Screening for hepatocellular carcinoma (HCC) is clinically important given that its early detection has remarkable survival benefits. We investigated the possible role of FIB-4, a recently developed noninvasive marker for liver fibrosis based on routine laboratory tests, as a clinical indicator for predicting future HCC among hepatitis B surface antigen (HBsAg) carriers. Our retrospective cohort study involved 986 Korean HBsAg carriers 40 years of age or older who visited Seoul National University Hospital for a health checkup. National medical service claims data were used to determine HCC incidence. Median follow-up time was 5.4 years (interquartile range: 4.4 years). Adjusted for age, sex, body mass index, smoking, alcohol, and antiviral medication for hepatitis B, compared to subjects with FIB-4 <1.25, subjects with 1.7 £ FIB-4 <2.4 showed an adjusted hazard ratio (aHR) of 4.57 (95% confidence interval [CI]: 1.50-13.92) and subjects with FIB-4 2.4 showed an aHR of 21.34 (95% CI: 7.73-58.92) for HCC incidence. FIB-4 was shown to have incremental predictive value to ultrasonographic liver cirrhosis for HCC incidence (C-index: 0.701 vs. 0.831; P 5 0.001). FIB-4 was also better predictive of HCC incidence, compared to that of ultrasonographic liver cirrhosis (C-index: 0.775 vs. 0.701; P 5 0.040). Conclusion: High FIB-4 is a highly predictive risk factor for HCC incidence among Korean HBsAg carriers. FIB-4 is a promising, easily applicable, and cost-effective clinical tool in identifying a subpopulation of HBsAg carriers who are at heightened risk. Our study needs to be replicated in larger future studies on various ethnic groups; nonetheless, our study suggests that FIB-4 may play a valuable role in HCC screening among HBsAg carriers. (HEPATOLOGY 2015;61:1261-1268 L iver cancer is the fifth-most frequently diagnosed cancer worldwide in men, also the secondleading cause of cancer mortality in the world. 1 For females, it is the seventh-most common cancer and sixth-leading cause of cancer mortality. 1 Liver cancer incidence is increasing in many parts of the world, including in the United States and Europe. 2,3 In Korea, liver cancer represents the second-highest cause of cancer mortality and is the fifth-most frequently diagnosed cancer. 4 Despite such high incidence and mortality, major risk factors for liver cancer are well established as chronic hepatitis and cirrhosis, 5 similarly in Korea where liver cancer has been attributed to chronic hepatitis B (CHB), C, or cirrhosis in 95% of
Introduction: Impairment in DNA damage response and repair (DDR) pathway is known as a predictive biomarker of platinum sensitivity. Recently, DDR alteration is reemphasized as a predictive biomarker of immune checkpoint inhibitor due to its positive correlation to tumor mutation burden (TMB). Methods: Target gene sequencing (381 genes) was conducted from 100 extensive disease (ED) and 66 limited disease (LD) patients with SCLC. Detected mutations were classified as double-strand breaks (DSB) (n ¼ 82): homologous recombination (n ¼ 54), non-homologous end joining (n ¼ 19), and Fanconi anemia (n ¼ 32); or singlestrand breaks (SSB) (n ¼ 31): mismatch repair (n ¼ 19), base excision repair (n ¼ 7), and nucleotide excision repair (n ¼ 6). Results: Compared to patients with an intact DDR pathway (n ¼ 70), a higher TMB was observed in patients with homologous recombination (p < 0.001), non-homologous end joining (p ¼ 0.002), mismatch repair (p < 0.001), DSB (p < 0.001), and SSB (p < 0.001). Survival analyses based on TMB level showed no predictive or prognostic values in ED patients. In LD patients, prolonged progression-free survival (hazard ratio [HR] ¼ 0.497, p ¼ 0.015), and overall survival (HR ¼ 0.383, p ¼ 0.010) to concurrent chemoradiotherapy were observed in those with TMB above median. Individual DDR pathway alteration showed no survival benefit in ED patients receiving platinum-based chemotherapy. In LD patients, those with mutations in the Fanconi anemia gene set had shorter progression-free survival (HR ¼ 2.048, p ¼ 0.036) to initial treatment. Conclusions: DDR pathway alterations, both DSB and SSB, in SCLC have a positive correlation with high TMB. However, it has shown limited value in prediction of platinum efficacy.
