Comparison of treatment outcome between first-line combination immunotherapy (anti-PD-L1 or anti-PD1) with or without chemotherapy and chemotherapy alone in advanced non-small cell lung cancer patients in tertiary care hospital.

BACKGROUND: Despite promising outcomes of first-line immunotherapy with or without chemotherapy in advanced non-small cell lung cancer (NSCLC), limited accessibility due to reimbursement was remain the problem in low to middle income countries. This study aimed to evaluate real-world effectiveness of immunotherapy in patients with advanced NSCLC in Northern Thailand. METHOD: A retrospective, single-centered cohort, was conducted. Patients with advanced NSCLC who underwent PD-L1 testing (excluding EGFR and ALK mutations) and were treated with immunotherapy or without chemotherapy or chemotherapy alone were included. The primary end point was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), and adverse events. RESULTS: A total of 123 patients, of which 21 patients received immunotherapy-based regimen and 102 patients received chemotherapy alone. The median PFS was 11.9 months in immunotherapy-based group compared to 5.93 months in the chemotherapy group, with a. hazard ratio (HR) of 0.4 (95% confidence interval [CI], 0.23 to 0.68; p = 0.001). Similarly, the median OS was 26.68 months in the immunotherapy-based group and 11.21 months in the chemotherapy group, with HR of 0.42 (95% CI 0.22-0.8; p = 0.009). ORRs were significantly higher in the immunotherapy-based group, with 65% of patients showing a response compared to 32% in the chemotherapy group (p = 0.006). CONCLUSION: The result of this real-world study in patients with advanced stage NSCLC indicate that first-line immunotherapy-based regimen was associated with significantly greater PFS, OS, and ORR with a safety profile consistent with pivotal studies.

Long-term posttransplant survival outcome following bridging locoregional therapy in hepatocellular carcinoma patients: A systematic review and meta-analysis.

Aim: Liver transplantation (LT) is essential due to its curative efficacy, but liver-graft shortages have limited its widespread application. Bridging locoregional therapy (LRT) before LT has been performed to prevent tumor progression, and a recent literature review revealed that it is associated with a nonsignificant trend toward better survival outcomes. However, much more information on bridging therapy has become available since then. This meta-analysis aimed to compare the posttransplant survival and HCC recurrence between patients with and without pretransplant bridging LRT. Methods: Studies were identified in MEDLINE, SCOPUS, and the Cochrane Library. Two independent researchers screened titles and full articles, extracted relevant data, and conducted a parametric survival analysis. Results: Out of 4794 studies, 18 cohort studies were eligible. The 1-, 3-, and 5-year overall survival (OS) rates were 93.1%, 85.0%, and 79.1% for those in the bridging LRT group, while they were 91.8%, 81.1%, and 75.5% for those who did not receive LRT, respectively. There were no differences in overall survival between these groups (HR 0.90; 0.78-1.05, P = 0.17). Interestingly, we discovered that bridging therapy helped prolong survival significantly in a high-risk population with a long waiting time (HR 0.76; 0.60-0.96, P = 0.02). Unfortunately, bridging LRT did not improve disease-free survival (HR 0.98; 0.86-1.11, P = 0.70). Conclusions: The results indicate that bridging LRT does not generally change post-LT outcomes. However, bridging LRT can significantly improve survival in patients with a long waiting time for LT.

Healthcare coverage affects survival of EGFR-mutant Thai lung cancer patients.

Background: Despite significant benefits of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in patients with EGFR-mutated NSCLC, access remains limited in Thailand and elsewhere. Methods: Retrospective analysis of patients with locally advanced/recurrent NSCLC and known EGFR mutation (EGFRm) status treated at Ramathibodi Hospital (2012-2017). Prognostic factors for overall survival (OS), including treatment type and healthcare coverage, were analyzed using Cox regression. Results: Of 750 patients, 56.3% were EGFRm-positive. After first-line therapy (n=646), 29.4% received no subsequent (second-line) treatment. EGFR-TKI-treated EGFRm-positive patients survived significantly longer than EGFRm-negative patients without EGFR-TKIs (median OS [mOS] 36.4 vs. 11.9 months; hazard ratio HR=0.38 [95%CI 0.32-0.46], P<0.001). Cox regression indicated significantly longer OS in patients with comprehensive healthcare coverage that included reimbursement of EGFR-TKIs, versus basic coverage (mOS 27.2 vs. 18.3 months; adjusted HR=0.73 [95%CI 0.59-0.90]). Compared with best supportive care (BSC; reference), EGFR-TKI-treated patients survived significantly longer (mOS 36.5 months; adjusted HR (aHR)=0.26 [95%CI 0.19-0.34]), and versus chemotherapy alone (14.5 months; aHR=0.60 [95%CI 0.47-0.78]). In EGFRm-positive patients (n=422), relative survival benefit of EGFR-TKI treatment remained highly significant (aHR[EGFR-TKI]=0.19 [95%CI 0.12-0.29]; aHR(chemotherapy only)=0.50 [95%CI 0.30-0.85]; reference:BSC), indicating that healthcare coverage (reimbursement) affected treatment choice and survival. Conclusion: Our analysis describes EGFRm prevalence and survival benefit of EGFR-TKI therapy for EGFRm-positive NSCLC patients treated from 2012-2017, one of the largest such Thai datasets. Together with research by others, these findings contributed evidence supporting the decision to broaden erlotinib access on healthcare schemes in Thailand from 2021, demonstrating the value of local real-world outcome data for healthcare policy decision-making.

