scholarly journals Multi-Analyte Liquid Biopsies for Treatment Guidance in Advanced Refractory Cancers: Findings of the LIQUID IMPACT Trial

2020 ◽  
Author(s):  
Rajnish Nagarkar ◽  
Darshana Patil ◽  
Timothy Crook ◽  
Vineet Datta ◽  
Shirsendu Roy ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Liquid Biopsy ◽  
Objective Response ◽  
Response To Treatment ◽  
Solid Organ ◽  
Liquid Biopsies ◽  
Clinical Trial Registry ◽  
Open Label ◽  
Non Invasive ◽  
Liquid Impact

Abstract Background LIQUID IMPACT (CTRI/2019/02/017548) is a single arm, open label, phase II/III study to evaluate the feasibility of providing therapeutic guidance in cancers based on non-invasive interrogation of circulating tumor analytes in peripheral blood (Encyclopedic Liquid Biopsy: eLB). The study enrolled patients with solid organ cancers where the disease had progressed following systemic therapy failure, where no (further) viable standard of care (SoC) therapy options were available, and where invasive biopsies to obtain tumor tissue (for molecular profiling) were contraindicated. Methods Encyclopedic Liquid Biopsy (eLB) interrogated gene alterations in cell-free tumor DNA (ctDNA), and differentially expressed genes in exosomal mRNA. eLB also evaluated Circulating Tumor Associated Cells for expression of therapeutically relevant cell-surface signaling receptors as well as the chemoresistance profile towards systemic anticancer agents. Patients who received personalized combination therapy regimens based on eLB findings were evaluated radiologically to determine response to treatment, Objective Response Rate (ORR) and Quality of Life (QoL). Results At the time of submission of this manuscript, Partial Response (PR) was observed in 14 of 43 patients evaluable per protocol (ORR = 32.6%). Majority of patients reported stable to improved QoL. Conclusion The present study demonstrated that refractory cancers have latent vulnerabilities which can be identified via non-invasive eLB to design personalized label- and organ-agnostic treatment regimens to yield meaningful treatment benefit. Trial registration Clinical Trial Registry – India, CTRI/2019/02/017548 [Registered on: 02/08/2019] - http://ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=31265&EncHid=&modid=&compid=%27,%2731265det%27; Trial Registered Prospectively.

Multi-analyte liquid biopsies based treatment in advanced refractory cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15623-e15623
Author(s):  
Sewanti Limaye ◽  
Darshana Patil ◽  
Dadasaheb B Akolkar ◽  
Timothy Crook ◽  
Anantbhushan Ranade ◽  
...  
Keyword(s):  
Treatment Response ◽  
Liquid Biopsy ◽  
Tumor Tissue ◽  
Single Gene ◽  
Objective Response ◽  
Specific Treatment ◽  
Patient Specific ◽  
Solid Organ ◽  
Liquid Biopsies ◽  
Blood Draw

e15623 Background: Tumor tissue profiling following invasive biopsies is presently the standard approach for indication-based therapy management in solid organ cancers. However, challenges in biopsy are traditionally described due to proximity to vital organs, or patients’ co-morbidities or unwillingness for an invasive procedure. Liquid biopsies for evaluation of cancers are also largely restricted to single gene testing for selection of targeted therapy agents. We developed a comprehensive liquid biopsy based multi-analyte (molecular and functional) investigation of the cancer (eLBx: Encyclopedic Liquid Biopsy) for selection and management of individualised treatments in a cohort of advanced refractory cancers. Methods: We obtained 20 mL blood from 65 patients with solid organ cancers where the disease had progressed following failure of at least two lines of systemic therapies and where biopsy to obtain tumor tissue for molecular profiling of tumor was unviable. Cell free tumor DNA (ctDNA) was interrogated for mutations, while exosomal mRNA was profiled for gene expression. Viable circulating tumor associated cells (C-TACs) were tested in vitro for chemoresistance and used to determine expression of cell surface signalling receptors by immunocytochemistry (ICC). The findings were integrated to generate patient-specific treatment regimens. In patients who received treatment, response was determined radiologically. Results: Fifty-one patients received eLBx-guided personalized treatments with combinations of cytotoxic, targeted and endocrine agents. No two patients received the same treatment regimen. Forty-three patients were evaluable for treatment response per protocol among whom Partial Response (PR) was observed in 14 patients yielding an Objective Response Rate (ORR) of 32.6%. Additionally, 23 patients showed Stable Disease thus yielding an overall Disease Control rate of 86.1%. Median Progression Free Survival (PFS) was 108 days. There were no Grade IV therapy related Adverse Events or therapy related deaths. Conclusions: The ability to make informed treatment choices from a convenient blood draw implies a reduced dependence on invasive biopsies for disease management. We demonstrate successful management of advanced refractory solid tumor malignancies using an integrational non-invasive multi-analyte liquid biopsy approach. Clinical trial information: CTRI/2019/02/017548.

