Comprehensive multiplatform biomarker analysis of 313 hepatocellular carcinoma to identify potential therapeutic options.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 283-283
Author(s):  
Ghassan K. Abou-Alfa ◽  
John Thomas Miura ◽  
T. Clark Gamblin ◽  
Joanne Xiu ◽  
Sherri Z. Millis ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitors ◽  
Therapeutic Option ◽  
Alkylating Agents ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Molecular Heterogeneity ◽  
Biomarker Analysis ◽  
Pi3 Kinase Pathway ◽  
Kinase Pathway

283 Background: Effective treatment strategies for hepatocellular carcinoma (HCC) remain limited. Identification of additional therapies remains paramount as currently available agents have resulted in marginal improvements in overall survival. Methods: 313 HCC sampleswere evaluated using a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ), including gene sequencing (Sanger, NGS [N=79]), protein expression (IHC) and gene amplification (ISH). Results: Biomarker changes of interest are shown. See Table. TP53 was mutated in 28%, CTNNB1 in 23%, and BRCA2 in 20%; other gene mutation rates were < 5%.TP53-mutated tumors show significantly higher TOPO2A (89% vs. 39%, p<0.0001), TS (70% vs. 32%, p=0.0067) and RRM1 expression (40% vs. 12%, p=0.017), implying high rates of proliferation and DNA synthesis. CTNNB1-mutated tumors showed significantly higher SPARC (67% vs. 21%, p=0.0013) and AR expression (53% vs. 22%, p=0.025). Primary HCC (N=209) exhibited significantly higher PD-1 (89% vs. 33%, p=0.01) and TS expression (35% vs. 13%, p<0.0001) than metastatic (N=105). Patient history/outcomes relative to biomarker status are being evaluated. Conclusions: These data suggest potential therapeutic targets, such as tyrosine kinase inhibitors, anti-PD1 agents, or PI3 kinase pathway inhibitors. Although no evidence shows that cytotoxics are effective in patients with HCC, irinotecan, alkylating agents, fluoropyrimidines, anthracyclines, nab-paclitaxel, gemcitabine, or taxanes may be therapeutically relevant. The protein changes associated with CTNNB1-mutated tumors suggest potential benefit of targeting WNT pathway in combination with nab-paclitaxel or anti-androgens. Immuno-modulatory agents may be a therapeutic option in primary HCC, based on the higher levels of PD-1. Multiplatform tumor profiling reveals molecular heterogeneity HCC, similar overall to previous reports, and identifies different potential treatment options for molecular subtypes. [Table: see text]

Comprehensive multiplatform biomarker analysis of 206 squamous cell anal cancers.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 603-603
Author(s):  
Patrick McKay Boland ◽  
Sherri Z. Millis ◽  
David Arguello ◽  
Zoran Gatalica ◽  
Sandeep K. Reddy ◽  
...  
Keyword(s):  
Protein Expression ◽  
Squamous Cell ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Gene Mutations ◽  
Therapeutic Options ◽  
Driver Mutations ◽  
Viral Origin ◽  
Anal Squamous Cell Carcinoma ◽  
Biomarker Analysis

603 Background: Anal squamous cell carcinoma (Anal SCC) is a rare, HPV-associated malignancy accounting for 2.4% of digestive system cancers. In most cases, these malignancies are detected in the early stages and successfully managed with chemoradiation therapy. Uncommonly, these cancers recur or present with metastases. In this setting, cisplatin and 5-fluorouracil represent the only endorsed regimen. Once beyond standard therapy, few therapeutic options exist for those patients with aggressive disease. The purpose of this study is to identify other novel, potential targets and therapeutic options for this disease, utilizing a multiplatform approach. Methods: 206 anal SCC specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH or FISH). 6 cases were documented as positive for HPV or HIV; status was not provided on the remaining 200. Results: Key results are shown in the table below, shown as percent change/total cases. Conclusions: Multiplatform tumor profiling identified a low incidence of gene mutations. Protein expression aberrations identified potential treatment options not routinely considered, such as topoisomerase inhibitors and taxanes. Mutations in PIK3CA, Akt1, and FBXW7 as well as PTEN loss indicate potential for targeting the PI3 kinase pathway. Additionally, immunomodulatory agents may be a therapeutic option, based on PD-1 expression levels. Targeting the ErbB-family receptors, namely with anti-EGFR agents or newer generation pan-HER - inhibitors, may represent another option, given EGFR and HER2 amplification as well as EGFR overexpression. It should be mentioned that differences in anal carcinomas whose etiology is of viral origin may present different treatment options based on the driver mutations. [Table: see text]

