Papers by Hiroaki Akamatsu
Cancers, 2021
Although programmed death-ligand 1 (PD-L1) expression on tumor tissue is a validated predictive b... more Although programmed death-ligand 1 (PD-L1) expression on tumor tissue is a validated predictive biomarker for a PD-1 pathway blockade in non-small cell lung cancer (NSCLC), longitudinal changes in its expression during treatment remains elusive. Circulating tumor cells (CTCs) are assumed to reflect the transition of characteristics of the primary tumor undergoing anticancer treatment. Here, we sequentially evaluated the PD-L1 expression on CTCs in NSCLC patients treated with nivolumab. Forty-five patients were enrolled, and CTCs were enriched from 3 mL of peripheral blood using a microcavity array system at baseline and weeks 4, 8, 12, and 24 or until progressive disease. The effective responses to therapy were compared between patients without progressive disease (PD) at week 8 (i.e., non-PD patients) and in those with PD between weeks 4 and 8 (PD patients) in terms of increased vs. decreased or equal CTC status at week 8 (for non-PD patients) or at the point of PD (for PD patients...
Clinical Cancer Research, 2021
Purpose: FGFR1 overexpression has been associated with endocrine resistance in ER+ breast cancer.... more Purpose: FGFR1 overexpression has been associated with endocrine resistance in ER+ breast cancer. We found FGFR1 localized in the nucleus of breast cancer cells in primary tumors resistant to estrogen suppression. We investigated a role of nuclear FGFR1 on gene transcription and antiestrogen resistance. Experimental Design: Tumors from patients treated with letrozole were subjected to Ki67 and FGFR1 IHC. MCF7 cells were transduced with FGFR1(SP-)(NLS) to promote nuclear FGFR1 overexpression. FGFR1 genomic activity in ER+/FGFR1-amplified breast cancer cells ± FOXA1 siRNA or ± the FGFR tyrosine kinase inhibitor (TKI) erdafitinib was examined by chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq). The nuclear and chromatin-bound FGFR1 interactome was investigated by mass spectrometry (MS). Results: High nuclear FGFR1 expression in ER+ primary tumors positively correlated with post-letrozole Ki67 values. Nuclear FGFR1 overexpression influenced gene transcrip...
Therapeutic Advances in Medical Oncology, 2021
Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is a standard... more Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is a standard treatment in EGFR-mutated advanced non-small-cell lung cancer (NSCLC); however, previous data have suggested that EGFR-TKI has limited potential as adjuvant therapy. On the contrary, based on subset analysis with the immune checkpoint inhibitor (ICI) plus platinum-doublet chemotherapy in advanced NSCLC with EGFR mutation, we hypothesized that this combination was worth testing as adjuvant therapy in patients with EGFR-mutated NSCLC. Methods: Herein, we introduce our phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected NSCLC with EGFR mutation. Accrued patients will be pathological stage II–IIIA with completely resected NSCLC and whose tumors have EGFR mutation. Treatment comprises four cycles of cisplatin plus vinorelbine combined with atezolizumab followed by maintenance with atezolizumab. The primary endpoint is the diseas...
Cancer Medicine, 2020
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Cancer Science, 2020
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Annals of Oncology, 2018
Background: Clinical and pathological features, as well as genomic IgG signature, and correlation... more Background: Clinical and pathological features, as well as genomic IgG signature, and correlation to HER2-enriched were independently prognostic in CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for HER2-positive breast cancer. Our aim was to build a prognostic model for HER2þ patients receiving trastuzumab using clinical, pathological and genomic signatures. Methods: We performed a comprehensive analyses on event-free survival, integrating clinic-pathological information (stage, treatment [dual vs single HER2 drugs], pathological complete response [pCR], and immunohistochemical hormonal receptor status) as well as 509 gene expression signatures using mRNA-sequencing data from 265 pre-treatment tumor samples. Excluding 6 Normal-like tumor samples, the dataset consisted of 259 patients including 82 HER2-enriched, 14 Basal-like, 81 Luminal A, and 82 Luminal B. We first analyzed univariate Cox regression analysis, and then built multivariate Cox models using the Elastic net for predicting event-free survival (EFS). Given the limitations of this sample size, we performed 10-fold cross validation analysis and identified the most commonly selected features. Results: Using the Elastic Net regression, we selected the best alpha and lambda. and using these combinations, the Elastic models comprised 70-80 features. Among these, 20 features were always selected including treatment, pCR, signatures of IgG, Helper T cell, response to chemotherapy, CD44þ cells as good prognostic factors, and a signature of lymph vessel as a poor prognostic factor. Those features were also significantly associated with EFS in univariate analysis. Conclusions: Our predictive model of EFS in HER2þ patients receiving trastuzumab regimen included key clinical and genomic features. These models need to be validated in independent datasets.
