Special Issue "Liquid Biopsy for Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 15 May 2019

Special Issue Editor

Guest Editor
Prof. Charles Lawrie

Oncology Area, Biodonostia Research Institute, San Sebastian, Spain
Website | E-Mail
Interests: liquid biopsies; biomarkers; non-coding RNA; next-generation sequencing; mutations; microRNAs

Special Issue Information

Dear Colleagues,

The current gold standard for cancer diagnosis remains the histological examination of invasively obtained biopsy tissue. This technique is sometimes risky, often difficult to perform, expensive, slow, and uncomfortable for the patient. As a consequence, there has been a great deal of interest in non-invasive biomarkers in biological fluids such as blood, urine, and saliva. So-called “liquid biopsies” are more economical, rapid, and easy to perform than current clinical protocols. Most importantly, liquid biopsies represent a paradigm shift in cancer patient management, as the ability to carry out repeat sampling permits for the first time the real-time monitoring of patient treatment response and disease progression, allowing for earlier intervention and dynamic treatment management, and therefore a more personalized approach. Moreover, there is an increasing awareness of the molecular heterogeneity of tumors and a realization that traditional tissue biopsies may miss this diversity. In contrast, liquid biopsies can capture the entire molecular panorama of the tumoral landscape. Furthermore, liquid biopsies are eminently suitable for use in screening programs.

In recognition of the potential of this field, in recent years there has been much interest in the field of circulating nucleic acids. Circulating DNA research which has its origins in the 1940s has recently been focused on the detection of cancer-associated mutations and other chromosomal aberrations. This research is now translating into the clinic, initially with EGFR mutation testing in lung cancer. In contrast, the field of circulating RNA was largely neglected after its initial discovery nearly 20 years ago, as the high levels of RNase present in blood and other biological fluids were believed to render these labile molecules useless. However, the recent discovery of circulating non-coding RNA, specifically circulating miRNAs, that are resistant to RNase activity has provided fresh impetus for this field.

This Special Issue welcomes original research concerning the discovery and/or validation of circulating biomarkers (nucleic acids or other molecules) in cancer, as well as reviews that critically provide an informative overview of the field.

Prof. Charles Lawrie
Guest Editor

Manuscript Submission Information

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Keywords

  • liquid biopsies
  • biomarkers
  • non-coding RNA
  • circulating transcriptome
  • mutanome
  • exosomes
  • microRNAs

Published Papers (11 papers)