ROS1-positive NSCLC has distinct clinical characteristics, with an effective and durable response to both TKIs and pemetrexed-based chemotherapies. Regardless, given its novel characteristics and distinct clinical responses to conventional chemotherapies and TKIs, the treatment strategy for ROS1-positive NSCLC remains to be further developed.
Introduction: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, efficiently penetrates the blood-brain barrier. This study explored whether treatment with osimertinib leads to improved overall survival (OS) for patients with EGFR-mutated NSCLC with leptomeningeal metastases (LM) compared with those not treated with osimertinib. Methods: From October 2008 to October 2019, patients with EGFR-mutated NSCLC and cytologically confirmed LM were retrospectively analyzed for OS according to osimertinib treatment and T790M mutational status. The OS was defined as the time from the diagnosis of LM to death. Results: For the 351 patients with LM included in the analysis, the median OS (mOS) was 8.1 months (95% confidence interval [CI]: 7.2-9.0). T790M mutation was detected in 88 of 197 patients tested, and a total of 110 patients were treated with osimertinib after LM. No difference in mOS according to T790M mutational status (10.1 mo [95% CI: 4.31-15.82] versus 9.0 [95% CI: 6.81-11.21], p ¼ 0.936) was found. Nevertheless, patients treated with osimertinib had a superior OS of 17.0 months (95% CI: 15.13-18.94) compared with those not treated with osimertinib who had a mOS of 5.5 months (95% CI: 4.34-6.63), regardless of T790M mutational status (hazard ratio: 0.36 [95% CI: 0.28-0.47], p < 0.001). This was also considerably longer even than the mOS of 8.7 months (95% CI: 7.01-10.39) of those who were never treated with osimertinib but had firstor second-generation EGFR tyrosine kinase inhibitors. Conclusions: Osimertinib is a promising treatment option for EGFR-mutated NSCLC with LM regardless of T790M mutational status.
Background HER2-low breast cancer (BC) is currently an area of active interest. This study evaluated the impact of low expression of HER2 on survival outcomes in HER2-negative non-metastatic breast cancer (BC). Methods Patients with HER2-negative non-metastatic BC from 6 centres within the Asian Breast Cancer Cooperative Group (ABCCG) (n = 28,280) were analysed. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization non-amplified (ISH−) and HER2-zero as IHC 0. Relapse-free survival (RFS) and overall survival (OS) by hormone receptor status and HER2 IHC 0, 1+ and 2+ ISH− status were the main outcomes. A combined TCGA-BRCA and METABRIC cohort (n = 1967) was also analysed to explore the association between HER2 expression, ERBB2 copy number variation (CNV) status and RFS. Results ABCCG cohort median follow-up was 6.6 years; there were 12,260 (43.4%) HER2-low BC and 16,020 (56.6%) HER2-zero BC. The outcomes were better in HER2-low BC than in HER2-zero BC (RFS: centre-adjusted hazard ratio (HR) 0.88, 95% CI 0.82–0.93, P < 0.001; OS: centre-adjusted HR 0.82, 95% CI 0.76–0.89, P < 0.001). On multivariable analysis, HER2-low status was prognostic (RFS: HR 0.90, 95% CI 0.85–0.96, P = 0.002; OS: HR 0.86, 95% CI 0.79–0.93, P < 0.001). These differences remained significant in hormone receptor-positive tumours and for OS in hormone receptor-negative tumours. Superior outcomes were observed for HER2 IHC1+ BC versus HER2-zero BC (RFS: HR 0.89, 95% CI 0.83–0.96, P = 0.001; OS: HR 0.85, 95% CI 0.78–0.93, P = 0.001). No significant differences were seen between HER2 IHC2+ ISH− and HER2-zero BCs. In the TCGA-BRCA and METABRIC cohorts, ERBB2 CNV status was an independent RFS prognostic factor (neutral versus non-neutral HR 0.71, 95% CI 0.59–0.86, P < 0.001); no differences in RFS by ERBB2 mRNA expression levels were found. Conclusions HER2-low BC had a superior prognosis compared to HER2-zero BC in the non-metastatic setting, though absolute differences were modest and driven by HER2 IHC 1+ BC. ERBB2 CNV merits further investigation in HER2-negative BC.
