Publications by authors named "Marco Gerlinger"

50 Publications

Mutational signatures impact the evolution of anti-EGFR antibody resistance in colorectal cancer.

Nat Ecol Evol 2021 07 20;5(7):1024-1032. Epub 2021 May 20.

Translational Oncogenomics Laboratory, The Institute of Cancer Research, London, UK.

Anti-EGFR antibodies such as cetuximab are active against KRAS/NRAS wild-type colorectal cancers (CRCs), but acquired resistance invariably evolves. It is unknown which mutational mechanisms enable resistance evolution and whether adaptive mutagenesis (a transient cetuximab-induced increase in mutation generation) contributes in patients. Here, we investigate these questions in exome sequencing data from 42 baseline and progression biopsies from cetuximab-treated CRCs. Mutation loads did not increase from baseline to progression, and evidence for a contribution of adaptive mutagenesis was limited. However, the chemotherapy-induced mutational signature SBS17b was the main contributor of specific KRAS/NRAS and EGFR driver mutations that are enriched at acquired resistance. Detectable SBS17b activity before treatment predicted shorter progression-free survival and the evolution of these specific mutations during subsequent cetuximab treatment. This result suggests that chemotherapy mutagenesis can accelerate resistance evolution. Mutational signatures may be a new class of cancer evolution predictor.
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http://dx.doi.org/10.1038/s41559-021-01470-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611134PMC
July 2021

Identifying key questions in the ecology and evolution of cancer.

Evol Appl 2021 Apr 8;14(4):877-892. Epub 2021 Feb 8.

Department of Data Science and Knowledge Engineering Maastricht University Maastricht The Netherlands.

The application of evolutionary and ecological principles to cancer prevention and treatment, as well as recognizing cancer as a selection force in nature, has gained impetus over the last 50 years. Following the initial theoretical approaches that combined knowledge from interdisciplinary fields, it became clear that using the eco-evolutionary framework is of key importance to understand cancer. We are now at a pivotal point where accumulating evidence starts to steer the future directions of the discipline and allows us to underpin the key challenges that remain to be addressed. Here, we aim to assess current advancements in the field and to suggest future directions for research. First, we summarize cancer research areas that, so far, have assimilated ecological and evolutionary principles into their approaches and illustrate their key importance. Then, we assembled 33 experts and identified 84 key questions, organized around nine major themes, to pave the foundations for research to come. We highlight the urgent need for broadening the portfolio of research directions to stimulate novel approaches at the interface of oncology and ecological and evolutionary sciences. We conclude that progressive and efficient cross-disciplinary collaborations that draw on the expertise of the fields of ecology, evolution and cancer are essential in order to efficiently address current and future questions about cancer.
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http://dx.doi.org/10.1111/eva.13190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061275PMC
April 2021

Immunotherapy Sensitivity of Mismatch Repair-Deficient Cancer: Mutation Load Is Not Enough.

Authors:
Marco Gerlinger

Cancer Cell 2021 01;39(1):16-18

The Institute of Cancer Research, London, UK; The Royal Marsden Hospital, GI Cancer Unit, London, UK. Electronic address:

Abundant neoantigens are considered responsible for the immunotherapy sensitivity of mismatch repair-deficient (MMRd) cancers. In this issue of Cancer Cell, two papers show that MLH1 mismatch repair gene loss promotes cGAS-STING activation, interferon secretion, and T cell priming. This may be essential for the high immunotherapy sensitivity in MMRd cancer.
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http://dx.doi.org/10.1016/j.ccell.2020.12.016DOI Listing
January 2021

Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy.

Cancers (Basel) 2020 Dec 11;12(12). Epub 2020 Dec 11.

Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.

