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1.
ESMO Open ; 8(4): 101588, 2023 08.
Article in English | MEDLINE | ID: mdl-37385153

ABSTRACT

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is a widely explored therapeutic target in solid tumors. We evaluated the efficacy and safety of trastuzumab-pkrb, a biosimilar of trastuzumab, in combination with paclitaxel, in HER2-positive recurrent or metastatic urothelial carcinoma (UC). PATIENTS AND METHODS: We enrolled 27 patients; they were administered a loading dose of 8 mg/kg trastuzumab-pkrb on day 1, followed by 6 mg/kg and 175 mg/m2 paclitaxel on day 1 every 3 weeks, intravenously. All patients received six cycles of the combination treatment and continued to receive trastuzumab-pkrb maintenance until disease progression, unacceptable toxicity, or for up to 2 years. HER2 positivity (based on immunohistochemistry analysis) was determined according to the 2013 American Society of Clinical Oncology /College of American Pathologists HER2 testing guidelines. The primary endpoint was objective response rate (ORR); the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. RESULTS: Twenty-six patients were evaluated via primary endpoint analysis. The ORR was 48.1% (1 complete and 12 partial responses) and the duration of response was 6.9 months [95% confidence interval (CI) 4.4-9.3 months]. With a median follow-up of 10.5 months, the median PFS and OS were 8.4 months (95% CI 6.2-8.8 months) and 13.5 months (95% CI 9.8 months-not reached), respectively. The most common treatment-related adverse event (TRAE) of any grade was peripheral neuropathy (88.9%). The most common grade 3/4 TRAEs were neutropenia (25.9%), thrombocytopenia (7.4%), and anemia (7.4%). CONCLUSIONS: Trastuzumab-pkrb plus paclitaxel demonstrates promising efficacy with manageable toxicity profiles in patients with HER2-positive recurrent or metastatic UC.


Subject(s)
Biosimilar Pharmaceuticals , Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Trastuzumab/adverse effects , Biosimilar Pharmaceuticals/adverse effects , Paclitaxel/pharmacology
2.
ESMO Open ; 8(2): 100877, 2023 04.
Article in English | MEDLINE | ID: mdl-36947985

ABSTRACT

BACKGROUND: Although introduction of immune checkpoint inhibitors has revolutionized the treatment of cancer, their response rates are generally low. Preclinical and early phase clinical data suggest that MEK inhibition may sensitize tumors to immune checkpoint inhibitors by upregulating tumor antigen expression, programmed death-ligand 1 (PD-L1) expression, and tumor T-cell infiltration. We evaluated the efficacy and safety of cobimetinib plus atezolizumab in patients with advanced solid tumors in the open-label, multicohort phase II COTEST study. PATIENTS AND METHODS: This analysis of the COTEST trial included patients from cohorts 1-4 [1-3: anti-programmed cell death protein 1 (PD-1)/PD-L1 treatment-naive patients; 4: patients with disease progression on anti-PD-1/anti-PD-L1 treatment] who received cobimetinib 60 mg once daily for the first 21 days and intravenous infusions of atezolizumab 840 mg on days 1 and 15 of each 28-day cycle. Efficacy endpoints included objective response rate, overall survival, progression-free survival (PFS), and disease control rate. RESULTS: Overall, 77 patients were enrolled in cohorts 1-4 (78% male; median age 62.8 years). Objective response rate was 20% in cohort 1 [squamous cell carcinoma of the head and neck (SCCHN)], 30% in cohort 2 (urothelial carcinoma), and 18% in cohort 3 (renal cell carcinoma); there were no responders among 20 patients in cohort 4 (SCCHN). The disease control rates in cohorts 1-4 were 50%, 40%, 24%, and 25%, respectively. The median PFS was 5.5, 3.4, 3.4, and 3.6 months in cohorts 1-4, respectively, and the median overall survival was 16.8, 18.7, 21.7, and 7.7 months, respectively. Most adverse events were of grade 1/2 and were manageable. CONCLUSIONS: Cobimetinib plus atezolizumab had moderate activity in patients with anti-PD-1/PD-L1 treatment-naive SCCHN and urothelial carcinoma, and weak activity in anti-PD-1/PD-L1 treatment-naive renal cell carcinoma, and no activity in checkpoint inhibitor-treated patients.


