Ying-Chun Shen

Phase Ii Study of Combining Sorafenib with Metronomic Tegafur/Uracil for Advanced Hepatocellular Carcinoma

BACKGROUND & AIMS Sorafenib, a multi-kinase inhibitor with anti-angiogenic activity, was recently approved for the treatment of advanced hepatocellular carcinoma (HCC). Metronomic chemotherapy using tegafur/uracil (4:1 molar ratio), an oral fluoropyrimidine, has been shown to enhance the anti-tumor effect of anti-angiogenic agents in preclinical models. This phase II study evaluated the efficacy and safety of combining metronomic tegafur/uracil with sorafenib in patients with advanced HCC. METHODS Patients with histologically- or cytologically-proven HCC and Child-Pugh class A liver function were treated with sorafenib (400mg twice daily) and tegafur/uracil (125 mg/m(2) based on tegafur twice daily) continuously as first-line therapy for metastatic or locally advanced disease that could not be treated by loco-regional therapies. The primary endpoint was progression-free survival (PFS). RESULTS The study enrolled 53 patients. Thirty-eight patients (72%) were hepatitis B surface antigen-positive. The median PFS was 3.7 months (95% C.I., 1.9-5.5) and the median overall survival was 7.4 months (95% C.I., 3.4-11.4). According to RECIST criteria, 4 patients (8%) had a partial response and 26 patients (49%) had a stable disease. Major grade 3/4 toxicities included fatigue (15%), abnormal liver function (13%), elevated serum lipase (10%) hand-foot skin reaction (HFSR) (9%), and bleeding (8%). HFSR was the major adverse event resulting in dose reduction (19%) or treatment delay (21%). CONCLUSIONS Metronomic chemotherapy with tegafur/uracil can be safely combined with sorafenib and shows preliminary activity to improve the efficacy of sorafenib in advanced HCC patients.

Early Alpha-Fetoprotein Response Predicts Treatment Efficacy of Antiangiogenic Systemic Therapy in Patients With Advanced Hepatocellular Carcinoma

Antiangiogenic therapy has become the most important treatment modality for patients with advanced hepatocellular carcinoma (HCC). In this study, the authors investigated levels of alpha‐fetoprotein (AFP) as a potential biomarker for treatment efficacy of antiangiogenic therapy.

Adjuvant interferon therapy after curative therapy for hepatocellular carcinoma (HCC): A meta-regression approach

BACKGROUND & AIMS Adjuvant anti-viral therapy after curative therapy for HCC has been studied extensively but the true clinical benefit and the predictors of efficacy remain unclear. METHODS MEDLINE, PubMed, and the Cochrane library were searched until December 2008, plus the meeting abstracts of the American Association for the Study of Liver Disease 2005-2008. Randomized trials and cohort studies were included if the studies (1) enrolled HCC patients who had underlying chronic viral hepatitis B or C and had undergone curative surgery or ablation therapy; (2) consisted of one or more treatment arms with interferon-based therapy and a control arm of no anti-viral therapy; and (3) included recurrence-free survival of HCC as an endpoint. Meta-analysis and meta-regression were done according to the Cochrane guidelines. RESULTS Thirteen studies (9 randomized trials and 4 cohort studies, totally 1180 patients) were eligible for meta-analysis. Surgery and ablation therapy were used in 9 and 8 studies, respectively. All studies used conventional interferon (natural or recombinant) as anti-viral therapy. Overall, interferon improved the 1-year, 2-year, and 3-year recurrence-free survival by 7.8% (95% CI 3.7-11.8%), 35.4% (95% CI 30.7-40.0%), and 14.0% (95% CI 8.6-19.4%), respectively (all p<0.01). Lower percentage of patients with multiple tumors and use of ablation therapy were independent predictors for better treatment efficacy. CONCLUSION The quantitative estimation of treatment efficacy and the identification of predictive factors in this study will help design future clinical trials of adjuvant therapy for HCC.

Dynamic contrast-enhanced magnetic resonance imaging biomarkers predict survival and response in hepatocellular carcinoma patients treated with sorafenib and metronomic tegafur/uracil