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Research

Open AccessArticle Circulating Cell-Free DNA and RNA Analysis as Liquid Biopsy: Optimal Centrifugation Protocol
Cancers 2019, 11(4), 458; https://doi.org/10.3390/cancers11040458
Received: 23 January 2019 / Revised: 15 March 2019 / Accepted: 27 March 2019 / Published: 30 March 2019
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Abstract
The combined analysis of circulating cell-free (tumor) DNA (cfDNA/ctDNA) and circulating cell-free (tumor) RNA (cfRNA/ctRNA) shows great promise in determining the molecular profile of cancer patients. Optimization of the workflow is necessary to achieve consistent and reproducible results. In this study, we compared [...] Read more.
The combined analysis of circulating cell-free (tumor) DNA (cfDNA/ctDNA) and circulating cell-free (tumor) RNA (cfRNA/ctRNA) shows great promise in determining the molecular profile of cancer patients. Optimization of the workflow is necessary to achieve consistent and reproducible results. In this study, we compared five centrifugation protocols for the optimal yield of both cfDNA/ctDNA and cfRNA/ctRNA. These protocols varied in centrifugation speed, ambient temperature, time, and number of centrifugation steps. Samples from 33 participants were collected in either BD Vacutainer K2EDTA (EDTA) tubes or cell-free DNA BCT® (Streck) tubes. cfDNA concentration and fragment size, and cfRNA concentration were quantitated in all samples by digital droplet PCR (ddPCR) and quantitative PCR (qPCR). The KRAS-mutated ctDNA and ctRNA fraction was determined via ddPCR. In EDTA tubes, the protocol generating both plasma and platelets was found to produce high quality cfDNA and cfRNA concentrations. Two-step, high-speed centrifugation protocols were associated with high cfDNA but low cfRNA concentrations. High cfRNA concentrations were generated by a one-step, low-speed protocol. However, this coincided with a high amount of genomic DNA (gDNA) contamination. In Streck tubes, two-step, high-speed centrifugation protocols also generated good quality, high cfDNA concentration. However, these tubes are not compatible with cfRNA analysis. Full article
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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Open AccessArticle A Pilot Clinical Study on the Prognostic Relevance of Plasmatic Exosomes Levels in Oral Squamous Cell Carcinoma Patients
Cancers 2019, 11(3), 429; https://doi.org/10.3390/cancers11030429
Received: 21 February 2019 / Revised: 18 March 2019 / Accepted: 20 March 2019 / Published: 26 March 2019
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Abstract
Background: To evaluate the relationship between the plasmatic CD63 and CAV1 positive exosome levels, in patients with OSCC before and after surgical treatment and to correlate it with their overall survival. Methods: A double-blind pilot study over 10 patients OSCC and T4 stage [...] Read more.
Background: To evaluate the relationship between the plasmatic CD63 and CAV1 positive exosome levels, in patients with OSCC before and after surgical treatment and to correlate it with their overall survival. Methods: A double-blind pilot study over 10 patients OSCC and T4 stage without distant metastases or local bone invasion has been performed. The average follow-up period was 37.64 months (34.3–40.84). We obtained 2 plasma tubes of 1 mL each before surgery and 7 days after surgery. Before performing the immunocapture-based analysis, EVs (Extracellular Vesicles) were isolated from the plasma and characterized with western blot analysis. Results: Mean values of CD63 positive plasmatic exosomes (EXO-CD63) after surgery decreased from 750.88 ± 286.67 to 541.71 ± 244.93 (p = 0.091). On the other hand, CAV-1 positive plasmatic exosomes (EXO-CAV-1) increased after surgery from 507 ± 483.39 to 1120.25 ± 1151.17 (p = 0.237). Patients with EXO-CD63 levels lower than the mean global value before the surgery had a survival of 36.04 months compared with the group with EXO-CD63 higher than the average who only survived 12.49 ± 1.67 months from the diagnosis, p = 0.225. When EXO-CAV-1 levels before surgery was lower than the average (813.94 ± 801.21) overall survival was 24.69 ± 22.23 months in contrast when it was higher that was only 11.64 months, p = 0.157. Patients with lower EXO-CD63 levels after surgery lived an average of 23.84 ± 23.9 months, while those with higher plasmatic levels of EXO-CD63 live 13.35 months, p = 0.808. When EXO-CAV-1 levels after surgery were lower, the average overall survival was 20.344 ± 15.40 months, in contrast when the EXO-CAV-1 levels were higher showing rather an estimate survival expectation of 1.64 months. Conclusions: Surgical treatment induced a dramatic reduction of the plasmatic levels of exosomes expressing CD63 as early as 1 week after resection. This first result suggests that the tumour mass is responsible of the high levels of circulating exosomes detected in cancer patients. At the same time point exosome expressing CAV-1 increased, possibly due to the inflammatory reaction immediately after surgery. Lastly, statistical analysis showed that lower levels of plasmatic exosomes both before and after surgery correlated with a better life expectancy of OSCC patients. Hopefully, this approach will prove useful in the clinical follow-up of cancer patients. Full article