Myopenia as a significant prognostic factor in BCLC-B intermediate-stage hepatocellular carcinoma treated with sorafenib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15639-e15639
Author(s):  
Mao Okada ◽  
Hiroyuki Nakanishi ◽  
Masayuki Kurosaki ◽  
Sakura Kirino ◽  
Leona Osawa ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Skeletal Muscle ◽  
Prognostic Factor ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Intermediate Stage ◽  
Significant Prognostic Factor ◽  
Poor Prognostic Factor ◽  
Skeletal Muscle Index ◽  
The Impact

e15639 Background: Tyrosine kinase inhibitors (TKI) are important treatment options for unresectable hepatocellular carcinoma (HCC). The survival benefit of sorafernib was demonstrated not only in advanced stage but also for BCLC-B intermediate stage who are refractory to transcatheter arterial chemoembolization by OPTIMIS study. Skeletal muscle mass depletion (Myopenia) is a poor prognostic factor in HCC treated by resection or loco-reginal ablation, but its effect on survival in TKI treated patients, especially in those within BCLC-B stage remains unclear. The aim of the present study is to elucidate the impact of myopenia on survival among HCC treated with sorafenib, especially in BCLC-B stage. Methods: In 213 patients who started treatment with sorafenib between 2009 and 2016, myopenia at baseline was determined by using skeletal muscle index calculated from CT images of the third lumber vertebra level. The impact of myopenia on survival was analyzed in whole patients, after stratification by BCLC stage, and after matching for backgrounds within BCLC-B patients. Results: The median survival in whole, BCLC-C, and –B was 13.7, 8.7 and 15.2 months, respectively. Myopenia was not a significant prognostic factor in whole patients and in BCLC-C stage. However, among BCLC-B patients (n = 104), survival was significantly better in patients with no myopenia (p = 0.05). Among them, 85 patients who continued sorafenib for more than 8 weeks were extracted and those with or without myopenia were matched for backgrounds by propensity score. Backgrounds including etiology, Child-Pugh score, BMI, AFP and PIVKA-Ⅱwas not different between myopenia (n = 30) and no myopenia group (n = 30) after matching. The overall survival at 6-, 12-, and 24-months was 96%, 74%, and 62% in no myopenia group which was significantly better compared to 89%, 64%, and 28% in myopenia group (p = 0.019). The hazard ratio was 2.12 (95% CI 1.11-4.03). Conclusions: Absence of myopenia predicts favorable outcome in sorafenib treated HCC patients within BCLC-B intermediate stage.

scholarly journals Treatment Strategies for Hepatocellular Carcinoma – a Multidisciplinary Approach

2019 ◽  
Vol 20 (6) ◽  
pp. 1465 ◽  
Author(s):  
Isabella Lurje ◽  
Zoltan Czigany ◽  
Jan Bednarsch ◽  
Christoph Roderburg ◽  
Peter Isfort ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Treatment Options ◽  
Multidisciplinary Treatment ◽  
Treatment Strategies ◽  
Future Liver Remnant ◽  
Liver Parenchyma ◽  
Tumor Stage ◽  
Organ Shortage ◽  
Liver Remnant

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and its mortality is third among all solid tumors, behind carcinomas of the lung and the colon. Despite continuous advancements in the management of this disease, the prognosis for HCC remains inferior compared to other tumor entities. While orthotopic liver transplantation (OLT) and surgical resection are the only two curative treatment options, OLT remains the best treatment strategy as it not only removes the tumor but cures the underlying liver disease. As the applicability of OLT is nowadays limited by organ shortage, major liver resections – even in patients with underlying chronic liver disease – are adopted increasingly into clinical practice. Against the background of the oftentimes present chronical liver disease, locoregional therapies have also gained increasing significance. These strategies range from radiofrequency ablation and trans-arterial chemoembolization to selective internal radiation therapy and are employed in both curative and palliative intent, individually, as a bridging to transplant or in combination with liver resection. The choice of the appropriate treatment, or combination of treatments, should consider the tumor stage, the function of the remaining liver parenchyma, the future liver remnant volume and the patient’s general condition. This review aims to address the topic of multimodal treatment strategies in HCC, highlighting a multidisciplinary treatment approach to further improve outcome in these patients.

