scholarly journals Clonal evolution of colorectal cancer in a patient with serially resected metastases and liquid biopsies: a case report and discussion of the literature

ESMO Open ◽  
2018 ◽  
Vol 3 (4) ◽  
pp. e000329 ◽  
Author(s):  
Myrto Kastrisiou ◽  
George Zarkavelis ◽  
Eleftherios Kampletsas ◽  
Eleni Panopoulou ◽  
Anna Goussia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liquid Biopsy ◽  
Clonal Evolution ◽  
Primary Tumour ◽  
Acquired Resistance ◽  
Liquid Biopsies ◽  
Clonal Heterogeneity ◽  
Clinical Endpoints ◽  
Multiple Metastases ◽  
Metastatic Sites

BackgroundMetastatic colorectal cancer represents a striking example of clonal heterogeneity and tumour evolution, which generates acquired resistance to therapy. Once hard to perform, the study of clonal heterogeneity is now significantly aided by the use of liquid biopsies.MethodWe herein report a case of a patient with colorectal cancer and serial development of multiple metastases which were all resected and genotyped. A rare point mutation was identified in the primary tumour (but not in any of the organ metastatic sites), as well as in the first and the last out of three consecutive liquid biopsies. The review of the literature offered some insight in the evolution of the patient’s tumour and general directions on how to interpret liquid biopsy results.ConclusionsThis patient case emphasises the need for large prospective studies designed to bridge liquid biopsy data with useful clinical endpoints, in order to optimally integrate this revolutionary tool in everyday practice.

scholarly journals Rapid response of stage IV colorectal cancer with APC/TP53/KRAS mutations to FOLFIRI and Bevacizumab combination chemotherapy: a case report of use of liquid biopsy

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Alexander Hendricks ◽  
Philip Rosenstiel ◽  
Sebastian Hinz ◽  
Greta Burmeister ◽  
Christoph Röcken ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Treatment Response ◽  
Liquid Biopsy ◽  
Metastatic Cancer ◽  
Stage Iv ◽  
Liquid Biopsies ◽  
Kras Mutations ◽  
Cell Free Dna ◽  
Stage Iv Colorectal Cancer ◽  
Free Dna

Abstract Background Liquid biopsies of blood plasma cell free DNA can be used to monitor treatment response and potentially detect mutations that are present in resistant clones in metastatic cancer patients. Case presentation In our non-interventional liquid biopsy study, a male patient in his fifties diagnosed with stage IV colorectal cancer and polytope liver metastases rapidly progressed after completing chemotherapy and deceased 8 months after diagnosis. Retrospective cell free DNA testing showed that the APC/TP53/KRAS major clone responded quickly after 3 cycles of FOLFIRI + Bevacizumab. Retrospective exome sequencing of pre-chemotherapy and post-chemotherapy tissue samples including metastases confirmed that the APC/TP53/KRAS and other major clonal mutations (GPR50, SLC5A, ZIC3, SF3A1 and others) were present in all samples. After the last chemotherapy cycle, CT imaging, CEA and CA19–9 markers validated the cfDNA findings of treatment response. However, 5 weeks later, the tumour had rapidly progressed. Conclusion As FOLFIRI+Bevacizumab has recently also been associated with sustained complete remission in a APC/TP53/KRAS triple-mutated patient, these driver genes should be tested and monitored in a more in-depth manner in future patients. Patients with metastatic disease should be monitored more closely during and after chemotherapy, ideally using cfDNA.