Subject(s)
Carcinoma, Renal Cell , Carcinoma, Transitional Cell , Kidney Neoplasms , Urinary Bladder Neoplasms , Humans , Male , Middle Aged , Female , Immune Checkpoint Inhibitors
3.
Ann Oncol ; 33(4): 406-415, 2022 04.
Article in English | MEDLINE | ID: mdl-35026411

ABSTRACT

BACKGROUND: Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up. PATIENTS AND METHODS: ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: At data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib. CONCLUSIONS: These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Thyroid Carcinoma, Anaplastic , Thyroid Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Humans , Imidazoles/therapeutic use , Mutation , Oximes/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Pyridones/therapeutic use , Pyrimidinones/therapeutic use , Thyroid Carcinoma, Anaplastic/drug therapy , Thyroid Carcinoma, Anaplastic/genetics , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/genetics
4.
ESMO Open ; 6(6): 100309, 2021 12.
Article in English | MEDLINE | ID: mdl-34844180

ABSTRACT

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of squamous cell carcinoma (SCC) of the oral cavity, larynx, oropharynx and hypopharynx was published in 2020. It was therefore decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special, virtual guidelines meeting in July 2021 to adapt the ESMO 2020 guidelines to consider the potential ethnic differences associated with the treatment of SCCs of the head and neck (SCCHN) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with SCCHN (excluding nasopharyngeal carcinomas) representing the oncological societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter was discussed when appropriate. This manuscript provides a series of expert recommendations (Clinical Practice Guidelines) which can be used to provide guidance to health care providers and clinicians for the optimisation of the diagnosis, treatment and management of patients with SCC of the oral cavity, larynx, oropharynx and hypopharynx across Asia.


Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/therapy , Follow-Up Studies , Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/therapy , Humans , Medical Oncology , Squamous Cell Carcinoma of Head and Neck/diagnosis , Squamous Cell Carcinoma of Head and Neck/therapy
5.
Ann Oncol ; 31(7): 942-950, 2020 07.
Article in English | MEDLINE | ID: mdl-32294530

ABSTRACT

BACKGROUND: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. PATIENTS AND METHODS: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. RESULTS: Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72-1.08; P = 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85-1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9-43.1), 30.4% (24.7-36.3), and 30.5% (24.7-36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. CONCLUSION: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02369874.


Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Head and Neck Neoplasms , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Head and Neck Neoplasms/drug therapy , Humans , Neoplasm Recurrence, Local/drug therapy , Squamous Cell Carcinoma of Head and Neck/drug therapy
6.
Ann Oncol ; 29(8): 1807-1813, 2018 08 01.
Article in English | MEDLINE | ID: mdl-29992241

ABSTRACT

Background: Patients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented. Materials and methods: Key eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review. Results: Median patient age in this cohort (n = 23) was 65 years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%-38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred. Conclusion: Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1-positive prostate cancer, and its side effect profile was favorable. ClinicalTrials.gov Identifier: NCT02054806.


Subject(s)
Adenocarcinoma/drug therapy , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Prostatic Neoplasms/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Humans , Male , Middle Aged , Nausea/chemically induced , Nausea/epidemiology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Progression-Free Survival , Prostate/pathology , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathology , Response Evaluation Criteria in Solid Tumors
7.
Ann Oncol ; 28(11): 2754-2760, 2017 Nov 01.
Article in English | MEDLINE | ID: mdl-28950297

ABSTRACT

BACKGROUND: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. PATIENTS AND METHODS: Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. RESULTS: In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. CONCLUSIONS: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. CLINICAL TRIAL IDENTIFICATION: NCT02187302 (NIH).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Standard of Care , Aged , Bevacizumab/administration & dosage , Camptothecin/administration & dosage , Carcinoma, Renal Cell/secondary , Cyclodextrins/administration & dosage , Female , Follow-Up Studies , Humans , Kidney Neoplasms/pathology , Lymphatic Metastasis , Male , Prognosis , Survival Rate
8.
Ann Oncol ; 28(4): 890-897, 2017 04 01.
Article in English | MEDLINE | ID: mdl-28203693

ABSTRACT

Background: Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare aggressive malignancy often occurring in the tissues of midline anatomical structures. Except for the pathognomonic BRD3/4-NUT rearrangement, the comprehensive landscape of genomic alterations in NMCs has been unexplored. Patients and methods: We investigated three NMC cases, including two newly diagnosed NMC patients in Seoul National University Hospital, and a previously reported cell line (Ty-82). Whole-genome and transcriptome sequencing were carried out for these cases, and findings were validated by multiplex fluorescence in situ hybridization and using individual fluorescence probes. Results: Here, we present the first integrative analysis of whole-genome sequencing, transcriptome sequencing and cytogenetic characterization of NUT midline carcinomas. By whole-genome sequencing, we identified a remarkably similar pattern of highly complex genomic rearrangements (previously denominated as chromoplexy) involving the BRD3/4-NUT oncogenic rearrangements in two newly diagnosed NMC cases. Transcriptome sequencing revealed that these complex rearrangements were transcribed as very simple BRD3/4-NUT fusion transcripts. In Ty-82 cells, we also identified a complex genomic rearrangement involving the BRD4-NUT rearrangement underlying the simple t(15;19) karyotype. Careful inspections of rearrangement breakpoints indicated that these rearrangements were likely attributable to single catastrophic events. Although the NMC genomes had >3000 somatic point mutations, canonical oncogenes or tumor suppressor genes were rarely affected, indicating that they were largely passenger events. Mutational signature analysis showed predominant molecular clock-like signatures in all three cases (accounting for 54%-75% of all base substitutions), suggesting that NMCs may arise from actively proliferating normal cells. Conclusion: Taken together, our findings suggest that a single catastrophic event in proliferating normal cells could be sufficient for neoplastic transformation into NMCs.