Clinical Lung Cancer, 2019
Circulating tumor cells (CTCs) and their programmed death receptor-ligand 1 (PD-L1) expression in... more Circulating tumor cells (CTCs) and their programmed death receptor-ligand 1 (PD-L1) expression in patients with lung cancer were detected using a microcavity array system. PD-L1 expression was detected in 73% of patients who harbored CTCs. The proportion of PD-L1-positive CTCs ranged from 3% to 100%, suggesting intra-patient heterogeneity. No correlation on PD-L1 expression was observed between tumor tissues and CTCs. Background: Blockade of the programmed death receptor-1 (PD-1) pathway is effective against solid tumors including lung cancer. PD-ligand 1 (PD-L1) expression on tumor tissue serves as a predictive biomarker for the efficacy of PD-1 pathway blockade. Here, we evaluated the expression of PD-L1 on circulating tumor cells (CTCs) in patients with lung cancer. Materials and Methods: Peripheral whole blood (3 mL) was collected from patients, and CTCs and PD-L1 expression were detected using a microcavity array (MCA) system. Immunohistochemistry for PD-L1 detection was also performed using matched tumor tissues. Results: Sixty-seven patients with lung cancer were enrolled in the study between July 2015 and April 2016 at Wakayama Medical University Hospital. The characteristics of the patients were as follows: median age, 71 years (range, 39-86 years); male, 72%; stage II to III/IV, 14%/85%; nonesmall-cell lung cancer/small-cell lung cancer/other, 73%/21%/6%. CTCs were detected in 66 of 67 patients (median, 19; range, 0-115), and more than 5 CTCs were detected in 78% of patients. PD-L1-expressing CTCs were detected in 73% of patients, and the proportion score of PD-L1-expressing CTCs ranged from 3% to 100%, suggesting intra-patient heterogeneity of PD-L1 expression on CTCs. Tumor tissues were available from 27 patients and were immunostained for PD-L1, and no correlation was observed between tumor tissues and CTCs based on the proportion score (R 2 ¼ 0.0103). Conclusion: PD-L1 expression was detectable on CTCs in patients with lung cancer, and intra-patient heterogeneity was observed. No correlation was observed between PD-L1 expression in tumor tissues and CTCs.
Lung Cancer, 2018
The authors regret that we mistook the PD-L1 immunohistochemistry data in Table 1 for that of cir... more The authors regret that we mistook the PD-L1 immunohistochemistry data in Table 1 for that of circulating tumor cell. The authors revised the figures of the PD-L1 in Table 1 (please see the details below) and the sentence "One-third of the patients were strongly positive for PD-L1 (≥50%)." in the results section to "One-fifth of the patients were strongly positive for PD-L1 (≥50%)". The authors would like to apologise for any inconvenience caused.
Cancer Science, 2018
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial ... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Journal of Thoracic Oncology, 2017
Background: In this study (NCT02206763), momelotinib, an inhibitor of Janus kinases 1 and 2, was ... more Background: In this study (NCT02206763), momelotinib, an inhibitor of Janus kinases 1 and 2, was administered in combination with erlotinib, a tyrosine kinase inhibitor (TKI) in patients with TKI-naïve epidermal growth factor receptor (EGFR)-mutated metastatic nonsmall cell lung cancer (NSCLC), to determine the maximum tolerated dose and safety of momelotinib in combination with erlotinib. As previously reported, dose limiting toxicities (DLTs) of grade 3 diarrhea (n¼1) and grade 4 neutropenia (n¼1) without fever were seen at dose level (DL) 2B and trial enrollment was halted. Here, we report the final results. Method: Patients received oral erlotinib 150 mg QD (including 11-31 day run-in). Momelotinib was administered orally in a standard 3+3 dose-escalation design: DL1, momelotinib 100 mg QD; DL2A, 200 mg QD; and DL2B, 100 mg BID. DLTs were evaluated in the first 28 days. Plasma samples were collected for PK/PD analyzes. Result: Eleven patients enrolled: 3 in DL1, 3 in DL2A, and 5 in DL2B. The median duration of exposure to momelotinib was 40 weeks (range 2.4-63.1) and median number of cycles was 10 (range 0.6-15.8). Treatment was discontinued for progressive disease (n¼7), adverse event (n¼3), and patient decision (n¼1). The objective response rate was 54.5% (90% CI: 27.1%e80.0%) and all responses (n¼6) were partial responses; 4 patients had stable disease and 1 patient had progressive disease. The median duration of response was 7.1 (90% CI: 4.4e9.6) months. The median progression-free survival was 9.2 (90% CI: 6.2e12.4) months. The estimated median overall survival was not reached. The most common treatment-emergent adverse events (TEAEs) were decreased appetite, dry skin, and fatigue (7 patients each) and diarrhea (6 patients). In addition to the patient with grade 4 neutropenia (DLT), decreased neutrophil count was recorded in 4 additional patients (grade 1-2 [n¼3], grade 3 [n¼1]); median time to first neutrophil abnormality was 0.5 (range 0.5e3.7) months. Momelotinib-related TEAEs of interest (one patient each) included grade 1 sensory peripheral neuropathy, grade 1 paresthesia, and reactivation of hepatitis B. There was one momelotinib-related serious adverse event, grade 3 pneumonitis. There was no PK interaction between momelotinib and erlotinib. Conclusion: The combination of momelotinib and erlotinib had more toxicity than expected at DL2B. Neutropenia was common. Although the small number of patients in this phase 1 study limits our ability to make a definitive conclusion regarding efficacy, the response rate and progression-free survival was similar to previous reports with erlotinib alone.