The occurrence of mutant KRAS clones in the blood of RAS wild type colorectal cancer patients: Impact of response or failure under anti-EGFR therapy.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 600-600
Author(s):  
Andreas W. Berger ◽  
Daniel Schwerdel ◽  
Hanna Welz ◽  
Thomas Jens Ettrich ◽  
Peter Moeller ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clonal Selection ◽  
Clonal Evolution ◽  
Acquired Resistance ◽  
Dynamic Monitoring ◽  
Tumor Evolution ◽  
Genetic Profile ◽  
Wild Type ◽  
Initial State ◽  
Kras Mutations

600 Background: Colorectal cancer (CRC) is characterized by a high level of genetic heterogeneity. In addition, changes in the genetic profile induced by chemotherapy affect treatment results. Acquired resistance of tumors is defined as a result of clonal evolution and clonal selection under systemic chemotherapy. Repeated tumor tissue biopsies are difficult to obtain and cannot be easily used for dynamic monitoring of therapy response or failure due to marked tumor heterogeneity. Promising data for circulating cell-free tumor DNA (ctDNA) as a tool for studying tumor evolution were recently published. Methods: In this study we analyzed ctDNA from patients with metastatic CRC during treatment with anti-epidermal growth factor receptor (EGFR) antibodies (cetuximab/panitumumab). By droplet digital PCR we performed genotyping of CRC tissue and tracking of clonal evolution of the most frequent KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, G13C, G13D, Q61R, A146T and A59T) in plasma ctDNA. Results: In initial KRAS wild type tumors several mutated KRAS clones occurred in plasma under the course of anti-EGFR-therapy indicating an increasing acquired resistance to the given therapy leading to a disease progression. Some of these mutations declined upon discontinuation of anti-EGFR therapy. Conclusions: Based on these results we hypothesize that the initial state of KRAS wild type situation seems to be restored in some cases. This opens up the possibility to reinduce anti-EGFR therapy in later therapy lines.

scholarly journals Concordance of Acquired Mutations between Metastatic Lesions and Liquid Biopsy in Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

2021 ◽  
Author(s):  
Fumitaka Taniguchi ◽  
Akihiro Nyuya ◽  
Toshiaki Toshima ◽  
Kazuya Yasui ◽  
Yoshiko Mori ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Acquired Resistance ◽  
Metastatic Tumor ◽  
Primary Tumors ◽  
Blood Samples ◽  
Activating Mutations ◽  
Metastatic Lesions ◽  
Mutational Status

Abstract Background: Acquired mutations are detected in plasma. However, still few reports examine the concordance between liquid biopsy and metastatic lesions with acquired resistance. Herein we evaluated whether a polymerase chain reaction-reverse sequence-specific oligonucleotide (PCR-rSSO) method can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance.Methods: Firstly, we examined the presence of acquired mutations in 7 chemoresistant metastatic lesions and blood samples obtained from a metastatic colorectal cancer (mCRC) patient without RAS activating mutations treated with anti-EGFR treatment. The patient (patient 1) displayed initial early tumor shrinkage and finally progressed to disease (PD). Blood samples were collected before the development of PD and after acquiring resistance. Next, we evaluated RAS and BRAF mutational status among blood samples, primary tumors, and metastatic lesions obtained from three additional mCRC patients without RAS activating mutations. Acquired mutations were examined using Sanger sequencing and the PCR-rSSO approach.Results: Of patient 1, metastatic tumor specimens harbored diverse acquired mutations in the KRAS gene in all of the 7 (100%) metastases, and the three acquired mutations were detected in blood specimens collected after acquiring resistance. Next, we analyzed primary tumors, metastatic lesions after chemotherapy, and blood samples from three additional mCRC patients but noted that none of the patients exhibited mutations in liquid biopsy except for one case with BRAF V600E mutation, which was confirmed in both primary tumor and peritoneal dissemination. Of the four cases, acquired mutations of RAS, as well as BRAF V600E mutation, was detected in the blood obtained only after confirmation of acquiring resistance by radiological examinations.Conclusions: Our results suggest liquid biopsy based on the PCR-rSSO is a successful procedure for capturing acquired mutations with precise information of mutational spectrum that may lend us to reach selective target agents for RAS mutations.

