Personalized Therapy and Liquid Biopsy—A Focus on Colorectal Cancer
Abstract
:1. Introduction
2. Liquid Biopsy (LB) and Targeted Approaches for Analysis
2.1. Types of Biopsies
2.1.1. Circulating Tumor Cells (CTCs)
Origin of CTCs
Epithelial to Mesenchymal Transition (EMT)
EMT, Stem Cells and Pathways
Mesenchymal-Epithelial Type (MET)
Characteristics of CTCs, Methods of Detection and Challenges
- Concentration gradient, Oncoquick®, because CTCs have a higher density than other cellular types [17]. While it was one of the first techniques that was developed, it is not seen as the most efficient. For example, in comparison with CellSearch® (Menarini Silicon Biosystems), in a cohort of 61 patients with cancers, only 23% of patients were found with at least 1 CTC with this technique while Cellsearch® (Menarini Silicon Biosystems), detected at least one CTC for more than 50% of patients [18].
- Filtration technique, Iset® [19], Rarecells Diagnostics SAS, since CTCs are larger than the other elements of the blood such as white cells. The main advantage of this technique relies on its independence from the presence of specific tumor cell markers. However, a drawback exists: some tumor cells are small and pass through filters [20].
2.1.2. Circulating Tumor DNA (ctDNA)
- Either necrosis or apoptosis of tumor cells in plasma;
- Or excreted from tumor cells within a vesicle called an exosome;
- Or contained within tumor cells.
2.2. Role of Liquid Biopsy in Adapted Cancer Treatment: Targeted Approaches for Analysis
2.2.1. Targeted Approaches with CTCs
2.2.2. Targeted Approaches with ctDNA
Droplet Digital PCR (ddPCR)
Beads, Emulsification, Amplification, and Magnetics (BEAMing)
3. Clinical Applications in Colorectal Cancer: Overview of the Current Literature
4. Contribution of the Omics to Personalize the Treatments
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
BEAMing | Beads: Emulsification, Amplification, and Magnetics |
cfDNA | Circulating free DNA |
CICs | Cancer initiating cells |
CTCs | Circulating tumor cells |
CRC | Colorectal cancer |
ctDNA | Circulating tumor DNA |
EMT | Epithelial to Mesenchymal Transition |
EpCAM | Epithelial cell adhesion molecule |
ECD | Extracellular domain |
FDA | Food and Drug Administration |
INCa | French National Cancer Institute |
LB | Liquid Biopsy (ies) |
MET | Mesenchymal-epithelial type |
MRD | Minimal Residual Disease |
TNF | Tumor necrosis factor |
TRAIL | Apoptosis-inducing ligand |
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CTCs | ctDNA | |
---|---|---|
Tumor cells Metastatic cells | Tumor cells Metastatic cells CTCs | |
Mode of isolation for further analysis | -Direct visualization -Physical separation -Biological separation/immunoaffinity | Nucleic acid samples pre-kit |
Analysis capability | -Phenotypic studies -Proteomics -Genomics -Transcriptomics | -Genetics -Epigenetics |
Technologies available | -FISH -Flow-cytometry in vitro/in vivo studies -RT-PCR | -NGS -RT -PCR -ddPCR |
Pros | -Wide analysis -Functional analysis possible -Molecular analysis at both cellular and sub-cellular levels | -Abundant -Encompasses genetic heterogeneity |
Cons | -Rare and fragile -False-negative and false-positive results | -Pre analytical conditions not standardized |
A step forward personalized treatments | Biological and immunological test: -drug sensitivity and drug resistance prediction -CTCs clusters-xenograft models | Molecular testing with targetable genomic alterations: gene expression and mutations, genomic signatures |
Clinical Trial | Inclusion Criteria and Type of Intervention | Main Outcome | Methodology for ctDNA Analysis | Results |
---|---|---|---|---|
NCT02994888 [52] | Patients with RAS wild-type (WT), refractory metastatic CRC (mCRC) | Mechanisms of resistance/response to anti-EGFR therapies | -ddPCR and ultra-deep next generation sequencing (NGS) | Primary and acquired resistance to anti-EGFR: polyclonal, and observed in both tissue and plasma samples |