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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Open AccessArticle Non-Metastatic Esophageal Adenocarcinoma: Circulating Tumor Cells in the Course of Multimodal Tumor Treatment
Cancers 2019, 11(3), 397; https://doi.org/10.3390/cancers11030397
Received: 15 February 2019 / Revised: 16 March 2019 / Accepted: 18 March 2019 / Published: 21 March 2019
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Abstract
Background: Isolation of circulating tumor cells (CTC) holds the promise to improve response-prediction and personalization of cancer treatment. In this study, we test a filtration device for CTC isolation in patients with non-metastatic esophageal adenocarcinoma (EAC) within recent multimodal treatment protocols. Methods: Peripheral [...] Read more.
Background: Isolation of circulating tumor cells (CTC) holds the promise to improve response-prediction and personalization of cancer treatment. In this study, we test a filtration device for CTC isolation in patients with non-metastatic esophageal adenocarcinoma (EAC) within recent multimodal treatment protocols. Methods: Peripheral blood specimens were drawn from EAC patients before and after neoadjuvant chemotherapy (FLOT)/chemoradiation (CROSS) as well as after surgery. Filtration using ScreenCell® devices captured CTC for cytologic analysis. Giemsa-stained specimens were evaluated by a cytopathologist; the cut-off was 1 CTC/specimen (6 mL). Immunohistochemistry with epithelial (pan-CK) and mesenchymal markers (vimentin) was performed. Results: Morphologically diverse malignant CTCs were found in 12/20 patients in at least one blood specimen. CTCs were positive for both vimentin and pan-CK. More patients were CTC positive after neoadjuvant therapy (6/20 vs. 9/15) and CTCs per/ml increased in most of the CTC-positive patients. After surgery, 8/13 patients with available blood specimens were still CTC positive. In clinical follow-up, 5/9 patients who died were CTC-positive. Conclusions: Detection of CTC by filtration within multimodal treatment protocols of non-metastatic EAC is feasible. The rate of CTC positive findings and the quantity of CTCs changes in the course of multimodal neoadjuvant chemoradiation/chemotherapy and surgery. Full article
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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Open AccessArticle Limited Sensitivity of Circulating Tumor DNA Detection by Droplet Digital PCR in Non-Metastatic Operable Gastric Cancer Patients
Cancers 2019, 11(3), 396; https://doi.org/10.3390/cancers11030396
Received: 13 February 2019 / Revised: 14 March 2019 / Accepted: 18 March 2019 / Published: 21 March 2019
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Abstract
This study was designed to monitor circulating tumor DNA (ctDNA) levels during perioperative chemotherapy in patients with non-metastatic gastric adenocarcinoma. Plasma samples were prospectively collected in patients undergoing perioperative chemotherapy for non-metastatic gastric adenocarcinoma (excluding T1N0) prior to the initiation of perioperative chemotherapy, [...] Read more.
This study was designed to monitor circulating tumor DNA (ctDNA) levels during perioperative chemotherapy in patients with non-metastatic gastric adenocarcinoma. Plasma samples were prospectively collected in patients undergoing perioperative chemotherapy for non-metastatic gastric adenocarcinoma (excluding T1N0) prior to the initiation of perioperative chemotherapy, before and after surgery (NCT02220556). In each patient, mutations retrieved by targeted next-generation sequencing (NGS) on tumor samples were then tracked in circulating cell-free DNA from 4 mL of plasma by droplet digital PCR. Thirty-two patients with a diagnosis of non-metastatic gastric adenocarcinoma were included. A trackable mutation was identified in the tumor in 20 patients, seven of whom experienced relapse during follow-up. ctDNA was detectable in four patients (N = 4/19, sensitivity: 21%; 95% confidence interval CI = 8.5–43%, no baseline plasma sample was available for one patient), with a median allelic frequency (MAF) of 1.6% (range: 0.8–2.3%). No patient with available plasma samples (N = 0/18) had detectable ctDNA levels before surgery. After surgery, one of the 13 patients with available plasma samples had a detectable ctDNA level with a low allelic frequency (0.7%); this patient experienced a very short-term distant relapse only 3 months after surgery. No ctDNA was detected after surgery in the other four patients with available plasma samples who experienced a later relapse (median = 14.4, range: 9.3–26 months). ctDNA monitoring during preoperative chemotherapy and after surgery does not appear to be a useful tool in clinical practice for non-metastatic gastric cancer to predict the efficacy of chemotherapy and subsequent relapse, essentially due to the poor sensitivity of ctDNA detection. Full article
