208 results on '"ctdna"'
Search Results
2. ctDNA-Response evaluation criteria in solid tumors – a new measure in medical oncology
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Anders K.M. Jakobsen and Karen-Lise G. Spindler
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Cancer Research ,RECIST ,Oncology ,ctDNA ,Metastatic solid tumours - Abstract
In the metastatic setting, most decisions during systemic palliative therapies are based on the imaging-based Response Evaluation Criteria in Solid Tumors (RECIST), which is, however, known to be a suboptimal surrogate marker for the clinical outcome overall survival. Over the past decade, research has brought focus to the potential of circulating tumour DNA in cancer. However, at present, there is no generally accepted classification of quantitative changes during the treatment course, and prospective investigations can therefore not be validated. We here propose, for the first time, a response classification based on circulating tumour DNA measurements and its confidence intervals, a “ctDNA-RECIST” that has proven valuable in retrospective studies and goes along with the conventional RECIST classification. We aim to raise the topic for discussion and to encourage analyses of ctDNA data along this line.
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- 2023
3. ctDNA as promising tool for the assessment of minimal residual disease (MRD) and the need of an adjuvant treatment in gastroesophageal adenocarcinoma
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Vittoria Matilde, Piva, Maria Caterina, De Grandis, Irene Sole, Zuin, Valentina, Angerilli, Floriana, Nappo, Rita, Alfieri, Selma, Ahcene Djaballah, Sabina, Murgioni, Francesca, Bergamo, Matteo, Fassan, Michele, Valmasoni, and Sara, Lonardi
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Esophageal cancer ,Gastric cancer ,Liquid biopsy ,Minimal residual disease ,ctDNA ,Surgery - Abstract
Gastroesophageal adenocarcinoma is a challenging disease due to its poor prognosis and the presence of few therapeutic options. For these reasons, it is mandatory to identify the subgroup of patients who are at high risk for relapse after curative-intention surgery. In the last years, liquid biopsy has aroused great interest in cancer treatment for its feasibility and the possibility to capture tumor heterogeneity in a real-time way. In postoperative setting, the interest is directed to the identification of Minimal Residual Disease (MRD), defined as isolated or small cluster of cancer cells that residues after curative-intention surgery, and are undetectable by conventional radiological and clinical exams. This review wants to summarize current evidence on the use of liquid biopsy in gastroesophageal cancer, focusing on the detection of ctDNA in the postoperative setting and its potential role as a guide for treatment decision.
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- 2022
4. Case Report: Potential role of selective venous sampling for liquid biopsy in complex clinical settings: Three case presentations
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Tichà V., Patelli G., Basso G., Prino A., Repetti E., Grugni M., Damascelli B., Tichà, V, Patelli, G, Basso, G, Prino, A, Repetti, E, Grugni, M, and Damascelli, B
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Liquid biopsy ,pancreatic cancer ,glioblastoma ,Genetics ,Molecular Medicine ,venous sampling ,ctDNA ,prostate cancer ,Genetics (clinical) - Abstract
Tumor mutation profiling from a blood sample, known as liquid biopsy, is a reality that has already been approved for some cancers. This molecular diagnostic method complements tissue biopsy but is less invasive and therefore more easily applied, especially during tumor evolution. Its use should allow detection of residual disease, evaluation of treatment response or resistance, and selection of targeted treatments. However, implementation of liquid biopsy in routine clinical practice is hindered by unsolved issues, one of which is the scarcity of circulating tumor DNA in blood samples drawn from peripheral veins. To address this problem, we propose minimally invasive selective venous sampling from the region of interest, as used for some hormonal studies and for mapping of endocrine tumors. Intuitively, selective sampling should improve the sensitivity of liquid biopsy by avoiding the dilution of tumor biomarkers that occurs in the peripheral circulation. We report three cases that illustrate the potential utility of selective liquid biopsy in complex clinical settings, providing implications for diagnosis and treatment as well as for monitoring over time, disease localization, identification of drug resistance, and differential diagnosis.
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- 2023
5. Pre- and Post-operative Circulating Tumoral DNA in Patients With Medullary Thyroid Carcinoma
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Raffaele Ciampi, Cristina Romei, Teresa Ramone, Antonio Matrone, Alessandro Prete, Carla Gambale, Gabriele Materazzi, Luigi De Napoli, Liborio Torregrossa, Fulvio Basolo, Maria Grazia Castagna, Lucia Brilli, Elisabetta Ferretti, and Rossella Elisei
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liquid biopsy ,Endocrinology, Diabetes and Metabolism ,Biochemistry (medical) ,Clinical Biochemistry ,ctDNA ,Biochemistry ,Medullary Thyroid Carcinoma ,Carcinoembryonic Antigen ,Carcinoma, Neuroendocrine ,Circulating Tumor DNA ,carcino-embryonic antigen ,Endocrinology ,NGS ,calcitonin ,Mutation ,Biomarkers, Tumor ,Humans ,Thyroid Neoplasms - Abstract
Context Measurement of driver mutations in circulating tumoral DNA (ctDNA) obtained by liquid biopsy has been shown to be a sensitive biomarker in several human tumors. Objective The aim of this study was to evaluate the clinical relevance of pre- and post-operative ctDNA in sporadic medullary thyroid cancer (sMTC). Methods We studied pre- and post-operative ctDNA in 26 and 23 sMTC patients, respectively. ctDNA results were correlated to serum calcitonin (Ct), carcinoembryonic antigen (CEA), and other clinical/pathological features. Results Twenty-six of 29 (89.7%) sMTCs were mutated either for RET or RAS and 3/29 (10.3%) were negative. Four of 26 (15.4%) cases showed positive pre-operative ctDNA with a significantly higher presence of RET M918T mutation (P = 0.0468). Patients with positive pre-operative ctDNA showed a higher variation allele frequency value of the somatic driver mutation (P = 0.0434) and a higher frequency of persistent disease (P = 0.0221). Post-operative ctDNA was positive only in 3/23 (13%) sMTCs and no one was positive for pre-operative ctDNA. Higher values of both Ct (P = 0.0307) and CEA (P = 0.0013) were found in positive ctDNA cases. Finally, the 7 cases harboring either pre- or post-operative positive ctDNA had a persistent disease (P = 0.0005) showing a higher post-operative serum Ct when compared with cases with negative ctDNA (P = 0.0092). Conclusions Pre-operative ctDNA in medullary thyroid cancer is not useful for diagnostic purposes, but it can be useful for predicting the outcome of the disease. In our series, post-operative ctDNA showed a potential for monitoring the response to therapies, but further studies are required to confirm our results.
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- 2022
6. Cell-Free Tumor DNA (ctDNA) Utility in Detection of Original Sensitizing and Resistant EGFR Mutations in Non-Small Cell Lung Cancer (NSCLC)
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Jason S. Agulnik, Andreas I. Papadakis, Carmela Pepe, Lama Sakr, David Small, Hangjun Wang, Goulnar Kasymjanova, Alan Spatz, and Victor Cohen
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ErbB Receptors ,Lung Neoplasms ,NSCLC ,ctDNA ,EGFR mutation ,liquid biopsy ,Carcinoma, Non-Small-Cell Lung ,Mutation ,Humans ,Prospective Studies ,Protein Kinase Inhibitors ,Circulating Tumor DNA ,respiratory tract diseases - Abstract
Background: Recent studies have demonstrated the utility of cell-free tumor DNA (ctDNA) from plasma as an alternative source of genomic material for detection of sensitizing and resistance mutations in NSCLC. We hypothesized that the plasma level of ctDNA is an effective biomarker to provide a non-invasive and thus a less risky method to determine new resistance mutations and to monitor response to treatment and tumor progression in lung cancer patients. Methods: This prospective cohort study was approved and conducted at the Peter Brojde Lung Cancer Centre, Montreal. Blood was collected in STRECK tubes at four time points. DNA was extracted from plasma, and ctDNA was analyzed for the presence of mutations in the EGFR gene using the COBAS® EGFR v2 qPCR (Roche) test. Results: Overall, 75 pts were enrolled in the study. In total, 23 pts were TKI-naïve, and 52 were already receiving first-line TKI treatment. ctDNA detected the original mutations (OM) in 35/75 (48%) patients. Significantly higher detection rates were observed in TKI-naïve patients compared to the TKI-treated group, 70% versus 37%, respectively (p = 0.012). The detection of the original mutation at the study baseline was a negative predictor of progression-free survival (PFS) and overall survival (OS). The resistance mutation (T790M) was detected in 32/74 (43%) patients. In 27/32 (84%), the T790M was detected during treatment with TKI: in 25/27 patients, T790M was detected at the time of radiologic progression, in one patient, T790M was detected before radiologic progression, and in one patient, T790M was detected four weeks after starting systemic chemotherapy post progression on TKI. At the time of progression, the detection of T790M significantly correlates with the re-appearance of OM (p = 0.001). Conclusion: Plasma ctDNA is a noninvasive patient-friendly test that can be used to monitor response to treatment, early progression, and detection of acquired resistant mutations. Monitoring of clearance and re-emergence of driver mutations during TKI treatment effectively identifies progression of the disease. As larger NGS panels are available for ctDNA testing, these findings may also have implications for other biomarkers. The results from ongoing and prospective studies will further determine the utility of plasma testing to diagnose, monitor for disease progression, and guide treatment decisions in NSCLC.
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- 2022
7. Circulating Tumour DNA in Melanoma—Clinic Ready?
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Ann Tivey, Fiona Britton, Julie-Ann Scott, Dominic Rothwell, Paul Lorigan, and Rebecca Lee
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Skin Neoplasms ,Manchester Cancer Research Centre ,ResearchInstitutes_Networks_Beacons/mcrc ,ctDNA ,Liquid biopsies ,Circulating Tumor DNA ,Targeted therapy ,Oncology ,Biomarkers, Tumor ,Humans ,Immunotherapy ,Neoplasm Recurrence, Local ,Melanoma ,Biomarkers - Abstract
Purpose of Review Liquid biopsies, including circulating tumour DNA (ctDNA), can inform a variety of clinical questions. This review examines the potential role of ctDNA as a clinical tool to inform clinical decision-making from early to late stage cutaneous melanoma. Recent Findings In pre-clinical studies, ctDNA has been shown to detect minimal residual disease and molecular relapse; predict and monitor response to therapy; and identify key resistance mechanisms. Here, we examine the potential utility of ctDNA and discuss its limitations for use in patients with melanoma. We present novel clinical trials, which are testing its value as a tool to augment clinical decision-making. Finally, we discuss the steps that are needed to ensure that ctDNA is used optimally in order to improve outcomes for patients with melanoma. Summary Preclinical studies have shown that ctDNA has huge potential to provide real-time information about disease status in patients with melanoma. It is now time to test it rigorously within clinical trials to assess how it can be optimally used to benefit patients in the clinic.
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- 2022
8. Detection of circulating tumor-derived material in peripheral blood of pediatric sarcoma patients: A systematic review
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Eva Kristine Ruud Kjær, Christian Bach Vase, Maria Rossing, Lise Barlebo Ahlborn, and Lisa Lyngsie Hjalgrim
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Osteosarcoma ,Cancer Research ,Oncology ,Rhabdomyosarcoma ,Ewing's sarcoma ,ctDNA ,ctRNA ,CTC - Abstract
Background: Detection of circulating tumor-derived material (cTM) in the peripheral blood (PB) of cancer patients has been shown to be useful in early diagnosis, prediction of prognosis, and disease monitoring. However, it has not yet been thoroughly evaluated for pediatric sarcoma patients. Methods: We searched the PubMed and EMBASE databases for studies reporting the detection of circulating tumor cells, circulating tumor DNA, and circulating RNA in PB of pediatric sarcoma patients. Data on performance in identifying cTM and its applicability in diagnosis, and evaluation of tumor characteristics, prognostic factors, and treatment response was extracted from publications. Results: A total of 79 studies were assigned for the present systematic review, including detection of circulating tumor cells (116 patients), circulating tumor DNA (716 patients), and circulating RNA (2887 patients). Circulating tumor cells were detected in 76% of patients. Circulating DNA was detected in 63% by targeted NGS, 66% by shallow WGS, and 79% by digital droplet PCR. Circulating RNA was detected in 37% of patients. Conclusion: Of the cTM from Ewing's sarcoma and rhabdomyosarcoma ctDNA proved to be the best target for clinical application including diagnosis, tumor characterization, prognosis, and monitoring of disease progression and treatment response. For osteosarcoma the most promising targets are copy number alterations or patient specific micro RNAs, however, further investigations are needed to obtain consensus on clinical utility.
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- 2023
9. Editorial: New insights in diagnosis and therapy of hormone-dependent cancer
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Rienzo, Monica, Pagano, Cristina, Crocetto, Felice, Di Zazzo, Erika, Rienzo, Monica, Pagano, Cristina, Crocetto, Felice, and Di Zazzo, Erika
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breast cancer ,Endocrinology, Diabetes and Metabolism ,endometrial cancer ,biomarker ,CtDNA ,metastasi ,prostate cancer ,hormone-dependent cancer ,prognosi - Published
- 2023
10. Liquid biopsies for residual disease and recurrence
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Jonathan Chee Ming Wan, Tariq Imdadali Mughal, Pedram Razavi, Sarah-Jane Dawson, Esther Louise Moss, Ramaswamy Govindan, Iain Beehuat Tan, Yoon-Sim Yap, William Allen Robinson, Clive Dylan Morris, Benjamin Besse, Alberto Bardelli, Jeanne Tie, Scott Kopetz, and Nitzan Rosenfeld
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clinical trials ,Neoplasm, Residual ,Liquid Biopsy ,residual disease and recurrence ,ctDNA ,General Medicine ,solid tumors ,Circulating Tumor DNA ,MRD ,RDR ,Biomarkers, Tumor ,Humans ,Neoplasm Recurrence, Local - Abstract
Detection of minimal residual disease in patients with cancer, who are in complete remission with no cancer cells detectable, has the potential to improve recurrence-free survival through treatment selection. Studies analyzing circulating tumor DNA (ctDNA) in patients with solid tumors suggest the potential to accurately predict and detect relapse, enabling treatment strategies that may improve clinical outcomes. Over the past decade, assays for ctDNA detection in plasma samples have steadily increased in sensitivity and specificity. These are applied for the detection of residual disease after treatment and for earlier detection of recurrence. Novel clinical trials are now assessing how assays for "residual disease and recurrence" (RDR) may influence current treatment paradigms and potentially change the landscape of risk classification for cancer recurrence. In this review, we appraise the progress of RDR detection using ctDNA and consider the emerging role of liquid biopsy in the monitoring and management of solid tumors.
