Publications by authors named "Ann-Lii Cheng"

402 Publications

Limited Predictive or Prognostic Role of Tumor-Infiltrating Tissue-Resident Memory CD8 T Cells in Patients with Hepatocellular Carcinoma Receiving Immunotherapy.

Cancers (Basel) 2021 Oct 14;13(20). Epub 2021 Oct 14.

Department of Medical Oncology, National Taiwan University Cancer Center, Taipei 10672, Taiwan.

Purpose: Tumor-infiltrating tissue-resident memory CD8 T cells (CD8 T; CD103+ CD8+) are considered tumor-specific and may correlate better with the tumor response to immune checkpoint blockade (ICB). This study evaluated the association of tumor-infiltrating CD8 T and their subsets with the efficacy of immunotherapy in patients with advanced hepatocellular carcinoma (HCC).

Experimental Design: Consecutive HCC patients who received ICB in prospective trials were analyzed. Formalin-fixed paraffin-embedded tumor sections were stained for DAPI, CD8, CD103, CD39, programmed cell death-1 (PD-1), and programmed cell death ligand 1 (PD-L1) using a multiplex immunohistochemical method. The densities of CD8 T cells, CD8 T, and CD39+ or PD-L1+ subsets of CD8 T were correlated with tumor response and overall survival (OS).

Results: A total of 73 patients were identified, and 48 patients with adequate pretreatment tumor specimens and complete follow-up were analyzed. A median of 32.7% (range: 0-92.6%) of tumor-infiltrating CD8 T cells were T. In subset analyses, 66.6% ± 34.2%, 69.8% ± 33.4%, and 0% of CD8 T cells coexpressed CD39, PD-L1, and PD-1, respectively. The objective response rates for CD8 T cell-high, CD8 T-high, CD39+ CD8 T-high, and PD-L1+ CD8 T-high groups were 41.7%, 37.5%, 37.5%, and 29.2%, respectively. Patients with CD8 T cell-high, but not those with CD8 T-high, CD39+ CD8 T-high, or PD-L1+ CD8 T-high, tumors, had significantly prolonged OS ( = 0.0429).

Conclusions: Compared with total tumor-infiltrating CD8 T cells, tumor-infiltrating CD8 T or their subsets failed to provide additional advantages in predicting the efficacy of immunotherapy for HCC.
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http://dx.doi.org/10.3390/cancers13205142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533865PMC
October 2021

Early Changes in DCE-MRI Biomarkers May Predict Survival Outcomes in Patients with Advanced Hepatocellular Carcinoma after Sorafenib Failure: Two Prospective Phase II Trials.

Cancers (Basel) 2021 Oct 1;13(19). Epub 2021 Oct 1.

Department of Medical Imaging, National Taiwan University Hospital, Taipei City 100, Taiwan.

In this paper, our main objective was to predict survival outcomes using DCE-MRI biomarkers in patients with advanced hepatocellular carcinoma (HCC) after progression from 1st-line sorafenib treatment in two prospective phase II trials. This study included 74 participants (men/women = 64/10, mean age 60 ± 11.8 years) with advanced HCC who received 2nd-line targeted therapy ( = 41 with lenalidomide in one clinical trial; = 33 with axitinib in another clinical trial) after sorafenib failure from two prospective phase II studies. Among them, all patients underwent DCE-MRI at baseline, and on days 3 and 14 of treatment. The relative changes (Δ) in the DCE-MRI parameters, including ΔPeak, ΔAUC, and ΔK, were derived from the largest hepatic tumor. The treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The Cox model was used to investigate the associations of the clinical variables and DCE-MRI biomarkers with progression-free survival (PFS) and overall survival (OS). The objective response rate (ORR) was 10.8% (8/74) and the disease control rate (DCR) was 58.1% (43/74). The median PFS and OS values were 1.9 and 7.8 months, respectively. On day 3 (D3), participants with high reductions in ΔPeak_D3 (hazard ratio (HR) 0.4, 95% confidence interval (CI) 0.17-0.93, = 0.017) or ΔAUC_D3 (HR 0.51, 95% CI 0.25-1.04, = 0.043) were associated with better PFS. On day 14, participants with high reductions in ΔPeak_D14 (HR 0.51, 95% CI 0.26-1.01, = 0.032), ΔAUC_D14 (HR 0.54, 95% CI 0.33-0.9, = 0.009), or ΔK_D14 (HR 0.26, 95% CI 0.12-0.56, < 0.001) had a higher PFS than those with lower reduction values. In addition, high reductions in ΔAUC_D14 (HR 0.53, 95% CI 0.32-0.9, = 0.016) or ΔK_D14 (HR 0.47, 95% CI 0.23-0.98, = 0.038) were associated with a better OS. Among the clinical variables, ORR was associated with both PFS ( = 0.001) and OS ( = 0.005). DCR was associated with PFS ( = 0.002), but not OS ( = 0.089). Cox multivariable analysis revealed that ΔK_D14 ( = 0.002) remained an independent predictor of PFS after controlling for ORR and DCR. An early reduction in tumor perfusion detected by DCE-MRI biomarkers, especially on day 14, may predict favorable survival outcomes in participants with HCC receiving 2nd-line targeted therapy after sorafenib failure.
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http://dx.doi.org/10.3390/cancers13194962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508238PMC
October 2021

Efficacy and safety of cabozantinib for patients with advanced hepatocellular carcinoma based on albumin-bilirubin grade.

Br J Cancer 2021 Oct 7. Epub 2021 Oct 7.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Albumin-bilirubin (ALBI) grade is an objective measure of liver function for patients with hepatocellular carcinoma (HCC). The tyrosine kinase inhibitor cabozantinib is approved for patients with advanced HCC who have received prior sorafenib based on the phase 3 CELESTIAL trial (NCT01908426). Cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated HCC.

Methods: Patients were randomised 2:1 to receive cabozantinib 60 mg or placebo orally every day. Clinical outcomes in patients with ALBI grade 1 or 2 at baseline were evaluated in CELESTIAL. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin, with an ALBI grade of 1 defined as  ≤ -2.60 score and a grade of 2 as a score of > -2.60 to  ≤ -1.39.

Results: Cabozantinib improved OS and PFS versus placebo in both ALBI grade 1 (hazard ratio [HR] [95% CI]: 0.63 [0.46-0.86] and 0.42 [0.32-0.56]) and ALBI grade 2 (HR [95% CI]: 0.84 [0.66-1.06] and 0.46 [0.37-0.58]) subgroups. Adverse events were consistent with those in the overall population. Rates of grade 3/4 adverse events associated with hepatic decompensation were generally low and were more common among patients in the ALBI grade 2 subgroup.

Discussion: These results provide initial support of cabozantinib in patients with advanced HCC irrespective of ALBI grade 1 or 2.

