Präzisionsonkologie und molekulare Tumorboards – Konzepte, Chancen und Herausforderungen

2017 ◽  
Vol 142 (22) ◽  
pp. 1676-1684 ◽  
Author(s):  
Julian Holch ◽  
Christoph Westphalen ◽  
Wolfgang Hiddemann ◽  
Volker Heinemann ◽  
Andreas Jung ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Genetic Analysis ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Tumor Board ◽  
Precision Oncology ◽  
Current Standard ◽  
Recent Developments ◽  
Tumor Types ◽  
New Strategies

AbstractRecent developments in genomics allow a more and more comprehensive genetic analysis of human malignancies, and have sparked hopes that this will contribute to the development of novel targeted, effective and well-tolerated therapies.While targeted therapies have improved the prognosis of many cancer patients with certain tumor types, “precision oncology” also brings along new challenges. Highly personalized treatment strategies require new strategies for clinical trials and translation into routine clinical practice. We review the current technical approaches for “universal genetic testing” in cancer, and potential pitfalls in the interpretation of such data. We then provide an overview of the available evidence supporting treatment strategies based on extended genetic analysis. Based on the available data, we conclude that “precision oncology” approaches that go beyond the current standard of care should be pursued within the framework of an interdisciplinary “molecular tumor board”, and preferably within clinical trials.

scholarly journals Individualized Molecular Profiling for Allocation to Clinical Trials Singapore Study—An Asian Tertiary Cancer Center Experience

2021 ◽  
pp. 859-875
Author(s):  
Amanda O. L. Seet ◽  
Aaron C. Tan ◽  
Tira J. Tan ◽  
Matthew C. H. Ng ◽  
David W. M. Tai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Tumor Tissue ◽  
Molecular Profiling ◽  
Tumor Board ◽  
Cancer Center ◽  
Precision Oncology ◽  
Molecular Tumor Board ◽  
Tumor Types ◽  
Tertiary Cancer Center

PURPOSE Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center. PATIENTS AND METHODS Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the Individualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made. RESULTS One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors. CONCLUSION Individualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology.

scholarly journals Updated Insights on EGFR Signaling Pathways in Glioma

2021 ◽  
Vol 22 (2) ◽  
pp. 587
Author(s):  
Alexandru Oprita ◽  
Stefania-Carina Baloi ◽  
Georgiana-Adeline Staicu ◽  
Oana Alexandru ◽  
Daniela Elise Tache ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Egfr Signaling ◽  
Current Standard ◽  
Egfr Amplification ◽  
Epidermal Growth ◽  
New Diagnosis ◽  
Clear Clinical Benefit

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood–brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.

scholarly journals Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma

2021 ◽  
Vol 14 (1) ◽  
pp. 51
Author(s):  
Brinda Balasubramanian ◽  
Simran Venkatraman ◽  
Kyaw Zwar Myint ◽  
Tavan Janvilisri ◽  
Kanokpan Wongprasert ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Drug Development ◽  
Surgical Resection ◽  
Treatment Options ◽  
Standard Of Care ◽  
Time Data ◽  
Current Standard ◽  
Innovative Drug ◽  
Curative Intent

Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA.

scholarly journals Towards Personalization in the Curative Treatment of Gastric Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Astrid E. Slagter ◽  
Marieke A. Vollebergh ◽  
Edwin P. M. Jansen ◽  
Johanna W. van Sandick ◽  
Annemieke Cats ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Molecular Characteristics ◽  
Perioperative Chemotherapy ◽  
Current Standard ◽  
Common Cancer ◽  
Resectable Gastric Cancer

Gastric cancer is the fifth most common cancer worldwide and has a high mortality rate. In the last decades, treatment strategy has shifted from an exclusive surgical approach to a multidisciplinary strategy. Treatment options for patients with resectable gastric cancer as recommended by different worldwide guidelines, include perioperative chemotherapy, pre- or postoperative chemoradiotherapy and postoperative chemotherapy. Although gastric cancer is a heterogeneous disease with respect to patient-, tumor-, and molecular characteristics, the current standard of care is still according to a one-size-fits-all approach. In this review, we discuss the background of the different treatment strategies in resectable gastric cancer including the current standard, the specific role of radiotherapy, and describe the current areas of research and potential strategies for personalization of therapy.