Management of recurrent ovarian cancer: when platinum-based regimens are not a therapeutic option

2019 ◽  
Vol 29 (9) ◽  
pp. 1431-1436 ◽  
Author(s):  
Alice Bergamini ◽  
Luca Bocciolone ◽  
Andrei Fodor ◽  
Massimo Candiani ◽  
Giorgia Mangili
Keyword(s):  
Ovarian Cancer ◽  
Personalized Medicine ◽  
Recurrent Disease ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Recurrent Ovarian Cancer ◽  
Best Management ◽  
Free Interval ◽  
Treatment Alternatives

Ovarian cancer relapses have been traditionally classified according to the platinum-free interval, leading to an arbitrary categorization of possible scenarios and treatment options. Its relevance in assessing treatment strategies has been revised in the last several years, as the panorama is constantly changing in the era of personalized medicine and targeted therapies. Factors to be considered while defining the best management of recurrent disease, and, consequently, the available treatment alternatives are increasing. Platinum remains one of the milestones of ovarian cancer treatment, but for some patients it might not be an ideal choice for several reasons other than limited platinum sensitivity. This review aims to analyze the scenarios in which platinum is not considered suitable in the management of patients with recurrent ovarian cancer, and the currently available alternatives.

scholarly journals Treatment Strategies of Adult Primary Focal Segmental Glomerulosclerosis: A Systematic Review Focusing on the Last Two Decades

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Arno Beer ◽  
Gert Mayer ◽  
Andreas Kronbichler
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Remission Rate ◽  
Alkylating Agents ◽  
Treatment Options ◽  
Unmet Need ◽  
Treatment Strategies ◽  
Calcineurin Inhibitors ◽  
Segmental Glomerulosclerosis ◽  
Steroid Dependent ◽  
Stage Renal Disease

Adult primary focal segmental glomerulosclerosis (FSGS) remains a therapeutic challenge for the treating physician. With the advent of novel immunosuppressive measures, our arsenal of therapeutic options increased considerably. The aim of this review was to summarize reports published over the last two decades which reported on treatment outcome. Most reports included patients with a steroid-resistant (SR) disease course, yet the cohort with the highest unmet need, since persistent nephrotic range proteinuria is associated with a poor renal prognosis and portends a high risk of developing end-stage renal disease. While in first-line treatment, steroid treatment remains the recommended standard with an overall remission rate of 50% and higher, optimal treatment strategies for steroid-dependent/multirelapsing (SD/MR) and SR patients have to be defined. In both entities, calcineurin inhibitors showed good efficacy, while mycophenolate mofetil was less effective in SR cases compared to those with SD/MR. The same was true for rituximab, a monoclonal antibody targeting B-cells. In resistant cases, addition of extracorporeal treatment options or treatment with alkylating agents may be considered. To shape the future for treatment of FSGS, international collaborations to conduct larger clinical trials are needed to identify potential novel efficacious immunosuppressive or immunomodulatory therapies.

Validation of Kinki Criteria, a Modified Substaging System, in Patients with Intermediate Stage Hepatocellular Carcinoma

2016 ◽  
Vol 34 (6) ◽  
pp. 671-678 ◽  
Author(s):  
Tadaaki Arizumi ◽  
Kazuomi Ueshima ◽  
Mina Iwanishi ◽  
Tomohiro Minami ◽  
Hirokazu Chishina ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Median Overall Survival ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Intermediate Stage ◽  
University Hospital ◽  
Survival Times ◽  
First Line ◽  
Hospital Patients

Background: The standard treatment option that is available for patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) is transarterial chemoembolization (TACE). However, the condition of the patients with BCLC stage B disease is heterogeneous showing different tumor statuses and Child-Pugh scores; treatment strategies other than TACE are frequently employed for the patients in this stage. Based on the subclassification system proposed by Bolondi et al. [Semin Liver Dis 2012;32:348-359], we developed the Kinki criteria focusing on a substaging for BCLC stage B disease, which is simpler and should be more suitable in actual clinical setting in Japan. In this study, we evaluated the performance of Kinki criteria. Summary: This study included 1,633 HCC patients who received first-line treatment at the Kindai University Hospital. Patients were classified into subgroups based on the Kinki criteria and the survival time was estimated for each group. There were 156 (33.3%) patients in subclass B1, 278 (59.3%) in B2, and 35 (7.4%) in B3. The median overall survival times and 95% CI for BCLC B subclasses B1, B2, and B3 were 4.3 years (3.7-4.9), 2.9 years (2.2-3.4), and 1.1 years (0.5-1.8), respectively (p < 0.001). Key Messages: Classification of HCC patients in BCLC stage B based on the Kinki criteria showed statistically significant differences in survival, indicating the performance of Kinki criteria, which takes Child-Pugh score and tumor status into account for determining treatment options for HCC in BCLC stage B.