Trial Registration Number: ClinicalTrials.gov number, NCT01908426.
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http://dx.doi.org/10.1038/s41416-021-01532-5DOI Listing
October 2021

ALBI score and outcomes in patients with hepatocellular carcinoma: analysis of the randomized controlled trial KEYNOTE-240.

Ther Adv Med Oncol 2021 30;13:17588359211039928. Epub 2021 Sep 30.

Faculty of Medicine, Kindai University, Osaka-Sayama, Osaka, Japan.

Aims: This post hoc analysis evaluated albumin/bilirubin (ALBI) score, an objective measure of liver function, in patients receiving pembrolizumab plus best supportive care (BSC) compared with placebo plus BSC in the KEYNOTE-240 study.

Methods: Patients with confirmed hepatocellular carcinoma (HCC) and progression after/intolerance to sorafenib, Child-Pugh class A liver function, and Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned 2:1 to pembrolizumab 200 mg or placebo intravenously every 3 weeks plus BSC for ⩽35 cycles or until confirmed progression/unacceptable toxicity. Outcomes were assessed by ALBI grade.

Results: Of 413 patients, at baseline 116 had an ALBI grade 1 score (pembrolizumab,  = 74; placebo,  = 42) and 279 had an ALBI grade 2 score ( = 193;  = 86). Change from baseline in ALBI score to the end of treatment was similar in both arms [difference in least squares mean, -0.039; 95% confidence interval (CI): -0.169 to 0.091]. Time to ALBI grade increase was similar in both arms [median for pembrolizumab placebo: 7.8 6.9 months; hazard ratio (HR) = 0.863 (95% CI: 0.625-1.192)]. Regardless of baseline ALBI grade, a trend toward improved overall survival was observed with pembrolizumab [grade 1: HR = 0.725 (95% CI: 0.454-1.158); grade 2: HR = 0.827 (95% CI: 0.612-1.119)].

Conclusion: Pembrolizumab did not adversely impact liver function compared with placebo in patients with HCC, as measured by changes in ALBI scores. A trend toward improved overall survival was observed with pembrolizumab in both ALBI grade groups. NCT02702401.
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http://dx.doi.org/10.1177/17588359211039928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488519PMC
September 2021

Negative prognostic implications of splenomegaly in nivolumab-treated advanced or recurrent pancreatic adenocarcinoma.

Oncoimmunology 2021 27;10(1):1973710. Epub 2021 Sep 27.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Immune checkpoint inhibitors have limited efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC). We investigated prognostic markers for nivolumab-based therapy in advanced or recurrent PDAC. Consecutive patients receiving nivolumab-based therapy at our institution between 2015 and 2020 were evaluated. Overall survival (OS) was analyzed through univariate and multivariate analyses. Spleen volume was estimated from the width, thickness, and length of the spleen. A total of 45 patients were identified. Biweekly nivolumab was administered as monotherapy ( = 5) or in combination with chemotherapy or targeted therapy ( = 40). Among 31 evaluable patients, the response and disease control rates were 7% and 36%, respectively. The baseline median spleen volume was 267 (110-674) mL. Patients with spleens ≥267 mL had significantly shorter median OS (1.9 months, 95% confidence interval [CI], 1.0-2.7) than did those with smaller spleens (8.2 months, 95% CI, 5.6-10.8; = .003). In the multivariate analysis, spleen volume of <267 mL, ≤2 lines of prior chemotherapy, ECOG performance status of 0-2, add-on nivolumab with stable disease after prior therapy, concomitant or sequential cell therapy, high lymphocyte count, and total bilirubin <1 mg/dL were independent favorable prognostic factors for OS. In the control groups of patients receiving gemcitabine-based chemotherapy ( = 142) or FOLFIRINOX regimen ( = 24), spleen volume exhibited no prognostic significance. In heavily pretreated PDAC, a large spleen may predict poor OS following nivolumab-based immunotherapy. Studies with larger cohorts should confirm the prognostic value of spleen volume.
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http://dx.doi.org/10.1080/2162402X.2021.1973710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477954PMC
October 2021

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma.

J Immunother Cancer 2021 09;9(9)

Clinica Universidad de Navarra-Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain

Patients with advanced hepatocellular carcinoma (HCC) have historically had few options and faced extremely poor prognoses if their disease progressed after standard-of-care tyrosine kinase inhibitors (TKIs). Recently, the standard of care for HCC has been transformed as a combination of the immune checkpoint inhibitor (ICI) atezolizumab plus the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was shown to offer improved overall survival in the first-line setting. Immunotherapy has demonstrated safety and efficacy in later lines of therapy as well, and ongoing trials are investigating novel combinations of ICIs and TKIs, in addition to interventions earlier in the course of disease or in combination with liver-directed therapies. Because HCC usually develops against a background of cirrhosis, immunotherapy for liver tumors is complex and oncologists need to account for both immunological and hepatological considerations when developing a treatment plan for their patients. To provide guidance to the oncology community on important concerns for the immunotherapeutic care of HCC, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for HCC, including diagnosis and staging, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with HCC.
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http://dx.doi.org/10.1136/jitc-2021-002794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438858PMC
September 2021

Dynamic Contrast-Enhanced and Intravoxel Incoherent Motion MRI Biomarkers Are Correlated to Survival Outcome in Advanced Hepatocellular Carcinoma.

Diagnostics (Basel) 2021 Jul 26;11(8). Epub 2021 Jul 26.

Department of Medical Imaging, National Taiwan University Hospital, Taipei 100, Taiwan.

Objective: This study assessed dynamic contrast-enhanced (DCE)-MRI and intravoxel incoherent motion diffusion-weighted imaging (IVIM DWI) parameters to prospectively predict survival outcomes in participants with advanced hepatocellular carcinoma (HCC) who received lenalidomide, a dual antiangiogenic and immunomodulatory agent, as second-line therapy in a Phase II clinical trial.

Materials And Methods: Forty-four participants with advanced HCC who had progression after sorafenib as first-line treatment were prospectively enrolled. Pretreatment MRI parameters-obtained from DCE-MRI (peak, slope, AUC, K, K, and V), apparent diffusion coefficient (ADC), and IVIM DWI (pure diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f))-were derived from the largest hepatic tumor. The Cox model was used to investigate the associations of the parameters with progression-free survival (PFS) and overall survival (OS).

Results: Median PFS and OS were 2.3 and 8.0 months, respectively. Univariate analysis showed that participants with a high slope ( = 0.024), K ( < 0.001), and ADC ( = 0.018) values had longer PFS than those with low values; participants with a small tumor size ( = 0.006), high slope ( = 0.01), ADC ( = 0.015), and f ( = 0.012) values had longer OS than those with low values did. Cox multivariable analysis revealed that K ( < 0.001) and ADC ( = 0.009) remained independent predictors of PFS; slope ( = 0.003) and ADC ( = 0.009) remained independent predictors of OS. Moreover, K and slope were still significant after Bonferroni correction was performed ( < 0.005).