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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Open AccessArticle Phenotypic Characterization of Circulating Lung Cancer Cells for Clinically Actionable Targets
Cancers 2019, 11(3), 380; https://doi.org/10.3390/cancers11030380
Received: 28 February 2019 / Revised: 14 March 2019 / Accepted: 14 March 2019 / Published: 18 March 2019
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Abstract
Objectives: In non-small cell lung cancers (NSCLC), tumour biopsy can often be an invasive procedure. The development of a non-invasive methodology to study genetic changes via circulating tumour cells (CTCs) is an appealing concept. Whilst CTCs typically remain as rare cells, improvements in [...] Read more.
Objectives: In non-small cell lung cancers (NSCLC), tumour biopsy can often be an invasive procedure. The development of a non-invasive methodology to study genetic changes via circulating tumour cells (CTCs) is an appealing concept. Whilst CTCs typically remain as rare cells, improvements in epitope-independent CTC isolation techniques has given rise to a greater capture of CTCs. In this cross sectional study, we demonstrate the capture and characterization of NSCLC CTCs for the clinically actionable markers epidermal growth factor receptor (EGFR) alterations, anaplastic lymphoma kinase (ALK) rearrangements and programmed death ligand-1 (PD-L1) expression. The study identified CTCs/CTC clusters in 26/35 Stage IV NSCLC patients, and subsequently characterized the CTCs for EGFR mutation, ALK status and PD-L1 status. This pilot study demonstrates the potential of a non-invasive fluid biopsy to determine clinically relevant biomarkers in NSCLC. Full article
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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Open AccessArticle Molecular Subtype Conversion between Primary and Metastatic Breast Cancer Corresponding to the Dynamics of Apoptotic and Intact Circulating Tumor Cells
Cancers 2019, 11(3), 342; https://doi.org/10.3390/cancers11030342
Received: 25 February 2019 / Accepted: 5 March 2019 / Published: 11 March 2019
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Abstract
The presence of circulating tumor cells (CTCs), detected as a form of liquid biopsy is associated with poor survival in both early and metastatic breast cancer. Monitoring tumor biology based on intrinsic subtypes delivers treatment-relevant information on the heterogeneity or biomarker conversion between [...] Read more.
The presence of circulating tumor cells (CTCs), detected as a form of liquid biopsy is associated with poor survival in both early and metastatic breast cancer. Monitoring tumor biology based on intrinsic subtypes delivers treatment-relevant information on the heterogeneity or biomarker conversion between primary and metastatic tumors. This study aimed to correlate the change of the apoptotic and intact CTC counts with mRNA-assessed intrinsic subtype change. Thirty-four breast cancer patients with available triplets of primary tumors, distant metastasis biopsies and data on intact and apoptotic CTC dynamics were included in the analysis. The intrinsic subtype was determined per RT-qPCR quantification of the gene expression ESR1, PGR, ERBB2 and MKI67. Both luminal (p = 0.038) and triple negative (p = 0.035) patients showed a significant downregulation of apoptotic CTCs. Repeated biopsies of distant metastatic sites, as well as determining a potential shift of the intrinsic subtype, combined with data on intact and apoptotic CTC dynamics from liquid biopsies might help personalize systemic therapy and generate additional surrogate markers for successful systemic therapy. Full article
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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Open AccessArticle Exosome Analysis in Tumor-Draining Pulmonary Vein Identifies NSCLC Patients with Higher Risk of Relapse after Curative Surgery
Cancers 2019, 11(2), 249; https://doi.org/10.3390/cancers11020249
Received: 21 January 2019 / Revised: 16 February 2019 / Accepted: 18 February 2019 / Published: 21 February 2019
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Abstract