Liquid biopsies to enable non-invasive real-time functional chemoresistance profiling in solid organ cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3525-3525
Author(s):  
Dadasaheb B Akolkar ◽  
Timothy Crook ◽  
Raymond Page ◽  
Darshana Patil ◽  
Sewanti Limaye ◽  
...  
Keyword(s):  
Real Time ◽  
Anticancer Agents ◽  
Tumor Tissue ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Treatment Strategies ◽  
Solid Organ ◽  
Liquid Biopsies ◽  
Non Invasive ◽  
Pretreated Patients

3525 Background: Despite the development of targeted therapy agents and immune checkpoint inhibitors (ICI), cytotoxic anticancer agents remain the mainstay of treatment in several solid organ cancers. However, instances of innate and acquired resistance towards these anticancer agents can lead to treatment failures, which remain undetectable until clinical or radiological manifestation of symptoms suggestive of disease progression. There are presently no viable means or markers to detect or monitor for chemoresistance in real time. Owing to this unmet need, cancer treatment strategies face risks of failure and poor outcomes. Methods: We obtained 15 mL blood from 3,662 patients with various solid organ cancers, of various states and including treatment-naïve and pretreated patients. Circulating Tumor Associated Cells (C-TACs) were enriched and harvested from PBMCs using an epigenetically activating medium that is cytotoxic towards non-malignant epithelial and hematolymphoid cells in blood, but confers survival benefit on apoptosis resistant cells of tumorigenic origin (Circulating Tumor Associated Cells, C-TACs). In a subset of patients, fresh tumor tissue was also obtained from which viable tumor derived cells (TDCs) were obtained. Viable TDCs and C-TACs were treated with a panel of anticancer agents and the surviving cell fraction estimated to determine chemoresistance. Results: Among the 1,325 therapy naïve patients, resistance towards treatment agents was observed in C-TACs from 56.3 % of samples. Among 2,201 pretreated patients’ samples, resistance towards treatment agents was observed in C-TACs from 77.8% of samples. The increased resistance in C-TACs from pretreated patients indicated that the C-TACs had been resistance-educated by prior therapies. In a subset of patients, Chemoresistance profile of C-TACs was observed to be 96.9% concordant with that of tumor derived cells (TDCs) which were concurrently obtained from tumor tissue indicating that C-TACs accurately represent chemo-antecedents of the tumor. Conclusions: Non-invasive chemoresistance profiling of C-TACs is a viable strategy to monitor treatment efficacy in real time. Adoption of this strategy in the clinic will not only guide treatment selection with reduced risk of failure, but will also enable timely therapeutic course correction upon detection of acquired chemoresistance.

Efficacy of gefitinib combined with bevacizumab versus gefitinib in advanced EGFR L858R NSCLC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21185-e21185
Author(s):  
Xinmin Zhao ◽  
Xianghua Wu ◽  
Huijie Wang ◽  
Hui Yu ◽  
Si Sun ◽  
...  
Keyword(s):  
Liquid Biopsy ◽  
Therapeutic Option ◽  
Objective Response ◽  
Acquired Resistance ◽  
Response To Treatment ◽  
Control Group ◽  
Special Cases ◽  
Significant Difference ◽  
Experimental Group ◽  
Egfr Tkis