Conclusion: Both pretreatment DCE-MRI and IVIM DWI parameters, especially slope and ADC, may predict PFS and OS in participants with HCC receiving lenalidomide as second-line therapy.
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http://dx.doi.org/10.3390/diagnostics11081340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391260PMC
July 2021

Prognostic value of PD-L1 expression on immune cells or tumor cells for locally advanced esophageal squamous cell carcinoma in patients treated with neoadjuvant chemoradiotherapy.

J Cancer Res Clin Oncol 2021 Aug 25. Epub 2021 Aug 25.

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.

Purpose: Programmed death-ligand 1 (PD-L1) expression may influence the prognosis of patients with localized esophageal cancer. The current study compared the prognostic value of PD-L1 expression between tumor cells and immune cells.

Methods: Archival esophageal tumor tissue samples were collected from patients who received paclitaxel and cisplatin-based neoadjuvant chemoradiotherapy (CRT) for locally advanced esophageal squamous cell carcinoma (ESCC) in three prospective phase II trials. PD-L1 expression on tumor and immune cells was examined immunohistochemically by using the SP142 antibody and scored by two independent pathologists. The association of PD-L1 expression with patient's outcomes was analyzed using a log-rank test and Cox regression multivariate analysis.

Results: A total of 100 patients were included. PD-L1 expression on tumor cells was positive (≥ 1%, TC-positive) in 55 patients; PD-L1 expression on immune cells was high (≥ 5%, IC-high) in 30 patients. TC-positive status was associated with poor overall survival (OS) (HR: 1.63, P = 0.035), whereas IC-high status was associated with improved OS (HR: 0.44, P = 0.0024). Multivariate analysis revealed that TC-positive, IC-high, and performance status were independent prognostic factors for progression-free survival and that IC-high and performance status were independent factors for OS. Furthermore, the combination of IC-high and TC-negative status was associated with the optimal OS, whereas that of TC-positive and IC-low status was associated with the worst OS.

Conclusion: PD-L1 expression on tumor and immune cells may have different prognostic value for patients with locally advanced ESCC receiving neoadjuvant CRT. A combination of these two indexes may further improve the prognostic prediction.
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http://dx.doi.org/10.1007/s00432-021-03772-7DOI Listing
August 2021

APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy.

Hepatol Int 2021 Oct 24;15(5):1031-1048. Epub 2021 Aug 24.

Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan.

Background & Aim: Hepatitis B reactivation related to the use of immunosuppressive therapy remains a major cause of liver-related morbidity and mortality in hepatitis B endemic Asia-Pacific region. This clinical practice guidelines aim to assist clinicians in all disciplines involved in the use of immunosuppressive therapy to effectively prevent and manage hepatitis B reactivation.

Methods: All publications related to hepatitis B reactivation with the use of immunosuppressive therapy since 1975 were reviewed. Advice from key opinion leaders in member countries/administrative regions of Asian-Pacific Association for the study of the liver was collected and synchronized. Immunosuppressive therapy was risk-stratified according to its reported rate of hepatitis B reactivation.

Recommendations: We recommend the necessity to screen all patients for hepatitis B prior to the initiation of immunosuppressive therapy and to administer pre-emptive nucleos(t)ide analogues to those patients with a substantial risk of hepatitis and acute-on-chronic liver failure due to hepatitis B reactivation.
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http://dx.doi.org/10.1007/s12072-021-10239-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382940PMC
October 2021

Exploring Markers of Exhausted CD8 T Cells to Predict Response to Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma.

Liver Cancer 2021 Jul 12;10(4):346-359. Epub 2021 May 12.

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.

Background: Reversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy.

Objectives: The aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC).

Methods: Immune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining.

Results: HCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy ( = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8LAG3 cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors ( = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy.

Conclusions: CD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC.
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http://dx.doi.org/10.1159/000515305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339511PMC
July 2021

Atezolizumab plus Bevacizumab versus Sorafenib in the Chinese Subpopulation with Unresectable Hepatocellular Carcinoma: Phase 3 Randomized, Open-Label IMbrave150 Study.

Liver Cancer 2021 Jul 23;10(4):296-308. Epub 2021 Apr 23.

Department of Medical Oncology, National Taiwan University Cancer Center and National Taiwan University Hospital, Taipei, Taiwan.

Introduction: Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) in IMbrave150. Efficacy and safety data from the Chinese subpopulation are reported.

Methods: IMbrave150, a global, randomized, open-label, phase 3 study in patients with systemic treatment-naive unresectable HCC, included an extension phase that enrolled additional patients from mainland China. Patients were randomized (2:1) to receive intravenous atezolizumab 1,200 mg plus bevacizumab 15 mg/kg once every 3 weeks or sorafenib 400 mg twice a day until unacceptable toxicity or loss of clinical benefit. Co-primary endpoints were OS and independent review facility-assessed PFS per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population.

Results: Of 194 Chinese patients enrolled from April 16, 2018, to April 8, 2019 (137 in the global study and 57 in the China extension phase), 133 received atezolizumab plus bevacizumab and 61 received sorafenib. At the data cutoff (August 29, 2019), the stratified hazard ratio for OS was 0.44 (95% CI, 0.25-0.76) and for PFS was 0.60 (95% CI, 0.40-0.90). The respective median OS and PFS with atezolizumab plus bevacizumab were not reached (NR; 95% CI, 13.5 months to NR) and 5.7 months (95% CI, 4.2-8.3) versus 11.4 months (95% CI, 6.7 to NR) and 3.2 months (95% CI, 2.6-4.8) with sorafenib. Grade 3-4 adverse events (AEs) occurred in 78 of 132 (59.1%) atezolizumab plus bevacizumab-treated and 27 of 58 (46.6%) sorafenib-treated patients. The most common grade 3-4 AE with atezolizumab plus bevacizumab was hypertension, occurring in 15.2% of patients; however, other high-grade AEs were infrequent.

Conclusion: Clinically meaningful improvements in OS and PFS observed with atezolizumab plus bevacizumab versus sorafenib suggest that atezolizumab plus bevacizumab may become a practice-changing treatment for Chinese patients with unresectable HCC.
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http://dx.doi.org/10.1159/000513486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339481PMC
July 2021

Contribution of nuclear BCL10 expression to tumor progression and poor prognosis of advanced and/or metastatic pancreatic ductal adenocarcinoma by activating NF-κB-related signaling.

Cancer Cell Int 2021 Aug 19;21(1):436. Epub 2021 Aug 19.

Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan S Rd, Taipei, Taiwan.