Since tumor-draining pulmonary vein blood (PV) is enriched in tumor-secreted products, we hypothesized that it would also be enriched in tumor-derived exosomes, which would be important in the metastasis process. We characterized exosomes from PV of 61 resected non-small cell lung cancer (NSCLC) [...] Read more.
Since tumor-draining pulmonary vein blood (PV) is enriched in tumor-secreted products, we hypothesized that it would also be enriched in tumor-derived exosomes, which would be important in the metastasis process. We characterized exosomes from PV of 61 resected non-small cell lung cancer (NSCLC) patients to evaluate its potential as relapse biomarkers. Exosomes were characterized using transmission electron microscopy, western blot and nanoparticle tracking analysis and we examined time to relapse (TTR) and overall survival (OS). Differences between PV and peripheral vein were found. PV was enriched in smaller exosomes than the paired peripheral vein (p = 0.01). Moreover, PV exosome size mode was able to identify relapsed patients (Area under the curve [AUC] = 0.781; 95%CI: 0.6641–0.8978), in whom exosome size was smaller (<112 nm; p < 0.001). The combination of PV exosome size and N (lymph node involvement) showed an AUC of 0.89 (95%CI: 0.80–0.97). Moreover, smaller PV exosome size was associated with shorter TTR (28.3 months vs. not reached, p < 0.001) and OS (43.9 months vs. not reached, p = 0.009). Multivariate analyses identified PV exosome size and stage as independent prognostic markers for TTR and OS. PV exosome size is a promising relapse biomarker after surgery that can add valuable information to clinical variables. Full article
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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Open AccessArticle Continuous Separation of Circulating Tumor Cells from Whole Blood Using a Slanted Weir Microfluidic Device
Cancers 2019, 11(2), 200; https://doi.org/10.3390/cancers11020200
Received: 19 December 2018 / Revised: 24 January 2019 / Accepted: 1 February 2019 / Published: 10 February 2019
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Abstract
The separation of circulating tumor cells (CTCs) from the peripheral blood is an important issue that has been highlighted because of their high clinical potential. However, techniques that depend solely on tumor-specific surface molecules or just the larger size of CTCs are limited [...] Read more.
The separation of circulating tumor cells (CTCs) from the peripheral blood is an important issue that has been highlighted because of their high clinical potential. However, techniques that depend solely on tumor-specific surface molecules or just the larger size of CTCs are limited by tumor heterogeneity. Here, we present a slanted weir microfluidic device that utilizes the size and deformability of CTCs to separate them from the unprocessed whole blood. By testing its ability using a highly invasive breast cancer cell line, our device achieved a 97% separation efficiency, while showing an 8-log depletion of erythrocytes and 5.6-log depletion of leukocytes. We also developed an image analysis tool that was able to characterize the various morphologies and differing deformability of the separating cells. From the results, we believe our system possesses a high potential for liquid biopsy, aiding future cancer research. Full article
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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Open AccessArticle Capture of Circulating Tumour Cell Clusters Using Straight Microfluidic Chips
Received: 17 December 2018 / Revised: 7 January 2019 / Accepted: 8 January 2019 / Published: 14 January 2019
Cited by 6 | PDF Full-text (2438 KB) | HTML Full-text | XML Full-text
Abstract
Circulating tumour cells (CTCs) are the metastatic precursors to distant disease in head and neck cancers (HNCs). Whilst the prognostic and predictive value of single CTCs have been well documented, the role of CTC clusters, which potentially have a higher metastatic capacity are [...] Read more.
Circulating tumour cells (CTCs) are the metastatic precursors to distant disease in head and neck cancers (HNCs). Whilst the prognostic and predictive value of single CTCs have been well documented, the role of CTC clusters, which potentially have a higher metastatic capacity are limited. In this study, the authors used a novel straight microfluidic chip to focus and capture CTCs. The chip offers high cell recoveries with clinically relevant numbers (10–500 cells/mL) without the need for further purification. Single CTCs were identified in 10/21 patient samples (range 2–24 CTCs/mL), CTC clusters in 9/21 patient samples (range 1–6 CTC clusters/mL) and circulating tumour microemboli (CTM) in 2/21 samples. This study demonstrated that CTC clusters contain EGFR amplified single CTCs within the cluster volume. This novel microfluidic chip demonstrates the efficient sorting and preservation of single CTCs, CTC clusters and CTMs. The authors intend to expand this study to a larger cohort to determine the clinical implication of the CTC subsets in HNC. Full article