scholarly journals CURATE.AI: Optimizing Personalized Medicine with Artificial Intelligence

2019 ◽  
Vol 25 (2) ◽  
pp. 95-105
Author(s):  
Agata Blasiak ◽  
Jeffrey Khong ◽  
Theodore Kee
Keyword(s):  
Clinical Trials ◽  
Personalized Medicine ◽  
Standard Of Care ◽  
Small Data ◽  
Current Standard ◽  
Dose Selection ◽  
Support Tool ◽  
Combination Treatments ◽  
Multiple Challenges ◽  
Over Time

The clinical team attending to a patient upon a diagnosis is faced with two main questions: what treatment, and at what dose? Clinical trials’ results provide the basis for guidance and support for official protocols that clinicians use to base their decisions upon. However, individuals rarely demonstrate the reported response from relevant clinical trials, often the average from a group representing a population or subpopulation. The decision complexity increases with combination treatments where drugs administered together can interact with each other, which is often the case. Additionally, the individual’s response to the treatment varies over time with the changes in his or her condition, whether via the indication or physiology. In practice, the drug and the dose selection depend greatly on the medical protocol of the healthcare provider and the medical team’s experience. As such, the results are inherently varied and often suboptimal. Big data approaches have emerged as an excellent decision-making support tool, but their application is limited by multiple challenges, the main one being the availability of sufficiently big datasets with good quality, representative information. An alternative approach—phenotypic personalized medicine (PPM)—finds an appropriate drug combination (quadratic phenotypic optimization platform [QPOP]) and an appropriate dosing strategy over time (CURATE.AI) based on small data collected exclusively from the treated individual. PPM-based approaches have demonstrated superior results over the current standard of care. The side effects are limited while the desired output is maximized, which directly translates into improving the length and quality of individuals’ lives.

scholarly journals Comparison of Treatment Recommendations by Molecular Tumor Boards Worldwide

2018 ◽  
pp. 1-14 ◽  
Author(s):  
Damian T. Rieke ◽  
Mario Lamping ◽  
Marissa Schuh ◽  
Christophe Le Tourneau ◽  
Neus Basté ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Treatment Recommendations ◽  
Tumor Board ◽  
Precision Oncology ◽  
Genomic Information ◽  
Specific Patient ◽  
Rational Decision Making ◽  
Copy Numbers ◽  
Tumor Boards ◽  
Molecular Profiles

Purpose Precision oncology holds the promise of improving patient outcome. It is based on the idea that the testing of genomic biomarkers can lead to the recommendation of a treatment option tailored to the specific patient. To derive treatment recommendations from molecular profiles, interdisciplinary molecular tumor boards (MTBs) have been established recently in many academic institutions. The recommendation process in MTBs, however, has not been well defined, which limits applicability to larger clinical trials and patient populations. Methods We created four fictional patients on the basis of recent real cases with genomic information on mutations, fusions, copy numbers, and gene expression. We identified 29 tumor boards from nine countries worldwide and asked them to provide treatment recommendations for the sample patients. In addition, a questionnaire regarding the setup and methods used by MTBs was circulated. Results Five MTBs from four countries provided treatment recommendations and answered the questionnaire. For one patient, three tumor board treatment recommendations were identical, and two tumor boards had identical treatment strategies for the other three patients. There was heterogeneity in the interpretation of tumor and germline aberrations as well as in standards of prioritization. Conclusion Differences in the interpretation and recommendation process contribute to heterogeneity in MTB recommendations. Additional comparative analyses of recommendations could help improve rational decision making and lead to standardization.

scholarly journals How I treat atypical chronic myeloid leukemia

Blood ◽  
2017 ◽  
Vol 129 (7) ◽  
pp. 838-845 ◽  
Author(s):  
Jason Gotlib
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasm ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
High Rate ◽  
Current Standard ◽  
Hematopoietic Stem ◽  
Genetic Features ◽  
Atypical Chronic Myeloid Leukemia

Abstract Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. The challenges of aCML relate to its heterogeneous clinical and genetic features, high rate of transformation to acute myeloid leukemia, and historically poor survival. Therefore, allogeneic hematopoietic stem cell transplantation should always be an initial consideration for eligible patients with a suitable donor. Nontransplant approaches for treating aCML have otherwise largely relied on adopting treatment strategies used for MDS and MPN. However, such therapies, including hypomethylating agents, are based on a paucity of data. With an eye toward making a more meaningful impact on response rates and modification of the natural history of the disease, progress will rely on enrollment of patients into clinical trials and molecular profiling of individuals so that opportunities for targeted therapy can be exploited.