Epidermal growth factor receptor antibodies (EGFR-Abs) confer a survival benefit in patients with wild-type metastatic colorectal cancer (mCRC), but resistance invariably occurs. Previous data showed that only a minority of cancer cells harboured known genetic resistance drivers when clinical resistance to single-agent EGFR-Abs had evolved, supporting the activity of non-genetic resistance mechanisms. Here, we used error-corrected ctDNA-sequencing (ctDNA-Seq) of 40 cancer genes to identify drivers of resistance and whether a genetic resistance-gap (a lack of detectable genetic resistance mechanisms in a large fraction of the cancer cell population) also occurs in wild-type mCRCs treated with a combination of EGFR-Abs and chemotherapy. We detected one mutation and one amplification in 2/3 patients with primary resistance and mutations and aberrations in 6/7 patients with acquired resistance. In vitro testing identified MAP2K1/MEK1 P124S as a novel driver of EGFR-Ab resistance. Mutation subclonality analyses confirmed a genetic resistance-gap in mCRCs treated with EGFR-Abs and chemotherapy, with only 13.42% of cancer cells harboring identifiable resistance drivers. Our results support the utility of ctDNA-Seq to guide treatment allocation for patients with resistance and the importance of investigating further non-canonical EGFR-Ab resistance mechanisms, such as microenvironmentally-mediated resistance. The detection of mutations could inform trials of MEK-inhibitors in these tumours.
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http://dx.doi.org/10.3390/cancers12123736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764102PMC
December 2020

Diagnostic Accuracy and Safety of Coaxial System in Oncology Patients Treated in a Specialist Cancer Center With Prospective Validation Within Clinical Trial Data.

Front Oncol 2020 4;10:1634. Epub 2020 Sep 4.

Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom.

Background: Image-guided tissue biopsies are critically important in the diagnosis and management of cancer patients. High-yield samples are also vital for biomarker and resistance mechanism discovery through molecular/genomic analyses.

Patients And Methods: All consecutive patients who underwent plugged image-guided biopsy at Royal Marsden from June 2013 until September 2016 were included in the analysis. In the next step, a second cohort of patients prospectively treated within two clinical trials (PROSPECT-C and PROSPECT-R) were assessed for the DNA yield from biopsies assessed for complex genomic analysis.

Results: A total of 522 plugged core biopsies were performed in 457 patients [men, 52%; median age, 63 years (range, 17-93)]. Histological diagnosis was achieved in 501 of 522 (96%) performed biopsies. Age, gender, modality, metastatic site, and seniority of the interventionist were not found to be significant factors associated with odds of failure on a logistic regression. Seventeen (3.3%) were admitted due to biopsy-related complications; nine, three, two, one, one, and one were admitted for grade I/II pain control, sepsis, vasovagal syncope, thrombosis, hematuria, and deranged liver functions, respectively; two patients with right upper quadrant pain after liver biopsy were found to have radiologically confirmed subcapsular hematoma requiring conservative treatment. One patient (0.2%) developed grade III hemorrhage following biopsy of a gastric gastrointestinal stromal tumor (GIST). Overall molecular analysis was successful in 89% (197/222 biopsies). Prospective validation in 62 biopsies gave success rates of 92.06 and 79.03% for DNA extraction of >1 μm and tmour content of >20%, respectively.

Conclusion: The probability of diagnostic success for complex molecular analysis is increased with plugged large coaxial needle biopsy technique, which also minimizes complications and reduces hospital stay. High-yield DNA acquisition allows genomic molecular characterization for personalized medicine.
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http://dx.doi.org/10.3389/fonc.2020.01634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500492PMC
September 2020

Comparison of a coaxial versus non-coaxial liver biopsy technique in an oncological setting: diagnostic yield, complications and seeding risk.

Eur Radiol 2020 Dec 14;30(12):6702-6708. Epub 2020 Jul 14.

Department of Radiology, The Royal Marsden NHS Foundation Trust, Downs Rd, Sutton, London, SW2 5PT, UK.

Objectives: Percutaneous liver biopsy (PLB) poses specific challenges in oncological patients such as bleeding and tumour seeding. This study's aim was to compare a coaxial (C-PLB) and non-coaxial (NC-PLB) biopsy technique in terms of diagnostic yield, safety and seeding risk of image-guided PLB techniques in an oncological setting.

Methods: Local research committee approval was obtained for this single-site retrospective study. Patients who underwent a PLB between November 2011 and December 2017 were consecutively included. Medical records were reviewed to determine diagnostic yield and complications. Follow-up imaging was re-reviewed for seeding, defined as visible tumour deposits along the PLB track. Mann-Whitney U and chi-squared tests were performed to investigate differences between biopsy techniques in sample number, complications and seeding rate.

