Publications by authors named "Madoka Kimura"

47 Publications

EML4-ALK fusion variant.3 and co-occurrent PIK3CA E542K mutation exhibiting primary resistance to three generations of ALK inhibitors.

Cancer Genet 2021 Aug 28;256-257:131-135. Epub 2021 May 28.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

The ALK inhibitors are promising therapeutic agents against lung cancer harboring ALK fusion genes and are currently under development up to the third generation. However, its therapeutic effects are reported to be affected by differences in ALK variants and co-occurrent mutations. Materials and Methods; We experienced an autopsy case of an ALK-positive lung cancer patient who showed primary resistance to three generations of ALK inhibitors. The poor survival time of the case was 14 months. To reveal the mechanism of primary resistance to three generations of ALK inhibitors, we performed next generation sequencing for 12 specimes obtained from an autopsy with covering whole exons of 53 significantly mutated, lung cancer-associated genes and amplicon-based target RNA sequenceing for the ALK fusion gene. The NGS analysis revealed a rare variant.3 of ALK fusion, in which 30 bp of base was inserted at the end of ALK intron.19 and was associated with EML exon.6 [E6_ins30A20] and a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. Structural analysis of the fusion protein ALK [E6_ins30A20] showed no interferance with the binding of ALK inhibitors to the kinase domain. The NGS analysis of primary and metastatic lesions obtained from an autopsy revealed a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. The constitutive activation of PI3K-Akt signal by PIK3CA E542K mutation occurred downstream of ALK signaling pathway, could lead to primary resistance to ALK inhibitors in all generations.
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http://dx.doi.org/10.1016/j.cancergen.2021.05.010DOI Listing
August 2021

Elective Nodal Irradiation for Non-small Cell Lung Cancer Complicated With Chronic Obstructive Pulmonary Disease Affects Immunotherapy Αfter Definitive Chemoradiotherapy.

Anticancer Res 2020 Dec 7;40(12):6957-6970. Epub 2020 Dec 7.

Department of Radiation Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background/aim: The aim of this retrospective study was to detect the frequency, reasons, and significant factors for not receiving immunotherapy after chemoradiotherapy in non-small cell lung cancer (NSCLC) patients.

Patients And Methods: Thirty-four patients with NSCLC received definitive chemoradiotherapy. The endpoint of this study was receiving durvalumab within 45 days after chemoradiotherapy for NSCLC.

Results: Twenty-five of 34 (73%) patients received immunotherapy within 45 days after chemoradiotherapy. The reasons for not receiving immunotherapy were radiation pneumonitis (50%), radiation esophagitis (10%), and four other reasons (40%). Univariate analysis showed that significant factors for not receiving immunotherapy were elective nodal irradiation (ENI)+ and chronic obstructive pulmonary disease (COPD)+. The rate of immunotherapy was 100% (17/17 cases) in the COPD- and ENI- group, and 16% (1/6 cases) in the COPD+ and ENI+ group.

Conclusion: ENI for NSCLC complicated with COPD decreased the rate of immunotherapy after definitive chemoradiotherapy.
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http://dx.doi.org/10.21873/anticanres.14720DOI Listing
December 2020

Effectiveness of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer patients with uncommon EGFR mutations: A multicenter observational study.

Thorac Cancer 2021 01 29;12(1):90-96. Epub 2020 Oct 29.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy is the standard treatment for advanced non-small cell lung cancer (NSCLC) harboring common EGFR mutations, such as exon 19 deletion or L858 point mutation. However, the effectiveness of EGFR-TKIs for patients with uncommon EGFR mutations remains unclear.

Methods: We retrospectively surveyed a consecutive database of NSCLC patients with EGFR mutations at five participating institutions. Data from NSCLC patients with uncommon mutations (including single or compound mutations), who were treated with systemic therapy between May 2016 and October 2018, were collected and analyzed.

Results: A total of 23 of the 524 patients whose data were collected had uncommon EGFR mutations. Of these, 22 received EGFR-TKIs (gefitinib = 6, erlotinib = 4, and afatinib = 12). Patients who received first EGFR-TKIs had overall response and disease control rates of 59.1% and 81.8%, respectively. The median progression-free survival (PFS) of patients with G719X mutation (n = 13, median PFS = 32.9 months) was favorable, compared with those of patients with L861Q mutation (n = 4, median PFS = 6.4 months) and compound mutations (n = 4, median PFS = 7.3 months). The PFS of patients who received first- and second-generation EGFR-TKIs was 14.0 months (n = 10) and 7.3 months (n = 12), respectively. The median cumulative duration of treatment (DOT) with EGFR-TKIs was 30.4 months, which was longer than those of cytotoxic chemotherapy (median DOT = 10.7 months) or immune checkpoint inhibitors (median DOT = 6.6 months).

Conclusions: EGFR-TKIs elicit favorable responses and contribute to long-term disease control in NSCLC patients with uncommon EGFR mutations.

Key Points: Significant findings of the study: Our results demonstrate that both first- and second-generation EGFR-TKIs elicit favorable responses in NSCLC patients with uncommon EGFR mutations. What this study adds This study revealed all clinical courses for NSCLC patients with uncommon EGFR mutations. In addition to EGFR-TKIs, CCT and ICIs were found to contribute to long-term disease control in this cohort.
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http://dx.doi.org/10.1111/1759-7714.13718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779206PMC
January 2021

Real-world osimertinib for mutation-positive non-small-cell lung cancer with acquired T790M mutation.

Future Oncol 2020 Jul 14;16(21):1537-1547. Epub 2020 Jul 14.

Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.