Background: We previously demonstrated that nuclear BCL10 translocation participates in the instigation of NF-κB in breast cancer and lymphoma cell lines. In this study, we assessed whether nuclear BCL10 translocation is clinically significant in advanced and metastatic pancreatic ductal adenocarcinoma (PDAC).

Method And Materials: We analyzed the expression of BCL10-, cell cycle-, and NF-κB- related signaling molecules, and the DNA-binding activity of NF-κB in three PDAC cell lines (mutant KRAS lines: PANC-1 and AsPC-1; wild-type KRAS line: BxPC-3) using BCL10 short hairpin RNA (shBCL10). To assess the anti-tumor effect of BCL10 knockdown in PDAC xenograft model, PANC-1 cells treated with or without shBCL10 transfection were inoculated into the flanks of mice. We assessed the expression patterns of BCL10 and NF-κB in tumor cells in 136 patients with recurrent, advanced, and metastatic PDAC using immunohistochemical staining.

Results: We revealed that shBCL10 transfection caused cytoplasmic translocation of BCL10 from the nuclei, inhibited cell viability, and enhanced the cytotoxicities of gemcitabine and oxaliplatin in three PDAC cell lines. Inhibition of BCL10 differentially blocked cell cycle progression in PDAC cell lines. Arrest at G1 phase was noted in wild-type KRAS cell lines; and arrest at G2/M phase was noted in mutant KRAS cell lines. Furthermore, shBCL10 transfection downregulated the expression of phospho-CDC2, phospho-CDC25C, Cyclin B1 (PANC-1), Cyclins A, D1, and E, CDK2, and CDK4 (BxPC-3), p-IκBα, nuclear expression of BCL10, BCL3, and NF-κB (p65), and attenuated the NF-κB pathway activation and its downstream molecule, c-Myc, while inhibition of BCL10 upregulated expression of p21, and p27 in both PANC-1 and BxPC-3 cells. In a PANC-1-xenograft mouse model, inhibition of BCL10 expression also attenuated the tumor growth of PDAC. In clinical samples, nuclear BCL10 expression was closely associated with nuclear NF-κB expression (p < 0.001), and patients with nuclear BCL10 expression had the worse median overall survival than those without nuclear BCL10 expression (6.90 months versus 9.53 months, p = 0.019).

Conclusion: Nuclear BCL10 translocation activates NF-κB signaling and contributes to tumor progression and poor prognosis of advanced/metastatic PDAC.
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http://dx.doi.org/10.1186/s12935-021-02143-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375138PMC
August 2021

as a Prognostic Biomarker and Potential Therapeutic Target for Hepatocellular Carcinoma.

Cells 2021 07 5;10(7). Epub 2021 Jul 5.

Department of Oncology, National Taiwan University Hospital, 7, Chung-Shan S. Rd., Taipei 100, Taiwan.

Background: The kinesin , a mitosis-associated protein, is overexpressed in many cancers. Here we explored the clinical significance of in hepatocellular carcinoma (HCC).

Methods: HCC tissues from surgical resection were collected. Total RNA was prepared from tumorous and nontumorous parts. expression levels were correlated with overall survival (OS) and disease-free survival (DFS). In vitro efficacy of LGI-147, a specific inhibitor, was tested in HCC cell lines. In vivo efficacy of inhibition was investigated in a xenograft model.

Results: A total of 108 HCC samples were included. The patients were divided into three tertile groups with high, medium, and low expression levels. OS of patients with low expression was better than that of patients with medium and high expression (median, 155.6 vs. 75.3 vs. 57.7 months, = 0.002). DFS of patients with low expression was also better than that of patients with medium and high expression (median, 126.3 vs. 46.2 vs. 39.4 months, = 0.001). In multivariate analyses, the associations between expression and OS ( < 0.001) or DFS remained ( < 0.001). LGI-147 reduced cell growth via cell cycle arrest and apoptosis and induced accumulation of abnormal mitotic cells. In the xenograft model, the tumor growth rate under LGI-147 treatment was significantly slower than under the control.

Conclusion: High expression was associated with poor HCC prognosis. In vitro and in vivo evidence suggests that may be a reasonable therapeutic target for HCC.
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http://dx.doi.org/10.3390/cells10071698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303881PMC
July 2021

An Exploratory Study for the Association of Gut Microbiome with Efficacy of Immune Checkpoint Inhibitor in Patients with Hepatocellular Carcinoma.

J Hepatocell Carcinoma 2021 24;8:809-822. Epub 2021 Jul 24.

Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.

Background: Gut microbiome has been associated with the efficacy of immune checkpoint inhibitors (ICI) in patients with various types of cancers but not yet in hepatocellular carcinoma (HCC).

Aims: To investigate the association between gut microbiome and efficacy of ICI in patients with HCC.

Methods: Patients with HCC who were scheduled to receive ICI were prospectively enrolled. Fecal samples were collected within 7 days before initiation of ICI (baseline) and 8 weeks later. Gut microbiome was assessed using 16S rRNA sequencing and shotgun whole-genome sequencing and correlated with objective response (complete or partial response), disease control (objective response or stable disease for ≥16 weeks), and overall survival.

Results: Thirty-six patients with HCC were enrolled, and 20 of them provided both baseline and 8-week feces. Alpha diversity, richness, and compositions of baseline gut microbiome indicated no difference between responders and nonresponders or between disease control and nondisease control groups. For the 20 paired feces, immunotherapy did not change any of the major microbiome features. No specific taxa were enriched in patients with objective response. Three taxa-, and -were enriched in patients with disease control. However, the baseline abundance of these three taxa did not predict overall survival benefit.

Conclusions: In this exploratory study, we failed to disclose any overt association of gut microbiome with the efficacy of ICI in patients with HCC. A larger prospective study is warranted for definite conclusion.
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http://dx.doi.org/10.2147/JHC.S315696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318216PMC
July 2021

Anti-HER2 antibody prolongs overall survival disproportionally more than progression-free survival in HER2-Positive metastatic breast cancer patients.

Breast 2021 Oct 8;59:211-220. Epub 2021 Jul 8.

Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

Background: This meta-analysis aimed to test the hypothesis that the HER2-positive metastatic breast cancer (mBC) patients treated with anti-HER2 antibodies in trial intervention arms have a greater prolongation of overall survival (OS) than of progression-free survival (PFS) and this extra-prolongation of median survival time in OS relates specifically to the anti-HER2 antibody.

Methods: The NCBI/Pubmed and Cochrane databases were searched systematically for HER2-positive or mBC trials published in English during January 1999-November 2017. Treatment arms with shorter PFS were considered as the "control" arm, whereas those with longer PFS as the "test" arm. The between-treatment drug differences were grouped into nine categories. Groups with or without anti-HER2 antibodies were pooled respectively for comparisons. The interrelationships between PFS and OS hazard ratios (HRs) and median survival time differences were investigated by conducting fixed-effects and mixed-effects linear meta-regression analyses.