Results: In total, 741 patients (62 ± 13 years, 378 women) underwent 932 PLB (C-PLB 72.9% (679/932); NC-PLB 27.1% (253/932)). More tissue cores (p < 0.001) were obtained with C-PLB (median 4 cores; range 1-12) compared with NC-PLB (2 cores; range 1-4) and diagnostic yield was similar for both techniques (C-PLB 92.6% (629/679); NC-PLB 92.5% (234/253); p = 0.940). Complication rate (9.3%; 87/932) using C-PLB (8.2% (56/679)) was lower compared with NC-PLB (12.3% (31/253); p = 0.024). Major complications were uncommon (C-PLB 2.7% (18/679); NC-PLB 2.8% (7/253)); bleeding developed in 1.2% (11/932; C-PLB 1.2% (8/679); NC-PLB 1.2% (3/253)). Seeding was a rare event, occurring significantly less in C-PLB cases (C-PLB 1.3% (7/544); NC-PLB 3.1% (6/197); p = 0.021).

Conclusions: C-PLB allows for high diagnostic tissue yield with a lower complication and seeding rate than a NC-PLB and should be the preferred method in an oncological setting.

Key Points: • A coaxial percutaneous liver biopsy achieves a significant higher number of cores and fewer complications than a non-coaxial biopsy technique. • The risk of tumour seeding is very low and is significantly lower using the coaxial biopsy technique. • In this study, a larger number of cores (median = 4) could be safely acquired using the coaxial technique, providing sufficient material for advanced molecular analysis.
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http://dx.doi.org/10.1007/s00330-020-07038-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599171PMC
December 2020

Defining the true impact of coronavirus disease 2019 in the at-risk population of patients with cancer.

Eur J Cancer 2020 09 7;136:99-106. Epub 2020 Jul 7.

Royal Marsden Hospital NHS Trust, Fulham Road, London, SW3 6JJ, UK. Electronic address:

Background: In light of the coronavirus disease 2019 (COVID-19) pandemic, cancer centres in the United Kingdom and Europe re-organised their services at an unprecedented pace, and many patients with cancer have had their treatments severely disrupted. Patients with cancer were considered at high risk on sparse evidence, and despite a small number of emerging observational studies, the true incidence and impact of COVID-19 in the 'at-risk' population of patients with cancer is yet to be defined.

Methods: Epidemiological and clinical data were collected prospectively for patients attending the Royal Marsden Hospital and three network hospitals between March 1st and April 30th 2020 that were confirmed to have Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Significance of clinical and pathological characteristics was assessed using the Fisher's exact test and Wilcoxon rank sum test, whilst univariate and multivariate logistic regression models were used to further assess risk. The number of patients attending in March/April 2020 for face-to-face attendances was also extracted.

Findings: During the 2-month study period, 867 of 13,489 (6.4%) patients met the criteria leading to swab testing. Of the total at-risk population, only 113 of 13,489 (0.84%) were swab positive, 101 of 13,489 (0.75%) required hospital admission and 29 of 13,489 (0.21%) died of COVID-19. Of the patients that attended the hospital to receive cytotoxic chemotherapy alone or in combination with other therapy, 59 of 2001 (2.9%) were admitted to the hospital for COVID-19-related issues and 20 of 2001 (1%) died. Of the patients that collected targeted treatments, 16 of 1126 (1.4%) were admitted and 1 of 1126 (0.1%) died. Of the 11 patients that had received radiotherapy, 6 of 1042 (0.6%) required inpatient admission and 2 of 1042 (0.2%) died.

Interpretations: Administration of systemic anticancer therapy appears to be associated with a modest risk of severe COVID-19 infection. Based on this snapshot taken as the first wave of COVID-19 hit our practice, we conclude that continuation of active cancer treatment, even in the palliative setting, is appropriate.
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http://dx.doi.org/10.1016/j.ejca.2020.06.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340059PMC
September 2020

Computational Image Analysis of T-Cell Infiltrates in Resectable Gastric Cancer: Association with Survival and Molecular Subtypes.