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- 2021
11. Intra-Tumor Heterogeneity of Colorectal Cancer Necessitates the Multi-Regional Sequencing for Comprehensive Mutational Profiling
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Guo, Shaohua, Ye, Yumeng, Liu, Xinyi, Gong, Yuan, Xu, Mingyan, Song, Lele, and Liu, Hongyi
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circulating tumor DNA ,Oncology ,Cancer Management and Research ,KRAS ,intra-tumor heterogeneity ,colorectal cancer ,ctDNA ,TP53 ,multi-region sequencing ,Original Research ,APC - Abstract
Shaohua Guo,1,2,* Yumeng Ye,3,* Xinyi Liu,4 Yuan Gong,5 Mingyan Xu,4 Lele Song,4,6 Hongyi Liu1 1Department of General Surgery, The First Medical Center of the Chinese PLA General Hospital, Beijing, Peopleâs Republic of China; 2Department of General Surgery, The Eighth Medical Center of the Chinese PLA General Hospital, Beijing, Peopleâs Republic of China; 3Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, Peopleâs Republic of China; 4Department of Medical Division, HaploX Biotechnology, Shenzhen, Peopleâs Republic of China; 5Department of Gastroenterology, The Second Medical Center of the Chinese PLA General Hospital, Beijing, Peopleâs Republic of China; 6Department of Radiotherapy, The Eighth Medical Center of the Chinese PLA General Hospital, Beijing, Peopleâs Republic of China*These authors contributed equally to this workCorrespondence: Hongyi LiuDepartment of General Surgery, The First Medical Center of the Chinese PLA General Hospital, Beijing, Peopleâs Republic of ChinaTel +86-10-66937533Email liushitou2003@163.comLele SongDepartment of Radiotherapy, The Eighth Medical Center of the Chinese PLA General Hospital, Beijing, Peopleâs Republic of ChinaTel +86-13240149188Email songlele@sina.comBackground: The panorama and details of quantitative intratumor heterogeneity have not been fully investigated in colorectal cancer (CRC) patients with solitary lesion without distal metastasis, and its influences on sequencing interpretation and therapeutic strategies have not been explored.Methods: Cancer tissues and matched blood from 70 sporadic CRC patients were collected and were divided into two cohorts. Four individual tissue biopsies were obtained from each of the 47 patients (multi-sample cohort). One random cancer tissue biopsy was obtained from each of the rest 23 patients (single-sample cohort). A 10 mL of blood was collected from all patients and the circulating cell-free DNA (cfDNA) was extracted. A 605-gene panel was used for targeted sequencing with tissue and paired blood.Results: Mutational landscape revealed significantly higher mutational frequency in APC, CARD11 and CSMD3 in multi-sample cohort than single-sample cohort (P< 0.05). The number of mutations and the ratio of trunk, shared and branch mutations showed extensive heterogeneity in multi-sample cohort, and the percentage of trunk mutations in major driver genes, including APC, TP53 and KRAS, was higher than 70%. A total of 929 mutations were detected in tissue/blood in multi-sample group, with 921(99.1%) from tissue and 472(50.8%) from blood (464 common mutations,49.9%). In contrast, 394 mutations were detected in tissue/blood in single-sample group, with 231 (58.6%) from tissue and 219 (55.6%) from blood (56 common mutations, 11.9%). The number of mutations of major driver genes detected in tissue was higher than that in blood in the multi-sample cohort, while it was similar in the single-sample group. Quantification analysis revealed differential correlation between tissue and blood VAF in trunk, shared and branch mutations. Meanwhile, VAF of trunk mutations was significantly higher than shared mutations and branch mutations. VAF exhibited significant differences among distinct stages, locations, differentiation and sex status.Conclusion: Characteristic extensive heterogeneity was revealed for solitary CRC without distal metastasis. Multi-regional biopsy was necessary for comprehensive mutation detection in CRC.Keywords: colorectal cancer, multi-region sequencing, intra-tumor heterogeneity, circulating tumor DNA, ctDNA, APC, KRAS, TP53
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- 2021
12. Personalized circulating tumor DNA in patients with hepatocellular carcinoma: a pilot study
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Andreas A. Rostved, C. L. Sørensen, Christina Westmose Yde, C. L. Andersen, T. V. Henriksen, Lise Barlebo Ahlborn, Kristoffer Staal Rohrberg, Finn Cilius Nielsen, Allan Rasmussen, Hans-Christian Pommergaard, and Jane Preuss Hasselby
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Oncology ,Circulating tumor DNA ,medicine.medical_specialty ,Liver resection ,business.industry ,Early detection ,ctDNA ,General Medicine ,medicine.disease ,digestive system diseases ,Mutational analysis ,Targeted ngs ,NGS ,Hepatocellular carcinoma ,Internal medicine ,Genetics ,medicine ,In patient ,HCC ,business ,Molecular Biology ,Small tumors ,Exome sequencing - Abstract
BACKGROUND: Mutational analysis of circulating tumor DNA (ctDNA) can potentially be used for early detection of recurrence after resection for hepatocellular carcinoma (HCC). Mutations from tumor may be identified in plasma as an early sign of recurrence. We conducted a pilot study investigating if somatic mutations could be detected in plasma in patients undergoing liver resection for HCC and in patients with advanced non-resectable HCC.METHODS AND RESULTS: We prospectively included patients undergoing curative liver resection for HCC. Tumor tissue was investigated with whole exome sequencing and preoperative blood samples were evaluated for ctDNA using targeted next-generation sequencing (NGS) with TruSight Oncology 500 including 523 cancer-associated genes. Subsequently, the method was evaluated in patients with advanced HCC. We included eight patients curatively resected for HCC, where tumor tissue mutations were identified in seven patients. However, only in one patient tumor specific mutations were found in the preoperative blood sample. In all three patients with advanced HCC, tumor mutations were detected in the blood.CONCLUSIONS: In patients with resectable HCC, ctDNA could not be reliably detected using the applied targeted NGS method. In contrast, ctDNA was detected in all patients with advanced HCC. Small tumors, tumor heterogeneity and limited sequencing coverage may explain the lack of detectable ctDNA.
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- 2021
13. Estimation of ALU Repetitive Element in Plasma as a Cost-Effective Liquid Biopsy Tool for Disease Prognosis in Breast Cancer
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Madhumathy G. Nair, Rakesh S. Ramesh, Chandrakala M. Naidu, Apoorva D. Mavatkar, Snijesh V. P., Vishakha Ramamurthy, Vidya M. Somashekaraiah, Anupama C. E., Kiruthiga Raghunathan, Anuradha Panigrahi, Manjula Das, Sujan K. Dhar, and Jyothi S. Prabhu
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Cancer Research ,breast cancer ,ALU 247 ,disease progression ,Oncology ,liquid biopsy ,ctDNA ,prognosis ,oncology_oncogenics - Abstract
Background: Liquid biopsy is widely recognized as an efficient diagnostic method in oncology for disease detection and monitoring. Though the examination of circulating tumor cells (CTC) is mostly implemented for the assessment of genomic aberrations, the need of complex methodologies for their detection has impeded its acceptance in low-resource settings. We evaluated cell-free DNA (cfDNA) as a liquid biopsy tool and investigated its utility in breast cancer patients. Methods: Total cell-free DNA was extracted from the plasma of breast cancer patients (n = 167) with a median follow-up of more than 5 years, at various stages of the disease. Quantitative PCR was performed to estimate the copy numbers of two fractions of ALU repetitive elements (ALU 115 and ALU 247), and DNA integrity (DI) was calculated as the ratio of ALU 247/115. Mutations in TP53 and PIK3CA in the cfDNA were estimated by next-gen sequencing (NGS) in a subset of samples. Associations of the levels of both the ALU fragments with various clinico-pathological factors and disease-free survival at various stages were examined. Nomogram models were constructed with clinical variables and ALU 247 levels to predict disease-free survival and the best performing model was evaluated by decision curve analysis. Results: DI and ALU 247 levels were significantly lower (p < 0.0001) in the post-operative plasma when compared to their pre-surgery levels. DI and ALU 247 were found to be significantly higher in patients with metastasis (p < 0.05). Patients with higher levels of ALU 247 in their post-operative plasma had significant poor disease-free survival (p = 0.005). Higher levels of ALU 247 in the circulation also correlated with low tumor-infiltrating lymphocytes (TIL) within their primary tumors in the ER-negative breast cancer subtype (p = 0.01). Cox proportional hazard analysis confirmed ALU 247 as an independent variable of disease-free survival both in univariate and multivariate analysis [HR 1.3 (95% CI 1.047 to 1.613, p = 0.017)]. The nomogram model showed that the addition of ALU 247 with other variables significantly improved (C-index 0.823) the predictive ability of the model. Conclusion: Our results confirm the utility of cfDNA as an evolving liquid biopsy tool for molecular analysis. Evaluation of larger fragments of cfDNA estimated through ALU 247 can provide vital information concurrent with the pathological process of disease evolution in breast cancer and warrants expansion to other cancer types.
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- 2022
14. Postoperative ctDNA detection guides omission of adjuvant therapy for resectable stage III non–small cell lung cancer
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Wang, Bolin
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lung cancer ,ctDNA - Abstract
Supplementary Figure 1. Univariate Cox regression analyses of the association between patients characteristics and the probability of recurrence-free survival in ctDNA-negative group.
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- 2022
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15. Liquid biopsy from research to clinical practice: focus on non-small cell lung cancer
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Christian Rolfo, Edward M. Pickering, Valeria Denninghoff, Umberto Malapelle, Andrés F. Cardona, Alfredo Addeo, Kenneth J. O'Byrne, Pier Vitale Nuzzo, Diego de Miguel-Pérez, Alessandro Russo, Ignacio Duran, David R. Gandara, María José Serrano, Eloisa Jantus-Lewintre, Giancarlo Troncone, Luis E. Raez, Massimo Cristofanilli, Pasquale Pisapia, Oscar Arrieta, Beatriz Bellosillo, Patrick Pauwels, Malapelle, Umberto, Pisapia, Pasquale, Addeo, Alfredo, Arrieta, Oscar, Bellosillo, Beatriz, Cardona, Andres F, Cristofanilli, Massimo, de Miguel-Perez, Diego, Denninghoff, Valeria, Durán, Ignacio, Jantus-Lewintre, Eloísa, Nuzzo, Pier Vitale, O'Byrne, Ken, Pauwels, Patrick, Pickering, Edward M, Raez, Luis E, Russo, Alessandro, Serrano, Maria José, Gandara, David R, Troncone, Giancarlo, and Rolfo, Christian
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medicine.medical_specialty ,Lung Neoplasms ,Context (language use) ,NSCLC ,Pathology and Forensic Medicine ,Carcinoma, Non-Small-Cell Lung ,Biomarkers, Tumor ,Genetics ,medicine ,Humans ,In patient ,Precision Medicine ,Liquid biopsy ,Intensive care medicine ,Lung cancer ,Molecular Biology ,Predictive biomarker ,liquid biopsy ,business.industry ,biomarkers ,ctDNA ,medicine.disease ,CTC ,Clinical Practice ,biomarker ,Molecular Medicine ,Personalized medicine ,Non small cell ,business - Abstract
INTRODUCTION: In the current era of personalized medicine, liquid biopsy has acquired a relevant importance in patient management of advanced stage non-small cell lung cancer (NSCLC). As a matter of fact, liquid biopsy may supplant the problem of inadequate tissue for molecular testing. The term 'liquid biopsy' refers to a number of different biological fluids, but is most clearly associated with plasma-related platforms. It must be taken into account that pre-analytical processing and the selection of the appropriate technology according to the clinical context may condition the results obtained. In addition, novel clinical applications beyond the evaluation of the molecular status of predictive biomarkers are currently under investigation. AREAS COVERED: This review summarizes the available evidence on pre-analytical issues and different clinical applications of liquid biopsies in NSCLC patients. EXPERT OPINION: Liquid biopsy should be considered not only as a valid alternative but as complementary to tissue-based molecular approaches. Careful attention should be paid to the optimization and standardization of all phases of liquid biopsy samples management in order to determine a significant improvement in either sensitivity or specificity, while significant reducing the number of 'false negative' or 'false positive' molecular results.