Results: Twenty-eight trials (10,928 patients) from 438 articles were collected, and four with missing data were excluded in meta-regression analysis. Overall median PFS (HR = 0.73, 95% CI: 0.68-0.78) and median OS (HR = 0.82, 95% CI: 0.77-0.87) weakly favored the longer PFS arm with a weak correlation between the PFS and OS HRs. However, the between-treatment drug difference was anti-HER2 antibody, the absolute increment in median OS time was double that of median PFS time (p < 0.001) and linearly correlated, which was not found with any non-anti-HER2 antibody drug differences.

Conclusions: Anti-HER2 antibody in patients with HER2-positive mBC prolonged OS more than PFS and mandates further investigation.
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http://dx.doi.org/10.1016/j.breast.2021.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321956PMC
October 2021

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study.

J Clin Oncol 2021 09 22;39(27):2991-3001. Epub 2021 Jul 22.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348).

Patients And Methods: Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles.

Results: A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively.

Conclusion: All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.
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http://dx.doi.org/10.1200/JCO.20.03555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445563PMC
September 2021

Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: A Subgroup Analysis of Asian Patients in the Phase 3 KEYNOTE-240 Trial.

Liver Cancer 2021 Jun 27;10(3):275-284. Epub 2021 Apr 27.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Introduction: KEYNOTE-240 investigated the efficacy and safety of pembrolizumab plus best supportive care (BSC) in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC). Results for the subgroup of patients from Asia are described.

Methods: Adults with advanced HCC previously treated with sorafenib were randomized 2:1 to pembrolizumab or placebo plus BSC. Here, the Asian subgroup comprised patients enrolled in Hong Kong, Japan, Korea, the Philippines, Taiwan, and Thailand. Primary endpoints were progression-free survival (PFS) per blinded central imaging review and overall survival (OS). Secondary endpoints included objective response rate (ORR) per blinded central imaging review, duration of response (DOR), and safety.

Results: The Asian subgroup included 157 patients. As of January 2, 2019, the median follow-up in this subgroup was 13.8 months for pembrolizumab and 8.3 months for placebo. The median PFS was 2.8 months for pembrolizumab (95% confidence interval [CI] 2.6-4.1) versus 1.4 months (95% CI 1.4-2.4) for placebo (hazard ratio [HR] 0.48; 95% CI 0.32-0.70). The median OS was 13.8 months (95% CI 10.1-16.9) for pembrolizumab versus 8.3 months (95% CI 6.3-11.8) for placebo (HR 0.55; 95% CI 0.37-0.80). ORR was 20.6% (95% CI 13.4-29.5) for pembrolizumab versus 2.0% (95% CI 0.1-10.6) for placebo (difference: 18.5%; 95% CI 8.3-27.6). The median DOR was 8.6 and 2.8 months for pembrolizumab and placebo, respectively. Any grade treatment-related adverse events (TRAEs) occurred in 63 patients (58.9%) receiving pembrolizumab and 24 patients (48.0%) receiving placebo; 14 (13.1%) and 2 (4.0%) patients experienced grade 3-5 TRAEs, respectively. No treatment-related deaths occurred.

Conclusion: Pembrolizumab demonstrated antitumor activity and was well tolerated in the Asian subgroup of KEYNOTE-240. A trend toward greater benefit with pembrolizumab in the Asian subgroup was observed compared with the overall cohort, supporting further evaluation of pembrolizumab treatment in this population.
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http://dx.doi.org/10.1159/000515553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237794PMC
June 2021

High prevalence of APOA1/C3/A4/A5 alterations in luminal breast cancers among young women in East Asia.

NPJ Breast Cancer 2021 Jul 5;7(1):88. Epub 2021 Jul 5.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

In East Asia, the breast cancer incidence rate among women aged <50 years has rapidly increased. Emerging tumors are distinctly characterized by a high prevalence of estrogen receptor (ER)-positive/human epidermal growth factor receptor (HER2)-negative cancer. In the present study, we identified unique genetic alterations in these emerging tumors. We analyzed gene copy number variations (CNVs) in breast tumors from 120 Taiwanese patients, and obtained public datasets of CNV and gene expression (GE). The data regarding CNV and GE were separately compared between East Asian and Western patients, and the overlapping genes identified in the comparisons were explored to identify the gene-gene interaction networks. In the age <50 years/ER + /HER2- subgroup, tumors of East Asian patients exhibited a higher frequency of copy number loss in APOA1/C3/A4/A5, a lipid-metabolizing gene cluster (33 vs. 10%, P < .001) and lower APOA1/C3/A4/A5 expressions than tumors of Western patients. These copy number loss related- and GE-related results were validated in another Taiwanese cohort and in two GE datasets, respectively. The copy number loss was significantly associated with poor survival among Western patients, but not among East Asian patients. Lower APOA1, APOC3, and APOA5 expressions were associated with higher ESTIMATE immune scores, indicating an abundance of tumor-infiltrating immune cells. In conclusion, APOA1/C3/A4/A5 copy number loss was more prevalent in luminal breast tumors among East Asian women aged <50 years, and its immunomodulatory effect on the tumor microenvironment possibly plays various roles in the tumor biology of East Asian patients.
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http://dx.doi.org/10.1038/s41523-021-00299-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257799PMC
July 2021

Evolution of systemic treatment for advanced hepatocellular carcinoma.

Kaohsiung J Med Sci 2021 Aug 2;37(8):643-653. Epub 2021 Jul 2.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Advanced hepatocellular carcinoma (HCC) was considered an inherently refractory tumor in the chemotherapy era (1950-2000). However, systemic therapy has evolved to molecular targeted therapy and immunotherapy, and nine treatment regimens have been approved worldwide during the past 20 years. The approved regimens target tumor angiogenesis or tumor immunity, the two cancer hallmarks. Recently, the combination of atezolizumab (antiprogrammed cell death ligand 1) and bevacizumab (anti-vascular endothelial growth factor) has improved the efficacy of systemic therapy in treating advanced HCC without excessive toxicities or deterioration of quality of life. This review summarizes the major advances in systemic therapy and provides future perspectives on the next-generation systemic therapy for advanced HCC.
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http://dx.doi.org/10.1002/kjm2.12401DOI Listing
August 2021

Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.

Clin Cancer Res 2021 Sep 9;27(17):4848-4858. Epub 2021 Jun 9.

Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK.

Purpose: In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT.

Experimental Design: Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated.

Results: Four hundred and seven patients were included in the serum analysis set (lenvatinib = 279, sorafenib = 128); 58 patients were included in the gene-expression analysis set (lenvatinib = 34, sorafenib = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, = 0.014; FGF23: 48.4% vs. 16.4%, = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; = 0.0253).

Conclusions: Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4219DOI Listing
September 2021

Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial.

Lancet Oncol 2021 07 27;22(7):991-1001. Epub 2021 May 27.