Osimertinib is a key drug for mutation-positive non-small-cell lung cancer (NSCLC). As the hazards ratio of overall survival in comparison with first-generation EGFR-tyrosine kinase inhibitors was almost similar between FLAURA and ARCHER 1050, salvage use of osimertinib is still a treatment option. We retrospectively analyzed the clinical courses of mutation-positive NSCLC patients who were potential candidates for salvage osimertinib. Among 524 patients enrolled from five hospitals, 302 patients underwent biopsy, with 52.6% detection rate of T790M. Osimertinib was administered in 93.6% of the T790M-positive patients. The overall response rate and median progression-free survival time of osimertinib were calculated with 147 patients, to be 55.6% and 17.2 months, respectively. Osimertinib is active for T790M-driven acquired resistance in -mutant NSCLC, but the detection of T790M was unsatisfactory. UMIN000028989 (UMIN Clinical Trials Registry).
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http://dx.doi.org/10.2217/fon-2020-0203DOI Listing
July 2020

The impact of EGFR mutation status and single brain metastasis on the survival of non-small-cell lung cancer patients with brain metastases.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa064. Epub 2020 May 28.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background: Molecular and genetic alterations of non-small-cell lung cancer (NSCLC) now play a vital role in patient care of this neoplasm. The authors focused on the impact of epidermal growth factor receptor mutation (EGFR-mt) status on the survival of patients after brain metastases (BMs) from NSCLC. The purpose of the study was to understand the most desirable management of BMs from NSCLC.

Methods: This was a retrospective observational study analyzing 647 patients with NSCLC, including 266 patients with BMs, diagnosed at our institute between January 2008 and December 2015. EGFR mutation status, overall survival (OS) following diagnosis, OS following BMs, duration from diagnosis to BMs, and other factors related to OS and survival after BMs were measured.

Results: Among 647 patients, 252 (38.8%) had EGFR mutations. The rate and frequency of developing BMs were higher in EGFR-mt patients compared with EGFR wildtype (EGFR-wt) patients. EGFR-mt patients showed longer median OS (22 vs 11 months, < .001) and a higher frequency of BMs. Univariate and multivariate analyses revealed that good performance status, presence of EGFR-mt, single BM, and receiving local therapies were significantly associated with favorable prognosis following BM diagnosis. Single metastasis, compared with multiple metastases, exhibited a positive impact on patient survival after BMs in EGFR-mt patients, but not in EGFR-wt NSCLC patients.

Conclusions: Single BM with EGFR-mt performed better than other groups. Furthermore, effective local therapies were recommended to achieve better outcomes.
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http://dx.doi.org/10.1093/noajnl/vdaa064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284117PMC
May 2020

Switching from first or second generation EGFR-TKI to osimertinib in mutation-positive NSCLC.

Lung Cancer Manag 2020 Mar 19;9(2):LMT29. Epub 2020 Mar 19.

Department of Thoracic Oncology, Osaka International Cancer Institute 3-1-69 Otemae, Chio-ku, Osaka 541-8567, Japan.

Aim: We evaluated the efficacy of a novel switch protocol for EGFR-TKIs for mutation-positive NSCLC.

Materials & Methods: Clinical records were collected from the patients who had received one of two sequential combination strategies of EGFR-TKIs: Salvage use of osimertinib for -mediated acquired resistance to an prior EGFR-TKI or switch use of osimertinib where an EGFR-TKI was switched to osimertinib before disease progression.

Results: Progression-free survival of osimertinib and time from the start of treatment until progression to osimertinib was comparable between the salvage use and switch use of osimertinib.

Conclusion: Switch use of osimertinib seemed to produce improved efficacy for patients with activating mutations, because of the lack of patient selection via .
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http://dx.doi.org/10.2217/lmt-2020-0005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186852PMC
March 2020

Favorable response to pembrolizumab after durvalumab failure in a stage III sarcomatoid carcinoma of the lung: a case report.

BMC Pharmacol Toxicol 2020 04 3;21(1):26. Epub 2020 Apr 3.

Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae Chuo-ku, Osaka, 541-8567, Japan.

Background: Pulmonary sarcomatoid carcinoma is a rare non-small-cell lung cancer (NSCLC) subtype with a poor prognosis. In the phase III PACIFIC study, durvalumab significantly improved progression-free survival and overall survival versus placebo, in patients with stage III NSCLC who do not have disease progression after concurrent chemoradiotherapy. However, treatments for patients who discontinue durvalumab due to disease progression, are unknown.

Case Presentation: We report a case of favorable response to pembrolizumab in a patient with disease progression during durvalumab consolidation therapy after chemoradiotherapy for stage III pulmonary sarcomatoid carcinoma with high programmed cell death ligand 1 (PD-L1) and PD-L2 expression.

Conclusion: Here, we present what, to the best of our knowledge, is the first reported case in which durvarumab resistance after definitive chemoradiotherapy in a patient with stage III pulmonary sarcomatoid carcinoma was overcome by pembrolizumab.
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http://dx.doi.org/10.1186/s40360-020-00404-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118808PMC
April 2020

Reconstruction and Characterization of Thermally Stable and Catalytically Active Proteins Comprising an Alphabet of ~ 13 Amino Acids.

J Mol Evol 2020 05 23;88(4):372-381. Epub 2020 Mar 23.

Faculty of Human Sciences, Waseda University, 2-579-15 Mikajima, Tokorozawa, Saitama, 359-1192, Japan.

While extant organisms synthesize proteins using approximately 20 kinds of genetically coded amino acids, the earliest protein synthesis system is likely to have been much simpler, utilizing a reduced set of amino acids. However, which types of building blocks were involved in primordial protein synthesis remains unclear. Herein, we reconstructed three convergent sequences of an ancestral nucleoside diphosphate kinase, each comprising a 10 amino acid "alphabet," and found that two of these variants folded into soluble and stable tertiary structures. Therefore, an alphabet consisting of 10 amino acids contains sufficient information for creating stable proteins. Furthermore, re-incorporation of a few more amino acid types into the active site of the 10 amino acid variants improved the catalytic activity, although the specific activity was not as high as that of extant proteins. Collectively, our results provide experimental support for the idea that robust protein scaffolds can be built with a subset of the current 20 amino acids that might have existed abundantly in the prebiotic environment, while the other amino acids, especially those with functional sidechains, evolved to contribute to efficient enzyme catalysis.
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http://dx.doi.org/10.1007/s00239-020-09938-0DOI Listing
May 2020

Which Is Better EGFR-TKI Followed by Osimertinib: Afatinib or Gefitinib/Erlotinib?