NCT02296203 [53] | Cetuximab plus irinotecan as third-line treatment for patients with RAS and BRAF WT mCRC who were initially sensitive to and then resistant to first-line irinotecan- and cetuximab-based therapy | Percentage of patients achieving a decrease ≥ 30% in the sum of the longest diameters of target lesions | -ddPCR and ultra-deep next generation sequencing (NGS) | Rechallenge by cetuximab plus irinotecan is an active option for patients with RAS and BRAF wild-type metastatic colorectal cancer who have acquired resistance to first-line irinotecan- and cetuximab-based therapy but with RAS and BRAF wild-type circulating tumor DNA at the time of rechallengeLB leads to track molecular events in (ctDNA) through the different lines of chemotherapy |
NCT01442935 [54] | Metastatic disease with synchronous or metachronous (>3 months after diagnosis of the primary tumor) non resectable liver metastasis (LM) | Compare resection rates (R0 or R1) for hepatic metastases | -CTC detected with Cellsearch® -KRAS ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. | -CTC detection at 4 weeks (≥1 or ≥3 CTC) was not significantly associated with the eventual R0/R1 resection of LM (p = 0.06) -Persistently detectable KRAS ctDNA at 4 weeks after neoadjuvant chemotherapy was associated with a lower R0/R1 liver metastasis (LM) resection rate Possible selection of eligible patients to thanks to ctDNA |
VEK nr. H-KA-20060094 [55] | Patients resistant to 5-FU, oxaliplatin and irinotecan and treated with 3rd line irinotecan and cetuximab | Clinical value of KRAS mutations when detected in plasma compared to tumor in patients from mCRC prior to anti-EGFR therapy | RT-PCR | KRAS detection in archival tumor tissue showed no correlation to survival, whereas plasma KRAS status remained a strong predictive and prognostic factor in multivariate analysis |
NCT02870920. [56] | -Patients with CRC receiving all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available)-Randomized in either Combined Immune Checkpoint Inhibition vs. Best Supportive Care Alone | Overall survival (OS) | cfDNA collected prior to study therapy, at 8 weeks, and at the time of disease progression, with GuardantOMNI next generation sequencing 2.15 Mb, 500-gene panel (Guardant Health, Inc) | Patients with Microsatellite Stable (MSS) status, had significantly improved OS with durvalumab and tremelimumab (p = 0.02). Patients who were MSS with plasma Tumor Mutation Burden (TMB) of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (p = 0.004). |
NCT03010722 [57] | Patients with chemorefractory RAS mutant metastatic CRC received Regorafenib | Overall survival (OS) and Progression Free Survival (PFS) | clonal RAS mutations by digital-droplet PCR. | RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (p = 0.01) and OS (p = 0.06) => ctDNA may predict duration of anti-angiogenic response to regorafenib |
NCT01704703 [58] | RAS-mutated patients with nonresectable metastases from CRC | Overall survival (OS) and Progression Free Survival (PFS) | RAS testing in ctDNA using BEAMing before first- and/or second-line treatment | RAS mutant allele fraction (MAFs) is an independent prognostic factor in both OS (p = 0.006) and first-line PFS (p = 0.049). |
NCT01001377 [59] | -Patients with chemo-refractory wild-type KRAS exon 2 mCRC- randomized 1:1 to receive either panitumumab or cetuximab | Overall survival (OS) | -Plasma samples analyzed at baseline and safety follow-up (SFU) by a next-generation sequencing-based approach for extended RAS mutant allele frequency (MAF)-Mutational status of EGFR pathway genes was also examined | Despite observed trend of higher RAS MAF correlating with worse outcomes, baseline extended RAS mutations did not preclude clinical response to panitumumab. Even though baseline mutations in EGFR pathway genes were associated with shorter OS, the prognostic model analyzing mutations as a continuous variable showed that patients who were mutant for EGFR pathway genes but with a low MAF may still derive clinical benefit from panitumumab. |
Appelt et al., 2020 [60] | Patients with MRI-staged T3-4N0-2M0 rectal cancer treated by neoadjuvant chemoradiotherapy | Overall survival (OS) and the rate of distant metastases were compared between meth-ctDNA (hypermethylation of the neuropeptide Y gene-ctDNA) positive and negative patients | ddPCR | Patients with meth-ctDNA had significantly worse 5-year OS |