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- 2021
16. Serial circulating tumor DNA to predict early recurrence in patients with hepatocellular carcinoma: a prospective study
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Wei-Ren Liu, Run Huang, Zhi Dai, Gui-Qi Zhu, Han Wang, Wei-Feng Qu, Zhen-Bin Ding, Xi-Fei Jiang, Yuan-Fei Peng, Yuan Fang, Hai-Xiang Sun, Jun Gao, Zheng Tang, Jia Fan, Ying-Hong Shi, Shushu Song, Pei-Yun Zhou, Chen-Yang Tao, and Jian Zhou
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Male ,Neuroblastoma RAS viral oncogene homolog ,Oncology ,Cancer Research ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Gene mutation ,Germline ,Circulating Tumor DNA ,Gene Frequency ,Internal medicine ,Genetics ,Humans ,Medicine ,In patient ,Prospective Studies ,Prospective cohort study ,RC254-282 ,Research Articles ,business.industry ,Liver Neoplasms ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,ctDNA ,hepatocellular carcinoma ,General Medicine ,Middle Aged ,medicine.disease ,tumor recurrence ,Circulating tumor DNA ,Hepatocellular carcinoma ,biomarker ,Molecular Medicine ,Biomarker (medicine) ,Female ,Neoplasm Recurrence, Local ,business ,Research Article - Abstract
We studied the value of circulating tumor DNA (ctDNA) in predicting early postoperative tumor recurrence and monitoring tumor burden in patients with hepatocellular carcinoma (HCC). Plasma‐free DNA, germline DNA, and tissue DNA were isolated from 41 patients with HCC. Serial ctDNAs were analyzed by next‐generation sequencing before and after operation. Whole‐exome sequencing was used to detect the DNA of HCC and adjacent tissues. In total, 47 gene mutations were identified in the ctDNA of the 41 patients analyzed before surgery. ctDNA was detected in 63.4% and 46% of the patient plasma pre‐ and postoperation, respectively. The preoperative ctDNA positivity rate was significantly lower in the nonrecurrence group than in the recurrence group. With a median follow‐up of 17.7 months, nine patients (22%) experienced tumor recurrence. ctDNA positivity at two time‐points was associated with significantly shorter recurrence‐free survival (RFS). Tumors with NRAS, NEF2L2, and MET mutations had significantly shorter times to recurrence than those without mutations and showed high recurrence prediction performance by machine learning. Multivariate analyses showed that the median variant allele frequency (VAF) of mutations in preoperative ctDNA was a strong independent predictor of RFS. ctDNA is a real‐time monitoring indicator that can accurately reflect tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of RFS in individuals with HCC., Here, we studied the value of circulating tumor DNA (ctDNA), in combination with germline and tissue DNA by whole‐exome sequencing in patients withhepatocellular carcinoma (HCC). Our analysis demonstrated that ctDNA may serve as a real‐time monitoring indicator by accurately reflecting tumor burden, and as a strong independent predictor of recurrence‐free survival in HCC.
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- 2021
17. Liquid Biopsy for Biomarker Testing in Non-Small Cell Lung Cancer: A European Perspective
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Marcello Tiseo, M. Josè Serrano, Markus Tiemann, Umberto Malapelle, Joshua Kapp, Ana Vivancos, Malapelle, Umberto, Tiseo, Marcello, Vivancos, Ana, Kapp, Joshua, Josè Serrano, M., and Tiemann, Markus
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Oncology ,medicine.medical_specialty ,Cancer prevention ,liquid biopsy ,Performance status ,business.industry ,ctDNA ,Disease ,medicine.disease ,Molecular diagnostics ,molecular diagnostics ,Internal medicine ,Pathology ,medicine ,RB1-214 ,Biomarker (medicine) ,next-generation sequencing ,cfDNA ,Liquid biopsy ,Stage (cooking) ,Lung cancer ,business ,non-small cell lung cancer - Abstract
The development of targeted therapies has improved survival rates for patients with advanced non-small cell lung cancer (NSCLC). However, tissue biopsy is unfeasible or inadequate in many patients, limiting biomarker testing and access to targeted therapies. The increasing numbers of established and emerging biomarkers with available targeted treatments highlights the challenges associated with sequential single-gene testing and limited tissue availability. Multiplex next-generation sequencing (NGS) offers an attractive alternative and represents a logical next step, and in cases where the tumour is inaccessible, tissue biopsy yields insufficient tumour content, or when the patient’s performance status does not allow a tissue biopsy, liquid biopsy can provide valuable material for molecular diagnosis. Here, we explore the role of liquid biopsy (i.e., circulating cell-free DNA analysis) in Europe. Liquid biopsies could be used as a complementary approach to increase rates of molecular diagnosis, with the ultimate aim of improving patient access to appropriate targeted therapies. Expert opinion is also provided on potential future applications of liquid biopsy in NSCLC, including for cancer prevention, detection of early stage and minimum residual disease, monitoring of response to therapy, selection of patients for immunotherapy, and monitoring of tumour evolution to enable optimal adaptation/combination of drug therapies.
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- 2021
18. Individualized Mini-Panel Sequencing of ctDNA Allows Tumor Monitoring in Complex Karyotype Sarcomas
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David Braig, Alexander Runkel, Anja E. Eisenhardt, Adrian Schmid, Johannes Zeller, Thomas Pauli, Ute Lausch, Julius Wehrle, Peter Bronsert, Matthias Jung, Jurij Kiefer, Melanie Boerries, and Steffen U. Eisenhardt
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Organic Chemistry ,Karyotype ,Sarcoma ,Soft Tissue Neoplasms ,General Medicine ,Catalysis ,Computer Science Applications ,Circulating Tumor DNA ,Inorganic Chemistry ,soft tissue sarcoma ,complex karyotype sarcoma ,ctDNA ,cfDNA ,biomarker ,liquid biopsy ,myxofibrosarcoma ,leiomyosarcoma ,pleomorphic sarcoma ,Mutation ,Biomarkers, Tumor ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Cell-Free Nucleic Acids ,Spectroscopy - Abstract
Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin with high mortality. After curative resection, about one third of patients suffer from distant metastases. Tumor follow-up only covers a portion of recurrences and is associated with high cost and radiation burden. For metastasized STS, only limited inferences can be drawn from imaging data regarding therapy response. To date there are no established and evidence-based diagnostic biomarkers for STS due to their rarity and diversity. In a proof-of-concept study, circulating tumor DNA (ctDNA) was quantified in (n = 25) plasma samples obtained from (n = 3) patients with complex karyotype STS collected over three years. Genotyping of tumor tissue was performed by exome sequencing. Patient-individual mini-panels for targeted next-generation sequencing were designed encompassing up to 30 mutated regions of interest. Circulating free DNA (cfDNA) was purified from plasma and ctDNA quantified therein. ctDNA values were correlated with clinical parameters. ctDNA concentrations correlated with the tumor burden. In case of full remission, no ctDNA was detectable. Patients with a recurrence at a later stage showed low levels of ctDNA during clinical remission, indicating minimal residual disease. In active disease (primary tumor or metastatic disease), ctDNA was highly elevated. We observed direct response to treatment, with a ctDNA decline after tumor resections, radiotherapy, and chemotherapy. Quantification of ctDNA allows for the early detection of recurrence or metastases and can be used to monitor treatment response in STS. Therapeutic decisions can be made earlier, such as the continuation of a targeted adjuvant therapy or the implementation of extended imaging to detect recurrences. In metastatic disease, therapy can be adjusted promptly in case of no response. These advantages may lead to a survival benefit for patients in the future.
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- 2022
19. Analysis of circulating tumour DNA to identify patients with epidermal growth factor receptor–positive non-small cell lung cancer who might benefit from sequential tyrosine kinase inhibitor treatment
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Berta Hernandez, J. Coves, María Ángeles Sala, Ana Blasco, Ana Royuela, Joaquim Bosch-Barrera, A. Padilla, Roberto Serna-Blasco, María Sereno, Juana Oramas, María de Julián Campayo, Coralia Bueno, V. Calvo, Atocha Romero, José Balsalobre, F. Franco, Ana Laura Ortega, Milda Auglytė, Jose Miguel Sanchez, Mariano Provencio, Eloisa Jantus-Lewintre, X. Mielgo, Remedios Blanco, Carlos García-Girón, L.E. Chara, Miguel Angel Molina-Vila, Manuel Domine, and Alfredo Sánchez-Hernández
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Time Factors ,DNA Mutational Analysis ,NSCLC ,Polymerase Chain Reaction ,Tyrosine-kinase inhibitor ,Circulating Tumor DNA ,chemistry.chemical_compound ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Medicine ,Osimertinib ,Digital polymerase chain reaction ,Prospective Studies ,Epidermal growth factor receptor ,Aniline Compounds ,biology ,Middle Aged ,TKI ,ErbB Receptors ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,Non small cell ,Tyrosine kinase ,medicine.drug_class ,EGFR ,Clinical Decision-Making ,Antineoplastic Agents ,03 medical and health sciences ,Predictive Value of Tests ,Biomarkers, Tumor ,Humans ,Lung cancer ,Protein Kinase Inhibitors ,Aged ,Neoplasm Staging ,Acrylamides ,business.industry ,ctDNA ,medicine.disease ,respiratory tract diseases ,Cross-Sectional Studies ,030104 developmental biology ,chemistry ,Spain ,Mutation ,Cancer research ,biology.protein ,business ,DNA - Abstract
Survival data support the use of first-line osimertinib as the standard of care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). However, it remains unclear whether upfront osimertinib is superior to sequential first- or second-generation tyrosine kinase inhibitors (TKIs) followed by osimertinib for all patients. It is impossible to predict which patients are at high risk of progression, and this constitutes a major limitation of the sequential TKI approach.A total of 830 plasma samples from 228 patients with stage IV, EGFR-positive NSCLC who were treated with first-line TKIs were analysed by digital polymerase chain reaction (dPCR).The circulating tumour DNA (ctDNA) levels helped to identify patients with significantly improved survival rate, regardless of the treatment. Patients treated with first- or second-generation TKIs (N = 189) with EGFR mutations in plasma at a mutant allele frequency (MAF)7% before treatment initiation (low-risk patients) or who were ctDNA negative after 3 or 6 months of treatment and with an MAF7% at diagnosis (high responders) had two-thirds lower risk of death than patients in the opposite situation (adjusted hazard ratio [HR] = 0.38; 95% confidence interval [CI]: 0.23-0.64 and HR = 0.22; 95% CI: 0.12-0.42, respectively). The median overall survival (OS) for low-risk patients and high responders treated with first- or second-generation TKIs was 34.2 months and not reached, respectively, regardless of second-line treatment. There were no significant difference in OS between low-risk or high-responder patients treated upfront with osimertinib (N = 39) and those treated under a sequential approach with osimertinib (N = 60). Median OS was not reached in both cases.Pre-treatment ctDNA levels identify low-risk patients, who may benefit from sequential TKI treatment. Information regarding EGFR mutation clearance can help to improve patient selection.
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- 2021
20. The evolving role of liquid biopsy in lung cancer
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Umberto Malapelle, Pasquale Pisapia, Francesco Pepe, Gianluca Russo, Mauro Buono, Alessandro Russo, Jorge Gomez, Ola Khorshid, Philip C. Mack, Christian Rolfo, Giancarlo Troncone, Malapelle, Umberto, Pisapia, Pasquale, Pepe, Francesco, Russo, Gianluca, Buono, Mauro, Russo, Alessandro, Gomez, Jorge, Khorshid, Ola, Mack, Philip C, Rolfo, Christian, and Troncone, Giancarlo
- Subjects
Pulmonary and Respiratory Medicine ,Cancer Research ,Lung Neoplasms ,Liquid Biopsy ,High-Throughput Nucleotide Sequencing ,Biomarker ,ctDNA ,NSCLC ,Circulating Tumor DNA ,Oncology ,Carcinoma, Non-Small-Cell Lung ,Mutation ,Biomarkers, Tumor ,Humans - Abstract
Liquid biopsy has revolutionized the management of cancer patients. In particular, liquid biopsy-based testing has proven to be highly beneficial for identifying actionable cancer markers, especially when solid tissue biopsies are insufficient or unattainable. Beyond the predictive role, liquid biopsy may be a useful tool for comprehensive tumor genotyping, identification of emergent resistance mechanisms, monitoring of minimal residual disease, early detection, and cancer interception. The application of next generation sequencing to liquid biopsy has led to the "quantum leap" of predictive molecular pathology. Here, we review the evolving role of liquid biopsy in lung cancer.
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- 2022
21. A phase Ib feasibility trial of response adapted neoadjuvant therapy in gastric cancer (RANT-GC)
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Farshid Dayyani, Brian R Smith, Ninh T Nguyen, Shaun Daly, Marcelo W Hinojosa, Steven N Seyedin, Jeffrey Kuo, Jason B Samarasena, John G Lee, Thomas H Taylor, May T Cho, and Maheswari Senthil
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Cancer Research ,Clinical Trial Protocol ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Phase I as Topic ,Gastrectomy ,Stomach Neoplasms ,Clinical Research ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Chemotherapy ,Clinical Trials ,Prospective Studies ,Oncology & Carcinogenesis ,Adjuvant ,Neoplasm Staging ,Cancer ,Clinical Trials, Phase I as Topic ,gastric cancer ,Evaluation of treatments and therapeutic interventions ,General Medicine ,ctDNA ,Neoadjuvant Therapy ,gastrectomy ,Good Health and Well Being ,Oncology ,Chemotherapy, Adjuvant ,6.1 Pharmaceuticals ,Feasibility Studies ,Digestive Diseases ,neoadjuvant chemotherapy - Abstract
Current guidelines recommend neoadjuvant (NAC) and/or adjuvant chemotherapy for locally advanced gastric cancers (LAGCs). However, the choice and duration of NAC regimen is standardized, rather than personalized to biologic response, despite the availability of several different classes of agents for the treatment of gastric cancer (GC). The current trial will use a tumor-informed ctDNA assay (Signatera™) and monitor response to NAC. Based on ctDNA kinetics, the treatment regimen is modified. This is a prospective single center, single-arm, open-label study in clinical stage IB-III GC. ctDNA is measured at baseline and repeated every 8 weeks. Imaging is performed at the same intervals. The primary end point is the feasibility of this approach, defined as percentage of patients completing gastrectomy.