Anticancer Res 2019 Jul;39(7):3923-3929

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background/aim: Treatment with EGFR-tyrosine kinase inhibitor (TKI) shows a durable response against NSCLC harboring EGFR mutation; however, treatment resistance occurs within 1-1.5 years following first-line EGFR-TKIs [first- and second-generation (G) TKIs]. When resistant NSCLC exhibits T790M mutations, osimertinib is the standard therapy. However, intratumoral heterogeneity and clonal evolution may occur in NSCLC. Afatinib may overcome tumor heterogeneity, leading to T790M colonal purity. We aimed to determine whether NSCLC treatment with afatinib followed by osimertinib (afatinib group) provides higher therapeutic efficacy than other 1st-G EFGR-TKIs followed by osimertinib (1st-G group).

Materials And Methods: This multicenter retrospective study evaluated outcomes between afatinib group and 1st-G group. We analyzed clinical data from NSCLC patients receiving osimertinib after progression following 1st- or 2nd-G EGFR-TKIs between March 28, 2016 and March 31, 2018. Patients with performance status (PS) 0-2 were enrolled to reduce bias of patients' conditions.

Results: We enrolled 111 patients treated with osimertinib. The median age was 69 (range: 39-88) years. Out of 111 patients, 33 (29.7%) were men, 100 (90%) had PS 0-1, and 35 (31.5%) were in the afatinib group. The objective RR and DCR were significantly higher in the afatinib group than in the 1st-G group [82.9% vs. 53.9% (p=0.0065); 91.4% vs. 71.1% (p=0.032)]. The median PFS tended higher in the afatinib group than in the 1st-G group (15.6 vs. 8.9 months, p=0.195).

Conclusion: Afatinib followed by osimertinib may provide better outcomes for T790M-positive NSCLC than 1st-G EGFR-TKIs. Afatinib followed by osimertinib may be a therapeutic option for NSCLC harboring EGFR mutation.
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http://dx.doi.org/10.21873/anticanres.13544DOI Listing
July 2019

A randomized phase II study of nutritional and exercise treatment for elderly patients with advanced non-small cell lung or pancreatic cancer: the NEXTAC-TWO study protocol.

BMC Cancer 2019 May 31;19(1):528. Epub 2019 May 31.

Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: Most advanced elderly cancer patients experience fatigue, anorexia, and declining physical function due to cancer cachexia, for which effective interventions have not been established. We performed a phase I study of a new nonpharmacological multimodal intervention called the nutritional and exercise treatment for advanced cancer (NEXTAC) program and reported the excellent feasibility of and compliance with this program in elderly patients with advanced cancer who were at risk for cancer cachexia. We report here the background, hypothesis, and design of the next-step multicenter, randomized phase II study to evaluate the efficacy of the program, the NEXTAC-TWO study.

Methods: Patients with chemo-naïve advanced non-small cell lung cancer or pancreatic cancer, age ≥ 70 years, performance status ≤2, with adequate organ function and without disability according to the modified Katz index will be eligible. In total, 130 participants will be recruited from 15 Japanese institutions and will be randomized into either the intervention group or a control group. Computer-generated random numbers are allocated to each participant. Stratification factors include performance status (0 to 1 vs. 2), site of primary cancer (lung vs. pancreas), stage (III vs. IV), and type of chemotherapy (cytotoxic vs. others). Interventions and assessment will be performed 4 times every 4 ± 2 weeks from the date of randomization. Interventions will consist of nutritional counseling, nutritional supplements (rich in branched-chain amino acids), and a home-based exercise program. The exercise program will include low-intensity daily muscle training and lifestyle education to promote physical activity. The primary endpoint is disability-free survival. It is defined as the period from the date of randomization to the date of developing disability or death due to any cause. This trial also plans to evaluate the improvements in nutritional status, physical condition, quality of life, activities of daily living, overall survival, and safety as secondary endpoints. Enrollment began in August 2017. The study results will demonstrate the efficacy of multimodal interventions for elderly cancer patients and their application for the maintenance of physical and nutritional conditions in patients with cancer cachexia. This work is supported by a grant-in-aid from the Japan Agency for Medical Research and Development.

Discussion: This is the first randomized trial to evaluate the efficacy and safety of a multimodal intervention specific for elderly patients with advanced cancer.

Trial Registration: Registered at August 23, 2017. Registry number: UMIN000028801 .
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http://dx.doi.org/10.1186/s12885-019-5762-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544995PMC
May 2019

Jasmonate production through chlorophyll a degradation by Stay-Green in Arabidopsis thaliana.

J Plant Physiol 2019 Jul 17;238:53-62. Epub 2019 May 17.