Department of Medical Oncology, Gustave Roussy, Villejuif, France.

Background: Understanding patients' experience of cancer treatment is important. We aimed to evaluate patient-reported outcomes (PROs) with atezolizumab plus bevacizumab versus sorafenib in patients with advanced hepatocellular carcinoma in the IMbrave150 trial, which has already shown significant overall survival and progression-free survival benefits with this combination therapy.

Methods: We did an open-label, randomised, phase 3 trial in 111 hospitals and cancer centres across 17 countries or regions. We included patients aged 18 years or older with systemic, treatment-naive, histologically, cytologically, or clinically confirmed unresectable hepatocellular carcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with disease that was not amenable to curative surgical or locoregional therapies, or progressive disease after surgical or locoregional therapies. Participants were randomly assigned (2:1; using permuted block randomisation [blocks of six], stratified by geographical region; macrovascular invasion, extrahepatic spread, or both; baseline alpha-fetoprotein concentration; and ECOG performance status) to receive 1200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously once every 3 weeks or 400 mg sorafenib orally twice a day, until loss of clinical benefit or unacceptable toxicity. The independent review facility for tumour assessment was masked to the treatment allocation. Previously reported coprimary endpoints were overall survival and independently assessed progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1. Prespecified secondary and exploratory analyses descriptively evaluated treatment effects on patient-reported quality of life, functioning, and disease symptoms per the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ-C30) and quality-of-life questionnaire for hepatocellular carcinoma (QLQ-HCC18). Time to confirmed deterioration of PROs was analysed in the intention-to-treat population; all other analyses were done in the PRO-evaluable population (patients who had a baseline PRO assessment and at least one assessment after baseline). The trial is ongoing; enrolment is closed. This trial is registered with ClinicalTrials.gov, NCT03434379.

Findings: Between March 15, 2018, and Jan 30, 2019, 725 patients were screened and 501 patients were enrolled and randomly assigned to atezolizumab plus bevacizumab (n=336) or sorafenib (n=165). 309 patients in the atezolizumab plus bevacizumab group and 145 patients in the sorafenib group were included in the PRO-evaluable population. At data cutoff (Aug 29, 2019) the median follow-up was 8·6 months (IQR 6·2-10·8). EORTC QLQ-C30 completion rates were 90% or greater for 23 of 24 treatment cycles in both groups (range 88-100% in the atezolizumab plus bevacizumab group and 80-100% in the sorafenib group). EORTC QLQ-HCC18 completion rates were 90% or greater for 20 of 24 cycles in the atezolizumab plus bevacizumab group (range 88-100%) and 21 of 24 cycles in the sorafenib group (range 89-100%). Compared with sorafenib, atezolizumab plus bevacizumab reduced the risk of deterioration on all EORTC QLQ-C30 generic cancer symptom scales that were prespecified for analysis (appetite loss [hazard ratio (HR) 0·57, 95% CI 0·40-0·81], diarrhoea [0·23, 0·16-0·34], fatigue [0·61, 0·46-0·81], pain [0·46, 0·34-0·62]), and two of three EORTC QLQ-HCC18 disease-specific symptom scales that were prespecified for analysis (fatigue [0·60, 0·45-0·80] and pain [0·65, 0·46-0·92], but not jaundice [0·76, 0·55-1·07]). At day 1 of treatment cycle five (after which attrition in the sorafenib group was more than 50%), the mean EORTC QLQ-C30 score changes from baseline in the atezolizumab plus bevacizumab versus sorafenib groups were: -3·29 (SD 17·56) versus -5·83 (20·63) for quality of life, -4·02 (19·42) versus -9·76 (21·33) for role functioning, and -3·77 (12·82) versus -7·60 (15·54) for physical functioning.

Interpretation: Prespecified analyses of PRO data showed clinically meaningful benefits in terms of patient-reported quality of life, functioning, and disease symptoms with atezolizumab plus bevacizumab compared with sorafenib, strengthening the combination therapy's positive benefit-risk profile versus that of sorafenib in patients with unresectable hepatocellular carcinoma.

Funding: F Hoffmann-La Roche and Genentech.
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http://dx.doi.org/10.1016/S1470-2045(21)00151-0DOI Listing
July 2021

Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT.

J Gastroenterol 2021 06 4;56(6):570-580. Epub 2021 May 4.

Toranomon Hospital, Tokyo, Japan.

Background: REFLECT was an open-label, phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). Based on phase 2 study (Study 202) results, body weight-based dosing for lenvatinib was used in REFLECT to minimize dose disruptions and modifications needed to address dose-related adverse events. This post hoc analysis of REFLECT data assessed lenvatinib efficacy and safety by body weight group.

Methods: The study randomly administered lenvatinib (n = 476) or sorafenib (n = 475) to patients with untreated (no prior systemic therapy) uHCC. Lenvatinib starting-dose data were stratified by body weight: patients weighing < 60 kg received 8 mg/day; patients weighing ≥ 60 kg received 12 mg/day. Overall survival (OS), progression-free survival (PFS), objective response rate, and safety were assessed.

Results: Survival outcomes and safety profiles appeared similar between the two body-weight-based lenvatinib starting-dose groups. Median OS for patients in the < 60 kg body weight group (n = 153) was 13.4 months [95% confidence interval (CI) 10.5-15.7] compared to 13.7 months (95% CI 12.0-15.6) in the ≥ 60 kg body weight group (n = 325). In both lenvatinib groups, PFS was 7.4 months (< 60 kg group: 95% CI 5.4-9.2; ≥ 60 kg group: 95% CI 6.9-9.0). Treatment-emergent adverse events (TEAEs) required dose modifications in 43.0% in the < 60 kg body weight group and 57.5% in the ≥ 60 kg body weight group.

Conclusions: This exploratory analysis of data from REFLECT indicated that body weight-based lenvatinib dosing in patients with uHCC was successful in maintaining efficacy, with comparable rates of TEAEs and dose modifications in the two body weight groups.

Clinincal Trial: Trial registration ID: ClinicalTrials.gov # NCT01761266.
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http://dx.doi.org/10.1007/s00535-021-01785-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137475PMC
June 2021

Association between risk factors, molecular features and CpG island methylator phenotype colorectal cancer among different age groups in a Taiwanese cohort.

Br J Cancer 2021 Jul 12;125(1):48-54. Epub 2021 Apr 12.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Background: CpG island methylator phenotype (CIMP) represents a carcinogenesis pathway of colorectal cancer (CRC) and the association between CIMP CRC, molecular features and risk factors in East Asian population is less studied.

Methods: We prospectively enrolled newly diagnosed CRC patients at the National Taiwan University Hospital. Clinicopathological data and risk factors for CRC were collected during interview. The tumour samples were subjected to CIMP, RAS/BRAF mutation and microsatellite instability tests. CIMP-high was determined when ≧3 methylated loci of p16, MINT1, MINT2, MINT31 and MLH1 were identified. Multivariate logistic regression was used to evaluate the association between risk factors and CIMP-high CRC.