Subject(s)
Carcinoma/genetics , Cell Transformation, Neoplastic/genetics , Nuclear Proteins/genetics , Oncogene Proteins, Fusion/genetics , Adult , Female , Gene Rearrangement , High-Throughput Nucleotide Sequencing , Humans , In Situ Hybridization, Fluorescence , Male , RNA-Binding Proteins/genetics , Transcription Factors , Transcriptome
9.
Ann Oncol ; 28(2): 292-297, 2017 02 01.
Article in English | MEDLINE | ID: mdl-27803005

ABSTRACT

Background: Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and safety of vandetanib 300 mg daily in this patient population. Patients and methods: This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0-2. The primary endpoint was the objective response rate. Results: A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35-71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity. Conclusion: Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Piperidines/therapeutic use , Proto-Oncogene Proteins c-ret/genetics , Quinazolines/therapeutic use , Adenocarcinoma/genetics , Adult , Aged , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Mutation , Treatment Outcome , Tumor Burden
10.
Ann Oncol ; 26(2): 348-54, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25403583

ABSTRACT

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation are considered mutually exclusive in nonsmall-cell lung cancer (NSCLC). However, sporadic cases having concomitant EGFR and ALK alterations have been reported. The present study aimed to assess the prevalence of NSCLCs with concomitant EGFR and ALK alterations using mutation detection methods with different sensitivity and to propose an effective diagnostic and therapeutic strategy. PATIENTS AND METHODS: A total of 1458 cases of lung cancer were screened for EGFR and ALK alterations by direct sequencing and flourescence in situ hybridization (FISH), respectively. For the 91 patients identified as having an ALK translocation, peptide nucleic acid (PNA)-clamping real-time PCR, targeted next-generation sequencing (NGS), and mutant-enriched NGS assays were carried out to detect EGFR mutation. RESULTS: EGFR mutations and ALK translocations were observed in 42.4% (612/1445) and 6.3% (91/1445) of NSCLCs by direct sequencing and FISH, respectively. Concomitant EGFR and ALK alterations were detected in four cases, which accounted for 4.4% (4/91) of ALK-translocated NSCLCs. Additional analyses for EGFR using PNA real-time PCR and ultra-deep sequencing by NGS, mutant-enriched NGS increased the detection rate of concomitant EGFR and ALK alterations to 8.8% (8/91), 12.1% (11/91), and 15.4% (14/91) of ALK-translocated NSCLCs, respectively. Of the 14 patients, 3 who were treated with gefitinib showed poor response to gefitinib with stable disease in one and progressive disease in two patients. However, eight patients who received ALK inhibitor (crizotinib or ceritinib) showed good response, with response rate of 87.5% (7/8 with partial response) and durable progression-free survival. CONCLUSIONS: A portion of NSCLC patients have concomitant EGFR and ALK alterations and the frequency of co-alteration detection increases when sensitive detection methods for EGFR mutation are applied. ALK inhibitors appear to be effective for patients with co-alterations.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , DNA Mutational Analysis/methods , Genes, erbB-1 , Lung Neoplasms/genetics , Protein Kinase Inhibitors/therapeutic use , Receptor Protein-Tyrosine Kinases/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Anaplastic Lymphoma Kinase , Carcinoma, Non-Small-Cell Lung/drug therapy , Crizotinib , Female , Gefitinib , High-Throughput Nucleotide Sequencing , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Lung Neoplasms/drug therapy , Male , Middle Aged , Mutation , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Pyrimidines/therapeutic use , Quinazolines/therapeutic use , Real-Time Polymerase Chain Reaction , Sensitivity and Specificity , Sulfones/therapeutic use , Translocation, Genetic
11.
Ann Oncol ; 25(11): 2260-2266, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25057172