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- 2022
22. Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy
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Takayuki Matsumae, Takahiro Kodama, Yuta Myojin, Kazuki Maesaka, Ryotaro Sakamori, Ayako Takuwa, Keiko Oku, Daisuke Motooka, Yoshiyuki Sawai, Masahide Oshita, Tasuku Nakabori, Kazuyoshi Ohkawa, Masanori Miyazaki, Satoshi Tanaka, Eiji Mita, Seiichi Tawara, Takayuki Yakushijin, Yasutoshi Nozaki, Hideki Hagiwara, Yuki Tahata, Ryoko Yamada, Hayato Hikita, Tomohide Tatsumi, and Tetsuo Takehara
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Cancer Research ,Oncology ,atezolizumab ,bevacizumab ,CTNNB1 ,TERT ,HCC ,AFP ,cfDNA ,ctDNA ,immunotherapy ,biomarker - Abstract
Combination immunotherapy with anti-programmed cell death1-ligand1 (PD-L1) and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for patients with unresectable HCC (u-HCC). However, limited patients obtain clinical benefits. Cell-free DNA (cfDNA) in peripheral blood contains circulating tumor DNA (ctDNA) that reflects molecular abnormalities in tumor tissue. We investigated the potential of cfDNA/ctDNA as biomarkers for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy. We enrolled a multicenter cohort of 85 HCC patients treated with atezolizumab and bevacizumab (Atezo/Bev) between 2020 and 2021. Pretreatment plasma was collected, and cfDNA levels were quantified. Ultradeep sequencing of cfDNA was performed with a custom-made panel for detecting mutations in 25 HCC-related cancer genes. We evaluated the association of cfDNA/ctDNA profiles and clinical outcomes. Patients with high plasma cfDNA levels showed a significantly lower response rate and shorter progression-free survival and overall survival (OS) than those with low cfDNA levels. ctDNA detected in 55% of HCC patients included the telomerase reverse transcriptase (TERT) promoter in 31% of these patients, tumor protein 53 (TP53) in 21%, catenin beta 1 (CTNNB1) in 13% and phosphatase and tensin homolog (PTEN) in 7%. The presence or absence of ctDNA did not predict the efficacy of Atezo/Bev therapy. Twenty-six patients with a TERT mutation had significantly shorter OS than those without. The presence of a TERT mutation and alpha-fetoprotein (AFP) ≥ 400 ng/mL were independent predictors of poor OS according to multivariate Cox proportional hazard analysis and could be used to stratify patients treated with Atezo/Bev therapy based on prognosis. In conclusion, pretreatment cfDNA/ctDNA profiling may be useful for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy.
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- 2022
23. Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients
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Ariane Hallermayr, Tobias Wohlfrom, Verena Steinke-Lange, Anna Benet-Pagès, Florentine Scharf, Ellen Heitzer, Ulrich Mansmann, Christopher Haberl, Maike de Wit, Holger Vogelsang, Markus Rentsch, Elke Holinski-Feder, and Julia M. A. Pickl
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Cancer Research ,Oncology ,DNA Copy Number Variations ,Mutation ,Biomarkers, Tumor ,Humans ,Hematology ,Colorectal Neoplasms ,Molecular Biology ,Cell-Free Nucleic Acids ,Early Detection of Cancer ,Ctdna ,Colorectal Cancer ,Liquid Biopsy ,Whole-genome Sequencing ,Somatic Copy Number Alterations ,Cfdna Fragmentation ,Chromatin Signatures ,Circulating Tumor DNA - Abstract
Background Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890.
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- 2022
24. Evaluation of ctDNA in the Prediction of Response to Neoadjuvant Therapy and Prognosis in Locally Advanced Rectal Cancer Patients: A Prospective Study
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Marina Morais, Telma Fonseca, Diogo Melo-Pinto, Isabel Prieto, Ana Teresa Vilares, Ana Luísa Duarte, Patrícia Leitão, Luís Cirnes, José Carlos Machado, and Silvestre Carneiro
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ctDNA ,next-generation sequencing ,locally advanced rectal cancer ,neoadjuvant chemoradiation ,prediction of response ,disease-free survival ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine - Abstract
“Watch and wait” is becoming a common treatment option for patients with locally advanced rectal cancer (LARC) submitted to neoadjuvant treatment. However, currently, no clinical modality has an acceptable accuracy for predicting pathological complete response (pCR). The aim of this study was to assess the clinical utility of circulating tumor DNA (ctDNA) in predicting the response and prognosis in these patients. We prospectively enrolled a cohort of three Iberian centers between January 2020 and December 2021 and performed an analysis on the association of ctDNA with the main response outcomes and disease-free survival (DFS). The rate of pCR in the total sample was 15.3%. A total of 24 plasma samples from 18 patients were analyzed by next-generation sequencing. At baseline, mutations were detected in 38.9%, with the most common being TP53 and KRAS. Combination of either positive magnetic resonance imaging (MRI) extramural venous invasion (mrEMVI) and ctDNA increased the risk of poor response (p = 0.021). Also, patients with two mutations vs. those with fewer than two mutations had a worse DFS (p = 0.005). Although these results should be read carefully due to sample size, this study suggests that baseline ctDNA combined with mrEMVI could potentially help to predict the response and baseline ctDNA number of mutations might allow the discrimination of groups with different DFS. Further studies are needed to clarify the role of ctDNA as an independent tool in the selection and management of LARC patients.
- Published
- 2023
25. CDK4/6 Inhibitors Overcome Endocrine ESR1 Mutation-Related Resistance in Metastatic Breast Cancer Patients
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Stefania Crucitta, Martina Ruglioni, Giulia Lorenzini, Irene Bargagna, Giovanna Irene Luculli, Irene Albanese, Diana Bilancio, Francesca Patanè, Andrea Fontana, Romano Danesi, and Marzia Del Re
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Cancer Research ,liquid biopsy ,Oncology ,ctDNA ,metastatic breast cancer ,ESR1 mutation ,CDK4/6 inhibitor - Abstract
ESR1 mutations contribute to endocrine resistance and occur in a high percentage of hormone-receptor-positive (HR+) metastatic breast cancer (mBC) cases. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) changed the treatment landscape of HR+ mBC, as they are able to overcome estrogen resistance. The present retrospective study investigates the clinical benefit of CDK4/6i in ESR1 mutant HR+ mBC patients treated with a CDK4/6i as first- or second-line therapy. Plasma was collected at baseline prior to CDK4/6i plus hormone therapy as a first- or second-line treatment. Circulating free DNA (cfDNA) was extracted from plasma, and ESR1 mutation analysis was performed on a ddPCR. Statistical analyses were performed to investigate the predictive power of ESR1 mutations and any association with clinical factors. A total of 42 patients with mBC treated with CDK4/6i plus endocrine therapy as first- (n = 35) or second-line (n = 7) were enrolled. Twenty-eight patients received hormonal therapy (AI or tamoxifen) in the adjuvant setting. ESR1 mutation status in blood was associated with shorter median disease-free survival (DFS) (30 vs. 110 months; p = 0.006). Multivariate analysis confirmed ESR1 mutations as independent factors of resistance in adjuvant hormone therapy. On the contrary, no difference in progression-free survival (PFS) was observed in the presence or absence of an ESR1 mutation in patients treated with CDK4/6i as first-line treatment (p = 0.29). No statistically significant correlation between the best response to CDK4/6i and ESR1 mutation was found (p = 0.46). This study indicates that the ESR1 mutation detected in cfDNA is an independent predictive factor of clinical recurrence in the adjuvant setting and that CDK4/6i can overcome ESR1-dependent resistance.
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- 2023
26. Monitoring of EGFR mutations in circulating tumor DNA of non-small cell lung cancer patients treated with EGFR inhibitors
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T T van Duijl, Alwin D. R. Huitema, Neeltje Steeghs, Jos H. Beijnen, Mirte Muller, D. Van Den Broek, Remy B. Verheijen, Daan C L Vessies, M. van den Heuvel, Julie M Janssen, and J. H. M. Schellens
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0301 basic medicine ,Cancer Research ,EGFR ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,NSCLC ,Toxicology ,medicine.disease_cause ,law.invention ,03 medical and health sciences ,T790M ,0302 clinical medicine ,Gefitinib ,law ,medicine ,Pharmacology (medical) ,Liquid biopsy ,Lung cancer ,Polymerase chain reaction ,EGFR inhibitors ,Pharmacology ,Mutation ,business.industry ,ctDNA ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,Erlotinib ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,business ,medicine.drug - Abstract
Contains fulltext : 242612.pdf (Publisher’s version ) (Closed access) PURPOSE: We studied EGFR mutations in circulating tumor DNA (ctDNA) and explored their role in predicting the progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients treated with erlotinib or gefitinib. METHODS: The L858R, T790M mutations and exon 19 deletions were quantified in plasma using digital droplet polymerase chain reaction (ddPCR). The dynamics of ctDNA mutations over time and relationships with PFS were explored. RESULTS: In total, 249 plasma samples (1-13 per patient) were available from 68 NSCLC patients. The T790M and L858R or exon 19 deletion were found in the ctDNA of 49 and 56% patients, respectively. The median (range) concentration in these samples were 7.3 (5.1-3688.7), 11.7 (5.1-12,393.3) and 27.9 (5.9-2896.7) copies/mL, respectively. Using local polynomial regression, the number of copies of EGFR mutations per mL increased several months prior to progression on standard response evaluation. CONCLUSION: This change was more pronounced for the driver mutations than for the resistance mutations. In conclusion, quantification of EGFR mutations in plasma ctDNA was predictive of treatment outcomes in NSCLC patients. In particular, an increase in driver mutation copy number could predict disease progression.
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- 2021
27. Anlotinib has good efficacy and low toxicity: a phase II study of anlotinib in pre-treated HER-2 negative metastatic breast cancer
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Nanlin Hu, Zhuqing Jia, Fei Ma, Yang Shao, Binghe Xu, Yiran Si, Yang Luo, Jian Yue, Songlin Gao, Xue Wang, Jiayu Wang, Peng Yuan, Tingting Sun, and Qiao Li
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Oncology ,Cancer Research ,medicine.medical_specialty ,Anthracycline ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Phases of clinical research ,Review ,ctdna ,medicine.disease ,Chemotherapy regimen ,Metastatic breast cancer ,angiogenesis ,her2-negative ,breast cancer ,Breast cancer ,Internal medicine ,Toxicity ,medicine ,Clinical endpoint ,anlotinib ,business ,Adverse effect ,RC254-282 - Abstract
Objective: Anlotinib is a novel tyrosine kinase inhibitor blocking angiogenesis. This study was performed to assess the efficacy and safety of anlotinib in patients with metastatic breast cancer. Methods: Patients with HER2-negative breast cancer, who were pre-treated with anthracycline or taxanes in a neoadjuvant, adjuvant, or metastatic setting, and had treatment failure after at least one prior chemotherapy regimen in the metastatic setting were enrolled. Anlotinib was administered at 12 mg daily for 14 days in a 21-day cycle until disease progression or unacceptable toxicity occurred. Simultaneously, 5–10 mL of venous blood was collected to perform circulating tumor DNA (ctDNA) testing every 2 treatment cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival, safety, and biomarkers. Results: Twenty-six eligible patients were enrolled, with a median age of 56 (30–75) years. The median follow-up time was 10.5 months. The ORR was 15.4%, the DCR was 80.8%, and the median PFS was 5.22 months (95% confidence interval 2.86–6.24). Fourteen (53.8%) patients survived for more than 10 months. The changes in the detectable ctDNA variant allele frequency were consistent with the tumor response. The most common treatment-related adverse events were hypertension (57.7%), thyroidstimulating hormone elevation (34.6%), and hand-foot syndrome (23.1%). Conclusion: Anlotinib showed objective efficacy with tolerable toxicity in heavily pre-treated, metastatic HER2-negative breast cancer. The dynamic changes in the ctDNA variant allele fraction may be predictive of the tumor response.
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- 2021
28. Dynamic monitoring of circulating tumor DNA to predict prognosis and efficacy of adjuvant chemotherapy after resection of colorectal liver metastases
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Hui Yang, Yuan-Chao Zheng, Xiao-Yun Liu, De Shen Wang, William Pat Fong, Yun Zheng, Zhizhong Pan, Rui-Hua Xu, Yunfei Yuan, Yun Wang, Zhi-gang Chen, Lele Song, Yu Hong Li, Binkui Li, Gong Chen, and Ming-Tao Hu
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Male ,Oncology ,medicine.medical_specialty ,Neoplasm, Residual ,Adjuvant chemotherapy ,medicine.medical_treatment ,Concordance ,Medicine (miscellaneous) ,Kaplan-Meier Estimate ,Circulating Tumor DNA ,Internal medicine ,Exome Sequencing ,Biomarkers, Tumor ,medicine ,Adjuvant therapy ,Hepatectomy ,Humans ,Correlation of Data ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Alleles ,Exome sequencing ,Chemotherapy ,business.industry ,Liver Neoplasms ,Cancer ,ctDNA ,Middle Aged ,Prognosis ,medicine.disease ,Minimal residual disease ,adjuvant chemotherapy ,Gene Expression Regulation, Neoplastic ,colorectal liver metastases ,ROC Curve ,Chemotherapy, Adjuvant ,Mutation ,next-generation sequencing ,Female ,Neoplasm Recurrence, Local ,Colorectal Neoplasms ,business ,Research Paper - Abstract
Rationale: Hepatectomy and adjuvant chemotherapy after resection of colorectal liver metastases (CRLM) may improve survival, however, patients which may benefit cannot currently be identified. Postoperative circulating tumor DNA (ctDNA) analysis can detect minimal residual disease (MRD) and predict the prognosis and efficacy of adjuvant chemotherapy. Our study aims to determine the impact of serial ctDNA analysis to predict the outcome among patients undergoing resection of CRLM. Methods: Between May 2018 and October 2019, 91 CRLM patients were prospectively enrolled. Whole exome sequencing was performed in 50 primary and 48 metastatic liver tissues. Targeted sequencing of 451 cancer relevant genes was performed in 50 baseline plasma to determine plasma-tissue concordance. We prospectively investigated changes in the amount and constitution of ctDNA in 271 serial plasma samples taken at different time points (baseline, pre-operation, post-operation, post-operative adjuvant chemotherapy (post-ACT) and recurrence) during the treatment of CRLM. Results: Detected molecular alterations were highly consistent among baseline ctDNA, primary and liver metastases tissue. Patients with a higher variant allele frequency (VAF) level at baseline ctDNA represent a higher tumor burden, and decreased ctDNA during pre-operative chemotherapy predicted better tumor response. Patients with detectable post-operative and post-ACT ctDNA were associated with significantly shorter recurrence-free survival (RFS). ROC analysis showed that post-ACT ctDNA status was superior to post-operative ctDNA status in predicting RFS with an AUROC of 0.79. A significant difference in overall recurrence rate was observed in patients with detectable vs undetectable levels of ctDNA after resection of CRLM (79.4% vs 41.7%) and after completion of adjuvant chemotherapy (77.3% vs 40.7%). During adjuvant chemotherapy, patients with decreased ctDNA VAF after adjuvant chemotherapy had a recurrence rate of 63.6%, compared to 92.3% in patients with increased ctDNA VAF. Conclusions: We envision that dynamic ctDNA analysis, especially in a post-ACT setting, might be used to not only reflect MRD but also to determine rational personalized adjuvant therapy after the resection of CRLM.