BACKGROUND & AIMS Sorafenib plus metronomic tegafur/uracil therapy can induce tumor stabilization in advanced hepatocellular carcinoma (HCC) patients. This study evaluated the correlation of vascular response measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and the clinical outcome. METHODS DCE-MRI was performed in advanced HCC patients treated with sorafenib (800 mg/d) plus tegafur/uracil (250 mg/m(2)/d based on tegafur) at baseline and after 14 days of treatment. An operator-defined region of interest was placed in the most strongly enhanced area of the tumor to measure the pharmacokinetic parameter K(trans). Changes in K(trans) after treatment were correlated with the best tumor response and survival. RESULTS Thirty-one patients were evaluable. There were one partial response (PR), 18 stable disease (SD), and 12 progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Baseline K(trans) was higher in patients with PR or SD (median 1215.2 × 10(-3)/min, range 582.5-4555.3 × 10(-3)/min) than patients with PD (median 702.0 × 10(-3)/min, range 375.2-1938.0 × 10(-3)/min, p = 0.008). After 14 days of study treatment, the median K(trans) change was -47.1% (range -87.0 to -18.0%) in patients with PR or SD, and 9.6% (range -44.8 to +81%) in those with PD (p<0.001). A vascular response, defined by a 40% or greater decrease in K(trans) after 14 days of study treatment, correlated with longer progression-free survival (median 29.1 vs. 8.7 weeks, p = 0.033) and overall survival (median 53.0 vs. 14.9 weeks, p = 0.016). Percentage of K(trans) change after treatment is an independent predictor of tumor response, progression-free survival, and overall survival. CONCLUSIONS K(trans) measured by DCE-MRI correlated well with tumor response and survival in HCC patients who received sorafenib plus metronomic tegafur/uracil therapy.

Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma

Background:Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC). The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance, but such correlation is unclear in sorafenib resistance of HCC.Methods:Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line (Huh-7R; derived from sorafenib-sensitive Huh-7) were used. The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, and siRNA of hexokinase 2 (HK2) were used to target relevant pathways of cancer metabolism. Cell viability, mitochondrial membrane potential, and sub-G1 fraction were measured for in vitro efficacy. Reactive oxygen species (ROS), adenosine triphosphate (ATP) and glucose uptake were also measured. A subcutaneous xenograft mouse model was used for in vivo efficacy.Results:The bioenergetic propensity for using glycolysis correlated with decreased sorafenib sensitivity (R2=0.9067, among sorafenib-naive cell lines; P=0.003, compared between Huh-7 and Huh-7 R). DCA reduced lactate production and increased ROS and ATP, indicating activation of oxidative phosphorylation (OXPHOS). DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis (sub-G1 (combination vs sorafenib): Hep3B, 65.4±8.4% vs 13±2.9%; Huh-7 R, 25.3± 5.7% vs 4.3±1.5%; each P<0.0001), whereas siRNA of HK2 did not. Sorafenib (10 mg kg−1 per day) plus DCA (100 mg kg−1 per day) also resulted in superior tumour regression than sorafenib alone in mice (tumour size: −87% vs −36%, P<0.001).Conclusion:The bioenergetic propensity is a potentially useful predictive biomarker of sorafenib sensitivity, and activation of OXPHOS by PDK inhibitors may overcome sorafenib resistance of HCC.

Molecular subtypes of breast cancer emerging in young women in Taiwan: evidence for more than just westernization as a reason for the disease in Asia.

Background: In the past two decades, the incidence of breast cancer in young Taiwanese females has been rapidly increasing, approaching the risk level of western countries. As a first step to investigate the possible etiology, we examined the molecular subtypes of female breast cancer in Taiwan. Methods: This study included 1,028 consecutive patients with breast cancer diagnosed in National Taiwan University Hospital between 2004 and 2006. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2, cytokeratin 5/6, and epidermal growth factor receptor expression and/or gene amplification were analyzed. Results: Younger (≤50 years) breast cancer patients had a higher prevalence of luminal A (67% versus 57%; P < 0.001) and a lower prevalence of basal-like subtype (9% versus 17%; P < 0.001) compared with older (>50 years) patients. The higher prevalence of luminal A subtype was mainly attributed to a higher ER (75% versus 63%; P < 0.001) and PR (47% versus 33%; P < 0.001) expression rate in younger patients than older patients. Tumors with histologic grade 3 were less prevalent in younger patients than in older patients (23% versus 30%; P = 0.01). For very young (<35 years) patients, the molecular subtype distribution, ER and/or PR expression rate, and histologic grade were not significantly different from those of less young (35-50 years) patients. Conclusions: Young breast cancer patients in Taiwan are characterized by a high prevalence of luminal A subtype and low prevalence of histologic grade 3 tumor and/or basal-like subtype. These features are distinct from young breast cancer patients in western countries. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1807–14)

Induction of DNA Damage-Inducible Gene GADD45β Contributes to Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Cells