Journal of Thoracic Oncology, 2017
Introduction: Alectinib has shown marked efficacy and safety in patients with anaplastic lymphoma... more Introduction: Alectinib has shown marked efficacy and safety in patients with anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement-positive NSCLC and a good performance status (PS). It has remained unclear whether alectinib might also be beneficial for such patients with a poor PS. Methods: Eligible patients with advanced ALK rearrangementpositive NSCLC and a PS of 2 to 4 received alectinib orally at 300 mg twice daily. The primary end point of the study was objective response rate (ORR), and the most informative secondary end point was rate of PS improvement. Results: Between September 2014 and December 2015, 18 patients were enrolled in this phase II study. Of those patients, 12, five, and one had a PS of 2, 3, or 4, respectively, whereas four patients had received prior crizotinib treatment. The ORR was 72.2% (90% confidence interval: 52.9-85.8%). The ORR did not differ significantly between patients with a PS of 2 and those with a PS of 3 or higher (58.3% and 100%, respectively [p ¼ 0.114]). The PS improvement rate was 83.3% (90% confidence interval: 64.8-93.1%, p < 0.0001), with the frequency of improvement to a PS of 0 or 1 being 72.2%. The median progression-free survival was 10.1 months. Toxicity was mild, with the frequency of adverse events of grade 3 or higher being low. Neither dose reduction nor withdrawal of alectinib because of toxicity was necessary. Conclusions: Alectinib is a treatment option for patients with ALK rearrangement-positive NSCLC and a poor PS.
The New England journal of medicine, Feb 6, 2016
Background Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI... more Background Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown. Methods In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was ...
Oncotarget, Jan 16, 2016
Next-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have be... more Next-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to overcome resistance to earlier generations of such drugs mediated by a secondary T790M mutation of EGFR, but the performance of a second tumor biopsy to assess T790M mutation status can be problematic. We developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance. A total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites fluid from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. T...
SpringerPlus, 2015
Platinum-based chemoradiotherapy (CRT) is a standard front-line treatment for locally advanced no... more Platinum-based chemoradiotherapy (CRT) is a standard front-line treatment for locally advanced non-small cell lung cancer (NSCLC). However, no clinical trials have compared the efficacy and toxicity of platinum combination and docetaxel as subsequent re-challenge chemotherapies after cancer recurrence following CRT. This study aimed to evaluate the efficacy and toxicity of platinum combination chemotherapy versus docetaxel monotherapy in NSCLC patients previously treated with platinum-based CRT. From September 2002 to December 2009, at three participating institutions, 24 patients with locally advanced NSCLC, who had previously received platinum-based CRT, were treated with platinum combination re-challenge therapy, whereas 61 received docetaxel monotherapy. We reviewed their medical charts to evaluate patient characteristics and data regarding treatment response, survival, and toxicity. The response rates were 16.7% and 6.6% in the platinum combination chemotherapy and docetaxel mo...