Institute of Low Temperature Science, Hokkaido University, Sapporo, 060-0819, Japan. Electronic address:

Leaf color change through chlorophyll degradation is a characteristic symptom of senescence. Magnesium removal from chlorophyll a is the initial step in chlorophyll a degradation, in a reaction catalyzed by Stay-Green (SGR). Arabidopsis thaliana has three SGR homologs, SGR1, SGR2, and SGR-like. When SGR1 is overexpressed, both chlorophyll a and b are degraded and leaves turn yellow. This process is visually identical to senescence, suggesting that SGR1 overexpression affects various physiological processes in plants. To examine this possibility, gene expression associated with chlorophyll metabolism and senescence was analyzed following dexamethasone-inducible SGR1 introduction into Arabidopsis. When SGR1 was overexpressed following 18 h of dexamethasone treatment, genes involved in chlorophyll degradation were upregulated, as were senescence-associated genes. These observations suggested that chlorophyll a degradation promotes senescence. As jasmonate is the plant hormone responsible for senescence and was expected to be involved in the regulation of gene expression after dexamethasone treatment, the level of jasmonoyl-isoleucine, the active form of jasmonate, was measured. The jasmonoyl-isoleucine level increased slightly after 10 h of SGR1 overexpression, and this increase became significant after 18 h. These observations suggest that jasmonate is produced through chlorophyll a degradation and affects the promotion of senescence.
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http://dx.doi.org/10.1016/j.jplph.2019.05.004DOI Listing
July 2019

Patients with SMARCA4-deficient thoracic sarcoma and severe skeletal-related events.

Lung Cancer 2019 06 8;132:59-64. Epub 2019 Apr 8.

Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae Chuoku, Osaka City, Japan.

Objectives: SMARCA4-deficient thoracic sarcoma(DTS) is a recently identified new entity of thoracic malignancies characterized by inactivation of SMARCA4. Patients with SMARCA4-DTS have a particulary aggresive clinical course and no effective treatments. However, the detailed clinical features of SMARCA4-DTS remain unclear. Here, we report the clinical courses and molecular profiles of two cases of SMARCA4-DTS.

Materials And Methods: We experienced strikingly similar two patients of SMARCA4-DTS. The clinicopathologic features were reviewed, and detailed immunohistochemical and comprehensive cancer panel analysis with next generation sequencing confirmed the diagnosis.

Results: Our cases had many clinical and radiological observations characteristic of SMARCA4-DTS in common. Immunohistochemical staing showed complete loss of SMARCA4 in tumor cells. Loss of function mutations were detected in SMARCA4. We found that severe SREs comprise a new significant clinical feature of SMARCA4-DTS.

Conclusion: Integrated clinico-radiologic-pathologic-genetic diagnosis is essential for SMARCA4-DTS and physicians should pay attention to severe SREs during the clinical course of this disease.
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http://dx.doi.org/10.1016/j.lungcan.2019.03.029DOI Listing
June 2019

Osimertinib for patients with EGFR T790M mutation-positive non-small-cell lung cancer and a poor performance status.

Jpn J Clin Oncol 2019 Jul;49(7):671-675

Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.

Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is effective against EGFR T790M mutation-positive non-small-cell lung cancer (NSCLC) in patients who have good performance status (PS). However, the efficacy and safety of osimertinib for patients with poor PS is unknown.

Methods: We retrospectively evaluated the efficacy and safety of osimertinib in patients with EGFR T790M mutation-positive NSCLC who had Eastern Cooperative Oncology Group PS scores of 2-4 and who were administered 80 mg of osimertinib once daily between March 2016 and February 2017.

Results: Thirty patients (8 men and 22 women) with EGFR T790M mutation-positive NSCLC were evaluated; their median age was 66 years (range: 39-89 years). Twenty-four and six patients had PS scores of 2 and 3, respectively; none had a PS score of 4. All patients had previously been treated with first- or second-generation EGFR-TKIs. T790M was detected in the tumor samples of 23 patients, the blood samples of two patients, and both the tumor and blood samples of five patients. The overall response rate was 53% (95% confidence interval: 36-70%), and the PS score improvement rate was 63%. The median progression-free survival was 8.2 months (95% confidence interval: 4.3-13.2 months), while the median overall survival time was not reached. No patient required treatment cessation owing to adverse events, and no treatment-related deaths occurred.

Conclusions: Osimertinib therapy demonstrates promising efficacy and acceptable safety in patients with EGFR T790M mutation-positive NSCLC who have poor PS.
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http://dx.doi.org/10.1093/jjco/hyz041DOI Listing
July 2019

Proliferative CD8(+) PD-1(+) T-cell infiltration in a pembrolizumab-induced cutaneous adverse reaction.

Invest New Drugs 2018 12 26;36(6):1138-1142. Epub 2018 Jun 26.

Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae Chuoku, Osaka City, 541-8567, Japan.

Pembrolizumab, a humanized monoclonal immunoglobulin (Ig) G4 antibody that is directed against the human cell surface receptor PD-1, is a PD-1 pathway inhibitor that has been approved to treat various malignant diseases, including advanced non-small cell lung cancer (NSCLC). PD-1 is the major inhibitory receptor regulating T-cell exhaustion, and T-cells with high PD-1 expression lose their ability to eliminate cancer. PD-1 pathway blockade by pembrolizumab reinvigorates exhausted T-cells and restores their antitumor immune responses. However, reinvigorated T-cells also evoke immune-related adverse effects (irAEs), which stem from the restored activity. Currently, the pathogenic mechanisms of irAEs have not been sufficiently determined. We experienced a patient with NSCLC with high PD-L1 expression and cervical lymph node metastases, who demonstrated a good clinical response to first line pembrolizumab but suffered from a severe cutaneous adverse event. Both of his skin lesions and cervical metastases showed extensive CD8(+) PD-1(+) T-cell infiltration in immunofluorescence analysis. This finding suggests a possible contribution of reinvigorated CD8(+) PD-1(+) T-cells in anti-PD-1 therapy-induced skin rash. Intriguingly, CD8(+) T-cells in the skin rash showed higher Ki-67 expression, a proliferation marker, than those in the cervical lymph node lesion. This is the first report of an association between proliferative CD8(+) PD-1(+) T-cells and irAEs.
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http://dx.doi.org/10.1007/s10637-018-0628-3DOI Listing
December 2018

Pembrolizumab-induced acute thrombosis: A case report.