Results: Compared with CIMP-low/negative CRC, CIMP-high CRC was associated with more stage IV disease, BRAF V600E mutation and high body mass index (BMI ≧ 27.5 kg/m) in younger patients (age < 50 y), and more right-sided tumour, BRAF V600E mutation, MSI-high and colorectal polyp in elder patients (age ≧ 50 y). Multivariate analyses showed that BMI ≧27.5 kg/m was significantly associated with CIMP-high CRC in younger patients.

Conclusions: We identified distinct clinicopathological features for CIMP-high CRC among different age groups in Taiwan. Our data suggest the association between BMI ≧27.5 kg/m and CIMP-high CRC in patients younger than 50 years.
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http://dx.doi.org/10.1038/s41416-021-01300-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257672PMC
July 2021

Regorafenib enhances antitumor immunity via inhibition of p38 kinase/Creb1/Klf4 axis in tumor-associated macrophages.

J Immunother Cancer 2021 03;9(3)

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan

Background: Regorafenib and other multikinase inhibitors may enhance antitumor efficacy of anti-program cell death-1 (anti-PD1) therapy in hepatocellular carcinoma (HCC). Its immunomodulatory effects, besides anti-angiogenesis, were not clearly defined.

Methods: In vivo antitumor efficacy was tested in multiple syngeneic liver cancer models. Murine bone marrow-derived macrophages (BMDMs) were tested in vitro for modulation of polarization by regorafenib and activation of cocultured T cells. Markers of M1/M2 polarization were measured by quantitative reverse transcription PCR (RT-PCR), arginase activity, flow cytometry, and ELISA. Knockdown of p38 kinase and downstream Creb1/Klf4 signaling on macrophage polarization were confirmed by using knockdown of the upstream MAPK14 kinase, chemical p38 kinase inhibitor, and chromatin immunoprecipitation.

Results: Regorafenib (5 mg/kg/day, corresponding to about half of human clinical dosage) inhibited tumor growth and angiogenesis in vivo similarly to DC-101 (anti-VEGFR2 antibody) but produced higher T cell activation and M1 macrophage polarization, increased the ratio of M1/M2 polarized BMDMs and proliferation/activation of cocultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream Creb1/Klf4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells. Synergistic antitumor efficacy between regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment.

Conclusion: Regorafenib may enhance antitumor immunity through modulation of macrophage polarization, independent of its anti-angiogenic effects. Optimization of regorafenib dosage for rational design of combination therapy regimen may improve the therapeutic index in the clinic.
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http://dx.doi.org/10.1136/jitc-2020-001657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986673PMC
March 2021

An Underdiagnosed Hypothyroidism and Its Clinical Significance in Patients with Advanced Hepatocellular Carcinoma.

Oncologist 2021 05 20;26(5):422-426. Epub 2021 Mar 20.

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.

Background: Many systemic therapies for advanced hepatocellular carcinoma (HCC) may cause hypothyroidism; however, in these patients, hypothyroidism prevalence before therapy and its prognostic impact remain unclear.

Materials And Methods: We previously established a prospective cohort of patients who received sorafenib as first-line therapy for advanced HCC. No patients had been clinically diagnosed with hypothyroidism before or during sorafenib treatment. We retrospectively determined the levels of thyrotropin and free thyroxine before initiation of systemic therapy. Hypothyroidism was defined as thyrotropin level higher than the upper limit of the normal range. Among patients with hypothyroidism, free thyroxine level less than the lower normal range was defined as overt hypothyroidism, and free thyroxine level within the normal range was defined as subclinical hypothyroidism.

Results: In total, 79 patients were enrolled; of them, 16 (20%) had hypothyroidism (overt hypothyroidism, 10; subclinical hypothyroidism, 6). Patients with hypothyroidism, compared with those without hypothyroidism, were more likely to be older than 65 years (56% vs. 29%, p = .037), have a serum α-fetoprotein level of >400 ng/mL (81% vs. 52%, p = .037), and have a significantly poorer overall survival (OS; median, 5.5 vs. 11.6 months, p = .043). After adjusting for other potential prognostic factors, hypothyroidism remained an independent predictor for poorer OS (hazard ratio, 2.53, p = .018). Patients with overt hypothyroidism and subclinical hypothyroidism exhibited similarly poor OS (p = .768).

Conclusion: Underdiagnosis of hypothyroidism in patients with advanced HCC was common. Hypothyroidism, whether overt or subclinical, is associated with poor prognosis of advanced HCC.

Implications For Practice: The results of this study showed the underdiagnosis of hypothyroidism in patients with advanced hepatocellular carcinoma (HCC) and its influence on prognosis. These findings implied the importance of thyroid function check before initiation of systemic therapy for patients with advanced HCC.
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http://dx.doi.org/10.1002/onco.13755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100545PMC
May 2021

Pursuing efficacious systemic therapy for hepatocellular carcinoma.

Authors:
Ann-Lii Cheng

Nat Rev Gastroenterol Hepatol 2021 02;18(2):95-96

Department of Medical Oncology, National Taiwan University Cancer Center, Taipei City, Taiwan.

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http://dx.doi.org/10.1038/s41575-020-00405-1DOI Listing
February 2021

Noninferiority of cetuximab every-2-weeks versus standard once-weekly administration schedule for the first-line treatment of RAS wild-type metastatic colorectal cancer.

Eur J Cancer 2021 02 28;144:291-301. Epub 2020 Dec 28.

Department of Medical Oncology, Internal Medicine 1, General Hospital - Medical University of Vienna, Vienna, Austria.

Aim: This study assessed whether cetuximab 500 mg/m administered every 2 weeks (Q2W), when combined with chemotherapy as a first-line (1L) treatment, was noninferior to the approved dose (400 mg/m followed by 250 mg/m once weekly [Q1W]) for overall survival (OS) in adults with RAS wild-type metastatic colorectal cancer (mCRC).

Methods: This pooled analysis included patients receiving 1L treatment with cetuximab Q1W or Q2W in combination with chemotherapy from post-authorisation studies with patient-level data available to the sponsor. Baseline characteristics were adjusted with a propensity score using inverse probability of treatment weighting (IPTW). Noninferiority in terms of OS was tested with a noninferiority margin for the hazard ratio (HR) of 1.25 using a Cox proportional hazards regression model. Secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and rates of lung/liver metastases resection and serious adverse events.