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, Jan 29, 2014
Cancer cachexia (CC) is commonly seen in advanced lung cancer patients and associated with poor p... more Cancer cachexia (CC) is commonly seen in advanced lung cancer patients and associated with poor prognosis. However, little is known about CC that develops during chemotherapy. We evaluated the prognostic impact of CC and skeletal muscle wasting that develops during the course of chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. The clinical data of 134 newly diagnosed NSCLC patients were retrospectively reviewed. CC was defined as a body weight loss >5 or >2 % in patients with a body mass index of <20 kg/m(2). CC was assessed at baseline (T1) and 3 months (T2), 6 months (T3), and 12 months (T4) after chemotherapy initiation. Skeletal muscle mass was assessed using the lumber skeletal muscle index (LSMI). The proportion of patients with CC at T1, T2, T3, and T4 was 45.6, 46.1, 25.5, and 26.0 %, respectively. The frequency of grade 3 chemotherapy-induced anorexia was higher in patients with CC than those without CC at T2 (15.4 vs. 0.0 %, P = 0.0044). At al...
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2014
Pleural effusion is frequently observed in patients with advanced lung cancer. Although effusion ... more Pleural effusion is frequently observed in patients with advanced lung cancer. Although effusion can be obtained less invasively and repeatedly, its use in multiplexed molecular profiling has not been fully investigated. Between July 2011 and April 2013, pleural effusion samples were obtained from patients with lung cancer at Shizuoka Cancer Center. They were analyzed for EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2 mutations, EGFR, MET, FGFR1, FGFR2, and PIK3CA amplifications, and ALK, ROS1, and RET fusion genes using pyrosequensing and/or capillary electrophoresis, quantitative reverse-transcriptase polymerase chain reaction, and reverse-transcriptase polymerase chain reaction, respectively. One hundred and two samples from 84 patients were analyzed. Adenocarcinoma was the most common histological subtype (82%). Genetic abnormalities were detected in 42% of patients. The most common abnormality was EGFR mutation (29%), followed by EML4-ALK rearrangement (5%), KRAS mu...
Neoplasma, 2014
The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent... more The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with non-small cell lung cancer (NSCLC). We examined whether progression-free survival (PFS), post-progression survival (PPS), or tumor response could be valid surrogate endpoints for OS after first-line chemotherapies in advanced NSCLC by using individual-level data, given the lack of research in this area. Between April 2009 and June 2011, 50 patients with advanced non-squamous NSCLC treated with cisplatin and pemetrexed as first-line chemotherapy were analyzed. The relationships of PFS, PPS, and tumor response with OS were analyzed at the individual level. Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.89, P < 0.05, R2 = 0.79), PFS was moderately correlated with OS (r = 0.67, P < 0.05, R2 = 0.39), and tumor shrinkage was weakly correlated with OS (r = 0.36, P < 0.05, R2 = 0.14). P...
Oncology letters, 2011
The active mutation of epidermal growth factor receptor (EGFR) and clinical characteristics are s... more The active mutation of epidermal growth factor receptor (EGFR) and clinical characteristics are significant biomarkers for chemotherapy selection in non-small cell lung cancer (NSCLC). Although docetaxel is a key agent in second-line therapy for NSCLC, predictive biomarkers for assessing its efficacy have yet to be determined. To assess the clinical efficacy of docetaxel in second-line therapy for NSCLC according to NSCLC histology and the therapeutic effect of EGFR-tyrosine kinase inhibitors (EGFR-TKIs), we retrospectively reviewed 454 NSCLC patients treated with docetaxel between April 2002 and April 2009. In total, 239 patients with advanced NSCLC treated with docetaxel as second-line therapy following failure of platinum-based chemotherapy were analyzed in this study. A total of 59 (25%) patients had squamous cell carcinoma. The overall response rate and median progression-free survival time in the squamous cell group were significantly inferior to those in the non-squamous cell...
Anticancer research, 2012
Based on the results of phase I/II studies, S-1 plus cisplatin (CDDP) and vinorelbine (VNR) plus ... more Based on the results of phase I/II studies, S-1 plus cisplatin (CDDP) and vinorelbine (VNR) plus CDDP are commonly used chemoradiotherapeutic regimens for the treatment of non-small cell lung cancer(NSCCLC) in Japan. However, there have been no studies that have compared S-1 and CDDP combined with thoracic radiotherapy (TRT) with VNR and CDDP combined with TRT. A total of 39 and 50 patients with stage III non-small cell lung cancer (NSCLC) were treated with S-1 and CDDP plus concurrent TRT, or with VNR and CDDP plus concurrent TRT, respectively, between 2002 and 2010. In the S-1 plus CDDP plus TRT group, the median progression-free survival (PFS) and the median overall survival (OS) were 327 days and 1012 days, respectively. In the VNR plus CDDP plus TRT group, the median PFS and the median OS were 328 days and 905 days, respectively. The differences in the PFS and OS were not statistically significant. Grade 3 or more leukopenia and neutropenia were significantly more common in the...
Uploads
Papers by Hiroaki Akamatsu