Characteristics of breast cancer patients tested for germline BRCA1/2 mutations by next-generation sequencing in Ramathibodi Hospital, Mahidol University.

INTRODUCTION: Germline mutations in BRCA1/2 are the most common cause of hereditary breast and ovarian cancer (HBOC) syndrome. Few studies published during the past decade reported the prevalence of germline BRCA mutations in Asian patients with breast cancer. We aimed to assess the prevalence and characteristics of Thai patients with breast cancer with germline BRCA1/2 mutations. METHODS: We retrospectively reviewed all breast cancer patients who were tested for germline BRCA1/2 mutations during 2014-2018. BRCA mutations were detected using next-generation sequencing and confirmed using Sanger sequencing. We analyzed the characteristics of patients with or without BRCA mutations. Disease-free survival (DFS) and the associated factors were determined. RESULTS: Among 67 patients, 12 (18%) were BRCA1/2 carriers (6 each), 4 (6%) harbored variants of uncertain significance, and 51 (76%) were non-carriers. We discovered two novel BRCA2 frameshift mutations (c.2380delA and c.8855dupT). Mean ages at breast cancer diagnosis of BRCA1, BRCA2, and non-carriers were 39.8, 46.2, and 42.0 years, respectively. The 12 tumors of BRCA carriers were mainly the luminal-B subtype. Two of these tumors were HER2-positive luminal-B, and the triple-negative subtype was not detected. After adjusting for stages and luminal subtypes, BRCA carriers experienced worse 3-year DFS than non-carriers (81.5% vs. 90.3%, HR 2.04 [0.64-6.49], p = .229). The stage at diagnosis was the sole factor significantly associated with 3-year DFS (100%, 84.8%, and 72.7%; stages I, II, and III, respectively). CONCLUSION: Thai patients with breast cancer with BRCA1/2 mutations were mainly the luminal-B subtypes with worse prognosis than those without mutations.

Treatment outcomes of advanced hepatocellular carcinoma in real-life practice: Chemotherapy versus multikinase inhibitors.

BACKGROUND: Multikinase inhibitors (MKIs) represent the main treatment options for advanced hepatocellular carcinoma (aHCC). However, accessibility in developing countries is limited. A chemotherapy, Fluorouracil and Oxaliplatin (FOLFOX), offers a less expensive treatment. Therefore, this study sought to compare the clinical effectiveness of FOLFOX with Sorafenib as a first-line treatment for aHCC in real-life practice. METHODS: A retrospective aHCC cohort from four Thai hospitals was investigated for patients who received FOLFOX or Sorafenib between 2013-2019. Multiple imputation by chained equations addressed missing covariate data in a treatment effect model using Weight-adjusted-censoring inverse-probability-weighted regression adjustment; overall survival (OS) and progression-free survival (PFS) were estimated. RESULTS: A total of 504 patients were included, (Sorafenib [n = 382] and FOLFOX [n = 122]). The treatment effect model estimated a median OS for Sorafenib and FOLFOX of 11.38 and 8.22 months, representing a significantly shorter OS (95% confidence interval) of -3.16 (-6.21, -0.11) months for FOLFOX, p = 0.042. A significant shorter median PFS of FOLFOX to Sorafenib of -2.13 (-3.03, -1.24) months, p < 0.001, was reported. CONCLUSION: Despite significantly shorter median OS and PFS than Sorafenib, FOLFOX still extended OS by 8.22 months. This evidence may offer clinical utility to physicians considering treatment options for aHCC in low resource settings.

Gastrointestinal microbiota profile and clinical correlations in advanced EGFR-WT and EGFR-mutant non-small cell lung cancer.