Medicine (Baltimore) 2018 May;97(20):e10772

Department of Thoracic Oncology, Osaka International Cancer Institute, Otemae Chuoku, Osaka City, Japan.

Rationale: Acute thrombosis has not been reported in the literature so far in lung cancer patients as an immune-related adverse event (irAE) associated with PD-1 pathway inhibitors.

Patients Concerns: Here, we for the first time present two NSCLC (non-small cell lung cancer) patients suffering from acute thrombosis as a pembrolizumab-induced irAE. Immediate treatment with continuous heparin infusion improved their symptoms and enabled them to continue pembrolizumab administration.

Methods: Ethical approval was given by the ethics committee of Osaka International Cancer Institute and the informed consents were given by the patients.

Diagnosis: Serum D-dimer level testing, venous ultrasonography, enhanced computed tomography (CT).

Interventions: Continuous heparin infusion, direct oral anticoagulants (DOAC).

Outcomes: Immediate continuous heparin infusion improved their symptoms and continuing pembrolizumab with direct oral anticoagulant successfully induced tumor shrinkage.

Lessons: Reinvigoration of exhausted T cells by pembrolizumab induced systemic inflammation possibly resulting in development of thrombosis. Although acute thrombosis is a rare irAE, it may lead to cessation of treatment and can be lethal.
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http://dx.doi.org/10.1097/MD.0000000000010772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976311PMC
May 2018

HER3 expression is enhanced during progression of lung adenocarcinoma without EGFR mutation from stage 0 to IA1.

Thorac Cancer 2018 04 23;9(4):466-471. Epub 2018 Feb 23.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background: Activating EGFR mutations, HER2, and HER3 are implicated in lung cancer; however, with the exception of EGFR gene amplification in lung adenocarcinoma harboring EGFR mutations, their involvement in disease progression during the early stages is poorly understood. In this paper, we focused on which receptor is correlated with lung adenocarcinoma progression in the presence or absence of EGFR mutation from stage 0 to IA1.

Methods: HER2 and HER3 expression and activating EGFR mutations in surgically resected lung adenocarcinoma exhibiting ground glass nodules on chest computed tomography and re-classified to stage 0 and IA1 were examined by immunohistochemistry and peptide nucleic acid-locked nucleic acid PCR clamp method, respectively.

Results: HER2 and HER3 expression was detected in 22.2% and 86.1% of samples, respectively. The frequency of EGFR mutation was 45.7% and was not significantly different between stage 0 and IA1 (40.0% and 48.0%, respectively), suggesting that EGFR mutation does not correlate with cancer progression from stage 0 to IA1. HER2 expression also did not correlate to progression. However, not only the frequency, but also the intensity of HER3 expression was increased in stage IA1 lung adenocarcinoma, particularly in lung adenocarcinoma without EGFR mutation.

Conclusion: HER3 tends to be intensively expressed during the progression of lung adenocarcinoma without EGFR mutation from carcinoma in situ to invasive carcinoma.
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http://dx.doi.org/10.1111/1759-7714.12609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879050PMC
April 2018

Metastatic site as a predictor of nivolumab efficacy in patients with advanced non-small cell lung cancer: A retrospective multicenter trial.

PLoS One 2018 22;13(2):e0192227. Epub 2018 Feb 22.

Osaka International Cancer Institute, Osaka, Japan.

Purpose: To conduct a retrospective multicenter trial to determine the significance of metastatic site as a predictor of nivolumab efficacy in patients with advanced non-small cell lung cancer.

Methods: This study was conducted across three medical centers in Japan. We retrospectively reviewed all patients who commenced nivolumab treatment at these centers between December 17, 2015 and July 31, 2016. Clinical data were collected, including age, sex, smoking status, Eastern Cooperative Oncology Group performance status, and metastatic site (lymph nodes, liver, brain, bone, lungs [intrapulmonary metastasis], and malignant pleural effusion) at the time of commencing nivolumab treatment. Patients were followed-up until March 31, 2017.

Results: Two hundred and one patients were enrolled. The median age at the time of commencing nivolumab treatment was 68 (range, 27-87) years. One hundred and thirty-five patients were male, 157 patients had a history of smoking, 153 patients had a performance status of 0-1, and 42 patients had squamous cell carcinoma. The median progression-free survival of all patients was 2.5 months. In the univariate analysis, a performance status of ≥2 (hazard ratio [HR]: 1.89, 95.0% confidence interval [CI]: 1.33-2.69; p < 0.001) and liver (HR: 2.09, 95.0% CI: 1.35-3.25; p < 0.001) and lung (HR: 1.57, 95.0% CI: 1.14-2.16; p < 0.01) metastases correlated with a significantly shorter progression-free survival in nivolumab-treated patients. In the multivariate analysis, a performance status of ≥2 (HR: 1.54, 95.0% CI: 1.05-2.25; p < 0.05) and liver (HR: 1.90, 95.0% CI: 1.21-2.98; p < 0.01) and lung (HR: 1.41, 95.0% CI: 1.00-1.99; p < 0.05) metastases were independently correlated with a significantly shorter progression-free survival in nivolumab-treated patients.

Conclusion: Liver and lung metastases and a poor performance status are independent predictors of nivolumab efficacy in patients with advanced non-small cell lung cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192227PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823394PMC
April 2018

Unfavorable impact of cancer cachexia on activity of daily living and need for inpatient care in elderly patients with advanced non-small-cell lung cancer in Japan: a prospective longitudinal observational study.

BMC Cancer 2017 Nov 28;17(1):800. Epub 2017 Nov 28.

Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.

Background: Cancer cachexia in elderly patients may substantially impact physical function and medical dependency. The aim of this study was to estimate the impact of cachexia on activity of daily living (ADL), length of hospital stay, and inpatient medical costs among elderly patients with advanced non-small-cell lung cancer (NSCLC) receiving chemotherapy.