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- 2021
29. Serial surveillance by circulating tumor DNA profiling after chimeric antigen receptor T therapy for the guidance of r/r diffuse large B cell lymphoma precise treatment
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Linghui Zhou, Yongxian Hu, Linqin Wang, He Huang, Arnon Nagler, Xin Chen, Fang Ni, Ruimin Hong, Yang Shao, and Houli Zhao
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Oncology ,medicine.medical_specialty ,business.industry ,Cancer ,ctDNA ,medicine.disease ,Minimal residual disease ,NFKBIE ,Chimeric antigen receptor ,CAR-T ,Lymphoma ,Cell therapy ,precise treatment ,DLBCL ,Internal medicine ,medicine ,business ,Diffuse large B-cell lymphoma ,Research Paper ,Lenalidomide ,medicine.drug - Abstract
Background: Circulating tumor DNA (ctDNA) released from tumor cells carries the tumor-associated genetic and epigenetic characteristics of cancer patients. Next-generation sequencing (NGS) facilitates the application of ctDNA profiling for identification and monitoring of minimal residual disease (MRD) in cancer, and can serve as the guidance for precise treatment. Methods: In this study, we profiled genomic alterations in the baseline, relapsed, and progressive tumor samples of eight diffuse large B cell lymphoma (DLBCL) patients (NCT03118180) after chimeric antigen receptor T (CAR-T) cell therapy. Results: The median follow-up was 41 months. 4 (50%) patients achieved complete remission (CR), 1 (12.5%) patient achieved partial remission (PR), and the other 3 (37.5%) patients showed no response. 3 of 5 patients who achieved remission relapsed within 4 months after CAR-T therapy, while the rest 2 patients remained CR for more than 3 years. Based on the positron emission tomography-computed tomography (PET-CT) scan, the current gold standard for evaluating response to therapy in lymphoma, the sensitivity and specificity of our ctDNA profiling in detecting tumor-related ctDNA mutations were 94.7% and 83.3%, respectively. The median numbers of baseline plasma ctDNA mutations in patients who remained long-term CR and patients who relapsed or became refractory to CAR-T therapy were 3 and 14.3, respectively. GNA13, SOCS1, TNFAIP3 and XPO1 mutations appeared to be associated with poor prognosis after CAR-T cell therapy. Our results also suggested that lenalidomide might relieve relapsed lymphoma with mutations in NFKBIA 202C>T (p.Q68*) and NFKBIE 433A>T (p.K145*) by targeting NF-Kappa B signaling. In addition, the inhibitor selinexor may be another choice for refractory or relapse (r/r) DLBCL patients after CAR-T cell treatment. Conclusion: Serial ctDNA monitoring is an emerging technology for the surveillance of disease status and prognosis prediction. In this work, we demonstrated the use of serial ctDNA monitoring in r/r DLBCL patients after CD19-targeted CAR-T cell therapy. Our longitudinal NGS profiling revealed the changes of ctDNA mutation in accordance with prognosis, and shed some light on exploring more targeted treatment options together with CAR-T cell therapy.
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- 2021
30. Early Assessment of Chemotherapy Response in Advanced Non-Small Cell Lung Cancer with Circulating Tumor DNA
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Stephanie J. Yaung, Corinna Woestmann, Christine Ju, Xiaoju Max Ma, Sandeep Gattam, Yiyong Zhou, Liu Xi, Subrata Pal, Aarthi Balasubramanyam, Nalin Tikoo, Claus Peter Heussel, Michael Thomas, Mark Kriegsmann, Michael Meister, Marc A. Schneider, Felix J. Herth, Birgit Wehnl, Maximilian Diehn, Ash A. Alizadeh, John F. Palma, and Thomas Muley
- Subjects
Cancer Research ,Oncology ,ctDNA ,NSCLC ,chemotherapy ,NGS ,early molecular response - Abstract
Monitoring treatment efficacy early during therapy could enable a change in treatment to improve patient outcomes. We report an early assessment of response to treatment in advanced NSCLC using a plasma-only strategy to measure changes in ctDNA levels after one cycle of chemotherapy. Plasma samples were collected from 92 patients with Stage IIIB-IV NSCLC treated with first-line chemo- or chemoradiation therapies in an observational, prospective study. Retrospective ctDNA analysis was performed using next-generation sequencing with a targeted 198-kb panel designed for lung cancer surveillance and monitoring. We assessed whether changes in ctDNA levels after one or two cycles of treatment were associated with clinical outcomes. Subjects with ≤50% decrease in ctDNA level after one cycle of chemotherapy had a lower 6-month progression-free survival rate (33% vs. 58%, HR 2.3, 95% CI 1.2 to 4.2, log-rank p = 0.009) and a lower 12-month overall survival rate (25% vs. 70%, HR 4.3, 95% CI 2.2 to 9.7, log-rank p < 0.001). Subjects with ≤50% decrease in ctDNA level after two cycles of chemotherapy also had shorter survival. Using non-invasive liquid biopsies to measure early changes in ctDNA levels in response to chemotherapy may help identify non-responders before standard-of-care imaging in advanced NSCLC.
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- 2022
31. SWOG 1918: A phase II/III randomized study of R-miniCHOP with or without oral azacitidine (CC-486) in participants age 75 years or older with newly diagnosed aggressive non-Hodgkin lymphomas - Aiming to improve therapy, outcomes, and validate a prospective frailty tool
- Author
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Brem, Elizabeth A, Li, Hongli, Beaven, Anne W, Caimi, Paolo F, Cerchietti, Leandro, Alizadeh, Ash A, Olin, Rebecca, Henry, N Lynn, Dillon, Hildy, Little, Richard F, Laubach, Cara, LeBlanc, Michael, Friedberg, Jonathan W, and Smith, Sonali M
- Subjects
Aging ,Lymphoma ,Frailty ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Non-Hodgkin ,Evaluation of treatments and therapeutic interventions ,ctDNA ,Hematology ,Diffuse ,Older ,Rare Diseases ,Clinical Research ,DLBCL ,6.1 Pharmaceuticals ,Antineoplastic Combined Chemotherapy Protocols ,Azacitidine ,Large B-Cell ,Humans ,Prospective Studies ,Rituximab ,Geriatric ,Aged ,Cancer - Abstract
Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy; however, cure is highly dependent on the ability to deliver intensive, anthracycline-based chemoimmunotherapy. Nearly one third of cases of DLBCL occur in patients over age 75years, and advanced age is an important adverse feature in prognostic models. Despite this incidence in older patients, there is no clear accepted standard of care due to under-representation of this group in large randomized clinical trials. Furthermore, insufficient assessments of baseline frailty and prediction of toxicity hamper clinical decision-making. Here, we present an ongoing randomized study of R-miniCHOP chemoimmunotherapy with or without oral azacitidine (CC-486, Onureg) for patients age 75 and older with newly diagnosed DLBCL and associated aggressive lymphomas. The incorporation of an oral hypomethylating agent is based on increased tumor methylation as a biologic feature of older patients with DLBCL and a desire to minimize the injection burden for this population. This is the first randomized study in this population conducted in North America by the National Clinical Trials Network (NCTN) and will enroll up to 422 patients including 40 patients in a safety run-in phase. This study incorporates an objective assessment of baseline frailty (the FIL Tool) and a serial comprehensive geriatric assessment (CGA). Key correlative tests will include circulating tumor DNA (ctDNA) assays at pre-specified timepoints to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has the potential to impact future trial design and to change the standard of care for patients 75years and older with aggressive lymphoma given its randomized design, prospective incorporation of geriatric assessments, and exploration of ctDNA correlatives. Trial registration: The trial is registered with ClinicalTrial.gov Identifier NCT04799275.
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- 2022
32. Liquid biopsy in oncology: A consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology
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José Luis Rodríguez-Peralto, Álvaro Rodríguez-Lescure, Ruth Vera, Enrique de Álava, Beatriz Bellosillo, Federico Rojo Todo, Ramiro Álvarez-Alegret, Pilar Garrido, Jordi Remon, and Rosario García-Campelo
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Perfil genómico ,ctADN ,CtDNA ,Disease ,Oncología ,Pathology and Forensic Medicine ,03 medical and health sciences ,Tumour tissue ,0302 clinical medicine ,Internal medicine ,Biopsy ,medicine ,Liquid biopsy ,Medicina de precisión ,medicine.diagnostic_test ,business.industry ,Genomic profiling ,Precision medicine ,Cancer ,medicine.disease ,Clinical Practice ,030104 developmental biology ,030220 oncology & carcinogenesis ,Biopsia líquida ,Genomic Profile ,business ,Tissue biopsy - Abstract
[ES] Los pacientes con cáncer y alteraciones oncogénicas potencialmente tratables están aumentando de forma considerable. El diagnóstico de estas alteraciones permite frecuentemente realizar un tratamiento personalizado inicial o a la progresión, así como conocer información predictiva sobre la eficacia de la inmunoterapia. Sin embargo, en un 25% de los casos, la biopsia de tejido inicial no es informativa o no es posible realizar el perfil genómico tumoral a la progresión por la dificultad para obtener nuevas biopsias de tejido tumoral. Por ello, son necesarias alternativas diagnósticas eficaces para la estratificación molecular, que permitan una valoración dinámica del perfil genómico tumoral, como la biopsia líquida, reflejando además la heterogeneidad genómica en el seno del mismo paciente. Actualmente, existen distintas técnicas diagnósticas de biopsia líquida, cada una con distintos grados de precisión y rendimiento. El objetivo de este consenso de la Sociedad Española de Anatomía Patológica (SEAP) y la Sociedad Española de Oncología Médica (SEOM) es evaluar la viabilidad y efectividad de las distintas técnicas de biopsia líquida en el paciente con cáncer en la práctica clínica diaria. Los expertos de este consenso concluyen que la biopsia líquida es una alternativa aceptable a la biopsia de tejido para el estudio de biomarcadores. Sin embargo, es importante estandarizar los procedimientos preanalíticos y analíticos, garantizar su reproducibilidad, así como generar informes clínicos estructurados y comprensibles. La implementación de comités multidisciplinares de evaluación de las alteraciones moleculares es fundamental para mejorar estos procesos y favorecer las decisiones terapéuticas más adecuadas para cada paciente con cáncer en función de perfil genómico., [EN] The proportion of cancer patients with tumours that harbour a potentially targetable genomic alteration is increasing considerably. The diagnosis of these genomic alterations can lead to tailoring of treatment, at the onset of disease or during progression, as well as providing additional, predictive information on the efficacy of immunotherapy. However, in up to 25% of cases, the initial tissue biopsy is inadequate for precision oncology and, in many cases, tumour genomic profiling at progression is not possible due to technical limitations of obtaining new tumour tissue specimens. Efficient diagnostic alternatives are therefore required for molecular stratification, such as liquid biopsy. This technique enables the evaluation of the tumour genomic profile dynamically and as well as capturing intra-patient genomic heterogeneity. To date, there are several diagnostic techniques available for use in liquid biopsy, each with different precision and performance levels. The objective of this consensus statement of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) is to evaluate the viability and effectiveness of the different methodological approaches of liquid biopsy in cancer patients, and the potential application of this method to current clinical practice. The experts contributing to this consensus statement agree that, according to current evidence, liquid biopsy is an acceptable alternative to tumour tissue biopsy for the study of biomarkers in various clinical settings. It is therefore important to standardise pre-analytical and analytical procedures to ensure reproducibility and to generate structured and accessible clinical reports. It is essential to appoint multidisciplinary tumour molecular committees to oversee these processes and to enable the most suitable therapeutic decisions for each patient according to the genomic profile.