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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Open AccessArticle The Circulating Transcriptome as a Source of Biomarkers for Melanoma
Received: 15 November 2018 / Revised: 2 January 2019 / Accepted: 4 January 2019 / Published: 10 January 2019
Cited by 2 | PDF Full-text (1963 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The circulating transcriptome is a valuable source of cancer biomarkers, which, with the exception of microRNAs (miRNAs), remains relatively unexplored. To elucidate which RNAs are present in plasma from melanoma patients and which could be used to distinguish cancer patients from healthy individuals, [...] Read more.
The circulating transcriptome is a valuable source of cancer biomarkers, which, with the exception of microRNAs (miRNAs), remains relatively unexplored. To elucidate which RNAs are present in plasma from melanoma patients and which could be used to distinguish cancer patients from healthy individuals, we used next generation sequencing (NGS), and validation was carried out by qPCR and/or ddPCR. We identified 442 different microRNAs in samples, eleven of which were differentially expressed (p < 0.05). Levels of miR-134-5p and miR-320a-3p were significantly down-regulated (p < 0.001) in melanoma samples (n = 96) compared to healthy controls (n = 28). Differentially expressed protein-encoding mRNA 5′-fragments were enriched for the angiopoietin, p21-activated kinase (PAK), and EIF2 pathways. Levels of ATM1, AMFR, SOS1, and CD109 gene fragments were up-regulated (p < 0.001) in melanoma samples (n = 144) compared to healthy controls (n = 41) (AUC = 0.825). Over 40% of mapped reads were YRNAs, a class of non-coding RNAs that to date has been little explored. Expression levels of RNY3P1, RNY4P1, and RNY4P25 were significantly higher in patients with stage 0 disease than either healthy controls or more advanced stage disease (p < 0.001). In conclusion, we have identified a number of novel RNA biomarkers, which, most importantly, we validated in multi-center retrospective and prospective cohorts, suggesting potential diagnostic use of these RNA species. Full article
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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Open AccessCommunication Transient Disappearance of RAS Mutant Clones in Plasma: A Counterintuitive Clinical Use of EGFR Inhibitors in RAS Mutant Metastatic Colorectal Cancer
Received: 12 December 2018 / Revised: 27 December 2018 / Accepted: 28 December 2018 / Published: 4 January 2019
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Abstract
Genomic studies performed through liquid biopsies widely elucidated the evolutionary trajectory of RAS mutant clones under the selective pressure of EGFR inhibitors in patients with wild type RAS primary colorectal tumors. Similarly, the disappearance of RAS mutant clones in plasma has been more [...] Read more.
Genomic studies performed through liquid biopsies widely elucidated the evolutionary trajectory of RAS mutant clones under the selective pressure of EGFR inhibitors in patients with wild type RAS primary colorectal tumors. Similarly, the disappearance of RAS mutant clones in plasma has been more recently reported in some patients with primary RAS mutant cancers, supporting for the first time an unexpected negative selection of RAS mutations during the clonal evolution of mCRC. To date, the extent of conversion to RAS wild type disease at the time of progression has not been clarified yet. As a proof of concept, we prospectively enrolled mCRC patients progressing under anti-VEGF based treatments. Idylla™ system was used to screen RAS mutations in plasma and the wild type status of RAS was further confirmed through IT-PGM (Ion Torrent Personal Genome Machine) sequencing. RAS was found mutant in 55% of cases, retaining the same plasma mutation as in the primary tumor at diagnosis, while it was found wild-type in 45%. Four patients testing negative for RAS mutations in plasma at the time of progression of disease (PD) were considered eligible for treatment with EGFR inhibitors and treated accordingly, achieving a clinical benefit. We here propose a hypothetical algorithm that accounts for the transient disappearance of RAS mutant clones over time, which might extend the continuum of care of mutant RAS colorectal cancer patients through the delivery of a further line of therapy. Full article
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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