INTRODUCTION: Difference in clinical responses to cancer therapy in each patient is from several factors. Gastrointestinal microbiota is one of the reasons. However, this correlation remains unknown. This study aims to explore correlation between gastrointestinal microbiota profile and clinical outcomes in Thai advanced non-small cell lung cancer (NSCLC) according to epidermal growth factor receptor (EGFR) status. METHODS: We enrolled 13 patients with advanced EGFR-wild-type (WT) NSCLC who received chemotherapy and 15 patients with EGFR-mutant NSCLC who received EGFR tyrosine kinase inhibitors. We collected fecal samples at baseline and first disease evaluation and performed 16S rRNA gene sequencing by NGS to assess microbiota profile. The correlations between gastrointestinal microbiota and clinical variables were studied. RESULTS: The clinical characteristics were balanced between the cohorts, excluding significantly higher albumin levels in the EGFR-mutant group. Albumin was the only significant clinical factor affecting the treatment response in multivariate analysis (ORR 15.6%, P = 0.03). Proteobacteria counts were higher in the EGFR-WT group, whereas Bacteroidetes and Firmicutes counts were higher in the EGFR-mutant group. The alpha diversity of the gastrointestinal microbiome was significantly higher in the EGFR-mutant group (Shannon index: 3.82 vs. 3.25, P = 0.022). Following treatment, Proteobacteria counts were lower and Bacteroidetes and Firmicutes counts were higher in both cohorts; the changes were more prominent in the EGFR-WT cohort. No significant correlation between microbiota profile and treatment response were demonstrated in our study. However, beta diversity was significantly different according to severity of adverse events. Enrichment of Clostridia and Bacteroidia was associated with higher adverse event risk in the EGFR-WT cohort. CONCLUSIONS: Proteobacteria was dominant in Thai lung cancer patients both EGFR-WT and EGFR-mutant, and this phylum maybe associate with lung cancer carcinogenesis. Chemotherapy altered the gastrointestinal microbiota, whereas EGFR-TKIs had less effects. Our findings highlight the potential predictive utility of the gastrointestinal microbiota for lung cancer carcinogenesis. Studies with larger cohorts and comparison with the healthy Thai population are ongoing to validate this pilot study.

Efficacy of First Line Systemic Chemotherapy and Multikinase Inhibitors in Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third most fatal cancer, with a 5-year survival rate of 18%. Standard frontline-therapy is multikinase inhibitors (MKIs), but accessibility is still limited, particularly in developing countries. This network meta-analysis (NMA) aimed to compare the efficacy of usual chemotherapy vs MKIs. METHOD: Randomised-controlled trials (RCTs) comparing any among chemotherapy vs MKIs in treatment-naïve patients with advanced HCCs were identified from MEDLINE and SCOPUS databases. Overall survival (OS) and progression-free survival (PFS) probabilities and times were extracted from Kaplan-Meier curves using Digitizer, and then converted to individual patient time-to-event data. A one-stage mixed-effect survival model was applied to estimate median OS and PFS. A two-stage NMA was applied for the overall response rate and adverse events (AEs) outcome. RESULTS: A total of 20 RCTs were eligible for NMA. Lenvatinib was the best treatment among single MKIs, with median OS and PFS of 9 and 6.3 months, without significant differences in AEs relative to other MKIs. Median OS and PFS were 0.70 (-0.42, 1.83) and 2.17 (1.41, 2.93) months longer with Lenvatinib than Sorafenib. Among chemotherapy agents, FOLFOX4 had the longest median OS and PFS at 7.9 and 4.3 months, respectively, without significant AEs compared to other chemotherapies. The combination of Sorafenib+Doxorubicin prolonged median OS and PFS to 12.7 and 6.3 months, respectively. CONCLUSION: Use of the MKIs Lenvatinib or Sorafenib as first line systemic treatment for advanced HCC could be beneficial. However, FOLFOX4 might be the optimal choice in a developing country where the health-care budget is limited.

Exosomal microRNAs as potential biomarkers for osimertinib resistance of non-small cell lung cancer patients.

BACKGROUND: Osimertinib is an epidermal growth factor receptor-tyrosine kinase inhibitor that specifically targets the T790M mutation in cancer.Unfortunately, most non-small cell lung cancer (NSCLC) patients develop osimertinib resistance. Currently, the molecular biomarkers for monitoring osimertinib resistance are not available. OBJECTIVE: This study aimed to examine the profile of exosomal miRNA in the plasma of osimertinib-resistant NSCLC patients. METHODS: Plasma exosomal miRNA profiles of 8 NSCLC patients were analyzed by next-generation sequencing at osimertinib-sensitive and osimertinib-resistance stage.The expression of dysregulated exosomal miRNAs was validated and confirmed in another cohort of 19 NSCLC patients by qPCR. The relationship between exosomal miRNA upregulation and clinical prognosis, survival analysis was evaluated by Kaplan-Meier curves. RESULTS: In osimertinib-resistant NSCLC patients, 10 exosomal miRNAs were significantly dysregulated compared to baseline. Upregulation of all 10 candidate exosomal miRNAs tended to correlate with increased latency to treatment failure and improved overall survival. Among them, 4 exosomal miRNAs, miR-323-3p, miR-1468-3p, miR-5189-5p and miR-6513-5p were essentially upregulated and show the potential to be markers for the discrimination of osimertinib-resistance from osimertinib-sensitive NSCLC patients with high accuracy (p< 0.0001). CONCLUSIONS: Our results highlight the potential role of these exosomal miRNAs as molecular biomarkers for the detection of osimertinib resistance.