Methods: Thirty patients aged ≥70 years with advanced NSCLC (stage III-IV) scheduled to receive first-line chemotherapy were prospectively enrolled between January 2013 and November 2014. ADL was assessed using the Barthel index. The disability-free survival time (DFS) was calculated as the time between the date of study entry and the date of onset of a disabling event, which was defined as a 10-point decrease in the Barthel index from that at baseline. The mean cumulative function of the length of hospital stay and inpatient medical costs (¥, Japanese yen) was calculated.

Results: The study patients comprised 11 women and 19 men, with a median age of 74 (range, 70-82) years. Cachexia was diagnosed in 19 (63%) patients. Cachectic patients had a shorter DFS (7.5 vs. 17.1 months, p < 0.05). During the first year from study entry, cachectic patients had longer cumulative lengths of hospital stay (80.7 vs. 38.5 days/person, p < 0.05), more frequent unplanned hospital visits or hospitalizations (4.2 vs. 1.7 times/person, p < 0.05), and higher inpatient medical costs (¥3.5 vs. ¥2.1 million/person, p < 0.05) than non-cachectic patients.

Conclusions: Elderly NSCLC patients with cachexia showed higher risks for disability, prolonged hospitalizations, and higher inpatient medical costs while receiving chemotherapy than patients without cachexia. Our results might indicate that there is a potential need for an early intervention to minimize progression to or development of cachexia, improve functional prognosis, and reduce healthcare resource burden in this population.

Trial Registration: Trial registration number: UMIN000009768 . Name of registry: UMIN (University hospital Medical Information Network). Date of registration: 14 January 2013. Date of enrolment of the first participant to the trial: 23 January 2013.
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http://dx.doi.org/10.1186/s12885-017-3795-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706408PMC
November 2017

Analysis of Early Death in Japanese Patients With Advanced Non-small-cell Lung Cancer Treated With Nivolumab.

Clin Lung Cancer 2018 03 13;19(2):e171-e176. Epub 2017 Oct 13.

Osaka International Cancer Institute, Osaka, Japan. Electronic address:

Background: The increased risk for early death owing to anti-programmed cell death 1 inhibitors is a major disadvantage that requires special management. We evaluated the frequency, causes, and risk factors of early death during nivolumab treatment for non-small cell lung cancer (NSCLC) in a Japanese clinical setting.

Patients And Methods: The medical records of patients with NSCLC who started receiving nivolumab between December 17, 2015 and July 31, 2016 in 3 Japanese institutes were collected. Early death was defined as any death within 3 months from the start of nivolumab treatment, irrespective of its cause. Treatment response was evaluated using the Response Evaluation Criteria In Solid Tumors criteria, version 1.1.

Results: A total of 201 patients with NSCLC were enrolled, and 38 (18.9%) died within the first 3 months. Thirty-one (81.6%) patients who experienced early death developed progressive disease, whereas 14 (36.8%) patients who experienced early death demonstrated nivolumab-induced immune-related adverse events, which required corticosteroid intervention, including interstitial lung disease in 7 (18.4%) patients. Multivariate logistic regression demonstrated that an Eastern Cooperative Oncology Group performance status score ≥ 2 (odds ratio [OR], 5.66; 95% confidence interval [CI], 2.01-15.61; P < .001), C-reactive protein-to-albumin ratio > 0.3 (OR, 10.56; 95% CI, 3.61-30.86; P < .001), and the response to prior treatment (OR, 2.07; 95% CI, 1.03-4.14; P = .041) were independent predictors for early death.

Conclusion: Disease progression and immune-related adverse events are 2 major causes of early death with nivolumab in patients with NSCLC. An Eastern Cooperative Oncology Group performance status score ≥ 2, pretreatment C-reactive protein-to-albumin ratio > 0.3, and poor response to prior treatment were associated with early death.
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http://dx.doi.org/10.1016/j.cllc.2017.09.002DOI Listing
March 2018

Skeletal muscle depletion during chemotherapy has a large impact on physical function in elderly Japanese patients with advanced non-small-cell lung cancer.

BMC Cancer 2017 Aug 25;17(1):571. Epub 2017 Aug 25.

Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.

Background: Elderly patient with advanced cancer is one of the most vulnerable populations. Skeletal muscle depletion during chemotherapy may have substantial impact on their physical function. However, there is little information about a direct relationship between quantity of muscle and physical function. We sought to explore the quantitative association between skeletal muscle depletion, and muscle strength and walking capacity in elderly patients with advanced non-small cell lung cancer (NSCLC).

Methods: Thirty patients aged ≥70 years with advanced NSCLC (stage III-IV) scheduled to initiate first-line chemotherapy were prospectively enrolled between January 2013 and November 2014. Lumbar skeletal muscle index (LSMI, cm/m), incremental shuttle walking distance (ISWD, m), and hand-grip strength (HGS, kg) were assessed at baseline, and 6 ± 2 weeks (T2) and 12 ± 4 weeks (T3) after study enrollment. Associations were analyzed using linear regression.

Results: Altogether, 11 women and 19 men with a median age of 74 (range, 70-82) years were included in the study; 24 received cytotoxic chemotherapy and 6, gefitinib. Mean ± standard deviation of LSMI, ISWD and HGS were 41.2 ± 7.8 cm/m, 326.0 ± 127.9 m, and 29.3 ± 8.5 kg, respectively. LSMI and ISWD significantly declined from baseline to T2 and T3. HGS significantly declined from baseline to T2 and T3 only in men. Change in LSMI was significantly associated with change in HGS (β = 0.3 ± 0.1, p = 0.0127) and ISWD (β = 8.8 ± 2.4, p = 0.0005).

Conclusions: Skeletal muscle depletion accompanied with physical functional decline started in the early phase of the chemotherapy in elderly patients with advanced NSCLC. Our results suggest that there may be a need for early supportive care in these patients to prevent functional decline during chemotherapy.