scholarly journals Exploring Better Strategies for RAS Mutation-Associated EGFR-Targeted Resistance in Colorectal Cancer: From the Perspective of Cancer Community Ecology

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaojie Wang ◽  
Wenchuan Wu ◽  
Zhifang Zheng ◽  
Pan Chi
Keyword(s):  
Colorectal Cancer ◽  
Community Ecology ◽  
Cancer Progression ◽  
Clonal Evolution ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Evolutionary Process ◽  
Continuous Treatment ◽  
Exclusion Principle ◽  
Competitive Release

RAS is the most common mutated gene in colorectal cancer (CRC), and its occurrence is associated with primary and acquired resistance to anti-epidermal growth factor receptor (EGFR) blockade. Cancer community ecology, such as the competitive exclusion principle, is a valuable focus and would contribute to the understanding of drug resistance. We have presented several articles on RAS mutant clonal evolution monitoring during anti-EGFR treatment in CRC. In these articles, the availability of serially collected samples provided a unique opportunity to model the tumor evolutionary process from the perspective of cancer community ecology in those patients upon treatment. In this perspective article, we presented a theoretical basis and evidence from several experimental or phase II clinical trials for the contemporary application of ecological mechanisms in CRC treatment. In general, a reduction in targetable RAS wild-type cells to a maximum tolerated extent, such as continuous treatment, might lead to the competitive release of inextirpable RAS mutant cells and cancer progression. A full understanding of subclonal competition might be beneficial in managing CRC. Several ecological strategies, including anti-EGFR treatment reintroduced at an appropriate point of time for RAS mutant patients, intermittent treatment instead of continuous treatment, the appropriate sequence of nonselective targeted therapy, and combination therapy, were proposed.

scholarly journals Mutational status of plasma exosomal KRAS predicts outcome in patients with metastatic colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Donatella Lucchetti ◽  
Ina Valeria Zurlo ◽  
Filomena Colella ◽  
Claudio Ricciardi-Tenore ◽  
Mariantonietta Di Salvatore ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Clinical Information ◽  
Wild Type ◽  
Blood Samples ◽  
Mutational Status ◽  
Fractional Abundance ◽  
Radiological Response ◽  
Metastatic Sites

AbstractLiquid biopsy has become a useful alternative in metastatic colorectal cancer (mCRC) patients when tissue biopsy of metastatic sites is not feasible. In this study we aimed to investigate the clinical utility of circulating exosomes DNA in the management of mCRC patients. Exosomes level and KRAS mutational status in exosomal DNA was assesed in 70 mCRC patients and 29 CRC primary tumor and were analysed at different disease steps evaluating serial blood samples (240 blood samples). There was a significant correlation between the extension of disease and exosomes level and the resection of primary localized tumor was correlated with a decrease of KRAS G12V/ D copies and fractional abundance in metastatic disease. CEA expression and liver metastasis correlated with a higher number of KRAS G12V/D copies/ml and a higher fractional abundance; in the subgroup of mCRC patients eligible for surgery, the size of tumor and the radiological response were related to exosomes level but only the size was related to the number of KRAS WT copies; both KRAS wild-type and mutated levels were identified as a prognostic factor related to OS. Finally, we found that 91% of mutated mCRC patients became wild type after the first line chemotherapy but this status reverted in mutated one at progression in 80% of cases. In a prospective cohort of mCRC patients, we show how longitudinal monitoring using exosome-based liquid biopsy provides clinical information relevant to therapeutic stratification.

scholarly journals Exosomal Non Coding RNA in LIQUID Biopsies as a Promising Biomarker for Colorectal Cancer

2020 ◽  
Vol 21 (4) ◽  
pp. 1398 ◽  
Author(s):  
Amro Baassiri ◽  
Farah Nassar ◽  
Deborah Mukherji ◽  
Ali Shamseddine ◽  
Rihab Nasr ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Sensitivity And Specificity ◽  
Liquid Biopsy ◽  
Early Stage ◽  
Noncoding Rnas ◽  
Predictive Biomarkers ◽  
Carbohydrate Antigen ◽  
Combination Regimen ◽  
Liquid Biopsies ◽  
Diagnostic Potential

