Kunimasa reports a relationship with Amgen Inc that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with AstraZeneca Pharmaceuticals LP that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with DAIICHI SANKYO COMPANY, LIMITED that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Eli Lilly Japan KK that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Janssen Pharmaceutical KK that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Merck & Co Inc that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with MSD that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Novartis Pharmaceuticals Corporation that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Ono Pharmaceutical Co Ltd that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Pfizer Inc that includes: speaking and lecture fees. Kei Kunimasa reports a relationship with Chugai Pharmaceutical Co Ltd that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Pfizer Inc that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with MSD that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Chugai Pharmaceutical Co Ltd that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Bristol Myers Squibb that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Johnson and Johnson KK that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Eli Lilly that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with AstraZeneca that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Ono Pharmaceutical Co Ltd that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Boehringer Ingelheim Ltd that includes: speaking and lecture fees. Motohiro Tamiya reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Takako Inoue reports a relationship with AstraZeneca that includes: speaking and lecture fees. Takako Inoue reports a relationship with Chugai Pharmaceutical Co Ltd that includes: speaking and lecture fees. Takako Inoue reports a relationship with Bristol Myers Squibb that includes: speaking and lecture fees. Takako Inoue reports a relationship with Ono Pharmaceutical Co Ltd that includes: speaking and lecture fees. Takako Inoue reports a relationship with MSD that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Ono Pharmaceutical Co Ltd that includes: funding grants. Kazumi Nishino reports a relationship with Taiho Pharmaceutical Co Ltd that includes: funding grants and paid expert testimony. Kazumi Nishino reports a relationship with Eli Lilly Japan KK that includes: funding grants. Kazumi Nishino reports a relationship with AbbVie Inc that includes: funding grants. Kazumi Nishino reports a relationship with DAIICHI SANKYO COMPANY, LIMITED that includes: funding grants. Kazumi Nishino reports a relationship with Amgen Inc that includes: funding grants and speaking and lecture fees. Kazumi Nishino reports a relationship with Eisai that includes: funding grants. Kazumi Nishino reports a relationship with Sanofi that includes: funding grants. Kazumi Nishino reports a relationship with Janssen Pharmaceuticals Inc that includes: funding grants and speaking and lecture fees. Kazumi Nishino reports a relationship with Novartis that includes: funding grants. Kazumi Nishino reports a relationship with Pfizer that includes: funding grants. Kazumi Nishino reports a relationship with Merck & Co Inc that includes: funding grants. Kazumi Nishino reports a relationship with Takeda Pharmaceutical Company Limited that includes: funding grants. Kazumi Nishino reports a relationship with AstraZeneca that includes: funding grants and speaking and lecture fees. Kazumi Nishino reports a relationship with Merus NV that includes: funding grants. Kazumi Nishino reports a relationship with MSD that includes: funding grants and speaking and lecture fees. Kazumi Nishino reports a relationship with Bayer Corporation that includes: funding grants. Kazumi Nishino reports a relationship with Delta-Fly Pharma, Inc. That includes: funding grants. Kazumi Nishino reports a relationship with IQVIA Holdings Inc that includes: funding grants. Kazumi Nishino reports a relationship with Nippon Boehringer Ingelheim Co Ltd that includes: funding grants. Kazumi Nishino reports a relationship with Parexel International (MA) Corporation that includes: funding grants. Kazumi Nishino reports a relationship with Asahi Kasei Pharma Corporation that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with DAIICHI SANKYO COMPANY, LIMITED that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Eli Lilly Japan KK that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Kyorin Pharmaceutical Co Ltd that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Kyowa Kirin Co., Ltd that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Merck Biopharma Co., Ltd. That includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Mochida Pharmaceutical Co Ltd that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Nippon Boehringer Ingelheim Co Ltd that includes: speaking and lecture fees. Kazumi Nishino reports a relationship with Nippon Kayaku Co Ltd that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
출처: PubMed Central (JATS). 라이선스는 원 publisher 정책을 따릅니다 — 인용 시 원문을 표기해 주세요.
🏷️ 같은 키워드 · 무료전문 — 이 논문 MeSH/keyword 기반
- Nanotechnology-Assisted Molecular Profiling: Emerging Advances in Circulating Tumor DNA Detection.
- From Time-Limited Therapy to Treatment-Free Observation: The Evolving Role of MRD in CLL Management.
- Neoadjuvant Therapy in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer: Recent Progress, Challenges, and Future Directions in the Era of TAR-200 and Enfortumab Vedotin Plus Pembrolizumab.
- From feasibility to translational pathways: a bibliometric and knowledge-mapping analysis of urine-based liquid biopsy in urologic cancers (2015-2025).
- A subset of MMR-proficient colon cancers responds to neoadjuvant immunotherapy.
- Prognostic Impact of Blood Tumor Mutational Burden in pMMR/MSS Metastatic Colorectal Cancer Assessed by FoundationOne Liquid CDx.