Trial Registration: Trial registration number: UMIN000009768 Name of registry: UMIN (University hospital Medical Information Network). URL of registry: Date of registration: 14 January 2013. Date of enrolment of the first participant to the trial: 23 January 2013.
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http://dx.doi.org/10.1186/s12885-017-3562-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574084PMC
August 2017

Protein and mRNA expression of folic acid-associated enzymes as biomarkers for the cytotoxicity of the thymidylate synthase-targeted drugs, pemetrexed and S-1, in non-small cell lung cancer.

Mol Clin Oncol 2017 Jul 16;7(1):15-23. Epub 2017 May 16.

Laboratory of Pathology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Hyogo 654-0142, Japan.

The thymidylate synthase (TS)-targeted drugs, pemetrexed and S-1, exert an important role in advanced non-small cell lung cancer (NSCLC) treatment; folic acid-associated enzymes are expected to behave as biomarkers, although their role has yet to be fully elucidated. In the present study, a single-institutional prospective analysis, in which the mRNA and protein expression levels of five folic acid-associated enzymes were evaluated with surgical specimens of NSCLC, was performed. Drug sensitivity was evaluated using a collagen gel droplet-embedded culture drug sensitivity test (CD-DST) . A total of 50 patients with NSCLC were enrolled, and the mRNA and protein expression levels of five enzymes were assessed in 47 and 46 patients, respectively. A significant association was identified between mRNA and protein expression in TS (r=0.6266), but the correlation between mRNA and protein expression levels for the other four enzymes was poor. TS mRNA expression was significantly higher in poorly differentiated tumors compared with moderately differentiated tumors (P=0.0399). TS protein expression was significantly higher in patients with pleural invasion or lymphatic invasion compared with those lacking them (P=0.027 and 0.030, respectively). CD-DST revealed that none of the tumors that were sensitive to pemetrexed, but not to S-1, were well differentiated, whereas none of the tumors that were sensitive to S-1, but not to pemetrexed, were poorly differentiated. More prominent vascular invasion was observed in the tumors that were sensitive to S-1. The only factors that exhibited the potential to discriminate the cytotoxicity of pemetrexed from S-1 were tumor differentiation grade and vascular invasion.
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http://dx.doi.org/10.3892/mco.2017.1262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492704PMC
July 2017

Delayed pseudoprogression of lung adenocarcinoma accompanied with interstitial lung disease during chemotherapy after nivolumab treatment.

Thorac Cancer 2017 05 30;8(3):275-277. Epub 2017 Mar 30.

Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.

A 62-year-old Japanese female with primary lung adenocarcinoma received seven cycles of nivolumab as an eighth line of chemotherapy until she presented with hemoptysis. After transcatheter arterial embolization therapy, she received subsequent chemotherapy with paclitaxel and S-1. Four weeks later, a chest computed tomography examination revealed infiltrative shadows mainly in the right lung field, in addition to enlargement of the lung metastasis in the right middle lung lobe. Bronchofiberscopic examination revealed infiltration of lymphocytes without any malignant cells in the right segment 1 of the lung, which suggested interstitial lung disease. Corticosteroid therapy not only improved the infiltrative shadows but also reduced the lung metastasis. Even after the infiltrative shadows improved, the lung metastasis reduced further. This phenomenon resembles manifestation of pseudoprogression during treatments with immune checkpoint inhibitors, such as nivolumab.
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http://dx.doi.org/10.1111/1759-7714.12431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415460PMC
May 2017

Afatinib-induced severe esophagitis in a lung cancer patient with an activated epidermal growth factor receptor mutation: A case report.

Respir Med Case Rep 2017 19;20:111-112. Epub 2017 Jan 19.

Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511, Japan.

A 58-year-old woman with lung cancer complaint odynophagia by sour food. Endoscopic examination revealed severe erosion strictly limited to the esophagus. Drug-induced esophagitis was suspected. She was taking afatinib, loxoprofen, pregabalin, lorazepam, a formulation of butyric acid bacteria, and amino acid supplements for more than 1 month at the time of developing esophagitis. Her appetite was very poor for several days before developing the esophagitis. Although not definitive, the most probable cause of her esophagitis is an increased blood concentration of afatinib due to prolonged starved condition.
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http://dx.doi.org/10.1016/j.rmcr.2017.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5262501PMC
January 2017

Aprepitant for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy.

Int J Clin Oncol 2017 Jun 31;22(3):600-604. Epub 2017 Jan 31.

Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka, Japan.

Background: Our aim was to evaluate the efficacy of oral aprepitant in rescue treatment after the primary rescue for breakthrough chemotherapy-induced nausea and vomiting (CINV) in chemotherapy-naive patients receiving moderately emetogenic chemotherapy (MEC).

Methods: This was a single-institutional phase 2 study. Patients who had received MEC regimens and developed breakthrough CINV despite antiemetic prophylaxis without aprepitant were treated with primary rescue antiemetic treatments chosen by physicians. When the primary rescue (1st rescue) failed, patients received oral aprepitant as the second rescue (2nd rescue). The primary endpoint of this study was the proportion of patients requiring aprepitant as the 2nd rescue and experiencing successful rescue (SR). SR was defined as no vomiting and no need for additional rescue therapy, with nausea up to grade 1 on Common Terminology Criteria for Adverse Events and a Visual Analog Scale score of 25 mm, for 48 h after initiation of aprepitant.

Results: Eighty patients were eligible for this analysis. Thirty-eight (47.5%) developed breakthrough emesis and received 1st rescue. The 1st rescue was ineffective in 29 (76.3%) patients, and they received the 2nd rescue with aprepitant. Thirteen of these 29 patients (16.3% of the total patients) satisfied the criteria for SR. The primary endpoint, SR rate, in patients treated with aprepitant, was 44.8% (95% confidence interval 26.4-64.4).