BACKGROUND:Because of the growing number of actionable biomarkers in non-small cell lung cancer (NSCLC), sufficient tissue availability for testing is becoming a greater challenge. Liquid biopsy offers a potential solution by complementing standard tissue-based methods. In this study, the authors analyzed the concordance of actionable genomic alterations sequenced from circulating tumor DNA (ctDNA; Guardant360) and tissue (Oncomine Focus Assay). METHODS: From September 2015 to May 2018, 421 paired plasma and tissue samples from patients with advanced NSCLC who had previously undergone tissue testing by standard methods were collected. Both types of samples were available for 287 patients (262 in cohort 1 [treatment-naive] and 25 in cohort 2 [treatment failure]), and only 1 sample type was available for 134 patients (50 in cohort 3 [plasma only] and 84 in cohort 4 [tissue only]). RESULTS: In cohort 1, 198 samples (77.6%) showed concordance between tissue and plasma next-generation sequencing (NGS). Among the discordant cases, plasma testing detected additional genomic alterations in 11 patients (4.2%). In 50 patients without tissue-based NGS results (cohort 3), the ctDNA-based test detected genomic alterations in 20 samples (40.0%). The median allele frequency (AF) of mutations identified with ctDNA-based NGS (0.74%) was lower than that identified with the tissue-based NGS test (13.90%). Clinical responses to matched targeted therapy occurred, regardless of the ctDNA AF. Upfront ctDNA-based testing identified 60.4% of patients with genomic alterations. In addition, ctDNA-based testing uncovered 12.0% more actionable alterations when it was performed after tissue-based NGS testing. CONCLUSIONS: The results indicate that a ctDNA-based test identifies additional patients with actionable genomic alterations and could, therefore, be used to complement traditional tissue-based testing for NSCLC.
Intratumoral heterogeneity has been suggested to be an important resistance mechanism leading to treatment failure. We hypothesized that radiologic images could be an alternative method for identification of tumor heterogeneity. We tested heterogeneity textural parameters on pretreatment FDG-PET/CT in order to assess the predictive value of target therapy. Recurred or metastatic non-small cell lung cancer (NSCLC) subjects with an activating EGFR mutation treated with either gefitinib or erlotinib were reviewed. An exploratory data set (n = 161) and a validation data set (n = 21) were evaluated, and eight parameters were selected for survival analysis. The optimal cutoff value was determined by the recursive partitioning method, and the predictive value was calculated using Harrell’s C-index. Univariate analysis revealed that all eight parameters showed an increased hazard ratio (HR) for progression-free survival (PFS). The highest HR was 6.41 (P<0.01) with co-occurrence (Co) entropy. Increased risk remained present after adjusting for initial stage, performance status (PS), and metabolic volume (MV) (aHR: 4.86, P<0.01). Textural parameters were found to have an incremental predictive value of early EGFR tyrosine kinase inhibitor (TKI) failure compared to that of the base model of the stage and PS (C-index 0.596 vs. 0.662, P = 0.02, by Co entropy). Heterogeneity textural parameters acquired from pretreatment FDG-PET/CT are highly predictive factors for PFS of EGFR TKI in EGFR-mutated NSCLC patients. These parameters are easily applicable to the identification of a subpopulation at increased risk of early EGFR TKI failure. Correlation to genomic alteration should be determined in future studies.
PurposePlatinum-based doublet chemotherapy is the treatment of choice for patients with non-small cell lung cancer (NSCLC); however, the role of a platinum-based doublet as second-line therapy after failure of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for NSCLC patients has not yet been elucidated. The purpose of this study was to compare the clinical efficacy of pemetrexed versus a platinum-based doublet as second-line therapy after failure of EGFR TKI used as first-line therapy for NSCLC patients with EGFR mutations.Materials and MethodsWe designed a multicenter retrospective cohort study of 314 NSCLC patients with EGFR mutations who received an EGFR TKI as first-line palliative chemotherapy. Our analysis included 83 patients who failed EGFR TKI therapy and received second-line cytotoxic chemotherapy.ResultsForty-six patients were treated using a platinum-based doublet and 37 patients were treated using singlet pemetrexed. The overall response rates of patients receiving a platinum-based doublet and patients receiving pemetrexed were17.4% and 32.4%, respectively (p=0.111). The median progression-free survival (PFS) of patients receiving pemetrexed was significantly longer than that of patients receiving a platinum-based doublet (4.2 months vs. 2.7 months, respectively; p=0.008). The hazard ratio was 0.54 (95% confidence interval, 0.34 to 0.86; p=0.009).ConclusionOur retrospective analysis found that second-line pemetrexed singlet therapy provided significantly prolonged PFS compared to second-line platinum-based doublet chemotherapy for NSCLC patients with EGFR mutations who failed first-line EGFR TKI. Conduct of prospective studies for confirmation of our results is warranted.
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