e21185 Background: 60-80% of EGFR+ NSCLC could benefit from the treatment of EGFR TKIs. However, as a result of acquired resistance, median progression-free survival (PFS) associated with EGFR-TKIs monotherapy was rarely longer than 11 months. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play an important role in the angiogenesis and progression of NSCLC. The combination of EGFR-TKIs and anti-vascular drugs that inhibit the EGFR and VEGF/VEGFR pathways may be a potential therapeutic option for EGFR-mutant NSCLC. The purpose of our study was to evaluate whether gefitinib combined with bevacizumab is associated with an increased PFS benefit compared with gefitinib alone. Methods: This study is a randomized, open-controlled, single-center study. A total of 43 advanced non-squamous NSCLC patients with EGFR L858R mutations were enrolled, including 24 in the experimental group and 19 in the control group. The experimental group received gefitinib combined with bevacizumab (gefitinib 250 mg, QD+bevacizumab 7.5 mg/kg, Q3W), and the control group received gefitinib monotherapy (250 mg, QD). Response to treatment was evaluated after one month of the treatment, followed by once every two months, and adverse events were graded. The primary endpoint was PFS, and secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety and tolerability evaluation. Samples at baseline (tissue or liquid biopsy), 43 days after treatment (liquid biopsy), and disease progression were subjected to genomic (139-gene NGS panel) profiling. Results: As of December 31, 2020, 22 patients were evaluable (12 for experimental group, 10 for control group). The ORR of the experimental group and the control group were 42% vs 60%, respectively, with no significant difference (experimental group: CR = 0, PR = 5, SD = 7, PD = 0; control group: CR = 0, PR = 6, SD = 4, PD = 0). Main adverse reactions included skin rash (n = 16), diarrhea (n = 24), hypertension (n = 2), proteinuria (n = 1). Other special cases developed fever, nausea and vomiting, elevated platelets, conjunctivitis, back pain, which were manageable. 36 patients with baseline liquid biopsy samples can be evaluated (33 plasma and 3 pleural fluid samples). Of these, EGFR L858R were detectable in 86% (n = 31) of patients. The most common co-mutated gene was TP53 (57%), followed by DNMT3A (49%) and TET2 (17%). Mutation profiles were comparable between the two groups. Conclusions: Compared to gefitinib monotherapy, gefitinib combined with bevacizumab in the treatment of non-squamous NSCLC with EGFR L858R showed similar efficacy and safety profiles.

scholarly journals The Translational Status of Cancer Liquid Biopsies

2019 ◽  
Author(s):  
Sinisa Bratulic ◽  
Francesco Gatto ◽  
Jens Nielsen
Keyword(s):  
Treatment Outcomes ◽  
Liquid Biopsy ◽  
Tumor Tissue ◽  
Body Fluids ◽  
Precision Oncology ◽  
Liquid Biopsies ◽  
Non Invasive ◽  
Biomarker Research ◽  
Successes And Challenges

Abstract Precision oncology aims to tailor clinical decisions specifically to patients with the objective of improving treatment outcomes. This can be achieved by leveraging omics information for accurate molecular characterization of tumors. Tumor tissue biopsies are currently the main source of information for molecular profiling. However, biopsies are invasive and limited in resolving spatiotemporal heterogeneity in tumor tissues. Alternative non-invasive liquid biopsies can exploit patient’s body fluids to access multiple layers of tumor-specific biological information (genomes, epigenomes, transcriptomes, proteomes, metabolomes, circulating tumor cells, and exosomes). Analysis and integration of these large and diverse datasets using statistical and machine learning approaches can yield important insights into tumor biology and lead to discovery of new diagnostic, predictive, and prognostic biomarkers. Translation of these new diagnostic tools into standard clinical practice could transform oncology, as demonstrated by a number of liquid biopsy assays already entering clinical use. In this review, we highlight successes and challenges facing the rapidly evolving field of cancer biomarker research. Lay Summary Precision oncology aims to tailor clinical decisions specifically to patients with the objective of improving treatment outcomes. The discovery of biomarkers for precision oncology has been accelerated by high-throughput experimental and computational methods, which can inform fine-grained characterization of tumors for clinical decision-making. Moreover, advances in the liquid biopsy field allow non-invasive sampling of patient’s body fluids with the aim of analyzing circulating biomarkers, obviating the need for invasive tumor tissue biopsies. In this review, we highlight successes and challenges facing the rapidly evolving field of liquid biopsy cancer biomarker research.

A single-arm, open-label, multicenter phase I/II study of the combination of panobinostat (pan) and carfilzomib (cfz) in patients (pts) with relapsed/refractory multiple myeloma (RR MM).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS8115-TPS8115
Author(s):  
Jesus G. Berdeja ◽  
Joseph Mace ◽  
Ruth E. Lamar ◽  
Victor Gian ◽  
Patrick Brian Murphy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Histone Deacetylase Inhibitors ◽  
Standard Dose ◽  
Objective Response ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Current Status ◽  
Open Label ◽  
Starting Dose