Conclusion: Since the lower end of the 95% confidence interval of SR is 26.4%, the SR in our study did not meet the predefined primary endpoint threshold. However, aprepitant was estimated to be useful in suppressing breakthrough CINV in 16% of the patients treated with MEC.
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http://dx.doi.org/10.1007/s10147-016-1081-yDOI Listing
June 2017

Transient appearance of circulating tumor DNA associated with de novo treatment.

Sci Rep 2016 12 9;6:38639. Epub 2016 Dec 9.

Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.

The limitation of circulating tumor DNA (ctDNA) is its inability to detect cancer cell subpopulations with few or no dying cells. Lung cancer patients subjected to the EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment were prospectively collected, and ctDNA levels represented by the activating and T790M mutations were measured. The first data set (21 patients) consisting of samples collected in the period from before initiation of EGFR-TKI to at least 2 weeks after initiation: the ctDNA dynamics generally exhibited a rapid decrease and/or a transient increase. In 4 patients, we detected a transient increase of ctDNA bearing activating mutations not identified in biopsy samples. ctDNA with the same genotypical pattern was identified in 7 out of the 39 patients of the second data set intended to include samples until the onset of disease progression. In 6 of the 7 patients, this unique ctDNA appeared in the early period after treatment initiation, and did not reappear even after disease progression or chemotherapy. In another patient, similar ctDNA appeared upon radiation therapy. The identification of ctDNA with a unique genotype indicates the presence of cancer cell subpopulations that normally contain few or no dying cells, but generate dead cells because of the treatment.
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http://dx.doi.org/10.1038/srep38639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5146655PMC
December 2016

A long-term survivor of non-small-cell lung cancer harboring concomitant EGFR mutation and ALK translocation.

Respir Med Case Rep 2016 30;19:137-139. Epub 2016 Sep 30.

Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.

In January 2003, a 55-year old, non-smoking woman visited our hospital to undergo treatment for T4N0M0 pulmonary adenocarcinoma of the left lung. Until death in October 2015, she received over 20 lines of treatment including a second line therapy with gefitinib, which showed long response. In March 2014, she noticed the left axillar lymph node swelling. Aspiration cytology of the lymph node revealed the presence of adenocarcinoma harboring EGFR exon 19 deletion (Ex19del) but not T790M. Concomitant ALK translocation of variant 1 was also detected. Crizotinib and alectinib showed marked decrease of serum CEA value from 731.9 to 122.2 and moderate radiologic response. In contrast, both Ex19del and T790M, but not ALK translocation, were detected in the metastasis to the left anterior chest wall.
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http://dx.doi.org/10.1016/j.rmcr.2016.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053035PMC
September 2016

Early responses of EGFR circulating tumor DNA to EGFR tyrosine kinase inhibitors in lung cancer treatment.

Oncotarget 2016 Nov;7(44):71782-71789

Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.

Objectives: Early evaluation of the effect of treatment is helpful in the management of cancer patients. Circulating biomarkers are an ideal tool for this if they are highly specific to tumors and respond rapidly to tumor volume changes. Circulating tumor DNA (ctDNA) is one such candidate. We conducted a prospective study to test the utility of EGFR ctDNA in early evaluation of EGFR-TKI effects.

Results: Twenty-one patients with EGFR-mutant lung cancer who were naïve to EGFR-TKI were enrolled. PM scores of EGFR ctDNA with activating mutations decreased rapidly in response to EGFR-TKI. Of the 14 patients with positive pretreatment PM scores, complete disappearance of major EGFR ctDNA was observed in 14.3%, 42.9%, and 57.1% on days 2 - 4, 8, and 15, respectively. These responses of EGFR ctDNA were most prominent among the measures used to evaluate responses, and correlated with early radiologic responses evaluated by chest X-rays.

Materials And Methods: EGFR ctDNA in serial plasma samples was amplified and 105 copies were sequenced with a next-generation sequencer. Plasma mutation (PM) score was defined as the number of reads containing deletions/substitutions in 105EGFR cell free DNA (cfDNA). When EGFR mutation in ctDNA was the same as that detected in cancer tissue, the ctDNA was defined as major EGFR ctDNA.

Conclusions: The results indicate the usefulness of ctDNA as a highly specific biomarker for prediction of early response to treatment and that it can be applied to various types of cancer.
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http://dx.doi.org/10.18632/oncotarget.12373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342122PMC
November 2016

Numerical indices based on circulating tumor DNA for the evaluation of therapeutic response and disease progression in lung cancer patients.

Sci Rep 2016 07 6;6:29093. Epub 2016 Jul 6.

Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.

Monitoring of disease/therapeutic conditions is an important application of circulating tumor DNA (ctDNA). We devised numerical indices, based on ctDNA dynamics, for therapeutic response and disease progression. 52 lung cancer patients subjected to the EGFR-TKI treatment were prospectively collected, and ctDNA levels represented by the activating and T790M mutations were measured using deep sequencing. Typically, ctDNA levels decreased sharply upon initiation of EGFR-TKI, however this did not occur in progressive disease (PD) cases. All 3 PD cases at initiation of EGFR-TKI were separated from other 27 cases in a two-dimensional space generated by the ratio of the ctDNA levels before and after therapy initiation (mutation allele ratio in therapy, MART) and the average ctDNA level. For responses to various agents after disease progression, PD/stable disease cases were separated from partial response cases using MART (accuracy, 94.7%; 95% CI, 73.5-100). For disease progression, the initiation of ctDNA elevation (initial positive point) was compared with the onset of objective disease progression. In 11 out of 28 eligible patients, both occurred within ±100 day range, suggesting a detection of the same change in disease condition. Our numerical indices have potential applicability in clinical practice, pending confirmation with designed prospective studies.
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http://dx.doi.org/10.1038/srep29093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933907PMC
July 2016
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