Genomic testing to enhance treatment choices and clinical trial accrual in metastatic colorectal cancer: Results of a prospective cohort study.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 593-593
Author(s):  
Davendra Sohal ◽  
Brian I. Rini ◽  
Robert James Pelley ◽  
Bassam N. Estfan ◽  
Dale Randall Shepard ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Cohort Study ◽  
Prospective Cohort Study ◽  
Prospective Cohort ◽  
Cleveland Clinic ◽  
Tumor Board ◽  
Genomic Testing ◽  
Precision Oncology ◽  
Tumor Genome

593 Background: Tumor genome sequencing is being used widely in clinical settings but its value to individual patients has not been well-studied. A prospective cohort study of outpatient genomic testing to identify prevalence of actionable alterations and their impact on management decisions was conducted. Methods: Eligibility requirements included pathologic diagnosis of select solid tumor malignancies without a known curative option, age ≥18 years, and an ECOG PS of 0-2. Data for the colorectal cancer (CRC) subgroup are presented here. Tumor samples were sequenced for up to 315 candidate genes using FoundationOne (Cambridge, MA). Results were discussed at the Cleveland Clinic Genomics Tumor Board that made therapeutic recommendations to treating physicians. Results: From Aug 2013 to Aug 2014, samples from 45 patients with CRC were analyzed. Median age was 60 years; 23 (51%) were female; 38 (84%) were white. Median time from consent to result was 25 (range, 7-75) days. One (2%) sample had inadequate tissue. A median of 5 (range, 2-19) mutations were detected per sample; APC (89%), TP53 (73%) and KRAS (66%) were most common. A therapy targeting an actionable alteration was recommended in 22 (51%) patients; 88% of these recommendations were for clinical trials. To date, 6 (33%) of 18 patients who switched management after test results received genomics-driven therapies (Table). Previously unknown RAS (KRAS Q61H, NRAS) mutations were detected in an additional 3 patients, influencing EGFR antibody use decisions. The commonest reason for non-receipt of therapy based on the test result was non-availability of clinical trials. Conclusions: Routine tumor genome profiling in CRC patients is feasible and influenced treatment decisions in a third of patients. A genomics tumor board for the interpretation of rapidly evolving information, and improved access to clinical trials of targeted agents are critical to the success of precision oncology. [Table: see text]

scholarly journals Rapamycin microparticles induce autophagy, prevent senescence and are effective in treatment of Osteoarthritis

2021 ◽  
Author(s):  
Kaamini M Dhanabalan ◽  
Ameya A Dravid ◽  
Smriti Agarwal ◽  
Ramanath K Sharath ◽  
Ashok K Padmanabhan ◽  
...  
Keyword(s):  
Articular Chondrocytes ◽  
Symptomatic Relief ◽  
Cartilage Damage ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Cartilage Degeneration ◽  
Current Standard ◽  
Disease Modifying Drugs ◽  
Post Traumatic ◽  
Sulphated Glycosaminoglycans

Trauma to the knee joint is associated with significant cartilage degeneration and erosion of subchondral bone, which eventually leads to osteoarthritis (OA), resulting in substantial morbidity and healthcare burden. With no disease-modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelioration by autophagy upregulation, yet its clinical use is hindered by difficulties in achieving therapeutic concentrations, necessitating multiple weekly injections. Here, we have synthesized rapamycin - loaded poly (lactic-co-glycolic acid) microparticles (RMPs) that induced autophagy, prevented senescence and sustained sulphated glycosaminoglycans(sGAG) production in primary human articular chondrocytes from OA patients. RMPs were potent, nontoxic, and exhibited high retention time (up to 35 days) in mice joints. Intra-articular delivery of RMPs effectively mitigated cartilage damage and inflammation in surgery-induced OA when administered as a prophylactic or therapeutic regimen. Together, our studies demonstrate the feasibility of using RMPs as a potential clinically translatable therapy to prevent and treat post-traumatic osteoarthritis.

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