TPS8115 Background: Despite novel therapies, MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM. Preclinical studies demonstrate synergistic anti-MM activity with histone deacetylase inhibitors (HDACi) and proteasome inhibitors (PI) through the dual inhibition of the proteasome and aggresome pathways. Pan is an oral pan-HDACi which has shown synergy with bortezomib in clinical studies. Cfz is a 2nd generation PI which has shown marked anti-MM activity with an improved safety profile. In this trial we evaluate the safety and efficacy of the combination of pan and cfz in pts with RR MM. Methods: This multi-center US study plans to enroll up to 52 adults with RR MM. The phase I study will determine the MTD of the combination of cfz and pan and follow a standard dose escalation design. Pan will be administered orally three times weekly during weeks 1 and 3 of each 28-day cycle (Days 1, 3, 5, 15, 17, 19) at a starting dose of 20 mg. Cfz will be administered intravenously on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cfz starting dose will be 20mg on days 1,2 of cycle 1 with escalation to the corresponding dose level beginning at 27 mg , if well tolerated. Dose modifications will not be permitted during cycle 1 unless a pt experiences a DLT. A maximum of four dose levels will be evaluated. Approximately 24 pts will be enrolled during the phase I portion to establish the MTD. In the phase II portion of this study, pts with RR MM will receive treatment with the optimal dose of pan and cfz established during phase I. Pts will be assessed for response to treatment after each cycle (4 weeks). Pts with objective response or stable disease will continue treatment until disease progression or unacceptable toxicity occurs. The primary endpoint is to establish the optimal doses of cfz and pan that can be administered to pts with RR MM (phase I) and to evaluate the overall response rate (phase II). Secondary endpoints include time-to-progression, progression-free survival, overall survival and safety. Approximately 25 pts are planned for the phase II portion. Current status: As of 1/27/12 3 patients have been enrolled.

scholarly journals Angiogenesis Inhibitors in Personalized Combination Regimens for the Treatment of Advanced Refractory Cancers

2021 ◽  
Author(s):  
Timothy Crook ◽  
Darshana Patil ◽  
Rajnish Nagarkar ◽  
Andrew Gaya ◽  
Nicholas Plowman ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Objective Response ◽  
Progression Free Survival ◽  
Angiogenesis Inhibitors ◽  
Cytotoxic Agents ◽  
Patient Specific ◽  
Solid Organ ◽  
Specific Combination ◽  
Anticancer Treatment ◽  
Combination Regimens

Abstract Background Angiogenic factors are commonly activated in solid tumors and present a viable therapeutic target. However, anticancer treatment with angiogenesis inhibitors (AGI) is limited to a few cancers, mostly as monotherapy and not selected based on molecular indications. We aimed to determine whether patient-specific combination regimens with AGI and other anticancer agents when selected based on multi-analyte tumor interrogation (ETA: Encyclopedic Tumor Analysis) can expand the scope of AGIs in advanced refractory solid organ cancers with improved treatment responses. Methods We evaluated treatment outcomes in 60 patients with advanced, refractory solid organ cancers who received ETA-guided combination regimens of AGI with other targeted, endocrine or cytotoxic agents. Radiological evaluation of treatment response was followed by determination of Objective Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Results Among the 60 patients, Partial Response (PR) was observed in 28 cases (46.7%), Stable Disease (SD) was observed in 29 cases (48.3%) and Disease Progression (PD, within 60 days) was observed in 3 cases (5.0%). The ORR was 46.7% and DCR was 95.0%. At the most recent follow, up the median PFS (mPFS) was 5.0 months and median OS (mOS) was 8.9 months. There were no Grade 4 therapy related adverse events or treatment related deaths. Conclusions ETA-guided patient-specific combination regimens with AGI and other anti-neoplastic agents, can yield improved outcomes over AGI monotherapy. Trial Registration Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011808. LIQUID IMPACT ID CTRI/2019/02/017548.

Cell-free DNA and RNA - measurement and applications in clinical diagnostics with focus on metabolic disorders

2020 ◽  
Author(s):  
Markus Hodal Drag ◽  
Tuomas Oskari Kilpeläinen
Keyword(s):  
Metabolic Disorders ◽  
Solid Organ Transplantation ◽  
Prenatal Testing ◽  
Clinical Diagnostics ◽  
Solid Organ ◽  
Liquid Biopsies ◽  
Cell Free Dna ◽  
Alcoholic Fatty Liver ◽  
Non Invasive ◽  
Free Dna

Circulating cell-free DNA (cfDNA) and RNA (cfRNA) hold enormous potential as a new class of biomarkers for the development of non-invasive liquid biopsies in many diseases and conditions. In recent years, cfDNA and cfRNA have been studied intensely as tools for non-invasive prenatal testing, solid organ transplantation, cancer screening, and monitoring of tumors. In obesity, higher cfDNA concentration indicates accelerated cellular turnover of adipocytes during expansion of adipose mass and may be directly involved in the development of adipose tissue insulin resistance by inducing inflammation. Furthermore, cfDNA and cfRNA have promising diagnostic value in a range of obesity-related metabolic disorders, such as non-alcoholic fatty liver disease, type 2 diabetes, and diabetic complications. Here, we review the current and future applications of cfDNA and cfRNA within clinical diagnostics, discuss technical and analytical challenges in the field, and summarise the opportunities of using cfDNA and cfRNA in the diagnostics and prognostics of obesity-related metabolic disorders.