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- 2020
33. Generic Protocols for the Analytical Validation of Next-Generation Sequencing-Based ctDNA Assays: A Joint Consensus Recommendation of the BloodPAC’s Analytical Variables Working Group
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James H Godsey, Aaron O Richardson, Angela Silvestro, James W. Hicks, Joe McMullen, Lisa M. McShane, Donald J Johann, Lauren C. Leiman, Kelli Tanzella, John D. Simmons, J. Carl Barrett, Rebecca Leary, Jennifer S Dickey, Darya Chudova, Ina L. Deras, Jerry S.H. Lee, Kelli Bramlett, Katherine Nakamura, Laura M. Yee, and Matthew Ryder
- Subjects
0301 basic medicine ,analytical validation ,Computer science ,Clinical Biochemistry ,Guidelines as Topic ,Validation Studies as Topic ,DNA sequencing ,Circulating Tumor DNA ,Food and drug administration ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Biomarkers, Tumor ,Humans ,Profiling (information science) ,cfDNA ,Liquid biopsy ,Special Report ,plasma ,Data collection ,liquid biopsy ,Biochemistry (medical) ,Context variable ,High-Throughput Nucleotide Sequencing ,ctDNA ,Reference Standards ,Presubmission ,Data science ,030104 developmental biology ,Circulating tumor DNA ,NGS ,030220 oncology & carcinogenesis - Abstract
Liquid biopsy, particularly the analysis of circulating tumor DNA (ctDNA), has demonstrated considerable promise for numerous clinical intended uses. Successful validation and commercialization of novel ctDNA tests have the potential to improve the outcomes of patients with cancer. The goal of the Blood Profiling Atlas Consortium (BloodPAC) is to accelerate the development and validation of liquid biopsy assays that will be introduced into the clinic. To accomplish this goal, the BloodPAC conducts research in the following areas: Data Collection and Analysis within the BloodPAC Data Commons; Preanalytical Variables; Analytical Variables; Patient Context Variables; and Reimbursement. In this document, the BloodPAC’s Analytical Variables Working Group (AV WG) attempts to define a set of generic analytical validation protocols tailored for ctDNA-based Next-Generation Sequencing (NGS) assays. Analytical validation of ctDNA assays poses several unique challenges that primarily arise from the fact that very few tumor-derived DNA molecules may be present in circulation relative to the amount of nontumor-derived cell-free DNA (cfDNA). These challenges include the exquisite level of sensitivity and specificity needed to detect ctDNA, the potential for false negatives in detecting these rare molecules, and the increased reliance on contrived samples to attain sufficient ctDNA for analytical validation. By addressing these unique challenges, the BloodPAC hopes to expedite sponsors’ presubmission discussions with the Food and Drug Administration (FDA) with the protocols presented herein. By sharing best practices with the broader community, this work may also save the time and capacity of FDA reviewers through increased efficiency.
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- 2020
34. Prediction of the prognosis of advanced hepatocellular carcinoma by TERT promoter mutations in circulating tumor DNA
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Hideaki Kinugasa, Atsushi Oyama, Takuya Adachi, Hidenori Shiraha, Kazuhiro Nouso, Hiroyuki Terasawa, Nozomu Wada, Yuma Onishi, Shumpei Yamamoto, Masahiro Sakata, Hideki Onishi, Akinobu Takaki, Hiroyuki Okada, Tetsuya Yasunaka, and Mami Hirai
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Male ,Carcinoma, Hepatocellular ,Tert promoter ,law.invention ,law ,Biomarkers, Tumor ,Humans ,Medicine ,Neoplasm Invasiveness ,Telomerase reverse transcriptase ,Liquid biopsy ,TERT promoter mutation ,Promoter Regions, Genetic ,Transcatheter arterial chemoembolization ,Telomerase ,Polymerase chain reaction ,Neoplasm Staging ,Hepatology ,liquid biopsy ,business.industry ,Liver Neoplasms ,Gastroenterology ,DNA, Neoplasm ,ctDNA ,hepatocellular carcinoma ,Prognosis ,medicine.disease ,Survival Rate ,Circulating tumor DNA ,Hepatocellular carcinoma ,Mutation ,Cancer research ,Biomarker (medicine) ,Female ,business ,prediction prognosis - Abstract
Background and Aim Human telomerase reverse transcriptase (TERT) promoter mutations were the most prevalent mutations in patients with hepatocellular carcinoma (HCC). We tried to detect the mutations with plasma circulating tumor DNA (ctDNA) in patients with advanced HCC and elucidated their clinical utility. Methods Circulating tumor DNA in plasma was extracted from 130 patients with advanced HCC who were treated with systemic chemotherapy (n = 86) or transcatheter arterial chemoembolization (n = 44), and TERT promoter mutations were examined with digital droplet polymerase chain reaction. The correlations between these mutations and the clinical outcome of patients were analyzed. Results Of the 130 patients examined, 71 patients (54.6%) were positive for TERT promoter mutations in ctDNA, of which 64 patients were −124bp G > A and 10 were −146bp G > A. The presence of TERT promoter mutations was correlated with large intrahepatic tumor size (P = 0.05) and high des‐gamma carboxyprothrombin (P = 0.005). Overall survival of the patients with the mutations was significantly shorter than those without them (P < 0.001), and the patients with high (≥ 1%) fractional abundance of the mutant alleles showed shorter survival than those with low (< 1%) fractional abundance. Multivariate analysis revealed that TERT promoter mutation (hazard ratio [HR]: 1.94; 95% confidence interval [CI], 1.18–3.24; P < 0.01), systemic chemotherapy (HR: 2.38; 95% CI, 1.29–4.57; P < 0.01), and vascular invasion (HR: 2.16; 95% CI, 1.22–3.76; P < 0.01) were significant factors for poor overall survival. Conclusions TERT promoter mutations in ctDNA were associated with short survival and could be a valuable biomarker for predicting the prognosis of patients with advanced HCC.
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- 2020
35. Safety and efficacy of sirolimus combined with endocrine therapy in patients with advanced hormone receptor-positive breast cancer and the exploration of biomarkers
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Binliang Liu, Haili Qian, Hui Li, Binghe Xu, Fei Ma, Xiaoying Sun, Zongbi Yi, Wenna Wang, Jingtong Zhai, Xiuwen Guan, Lixi Li, Guohua Rong, and Chunxiao Li
- Subjects
Adult ,Oncology ,China ,medicine.medical_specialty ,mTOR inhibitor ,medicine.medical_treatment ,Breast Neoplasms ,lcsh:RC254-282 ,Circulating Tumor DNA ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Humans ,Everolimus ,030212 general & internal medicine ,Adverse effect ,Fulvestrant ,Retrospective Studies ,Sirolimus ,Chemotherapy ,Aromatase Inhibitors ,business.industry ,TOR Serine-Threonine Kinases ,Hazard ratio ,Cancer ,ctDNA ,General Medicine ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Metastatic breast cancer ,Progression-Free Survival ,Tamoxifen ,030220 oncology & carcinogenesis ,Female ,Original Article ,Surgery ,Toremifene ,business ,Signal Transduction ,medicine.drug - Abstract
Background We performed a retrospective study on the efficacy and safety of sirolimus (an mTOR inhibitor) in hormone receptor (HR)-positive advanced breast cancer and searched for biomarkers to predict its efficacy. Methods All patients with HR-positive metastatic breast cancer treated with sirolimus plus endocrine therapy between December 2017 and July 2018 at the Cancer Hospital, Chinese Academy of Medical Sciences were consecutively and retrospectively reviewed. Mutations in circulating tumour DNA (ctDNA) were assayed for 1021 tumour-related genes via gene panel target capture-based next-generation sequencing. Results Thirty-six patients with metastatic breast cancer treated with sirolimus plus endocrine therapy were included. The progression-free survival (PFS) rates between the sirolimus group and everolimus group were similar, and the median PFS was 4.9 months and 5.5 months, respectively (hazard ratio 1.56, 95% CI 0.86–2.81, P = 0.142). The objective response rate in the 36 patients was 19.4%, and the clinical benefit rate was 41.7%. Lipid metabolism disorder was the most common adverse event (69.4%), and 13.9% of patients had stomatitis. Most (94.4%) adverse events were grade 1–2. Twenty patients (55.6%) underwent ctDNA analysis before receiving sirolimus therapy. For patients who received less than 3 lines of chemotherapy, those with PI3K/Akt/mTOR pathway alterations had a better response to sirolimus than those without alterations, with a median PFS of 7.0 months vs 4.3 months (hazard ratio = 0.01, 95% CI 0.00–0.34, P = 0.010). Conclusions Sirolimus is a potentially effective treatment option for patients with HR-positive advanced breast cancer., Highlights • Sirolimus is a potentially effective treatment option for patients with hormone receptor-positive advanced breast cancer. • A previous chemotherapy line was a poor predictor of sirolimus efficacy. • PI3K/Akt/mTOR pathway alterations may affect the efficacy of sirolimus.
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- 2020
36. Preoperative evaluation of microvascular invasion with circulating tumour DNA in operable hepatocellular carcinoma
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Ke Ye, Xin Yi, Jianjun Zhang, Jennifer Brooke Goldstein, Yaping Xu, Yanfang Guan, Xuefeng Xia, Lifeng Li, Qiongzhi He, Guo Long, Liang Xiao, Zhiming Wang, Dong Wang, Lianpeng Chang, Xi Hu, and Ledu Zhou
- Subjects
Liver Cancer ,Oncology ,medicine.medical_specialty ,Multivariate analysis ,medicine.medical_treatment ,microvascular invasion ,Tissue sample ,surgical management ,03 medical and health sciences ,hepatectomy ,0302 clinical medicine ,Internal medicine ,Medicine ,Risk factor ,Allele frequency ,Univariate analysis ,Hepatology ,business.industry ,ctDNA ,hepatocellular carcinoma ,medicine.disease ,Training cohort ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Original Article ,030211 gastroenterology & hepatology ,Hepatectomy ,business - Abstract
Background & Aims Microvascular invasion (MVI) is a critical prognostic factor for operable hepatocellular carcinoma (HCC). This study aimed to explore the performance of circulating tumour DNA (ctDNA) in evaluating MVI status preoperatively. Methods Seventy‐three HCC patients were enrolled and randomly divided into a training cohort and a validation cohort in a 2:1 ratio, and preoperative blood and surgical tissue samples were obtained. Genomic alterations were analysed using targeted deep sequencing with a 1021‐gene panel. Results In training cohort, 260 somatic mutations were identified in 40 blood samples (81.6%). CtDNA mutation was verified in paired tissue sample in 39 patients (97.5%). In univariate analysis, ctDNA allele frequency (AF) and largest tumour diameter were associated with the presence of MVI, but ctDNA AF was the only independent risk factor in multivariate analysis. With the cut‐off value of 0.83%, ctDNA AF determined the presence of MVI with the sensitivity of 89.7% and specificity of 80.0% in the training cohort, and the sensitivity of 78.6% and the specificity of 81.8% in the validation cohort. In preoperative evaluation, ctDNA AF, AFP level and BCLC staging were associated with recurrence‐free survival in both univariate and multivariate analysis. Conclusions CtDNA can serve as an independent risk factor of MVI for operable HCC and help determining precise treatment strategies. The integration of ctDNA in the management of operable HCC may achieve better clinical outcomes.
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- 2020
37. Clinical utility of circulating tumor DNA as a response and follow-up marker in cancer therapy
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Geke A. P. Hospers, Rudolf S N Fehrmann, Derk-Jan de Groot, Ed Schuuring, Anna K.L. Reyners, Michel van Kruchten, Pieter A. Boonstra, Thijs T Wind, Anthonie J. van der Wekken, and Carolien P. Schröder
- Subjects
0301 basic medicine ,Oncology ,ESR1 MUTATIONS ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,MONITOR TREATMENT RESPONSE ,Circulating Tumor DNA ,Clinical ,03 medical and health sciences ,LUNG-CANCER ,0302 clinical medicine ,Breast cancer ,Predictive Value of Tests ,Neoplasms ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Digital polymerase chain reaction ,NSCLC PATIENTS ,Predictive testing ,Lung cancer ,DIGITAL PCR ,Therapy monitoring ,business.industry ,Follow-up ,EGFR MUTATIONS ,Melanoma ,Liquid Biopsy ,Driver mutations ,ctDNA ,medicine.disease ,Mutation detection ,METASTATIC COLORECTAL-CANCER ,030104 developmental biology ,Cell-free fetal DNA ,Circulating tumor DNA ,CELL-FREE DNA ,030220 oncology & carcinogenesis ,Mutation ,LIQUID BIOPSIES ,business ,ACQUIRED-RESISTANCE - Abstract
Response evaluation for cancer treatment consists primarily of clinical and radiological assessments. In addition, a limited number of serum biomarkers that assess treatment response are available for a small subset of malignancies. Through recent technological innovations, new methods for measuring tumor burden and treatment response are becoming available. By utilization of highly sensitive techniques, tumor-specific mutations in circulating DNA can be detected and circulating tumor DNA (ctDNA) can be quantified. These so-called liquid biopsies provide both molecular information about the genomic composition of the tumor and opportunities to evaluate tumor response during therapy. Quantification of tumor-specific mutations in plasma correlates well with tumor burden. Moreover, with liquid biopsies, it is also possible to detect mutations causing secondary resistance during treatment. This review focuses on the clinical utility of ctDNA as a response and follow-up marker in patients with non-small cell lung cancer, melanoma, colorectal cancer, and breast cancer. Relevant studies were retrieved from a literature search using PubMed database. An overview of the available literature is provided and the relevance of ctDNA as a response marker in anti-cancer therapy for clinical practice is discussed. We conclude that the use of plasma-derived ctDNA is a promising tool for treatment decision-making based on predictive testing, detection of resistance mechanisms, and monitoring tumor response. Necessary steps for translation to daily practice and future perspectives are discussed.