ABSTRACT

BACKGROUND: Chronic inflammation is known to be one of the main steps in carcinogenesis. Identification of those with chronic inflammation may help identify subjects at risk of cancer. Previous studies have reported low albumin-to-globulin ratio (AGR) to be associated with increased cancer mortality in cancer patients, but there has been no study based on healthy populations. PATIENTS AND METHODS: Our retrospective cohort study involved 26 974 generally healthy adults aged 30 or older who visited Seoul National University Hospital Health Promotion Center for self-referred health checkup. National medical service claims data were used to determine cancer incidence, and Korean death registry data was used to determine mortality. Median follow-up time for survival was 5.9 years (interquartile range 4.1 years). RESULTS: Compared with subjects with AGR ≥ 1.5, subjects with 1.1 > AGR ≥ 1.0 and 1.0 > AGR showed adjusted hazard ratio (aHR) 2.69 (95% confidence interval, CI, 1.54-4.72) and aHR 6.71 (95% CI 3.56-12.66) for all-cause mortality, aHR 2.95 (95% CI 1.42-6.11) and aHR 4.38 (95% CI 1.57-12.25) for cancer mortality, and aHR 2.07 (95% CI 1.28-3.36) and aHR 3.99 (95% CI 2.10-7.58) for cancer incidence, respectively. When cancer incidence events after 2 years from baseline were separately analyzed, subjects with 1.1 > AGR ≥ 1.0 and 1.0 > AGR were associated with aHR 1.88 (95% CI 1.01-3.48) and aHR 2.55 (95% CI 1.03-7.11) for cancer incidence, respectively. Cancer events were increased in all types of cancer, but especially in liver and hematologic malignancies. CONCLUSIONS: Low AGR is a risk factor for cancer incidence and mortality, both short- and long terms, in a generally healthy screened population. The results of this study need to be replicated in larger studies, along with the determination of the sensitivity and other diagnostic values of low AGR.


Subject(s)
Inflammation/blood , Neoplasms/blood , Serum Albumin , Serum Globulins , Adult , Female , Follow-Up Studies , Humans , Inflammation/pathology , Male , Middle Aged , Neoplasms/mortality , Neoplasms/pathology , Prognosis , Risk Factors , Survival Analysis
12.
Ann Oncol ; 24(8): 2080-7, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23559152

ABSTRACT

BACKGROUND: The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood. PATIENTS AND METHODS: Eleven patients exhibiting primary resistance (disease progression <3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naïve tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome. RESULTS: The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs. CONCLUSIONS: We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Apoptosis Regulatory Proteins/genetics , Base Sequence , Bcl-2-Like Protein 11 , Carcinoma, Non-Small-Cell Lung/genetics , Cell Transdifferentiation/genetics , Disease-Free Survival , Drug Resistance, Neoplasm , Erlotinib Hydrochloride , Female , Gefitinib , Genotype , Humans , Lung Neoplasms/genetics , Male , Membrane Proteins/genetics , Middle Aged , Mutation , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Quinazolines/therapeutic use , Sequence Analysis, DNA , Sequence Deletion/genetics
13.
J Viral Hepat ; 16(6): 444-52, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19200133

ABSTRACT

To optimize management of chronic liver disease (CLD), a simple and noninvasive test to determine oesophageal varices (EV) and liver fibrosis is necessary. We performed a cohort study in a single tertiary care centre in order to devise a simple index reflecting EV and liver fibrosis. We derived an index reflecting EV which resulted from portal hypertension (the first part) and evaluated the index's ability to detect liver fibrosis which resulted in portal hypertension (the second part). Five hundred fifty-six patients (the first part, n = 409, mean age = 55.4 years, EV prevalence = 34.0%; the second part, n = 147, mean age = 48.8 years, cirrhosis prevalence = 12.9%) with virus-related CLD were included. P2/MS [(platelet count [10(9)/L])(2)/(monocyte fraction [%] x segmented neutrophil fraction [%])] was derived to detect EV. The area under the receiver-operating characteristic curve (AUROC) of P2/MS was 0.916 (95% confidence interval, 0.879-0.954) for detecting EV, and 0.905 (0.862-0.947) for detecting high-risk EV (grade >or= II or with red colour signs). P2/MS had AUROCs of 0.952 (0.904-0.999) and 0.873 (0.792-0.955) for histological cirrhosis (METAVIR F4) and significant fibrosis (METAVIR F2-F4), respectively, which were significantly greater than those of AST-to-platelet count ratio index (0.658, P < 0.001; 0.644, P = 0.003) and FIB-4 (0.776, P = 0.031; 0.707, P = 0.026). The predictive values of P2/MS were maintained at similar accuracy in subsequent validation sets. Our study suggests that P2/MS comprising only the complete blood count results is an efficient and noninvasive marker reflecting the presence of EV and the grade of liver fibrosis in patients with virus-related CLD. An independent external validation of P2/MS is required.


Subject(s)
Blood Cell Count , Esophagus/pathology , Hepatitis, Chronic/complications , Liver Cirrhosis/complications , Liver Cirrhosis/diagnosis , Varicose Veins/complications , Varicose Veins/diagnosis , Adult , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Predictive Value of Tests
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