scholarly journals Relapsed Mantle Cell Lymphoma: Current Management, Recent Progress, and Future Directions

2021 ◽  
Vol 10 (6) ◽  
pp. 1207
Author(s):  
David A Bond ◽  
Peter Martin ◽  
Kami J Maddocks
Keyword(s):  
Mantle Cell Lymphoma ◽  
Kinase Inhibitors ◽  
Cell Lymphoma ◽  
Treatment Options ◽  
Single Agent ◽  
Treatment Strategies ◽  
Future Directions ◽  
Car T ◽  
Mantle Cell ◽  
Relapsed Disease

The increasing number of approved therapies for relapsed mantle cell lymphoma (MCL) provides patients effective treatment options, with increasing complexity in prioritization and sequencing of these therapies. Chemo-immunotherapy remains widely used as frontline MCL treatment with multiple targeted therapies available for relapsed disease. The Bruton’s tyrosine kinase inhibitors (BTKi) ibrutinib, acalabrutinib, and zanubrutinib achieve objective responses in the majority of patients as single agent therapy for relapsed MCL, but differ with regard to toxicity profile and dosing schedule. Lenalidomide and bortezomib are likewise approved for relapsed MCL and are active as monotherapy or in combination with other agents. Venetoclax has been used off-label for the treatment of relapsed and refractory MCL, however data are lacking regarding the efficacy of this approach particularly following BTKi treatment. Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies have emerged as highly effective therapy for relapsed MCL, with the CAR-T treatment brexucabtagene autoleucel now approved for relapsed MCL. In this review the authors summarize evidence to date for currently approved MCL treatments for relapsed disease including sequencing of therapies, and discuss future directions including combination treatment strategies and new therapies under investigation.

scholarly journals Immunotherapy in Hepatocellular Carcinoma

2021 ◽  
Vol 22 (10) ◽  
Author(s):  
Claudia A. M. Fulgenzi ◽  
Thomas Talbot ◽  
Sam M. Murray ◽  
Marianna Silletta ◽  
Bruno Vincenzi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Cytotoxic T Lymphocyte ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Intermediate Stage ◽  
Routine Practice ◽  
Advanced Hcc

Opinion statementPatients with hepatocellular carcinoma (HCC) have been traditionally deprived from highly effective systemic therapy options in the past decades. The multi-targeted tyrosine kinase inhibitor sorafenib, approved in 2008, remained the only treatment option for advanced HCC for over a decade. A number of molecularly targeted therapies such as lenvatinib, regorafenib, cabozantinib, and ramucirumab have significantly widened treatment options in patients with advanced HCC. However, emergence of resistance and long-term toxicity from treatment are barriers to long-term survivorship. Immunotherapy is at the focus of intense research efforts in HCC. Whilst targeting of programmed cell death 1 (PD-1) and cytotoxic T lymphocyte 4 (CTLA-4) is associated with radiologically measurable disease-modulating effects in HCC, monotherapies fell short of demonstrating evidence of significant survival extension in advanced disease. Atezolizumab and bevacizumab were the first immunotherapy regimen to demonstrate clear superiority in improving the survival of patients with unresectable HCC compared to sorafenib, paving the way for immunotherapy combinations. As the treatment landscape of HCC rapidly evolves, with immunotherapy integrating within early- and intermediate-stage disease treatment algorithms, lack of level 1 evidence on sequencing of therapeutic strategies and lack of head-to-head comparisons across immunotherapy combinations will affect prescribing of immunotherapy in routine practice. In the absence of predictive biomarkers, choice of immunotherapy over kinase inhibitors will continue to remain an empirical exercise, guided by balancing anti-tumour efficacy with toxicity considerations in the individual patient.