Janowski et al., 2017 [61] | Patients benefited from resin-based yttrium-90 (90Y) radioembolization for unresectable liver metastasis from CRC | Overall survival (OS) and DNA fragmentation index (FI) quantification | circulating cell-free DNA (ccfDNA) concentration and fragmentation index (FI) were measured using quantitative PCR and atomic-force microscopy (AFM) | In the WT and KRAS mutant patients, DNA FI was reduced after treatment. This reduction was associated with an improved OS (p = 0.046). Analysis by AFM of paired pre- and post-treatment samples from KRAS mutant and WT patients revealed significant decrease in fragment size in the WT patients (p = 0.013). |
NCT01531595 [62] | Metastatic colorectal cancer (mCRC) patients with a known KRAS mutation in their primary tumor underwent oncological treatment with bevacizumab in combination with alternating capecitabine and oxaliplatin or irinotecan | Compare multiple methods for measuring KRAS mutations in periodically collected liquid biopsies | Plasma ddPCR KRAS mutation allele frequency (MAF) versus Plasma real-time PCR based molecular testing system (IdyllaTM ctKRAS cartridge) versusPlasma Next-generation sequencing (NGS) [Ion AmpliSeq Hotspot Panel v2, which surveys the hotspot regions of 50 oncogenes and tumor suppressor genes (Thermo Fisher Scientific, Waltham, MD, USA)] | ddPCR and IdyllaTM are equally efficient for the detection of KRAS mutations in LB from mCRC patients and that ctDNA may indicate the disappearance of treatment responsive KRAS positive mCRC clones, thereby serving as an early sign of disease progression |
Ning et al., 2018 [63] | mCRC patients having received standard Food and Drug Administration (FDA)-approved therapies (including fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab, panitumumab, regorafenib), or received experimental agents being tested in three phase I or II clinical trials examining 5-FU plus brivanib (NCT01046864), PRI-724 (NCT01302405) and celecoxib plus EpO906 (NCT00159484). | Measure mRNA expression of EMT (PI3Ka, Akt-2, Twist1) and stem cell (ALDH1) markers in CTCs | -CTCs enrichment: negative immunomagnetic selection using anti- CD45 specific antibodies (Dynabeads M-450 CD45 pan Leukocyte, Invitrogen, Waltham, MA, USA) and then, CD45-negative (CD45−) supernatant s transferred for immune separation and selection using Dynabeads (Dynabeads Epithelial Enrich, #161.02, Invitrogen) with a monoclonal antibody towards human EpCAM,-mRNA expression of EMT (PI3Ka, Akt-2, Twist1) and stem cell (ALDH1) markers was measured | Patients with positive CTC Akt-2 expression had a significantly shorter median PFS in multivariable analyses (HR = 1.70; adjusted p = 0.041) |
NCT02624726 [64] | Patients treated with FOLFIRI (Folinic acid, fluorouracil and irinotecan)/aflibercept (vascular endothelial growth factor (VEGF) inhibitor) | Objective Response Rate (ORR) | Detection of CEACAM5 mRNA-positive CTCs performed using a real-time PCR assay | At preplanned interim analysis, all patients had discontinued treatment and the ORR was 61.3%, crossing the activity threshold for trial discontinuation.Retaining CTC-negative status predicted better OS compared to continuous detection of CTCs (p = 0.015) |
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Christou, N.; Veyrune, L.; Popeskou, S.G.; Mathonnet, M. Personalized Therapy and Liquid Biopsy—A Focus on Colorectal Cancer. J. Pers. Med. 2021, 11, 630. https://doi.org/10.3390/jpm11070630
Christou N, Veyrune L, Popeskou SG, Mathonnet M. Personalized Therapy and Liquid Biopsy—A Focus on Colorectal Cancer. Journal of Personalized Medicine. 2021; 11(7):630. https://doi.org/10.3390/jpm11070630
Chicago/Turabian StyleChristou, Niki, Léa Veyrune, Sotirios Georgios Popeskou, and Muriel Mathonnet. 2021. "Personalized Therapy and Liquid Biopsy—A Focus on Colorectal Cancer" Journal of Personalized Medicine 11, no. 7: 630. https://doi.org/10.3390/jpm11070630