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- 2020
38. Concordance between TP53 alterations in blood and tissue: impact of time interval, biopsy site, cancer type and circulating tumor DNA burden
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Ryosuke Okamura, Razelle Kurzrock, and Cheyennedra C. Bieg-Bourne
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Time Factors ,Colorectal cancer ,Biopsy ,Gastroenterology ,Circulating Tumor DNA ,0302 clinical medicine ,Biopsy Site ,Neoplasms ,TP53 ,Neoplasm Metastasis ,Research Articles ,Aged, 80 and over ,General Medicine ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Oncology ,Circulating tumor DNA ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,Research Article ,Tissue biopsy ,Adult ,concordance ,medicine.medical_specialty ,Concordance ,Context (language use) ,lcsh:RC254-282 ,Young Adult ,03 medical and health sciences ,Internal medicine ,genomics ,Genetics ,medicine ,Humans ,cancer ,Aged ,Genome, Human ,business.industry ,Cancer type ,Cancer ,ctDNA ,medicine.disease ,030104 developmental biology ,Genetic Loci ,Tumor Suppressor Protein p53 ,business - Abstract
We examined the impact of spatial, temporal, histologic, and quantitative factors on concordance between TP53 alterations in tissue DNA vs in circulating tumor DNA (ctDNA). Four hundred and thirty‐three patients underwent next‐generation sequencing (NGS) in which both tissue and blood samples were evaluated. TP53 was detected in 258 of 433 patients (59.6%); 215 had tissue TP53 alterations (49.7%); 159, ctDNA (36.7%); and 116, both tissue and ctDNA (27.8%). Overall concordance rate between ctDNA and tissue biopsies for TP53 alterations was 67.2%; positive concordance was 45.0%. Overall concordance for TP53 did not vary among patients with ≤ 2 months vs > 6 months between test samples; however, positive concordance trended higher when time intervals between test samples were shorter, suggesting that the lack of difference in overall concordance may be due to the large number of negative/negative tests. There was a trend toward higher overall concordance based on biopsy site (metastatic vs primary) (P = 0.07) and significantly higher positive concordance if the tissue biopsy site was a metastatic lesion (P = 0.03). Positive concordance significantly decreased in noncolorectal cancer patients vs colorectal cancer patients (P = 0.02). Finally, higher %ctDNA was associated with higher concordance rates between blood and tissue (P, This study presents evidence that the evaluation of the full spectrum of TP53 alterations in patients with diverse malignancies requires sequencing of both blood‐derived circulating tumor DNA and tissue DNA. Multiple factors can influence positive concordance rates between the tests, including site of tissue biopsy, %ctDNA, time between tissue biopsy and blood sample, and histologic context.
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- 2020
39. Pre‐analytical factors affecting the establishment of a single tube assay for multiparameter liquid biopsy detection in melanoma patients
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Peter Mohr, Klaus Pantel, Janina Staub, Harriet Wikman, Taija af Hällström, Julia-Christina Stadler, Stefan W. Schneider, Svenja Schneegans, Alexander Sartori, Evi Lianidou, Leonie Bluhm, Mikael Kubista, Jonathan M Shaffer, Darryl Irwin, Katharina Besler, Rüdiger Greinert, Elina Serkkola, Lelia Lück, Beate Volkmer, Christoffer Gebhardt, Melanie A. Hussong, and Markus Sprenger-Haussels
- Subjects
Male ,0301 basic medicine ,Cancer Research ,lcsh:RC254-282 ,Peripheral blood mononuclear cell ,Circulating Tumor DNA ,Extracellular Vesicles ,03 medical and health sciences ,0302 clinical medicine ,Circulating tumor cell ,Microscopy, Electron, Transmission ,Cell Line, Tumor ,microRNA ,Biomarkers, Tumor ,melanoma ,Genetics ,medicine ,Humans ,Liquid biopsy ,Research Articles ,Aged ,Neoplasm Staging ,miRNA ,liquid biopsy ,Chemistry ,Melanoma ,High-Throughput Nucleotide Sequencing ,Cancer ,ctDNA ,General Medicine ,Neoplastic Cells, Circulating ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,CTC ,Molecular biology ,Hemolysis ,MicroRNAs ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,Molecular Medicine ,Female ,Blood Collection Tube ,Research Article ,EV - Abstract
The combination of liquid biomarkers from a single blood tube can provide more comprehensive information on tumor development and progression in cancer patients compared to single analysis. Here, we evaluated whether a combined analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and circulating cell‐free microRNA (miRNA) in total plasma and extracellular vesicles (EV) from the same blood sample is feasible and how the results are influenced by the choice of different blood tubes. Peripheral blood from 20 stage IV melanoma patients and five healthy donors (HD) was collected in EDTA, Streck, and Transfix tubes. Peripheral blood mononuclear cell fraction was used for CTC analysis, whereas plasma and EV fractions were used for ctDNA mutation and miRNA analysis. Mutations in cell‐free circulating DNA were detected in 67% of patients, with no significant difference between the tubes. CTC was detected in only EDTA blood and only in 15% of patients. miRNA NGS (next‐generation sequencing) results were highly influenced by the collection tubes and could only be performed from EDTA and Streck tubes due to hemolysis in Transfix tubes. No overlap of significantly differentially expressed miRNA (patients versus HD) could be found between the tubes in total plasma, whereas eight miRNA were commonly differentially regulated in the EV fraction. In summary, high‐quality CTCs, ctDNA, and miRNA data from a single blood tube can be obtained. However, the choice of blood collection tubes is a critical pre‐analytical variable., We assessed whether a combined analysis of circulating tumor cells, circulating tumor DNA, and microRNA in total plasma or extracellular vesicles from one blood sample is feasible. We show that high‐quality data from a single blood tube can be obtained in melanoma patients. However, the choice of the tube affects the outcome of the analysis, underlining the importance of pre‐analytical factors.
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- 2020
40. Detection of plasmaEGFRmutations for personalized treatment of lung cancer patients without pathologic diagnosis
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Aditi P. Singh, Songwen Zhou, Mariam Alexander, Shenduo Li, Hui Sun, Qiyu Fang, Haiying Cheng, and Qinfang Deng
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,Lung Neoplasms ,DNA Mutational Analysis ,Personalized treatment ,Circulating Tumor DNA ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Digital polymerase chain reaction ,Prospective Studies ,Precision Medicine ,Prospective cohort study ,Original Research ,Aged, 80 and over ,medicine.diagnostic_test ,High-Throughput Nucleotide Sequencing ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,personalized treatment ,Progression-Free Survival ,ErbB Receptors ,030220 oncology & carcinogenesis ,Female ,Tyrosine kinase ,Adult ,medicine.medical_specialty ,lcsh:RC254-282 ,03 medical and health sciences ,Internal medicine ,Biopsy ,Biomarkers, Tumor ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Lung cancer ,Protein Kinase Inhibitors ,Genotyping ,Aged ,business.industry ,Clinical Cancer Research ,ctDNA ,medicine.disease ,EGFR mutations ,lung cancer ,030104 developmental biology ,Egfr mutation ,Case-Control Studies ,Mutation ,Feasibility Studies ,business ,Follow-Up Studies - Abstract
Introduction Next‐generation sequencing (NGS) and digital polymerase chain reaction (PCR) based platforms have been used to detect EGFR mutations in plasma circulating tumor DNA (ctDNA) with high accuracy. Generally, molecular testing is performed after histopathological analysis. However, many patients with suspected advanced nonsmall cell lung cancer are unable to undergo biopsy thus forgoing potential treatment with highly effective tyrosine kinase inhibitors (TKIs) in patients with sensitizing EGFR mutations. We examined the utility of ctDNA testing to detect EGFR mutations in patients' plasma, where tissue biopsy is not feasible. Methods We conducted a single‐center, prospective study of 30 Chinese patients with suspected advanced lung cancer, who were unable to undergo a biopsy for initial diagnosis due to comorbidities or poor performance status. Patients with plasma EGFR sensitizing mutations were treated with first‐generation EGFR TKIs. Results Twenty of 30 patients enrolled had sensitizing EGFR mutations in ctDNA and were started on EGFR TKIs. After a median follow‐up of 12 months, median progression‐free survival (PFS) was 10 months and median overall survival (OS) was not reached. The median OS for the 10 untreated patients was 3 months. Conclusions In our study, patients with plasma EGFR mutations treated with TKIs showed disease control rate (DCR) and PFS similar to historical controls that were treated based on tissue testing. This is the first prospective study showing that ctDNA genotyping provides a feasible diagnostic approach for frail lung cancer patients who are unable to undergo biopsy, which subsequently leads to EGFR‐targeted therapy, and improved outcomes in this subgroup of patients., This study is the first to prospectively evaluate the utility and feasibility of plasma circulating tumor DNA to detect EGFR mutations in frail patients with lung cancer, when tissue biopsy was not feasible. Incorporating plasma molecular profiling with clinical data allowed patients with sensitizing EGFR mutations to undergo treatment with highly effective tyrosine kinase inhibitors in a timely manner and gain significant improvement in overall survival, disease control rate, and progression free survival.
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- 2020
41. Overview on Molecular Biomarkers for Laryngeal Cancer: Looking for New Answers to an Old Problem
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Michela Falco, Chiara Tammaro, Takashi Takeuchi, Alessia Maria Cossu, Giuseppe Scafuro, Silvia Zappavigna, Annalisa Itro, Raffaele Addeo, Marianna Scrima, Angela Lombardi, Filippo Ricciardiello, Carlo Irace, Michele Caraglia, Gabriella Misso, Falco, M., Tammaro, C., Takeuchi, T., Cossu, A. M., Scafuro, G., Zappavigna, S., Itro, A., Addeo, R., Scrima, M., Lombardi, A., Ricciardiello, F., Irace, C., Caraglia, M., Misso, G., and Irace, Carlo
- Subjects
Cancer Research ,lncRNA ,TME (tumor microenvironment) ,Oncology ,LSCC (laryngeal squamous cell carcinoma) ,epigenetic modification ,biomarker ,ctDNA ,CTC ,inflammatory marker ,miRNA - Abstract
Laryngeal squamous cell cancer (LSCC) accounts for almost 25–30% of all head and neck squamous cell cancers and is clustered according to the affected districts, as this determines distinct tendency to recur and metastasize. A major role for numerous genetic alterations in driving the onset and progression of this neoplasm is emerging. However, major efforts are still required for the identification of molecular markers useful for both early diagnosis and prognostic definition of LSCC that is still characterized by significant morbidity and mortality. Non-coding RNAs appear the most promising as they circulate in all the biological fluids allowing liquid biopsy determination, as well as due to their quick and characteristic modulation useful for non-invasive detection and monitoring of cancer. Other critical aspects are related to recent progress in circulating tumor cells and DNA detection, in metastatic status and chemo-refractoriness prediction, and in the functional interaction of LSCC with chronic inflammation and innate immunity. We review all these aspects taking into account the progress of the technologies in the field of next generation sequencing.
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- 2022
42. Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring
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Wen Li, Ji-Bin Liu, Li-Kun Hou, Fei Yu, Jie Zhang, Wei Wu, Xiao-Mei Tang, Feng Sun, Hai-Min Lu, Jing Deng, Jie Bai, Juan Li, Chun-Yan Wu, Qin-Lu Lin, Zhong-Wei Lv, Gao-Ren Wang, Geng-Xi Jiang, Yu-Shui Ma, and Da Fu
- Subjects
Cancer Research ,Lung Neoplasms ,Liquid biopsy ,Clinical Decision-Making ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Disease Management ,High-Throughput Nucleotide Sequencing ,Review ,ctDNA ,Exosomes ,Neoplastic Cells, Circulating ,Prognosis ,Circulating Tumor DNA ,Oncology ,Biomarkers, Tumor ,Animals ,Humans ,Molecular Medicine ,Disease Susceptibility ,Lung cancer ,CTCs ,Diagnostics ,RC254-282 - Abstract
Primary lung cancer is one of the most common malignant tumors in China. Approximately 60% of lung cancer patients have distant metastasis at the initial diagnosis, so it is necessary to find new tumor markers for early diagnosis and individualized treatment. Tumor markers contribute to the early diagnosis of lung cancer and play important roles in early detection and treatment, as well as in precision medicine, efficacy monitoring, and prognosis prediction. The pathological diagnosis of lung cancer in small biopsy specimens determines whether there are tumor cells in the biopsy and tumor type. Because biopsy is traumatic and the compliance of patients with multiple biopsies is poor, liquid biopsy has become a hot research direction. Liquid biopsies are advantageous because they are nontraumatic, easy to obtain, reflect the overall state of the tumor, and allow for real-time monitoring. At present, liquid biopsies mainly include circulating tumor cells, circulating tumor DNA, exosomes, microRNA, circulating RNA, tumor platelets, and tumor endothelial cells. This review introduces the research progress and clinical application prospect of liquid biopsy technology for lung cancer.