scholarly journals TMOD-25. GLIOBLASTOMA ORGANOIDS: A MODEL SYSTEM FOR PATIENT-SPECIFIC THERAPEUTIC TESTING

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi268-vi268
Author(s):  
Ryan Salinas ◽  
Daniel Zhang ◽  
Fadi Jacob ◽  
Phuong Nguyen ◽  
Saad Sheikh ◽  
...  
Keyword(s):  
Treatment Options ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Patient Specific ◽  
Molecular Heterogeneity ◽  
Ras Signaling ◽  
Sequencing Data ◽  
Mtor Inhibition ◽  
Primary Tumors ◽  
Egfr Inhibition

Abstract Glioblastoma treatment options remain limited due to its aggressive and invasive nature. It is increasingly appreciated that molecular heterogeneity between tumors and within tumors likely contributes to the lack of therapeutic advances. To maintain the inherent heterogeneity of glioblastoma, we employed a novel method to rapidly culture glioblastoma organoids (GBOs) directly from neurosurgical resection. GBOs are routinely generated around two weeks following initial resection. Comprehensive histologic and sequencing analyses demonstrated similarity to primary tumors. Leveraging clinical molecular and sequencing data, selected GBOs were treated with radiation/temozolamide and targeted inhibitor therapies. The effect on proliferation was measured by the percentage of KI67+ cells and gene set enrichment (GSEA) analysis was performed to compare the pre-treated expression signature amongst responsive and non-responsive tumors. Treatment of organoids with radiation/temozolamide led to a decrease in the percentage of KI67+ cells in four of eight patient-derived organoid lines with some evidence of correlative radiographic response Gene sets associated with radiation response and TNF signaling were enriched in radiation/temozolamide sensitive GBOs. GBO response to EGFR inhibition via gefitinib treatment was specific to EGFR altered tumors, whose expression also enriched for EGF signaling pathway expression. Two GBOs had downstream NF1 mutations that responded to the MEK inhibitor trametinib. On GSEA, gene expression of NF1 mutated GBOs enriched for RAS signaling. One GBO line was found to have a PI3K mutation and responded dramatically to mTOR inhibition via everolimus. Dichotomous efficacy of MEK and mTOR inhibition was also noted by tumor-specific changes in GBO diameter following treatment. This novel culturing method of GBOs maintains intertumoral and intratumoral heterogeneity and allows for therapeutic testing within two weeks of neurosurgical resection. As clinical sequencing because increasingly prevalent, GBOs may become a valuable tool to functionally test mutation-specific treatment strategies in a patient-specific manner within a clinically relevant time frame.

scholarly journals Karonudib is a promising anticancer therapy in hepatocellular carcinoma

2019 ◽  
Vol 11 ◽  
pp. 175883591986696 ◽  
Author(s):  
Xiangwei Hua ◽  
Kumar Sanjiv ◽  
Helge Gad ◽  
Therese Pham ◽  
Camilla Gokturk ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Protein Level ◽  
Kinase Inhibitors ◽  
Viral Infections ◽  
Treatment Options ◽  
In Vivo Models ◽  
Polymerase Chain

Background: Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is generally caused by viral infections or consumption of mutagens, such as alcohol. While liver transplantation and hepatectomy is curative for some patients, many relapse into disease with few treatment options such as tyrosine kinase inhibitors, for example, sorafenib or lenvatinib. The need for novel systemic treatment approaches is urgent. Methods: MTH1 expression profile was first analyzed in a HCC database and MTH1 mRNA/protein level was determined in resected HCC and paired paracancerous tissues with polymerase chain reaction (PCR) and immunohistochemistry. HCC cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA. 8-oxoG was measured by the modified comet assay. The effect of MTH1 inhibition on tumor growth was explored in HCC xenograft in vivo models. Results: MTH1 protein level is elevated in HCC tissue compared with paracancerous liver tissue and indicates poor prognosis. The MTH1 inhibitor Karonudib (TH1579) and siRNA effectively introduce toxic oxidized nucleotides into DNA, 8-oxoG, and kill HCC cell lines in vitro. Furthermore, we demonstrate that HCC growth in a xenograft mouse model in vivo is efficiently suppressed by Karonudib. Conclusion: Altogether, these data suggest HCC relies on MTH1 for survival, which can be targeted and may open up a novel treatment option for HCC in the future.

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