Markers that could accurately predict responses to the general kinase inhibitor sorafenib are needed to better leverage its clinical applications. In this study, we examined a hypothesized role in the drug response for the growth arrest DNA damage-inducible gene 45β (GADD45β), which is commonly underexpressed in hepatocellular carcinoma (HCC) where sorafenib may offer an important new therapeutic option. The anticancer activity of sorafenib-induced GADD45β expression was tested in a panel of HCC cell lines and xenograft models. We found that GADD45β mRNA and protein expression were induced relatively more prominently in HCC cells that were biologically sensitive to sorafenib treatment. GADD45β induction was not found after treatment with either the mitogen-activated protein kinase-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126 or the Raf inhibitor ZM336372, suggesting that GADD45β induction by sorafenib was independent of Raf/MEK/ERK signaling activity. However, c-Jun NH2-terminal kinase (JNK) kinase activation occurred preferentially in sorafenib-sensitive cells. Small interfering RNA-mediated knockdown of GADD45βor JNK kinase limited the proapoptotic effects of sorafenib in sorafenib-sensitive cells. We defined the -339/-267 region in the GADD45β promoter containing activator protein-1 and SP1-binding sites as a crucial region for GADD45β induction by sorafenib. Together, our findings suggest that GADD45β induction contributes to sorafenib-induced apoptosis in HCC cells, prompting further studies to validate its potential value in predicting sorafenib efficacy.

Difference in the Incidence Trend of Nasopharyngeal and Oropharyngeal Carcinomas in Taiwan: Implication from Age-Period-Cohort Analysis

Lifestyle factors are considered important for the pathogenesis of both nasopharyngeal and oropharyngeal carcinomas. In Taiwan, the incidence of nasopharyngeal carcinoma gradually decreased over the past 20 years, whereas that of oropharyngeal carcinoma increased rapidly. To compare the incidence trends of nasopharyngeal and oropharyngeal carcinomas in Taiwan, the age-period-cohort model was used to analyze epidemiologic data from 1981 to 2000 obtained from the Taiwan Cancer Registry. The calendar time period of 1986 to 1990 and the 1931 to 1940 birth cohort were used as reference groups for estimates of relative risk. For nasopharyngeal carcinoma, the incidence seemed to decrease in most age groups and was more prominent in women (30%) than in men (23%). For oropharyngeal carcinoma, the incidence increased in all age groups and was more prominent in men (391.4%) than in women (59.2%). Cohort effect was found for both nasopharyngeal and oropharyngeal carcinomas. The relative risk of nasopharyngeal carcinoma for the 1971 to 1980 birth cohort was 0.38 for women and 0.68 for men. The relative risk of oropharyngeal carcinoma for the 1971 to 1980 cohort was 45.67 for men and 2.69 for women. Change in lifestyle seemed to be an important factor for the difference in the incidence trend between nasopharyngeal and oropharyngeal carcinomas and between men and women. (Cancer Epidemiol Biomarkers Prev 2006;15(5):856–61)

Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives

Sorafenib, a multikinase inhibitor targeting vascular endothelial growth factor (VEGF)-mediated angiogenesis, is the first drug found to prolong survival of patients with advanced hepatocellular carcinoma (HCC). This advance has shifted the paradigm of systemic treatment for HCC toward molecular targeted therapy (MTT). However, the disease-stabilizing effect of VEGF signaling-targeted MTT normally lasts only for a few months, suggesting a rapid emergence of resistance in the majority of patients. To overcome the resistance to VEGF signaling-targeted MTT, strategies incorporating inhibition of either compensatory pro-angiogenic pathways or recruitment of bone marrow-derived circulating endothelial progenitors, as well as suppression of other oncogenic pathways, are currently being investigated. The combination of multiple molecular targeted agents or the use of multi-target agents may enhance the efficacy at the expense of increased toxicities. To facilitate the development of MTT for HCC, current methodologies for pharmacodynamic assessment, patient selection and target identification need to be improved. Patient selection according to the individual molecular signature of the tumor and correlative biomarker studies are encouraged while planning a clinical trial of novel MTT.

Clinical trials in hepatocellular carcinoma: an update.

The success of sorafenib has spurred an explosive increase of clinical trials testing novel molecular targets and other agents in the treatment of hepatocellular carcinoma (HCC). The paradigm of the studies has been characterized by three noticeable changes. First, the molecular targets of interest have expanded from angiogenesis to cancer cell-directed oncogenic signaling pathways for advanced HCC treatment. Agents targeting EGFR, FGFR, PI3K/Akt/mTOR, TGF-β, c-Met, MEK, IGF signaling, and histone deacetylase have been actively explored. Second, the target indication has shifted from advanced stage to early or intermediate stages of disease. The feasibility of combining locoregional therapies and targeted agents, and the use of novel agents after curative treatments are currently under active investigation. Finally, the therapeutic strategy has shifted from monotherapy to combination targeted therapy. We aim to provide a comprehensive overview of newly disclosed and ongoing clinical trials for the treatment of HCC.