Total microfluidic platform strategy for liquid biopsy

2020 ◽  
pp. 1-25
Author(s):  
Sehyun Shin
Keyword(s):  
Liquid Biopsy ◽  
Residual Disease ◽  
Future Research ◽  
Microfluidic Platforms ◽  
Liquid Biopsies ◽  
Related Area ◽  
Detailed Review ◽  
Non Invasive ◽  
Clinical Benefits ◽  
Minimal Residual

A liquid biopsy is a simple and non-invasive biopsy that examines a range of information about a tumor through a simple blood sample. Due to its non-invasive nature, liquid biopsy has many outstanding clinical benefits, including repetitive sampling and examination, representation of whole mutations, observation of minimal residual disease etc. However, liquid biopsy requires various processes such as sample preparation, amplification, and target detection. These processes can be integrated onto microfluidic platforms, which may provide a sample-to-answer system. The present review provides a brief overview of liquid biopsies, a detailed review of the technologies in each process, and prospective concluding remarks. Through this review, one can have a basic but cross-disciplinary understanding of liquid biopsy, as well as knowledge of new starting points for future research in each related area.

scholarly journals Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as a Liquid Biopsy Marker in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4500
Author(s):  
Isabel Heidrich ◽  
Thaer S. A. Abdalla ◽  
Matthias Reeh ◽  
Klaus Pantel
Keyword(s):  
Colorectal Cancer ◽  
Disease Progression ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Liquid Biopsy ◽  
Personalized Therapy ◽  
Liquid Biopsies ◽  
Curative Surgery ◽  
Non Invasive ◽  
Staging Systems

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. It is a heterogeneous tumor with a wide genomic instability, leading to tumor recurrence, distant metastasis, and therapy resistance. Therefore, adjunct non-invasive tools are urgently needed to help the current classical staging systems for more accurate prognostication and guiding personalized therapy. In recent decades, there has been an increasing interest in the diagnostic, prognostic, and predictive value of circulating cancer-derived material in CRC. Liquid biopsies provide direct non-invasive access to tumor material, which is shed into the circulation; this enables the analysis of circulating tumor cells (CTC) and genomic components such as circulating free DNA (cfDNA), which could provide the key for personalized therapy. Liquid biopsy (LB) allows for the identification of patients with a high risk for disease progression after curative surgery, as well as longitudinal monitoring for disease progression and therapy response. Here, we will review the most recent studies on CRC, demonstrating the clinical potential and utility of CTCs and ctDNA. We will discuss some of the advantages and limitations of LBs and the future perspectives in the field of CRC management.

scholarly journals Epigenetic Biomarkers of Renal Cell Carcinoma for Liquid Biopsy Tests

2021 ◽  
Vol 22 (16) ◽  
pp. 8846
Author(s):  
Raimonda Kubiliute ◽  
Sonata Jarmalaite
Keyword(s):  
Dna Methylation ◽  
Liquid Biopsy ◽  
Renal Cell ◽  
Morphological Changes ◽  
Diagnostic Tools ◽  
Liquid Biopsies ◽  
Non Invasive ◽  
Epigenetic Biomarkers ◽  
Treatment Changes

Renal cell carcinomas (RCC) account for 2–3% of the global cancer burden and are characterized by the highest mortality rate among all genitourinary cancers. However, excluding conventional imagining approaches, there are no reliable diagnostic and prognostic tools available for clinical use at present. Liquid biopsies, such as urine, serum, and plasma, contain a significant amount of tumor-derived nucleic acids, which may serve as non-invasive biomarkers that are particularly useful for early cancer detection, follow-up, and personalization of treatment. Changes in epigenetic phenomena, such as DNA methylation level, expression of microRNAs (miRNAs), and long noncoding RNAs (lncRNAs), are observed early during cancer development and are easily detectable in biofluids when morphological changes are still undetermined by conventional diagnostic tools. Here, we reviewed recent advances made in the development of liquid biopsy-derived DNA methylation-, miRNAs- and lncRNAs-based biomarkers for RCC, with an emphasis on the performance characteristics. In the last two decades, a mass of circulating epigenetic biomarkers of RCC were suggested, however, most of the studies done thus far analyzed biomarkers selected from the literature, used relatively miniature, local, and heterogeneous cohorts, and suffered from a lack of sufficient validations. In summary, for improved translation into the clinical setting, there is considerable demand for the validation of the existing pool of RCC biomarkers and the discovery of novel ones with better performance and clinical utility.

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