Results: OS time was noninferior in the Q2W cohort (n = 554) compared to the Q1W cohort (n = 763), with a HR after IPTW (95% confidence interval) of 0.827 (0.715-0.956) and median OS times of 24.7 (Q1W) and 27.9 (Q2W) months. There were no major differences in PFS (HR: 0.915 [0.804-1.042]). The odds ratios (ORs) after IPTW for ORR (1.292 [1.031-1.617]) and the rates of lung/liver metastases resection (1.419 [1.043-1.932]) favoured the Q2W regimen. No differences were noted in the occurrence rate of any SAE between groups; the OR after IPTW was 1.089 (0.858-1.382).

Conclusions: The cetuximab Q2W regimen was noninferior to the Q1W regimen for OS in the 1L treatment of mCRC.
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http://dx.doi.org/10.1016/j.ejca.2020.11.013DOI Listing
February 2021

Comparison of clinicopathological features and treatment outcomes in aggressive primary intestinal B- and T/NK-cell lymphomas.

J Formos Med Assoc 2021 Jan 21;120(1 Pt 2):293-302. Epub 2020 Oct 21.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Oncology, National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Radiation Oncology, National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

Background: Primary intestinal lymphomas (PILs) are rare, and this study compared the clinical outcomes of aggressive primary intestinal B-cell lymphomas (aB-PILs) and T/natural killer-cell lymphomas (T/NK-PILs).

Methods: The clinical information of patients diagnosed with aggressive PILs at our institution between 1995 and 2015 were retrospectively investigated. Pathological subtypes were confirmed according to the 2016 revision of the World Health Organization classification. The correlation between clinicopathological features and overall survival (OS) was determined using univariate and multivariate analyses.

Results: Cases of T/NK-PILs had higher initial bowel perforation incidence (67% vs. 7%, P < 0.001) and lower complete response rate to first-line chemotherapy regimens (22% vs. 69%, P = 0.009) than aB-PILs. Patients with aB-PILs had a better 5-year event-free survival rate (55.8% vs. 13.9%, P = 0.026) and a 5-year OS rate (74.3% vs. 29.6%, P = 0.036) than those with T/NK-cell lymphomas. Multivariate analysis identified that female gender and stage III/IV were unfavorable prognostic factors. Among the 54 patients with diffuse large B-cell lymphoma (DLBCL), those with International Prognostic Index (IPI) scores of 0-2 had a better 5-year OS rate than those with scores of 3-5 (84.2% vs. 46.8%, P = 0.002). IPI scores of 3-5 (P = 0.026) and tumors located in the large intestine (P = 0.015) were poor prognostic factors based on the multivariate analysis.

Conclusion: The prognosis of T/NK-PILs was less favorable than that of aB-PILs. Female gender, stage III/IV disease, DLBCL with IPI scores of 3-5, or tumors in the large intestine were poor prognostic factors.
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http://dx.doi.org/10.1016/j.jfma.2020.10.001DOI Listing
January 2021

Health-related quality-of-life impact of pembrolizumab versus best supportive care in previously systemically treated patients with advanced hepatocellular carcinoma: KEYNOTE-240.

Cancer 2021 03 24;127(6):865-874. Epub 2020 Nov 24.

Kindai University School of Medicine, Osaka, Japan.

Background: Health-related quality of life (HRQoL) is an important outcome measure and prognostic indicator in hepatocellular carcinoma (HCC). KEYNOTE-240 (NCT02702401) assessed the efficacy and safety of pembrolizumab plus best supportive care (BSC) versus placebo plus BSC in patients with HCC who previously received sorafenib. This study presents the results of a prespecified exploratory analysis of patient-reported outcomes.

Methods: Patients completed the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and its HCC supplement (EORTC QLQ-HCC18) electronically at baseline; at weeks 2, 3, 4, 6, 9, 12, and 18; and then every 9 weeks until 1 year or end of treatment, and at the 30-day safety follow-up visit.

Results: The HRQoL population included 271 and 127 patients randomly assigned to pembrolizumab and placebo, respectively. From baseline to week 12, changes in both scores were similar between pembrolizumab and placebo; global health status/QoL scores were stable. The proportions of patients who improved, remained stable, or deteriorated across all functional domain and symptom scores were generally similar between pembrolizumab and placebo. Time to deterioration was similar between the 2 arms based on the prespecified analysis of EORTC QLQ-HCC18 domains of abdominal swelling, fatigue, and pain.

Conclusion: Pembrolizumab preserved HRQoL during treatment for advanced HCC. Combined with efficacy and safety results from KEYNOTE-240, these findings support a positive benefit/risk profile for pembrolizumab in a second-line treatment setting for patients with HCC who previously received sorafenib.
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http://dx.doi.org/10.1002/cncr.33317DOI Listing
March 2021

Second-line cabozantinib after sorafenib treatment for advanced hepatocellular carcinoma: a subgroup analysis of the phase 3 CELESTIAL trial.

ESMO Open 2020 08;5(4)

Memorial Sloan Kettering Cancer Center, New York, United States.

Objective: In the phase 3 CELESTIAL trial, cabozantinib improved overall survival (OS) and progression-free survival (PFS) compared with placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). This subgroup analysis evaluated cabozantinib in patients who had received sorafenib as the only prior systemic therapy.

Methods: CELESTIAL randomised (2:1) patients with advanced HCC and Child-Pugh class A liver function to treatment with cabozantinib (60 mg daily) or placebo. Eligibility required prior treatment with sorafenib, and patients could have received ≤2 prior systemic regimens. The primary endpoint was OS. Outcomes in patients who had received sorafenib as the only prior therapy were analysed by duration of prior sorafenib (<3 months, 3 to <6 months and ≥6 months).

Results: Of patients who had received only prior sorafenib, 331 were randomised to cabozantinib and 164 to placebo; 136 patients had received sorafenib for <3 months, 141 for 3 to <6 months and 217 for ≥6 months. Cabozantinib improved OS relative to placebo in the overall second-line population who had received only prior sorafenib (median 11.3 vs 7.2 months; HR=0.70, 95% CI 0.55 to 0.88). This improvement was maintained in analyses by prior sorafenib duration with longer duration generally corresponding to longer median OS-median OS 8.9 vs 6.9 months (HR=0.72, 95% CI 0.47 to 1.10) for prior sorafenib <3 months, 11.5 vs 6.5 months (HR=0.65, 95% CI 0.43 to 1.00) for 3 to <6 months and 12.3 vs 9.2 months (HR=0.82, 95% CI 0.58 to 1.16) for ≥6 months. Cabozantinib also improved PFS in all duration subgroups. Safety data were consistent with the overall study population.

Conclusion: Cabozantinib improved efficacy outcomes versus placebo in the second-line population who had received only prior sorafenib irrespective of duration of prior sorafenib treatment, further supporting the utility of cabozantinib in the evolving treatment landscape of HCC.

Clinical Trial Number: NCT01908426.
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http://dx.doi.org/10.1136/esmoopen-2020-000714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451459PMC
August 2020
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