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- 2022
43. Circulating Cell-Free Tumor DNA in Advanced Pancreatic Adenocarcinoma Identifies Patients With Worse Overall Survival
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Gehan Botrus, Pedro Luiz Serrano Uson Junior, Puneet Raman, Adrienne E. Kaufman, Heidi Kosiorek, Jun Yin, Yu Fu, Umair Majeed, Mohamad Bassam Sonbol, Daniel H. Ahn, Isabela W. Chang, Leylah M. Drusbosky, Hiba Dada, Jason Starr, Mitesh Borad, Kabir Mody, and Tanios S. Bekaii-Saab
- Subjects
circulating tumor DNA ,Cancer Research ,Oncology ,pancreatic cancer ,KRAS ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,ctDNA ,TP53 ,RC254-282 ,Original Research - Abstract
BackgroundPlasma-based circulating cell-free tumor DNA (ctDNA) genomic profiling by next-generation sequencing (NGS)is an emerging diagnostic tool for pancreatic cancer (PC). The impact of detected genomic alterations and variant allele fraction (VAF) in tumor response to systemic treatments and outcomes is under investigation.MethodsPatients with advanced PC who had ctDNA profiled at time of initial diagnosis were retrospectively evaluated. We considered the somatic alteration with the highest VAF as the dominant clone allele frequency (DCAF). ctDNA NGS results were related to clinical demographics, progression-free survival (PFS) and overall survival (OS).ResultsA total of 104 patients were evaluated. Somatic alterations were detected in 84.6% of the patients. Patients with ≥ 2 detectable genomic alterations had worse median PFS (p < 0.001) and worse median OS (p = 0.001). KRAS was associated with disease progression to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (p < 0.001) and worse median OS (p = 0.002). TP53 was associated with worse median PFS (p = 0.02) and worse median OS (p = 0.001). The median DCAF was 0.45% (range 0-55%). DCAF >0.45% was associated with worse median PFS (pKRAS had better PFS (p=0.047), while patients that achieved clearance of TP53 had better PFS (p=0.0056) and OS (p=0.037).ConclusionsInitial detection of ctDNA in advanced PC can identify somatic alterations that may help predict clinical outcomes. The dynamics of ctDNA are prognostic of outcomes and should be evaluated in prospective studies.
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- 2022
44. The Prognostic Value of a Single, Randomly Timed Circulating Tumor DNA Measurement in Patients with Metastatic Melanoma
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Boerlin, Aurelio, Bellini, Elisa, Turko, Patrick, Cheng, Phil F, Levesque, Mitchell P, Dummer, Reinhard, Ramelyte, Egle, University of Zurich, and Ramelyte, Egle
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Cancer Research ,Oncology ,10177 Dermatology Clinic ,610 Medicine & health ,2730 Oncology ,1306 Cancer Research ,ctDNA ,melanoma ,tumor progression ,PET-CT ,S100 ,biomarker - Abstract
Melanoma currently lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Circulating tumor DNA (ctDNA), originating from tumor cells and detectable in plasma, has emerged as a possible biomarker in patients with metastatic melanoma. In this retrospective, single-center study, we collected 129 plasma samples from 79 patients with stage IIIB–IV melanoma as determined by the American Joint Committee on Cancer (AJCC, 8th edition). For the determination of ctDNA levels, we used eight different assays of droplet digital polymerase chain reaction (ddPCR) to detect the most common hotspot mutations in the BRAF and NRAS genes. The aim of the study was to investigate the association of the detectability of ctDNA at a non-prespecified time point in a patient’s treatment with tumor progression, and to correlate ctDNA with commonly used biomarkers (protein S100, LDH, and CRP). Patients with detectable ctDNA progressed more frequently in PET-CT within 12 months than those without detectable ctDNA. Detectability of ctDNA was associated with shorter OS in univariate and multivariate analyses. ctDNA was detectable in a statistically significantly larger proportion of patients with distant metastases (79%) than in patients with no distant metastases or only intracranial metastases (32%). Elevated protein S100 and CRP correlated better with detectable ctDNA than LDH. This study supports the potential of ctDNA as a prognostic biomarker in patients with metastatic melanoma. However, additional prospective longitudinal studies with quantitative assessments of ctDNA are necessary to investigate the limitations and strengths of ctDNA as a biomarker.
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- 2022
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45. Role of ctDNA in Breast Cancer
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Sant, M, Bernat-Peguera, A, Felip, E, and Margeli, M
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breast cancer ,liquid biopsy ,cancer diagnosis ,ctDNA ,personalized medicine - Abstract
Simple Summary Circulating tumor DNA is DNA released by the tumor into the bloodstream. In breast cancer, it is used mainly in research or in clinical trials, but it will likely be used in routine clinical practice once certain issues have been worked out and methods of analysis have been improved and standardized. Breast cancer classification and treatment selection are now based on analysis of the tumor but circulating tumor DNA carries many features of the original tumor and can be analyzed from a simple, non-invasive blood extraction. Here, we review its potential role in early breast cancer (for screening, diagnosis, detection of minimal residual disease after surgery, follow up, and treatment) and in metastatic breast cancer (for the detection of mutations, prognosis and treatment). Breast cancer is currently classified by immunohistochemistry. However, technological advances in the detection of circulating tumor DNA (ctDNA) have made new options available for diagnosis, classification, biological knowledge, and treatment selection. Breast cancer is a heterogeneous disease and ctDNA can accurately reflect this heterogeneity, allowing us to detect, monitor, and understand the evolution of the disease. Breast cancer patients have higher levels of circulating DNA than healthy subjects, and ctDNA can be used for different objectives at different timepoints of the disease, ranging from screening and early detection to monitoring for resistance mutations in advanced disease. In early breast cancer, ctDNA clearance has been associated with higher rates of complete pathological response after neoadjuvant treatment and with fewer recurrences after radical treatments. In metastatic disease, ctDNA can help select the optimal sequencing of treatments. In the future, thanks to new bioinformatics tools, the use of ctDNA in breast cancer will become more frequent, enhancing our knowledge of the biology of tumors. Moreover, deep learning algorithms may also be able to predict breast cancer evolution or treatment sensitivity. In the coming years, continued research and the improvement of liquid biopsy techniques will be key to the implementation of ctDNA analysis in routine clinical practice.
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- 2022
46. Evolving Applications of Circulating Tumor DNA in Merkel Cell Carcinoma
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Prakash, Varsha, Gao, Ling, and Park, Soo J
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screening and diagnosis ,Cancer Research ,liquid biopsy ,Prevention ,Human Genome ,Oncology and Carcinogenesis ,ctDNA ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,Merkel cell carcinoma ,Rare Diseases ,Good Health and Well Being ,Oncology ,Genetics ,Cancer ,4.2 Evaluation of markers and technologies - Abstract
Circulating tumor DNA (ctDNA) is a subset of circulating cell-free DNA released by lysed tumor cells that can be characterized by its shorter strand length and tumor genome-specific information. The relatively short half-life of ctDNA allows it to provide a real-time measure of tumor burden which has potential prognostic and surveillance value as a tumor biomarker. Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer that requires close monitoring due to the high risk of relapse. There are currently no good tumor biomarkers for MCC patients, especially those who are negative for Merkel cell polyomavirus. ctDNA shows promise for improving the prognoses of MCC patients by monitoring tumor burden, identifying minimal residual disease (MRD), and stratifying patients by their likelihood of response to immune checkpoint inhibition or risk of relapse. In particular, bespoke ultra-sequencing platforms allow for the creation of patient-specific mutation panels that improve ctDNA detection, especially for patients with rare or uncharacteristic mutations. Leveraging bespoke ctDNA assays may improve physicians’ ability to alter treatment plans for non-responsive or high-risk patients. In addition, ctDNA MRD monitoring may allow physicians to treat relapses early before clinically evident disease is present.
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- 2023
47. The potential mechanism, recognition and clinical significance of tumor pseudoprogression after immunotherapy
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Wenxiao Jia, Hui Zhu, Anqin Han, Jinming Yu, and Qianqian Gao
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,pseudoprogression ,Review ,lcsh:RC254-282 ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Clinical significance ,Pseudoprogression ,Potential mechanism ,Cancer ,IL-8 ,Tumor size ,business.industry ,Mechanism (biology) ,ctDNA ,Immunotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Discontinuation ,RECIST ,030220 oncology & carcinogenesis ,immunotherapy ,business - Abstract
As immunotherapy has gained increasing interest as a new foundation for cancer therapy, some atypical response patterns, such aspseudoprogression and hyperprogression, have garnered the attention of physicians. Pseudoprogression is a phenomenon inwhich an initial increase in tumor size is observed or new lesions appear, followed by a decrease in tumor burden; thisphenomenon can benefit patients receiving immunotherapy but often leads to premature discontinuation of treatment owing tothe false judgment of progression. Accurately recognizing pseudoprogression is also a challenge for physicians. Because of theextensive attention on pseudoprogression, significant progress has been made. Some new criteria for immunotherapy, such asirRC, iRECIST and imRECIST, were proposed to accurately evaluate the response to immunotherapy. Many new detectionindexes, such as ctDNA and IL-8, have also been used to identify pseudoprogression. In this review, the definition, evaluationcriteria, mechanism, monitoring, management and prognosis of pseudoprogression are summarized, and diagnostic andtreatment processes for patients with progression but with a suspicion of pseudoprogression are proposed; these processes couldbe helpful for physicians in clinical practice and enhances the understanding of pseudoprogression. Cite this article as: Jia W, Gao Q, Han A, Zhu H, Yu J. The potentialmechanism, recognition and clinical significance of tumor pseudoprogressionafter immunotherapy. Cancer Biol Med. 2019; 16: 655-70. doi:10.20892/j.issn.2095-3941.2019.0144
- Published
- 2019
48. Current and Emerging Biomarkers in Metastatic Colorectal Cancer
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Jonathan M. Loree and Michael K.C. Lee
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Male ,Oncology ,medicine.medical_specialty ,Routine testing ,Colorectal cancer ,colorectal cancer ,Review Article ,ctdna ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Biomarkers, Tumor ,Humans ,Medicine ,HER2 Amplification ,030212 general & internal medicine ,Neoplasm Metastasis ,anti-egfr ,business.industry ,Optimal treatment ,Microsatellite instability ,Prognosis ,medicine.disease ,digestive system diseases ,metastatic ,030220 oncology & carcinogenesis ,RAS Mutation ,next-generation sequencing ,Female ,DNA mismatch repair ,Erratum ,Colorectal Neoplasms ,business ,Biomarkers - Abstract
Background The incorporation of novel biomarkers into therapy selection for patients with metastatic colorectal cancer (mcrc) has significantly improved outcomes. Optimal treatment planning now takes into account diverse characteristics of patients and their tumours to create personalized therapeutic plans. Discussion This review is split into two sections. In the first section, we review the prognostic and predictive significance of expanded RAS mutation testing, BRAF mutations, ERBB2 (her2) amplification, microsatellite instability (msi) and deficient mismatch repair (dmmr) protein, NTRK fusions, PIK3CA mutations, and met amplifications. The therapeutic implication of each of those biomarkers for personalizing therapies for each patient with mcrc is discussed. In the second section, we touch on testing methods and considerations of relevance to clinicians when they interpret companion diagnostics meant to guide therapy selection. The advantages and pitfalls of various methods are evaluated, and we also look at the potential of liquid biopsies and circulating tumour dna (ctdna) to change the landscape of therapeutic choice and biologic understanding of the disease. Summary Routine testing for extended RAS, BRAF, dmmr or high msi, and NTRK fusions is necessary to determine the best sequencing of chemotherapy and biologic agents for patients with mcrc. Although next generation sequencing and ctdna are increasingly being adopted, other techniques such as immunohistochemistry retain their relevance in detection of her2 amplification, NTRK fusions, and dmmr.
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- 2019
49. Liquid biopsy to identify biomarkers for immunotherapy in hepatocellular carcinoma
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Huang Ao, Zhang Xin, and Zhou Jian
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Immune checkpoint inhibitors ,Liquid biopsy ,Hepatocellular carcinoma ,Biochemistry (medical) ,Clinical Biochemistry ,Molecular Medicine ,Therapeutics. Pharmacology ,RM1-950 ,Review ,Immunotherapy ,ctDNA ,CTC - Abstract
The past years have witnessed the vigorous development of immunotherapy, mainly immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) protein and its ligand, PD-L1, and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Indeed, ICIs have largely revolutionized the management and improved the prognosis of patients with intermediate and advanced hepatocellular carcinoma (HCC). However, biomarker-based stratification of HCC patients for optimal response to ICI treatment is still of unmet need and again, there exists the necessity to dynamically monitor treatment effect in real-time manner. The role of conventional biomarkers in immunotherapy surveillance is largely limited by spatial and temporal tumor heterogeneity whereas liquid biopsy seems to be promising to circumvent tumor heterogeneity to identify candidate patients who may response to immunotherapy, to dynamically monitor treatment effect and to unveil resistance mechanism. Herein, we provide a thorough review about the potential utility of liquid biopsy in immunotherapy for HCC and discuss its future perspectives.
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- 2021
50. Use of Circulating Tumour DNA (ctDNA) for Measurement of Therapy Predictive Biomarkers in Patients with Cancer
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Michael J. Duffy and John Crown
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liquid biopsy ,Medicine ,Medicine (miscellaneous) ,biomarker ,cancer ,companion diagnostic ,Review ,predictive ,ctDNA - Abstract
Biomarkers that predict likely response or resistance to specific therapies are critical in personalising treatment for cancer patients. Such biomarkers are now available for an increasing number of anti-cancer therapies, especially targeted therapy and immunotherapy. The gold-standard method for determining predictive biomarkers requires tumour tissue. Obtaining tissue, however, is not always possible and even if possible, the amount or quality of tissue obtained may be inadequate for biomarker analysis. Tumour DNA, however, can be released into the bloodstream, giving rise to what is referred to as circulating tumour DNA (ctDNA). In contrast to tissue, blood can be obtained from effectively all patients in a minimally invasive and safe manner. Other advantages of blood over tissue for biomarker testing include a shorter turn-around time and an ability to perform serial measurements. Furthermore, blood should provide a more complete profile of mutations present in heterogeneous tumours than a single-needle tissue biopsy. A limitation of blood vis-à-vis tissue, however, is lower sensitivity and, thus, the possibility of missing an actionable mutation. Despite this limitation, blood-based predictive biomarkers, such as mutant EGFR for predicting response to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer and mutant PIK3CA for predicting response to alpelisib in combination with fulvestrant in advanced breast cancer, may be used when tissue is unavailable. Although tissue remains the gold standard for detecting predictive biomarkers, it is likely that several further blood-based assays will soon be validated and used when tissue is unavailable or unsuitable for analysis.
- Published
- 2021
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