Colorectal cancer (CRC) is one of the most common cancers worldwide, with a high mortality rate, especially in those that are diagnosed in late stages of the disease. The current screening blood-based markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), have low sensitivity and specificity. Meanwhile, other modalities are either expensive or invasive. Therefore, recent research has shifted towards a minimally invasive test, namely, liquid biopsy. Exosomes are favorable molecules sought in blood samples, since they are abundant, stable in circulation, and harbor genetic information and other biomolecules that could serve as biomarkers or even therapeutic targets. Furthermore, exosomal noncoding RNAs, such as miRNAs, lncRNAs, and circRNAs, have demonstrated the diagnostic potential to detect CRC at an early stage with a higher sensitivity and specificity than CEA and CA19-9 alone. Moreover, they have prognostic potential that is TNM stage specific and could serve as predictive biomarkers for the most common chemotherapeutic drug and combination regimen in CRC, which are 5-FU and FOLFOX, respectively. Therefore, in this review, we focus on the role of these exosomal noncoding RNAs as diagnostic, prognostic, and predictive biomarkers. In addition, we discuss the advantages and challenges of exosomes as a liquid biopsy target.

Abstract B168: Monitoring acquired resistance to EGFR-TKIs and clonal evolution in metastatic NSCLC patients using liquid biopsies

2018 ◽  
Author(s):  
Franciele Knebel ◽  
Fabiana Bettoni ◽  
Andrea Shimada ◽  
Manoel Cruz ◽  
João Victor Alessi ◽  
...  
Keyword(s):  
Clonal Evolution ◽  
Acquired Resistance ◽  
Liquid Biopsies ◽  
Metastatic Nsclc ◽  
Nsclc Patients ◽  
Egfr Tkis

Beta-catenin expression in pilomatrix carcinoma with multiple visceral metastases in a dog

2012 ◽  
Vol 60 (4) ◽  
pp. 449-457
Author(s):  
Vincenzo Galofaro ◽  
Giuseppe Rapisarda ◽  
Alessandra Sfacteria ◽  
Giovanni Lanteri ◽  
Fabio Marino
Keyword(s):  
Primary Tumour ◽  
Beta Catenin ◽  
Cytoplasmic Staining ◽  
Multiple Metastases ◽  
Visceral Metastases ◽  
Skin Nodules ◽  
Metastatic Sites ◽  
Cell To Cell Adhesion ◽  
Kidney Liver ◽  
Pilomatrix Carcinoma

Beta-catenin is a protein initially identified as a submembrane component of the E-cadherin-mediated cell-to-cell adhesion system. It plays a role as a transcriptional factor in the wingless/Wnt signalling pathway. Beta-catenin has been associated with oncogenic activity in human benign and malignant pilomatrix neoplasms where the immunohistochemical profile of β-catenin expression displayed both nuclear and cytoplasmic staining in basaloid cells. In this study, an 8-year-old female Irish setter dog was examined because of the presence of skin nodules. Tissue biopsies from different nodules were obtained and histological examination suggested a diagnosis of pilomatrix carcinoma. The dog spontaneously died after 2 months and necropsy showed multiple metastases in the nasal cavity, lungs, heart, kidney, liver and colon. Routine histopathology of metastatic sites showed features consistent with the pattern of primary neoplastic nodules. Immunohistochemical detection of β-catenin was performed in both the primary tumour and the metastases. Beta-catenin expression was located in the nuclei, cytoplasm and membrane of squamoid cells and in the cytoplasm of basaloid cells, while shadow cells were completely negative. To the best of our knowledge, these data represent the first report on the immunohistochemical expression profile of β-catenin in canine pilomatrix carcinoma.

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

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

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

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