J Natl Cancer Inst 2021 01;113(1):88-98

Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Background: Gastric and gastro-esophageal junction cancers (GCs) frequently recur after resection, but markers to predict recurrence risk are missing. T-cell infiltrates have been validated as prognostic markers in other cancer types, but not in GC because of methodological limitations of past studies. We aimed to define and validate the prognostic role of major T-cell subtypes in GC by objective computational quantification.

Methods: Surgically resected chemotherapy-naïve GCs were split into discovery (n = 327) and validation (n = 147) cohorts. CD8 (cytotoxic), CD45RO (memory), and FOXP3 (regulatory) T-cell densities were measured through multicolor immunofluorescence and computational image analysis. Cancer-specific survival (CSS) was assessed. All statistical tests were two-sided.

Results: CD45RO-cell and FOXP3-cell densities statistically significantly predicted CSS in both cohorts. Stage, CD45RO-cell, and FOXP3-cell densities were independent predictors of CSS in multivariable analysis; mismatch repair (MMR) and Epstein-Barr virus (EBV) status were not statistically significant. Combining CD45RO-cell and FOXP3-cell densities into the Stomach Cancer Immune Score showed highly statistically significant (all P ≤ .002) CSS differences (0.9 years median CSS to not reached). T-cell infiltrates were highest in EBV-positive GCs and similar in MMR-deficient and MMR-proficient GCs.

Conclusion: The validation of CD45RO-cell and FOXP3-cell densities as prognostic markers in GC may guide personalized follow-up or (neo)adjuvant treatment strategies. Only those 20% of GCs with the highest T-cell infiltrates showed particularly good CSS, suggesting that a small subgroup of GCs is highly immunogenic. The potential for T-cell densities to predict immunotherapy responses should be assessed. The association of high FOXP3-cell densities with longer CSS warrants studies into the biology of regulatory T cells in GC.
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http://dx.doi.org/10.1093/jnci/djaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781469PMC
January 2021

Rationale and design of the POLEM trial: avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III mismatch repair deficient or POLE exonuclease domain mutant colon cancer: a phase III randomised study.

ESMO Open 2020 02;5(1)

Royal Surrey NHS Foundation Trust, Guildford, UK

Background: 10%-15% of early-stage colon cancers harbour either deficient mismatch repair (dMMR), microsatellite instability high (MSI-H) or exonuclease domain mutations, and are characterised by high tumour mutational burden and increased lymphocytic infiltrate. Metastatic dMMR colon cancers are highly sensitive to immune checkpoint inhibition, and recent data show -mutant tumours are similarly responsive. We are conducting a phase III randomised trial to determine if the addition of the anti-PD-L1 antibody avelumab following adjuvant chemotherapy improves disease-free survival (DFS) in patients with stage III dMMR/MSI-H or mutant colon cancer and is a cost-effective approach for the UK National Health Service (NHS).

Methods: We are recruiting patients with completely resected, stage III colon cancer confirmed to have dMMR/MSI-H, locally or exonuclease domain mutation on central testing. Eligible patients are randomised in a 1:1 ratio to standard fluoropyrimidine-based chemotherapy (capecitabine, oxaliplatin for 12 weeks or capecitabine for 24 weeks) or chemotherapy, followed by avelumab (10 mg/kg, 2 weekly for 24 weeks). Stratification is by chemotherapy received and MMR/MSI-H status. The primary endpoint is DFS. Secondary endpoints include overall survival, toxicity, quality of life and health resource use. The 3-year DFS rate in the control arm is expected to be ~75%. Avelumab is expected to improve the 3-year DFS rate by 12% (ie, 87%). Target accrual is 402 patients, which provides 80% power to detect an HR of 0.48 for DFS at a two-sided alpha of 0.05. This national, multicentre phase III trial is sponsored by the Royal Marsden NHS Foundation Trust and it is anticipated that approximately 40 centres in the UK will participate. This study opened to recruitment in August 2018.

Trial Registration Number: NCT03827044.
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http://dx.doi.org/10.1136/esmoopen-2019-000638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046393PMC
February 2020

Author Correction: Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer.

Nat Commun 2020 Jan 29;11(1):675. Epub 2020 Jan 29.

Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-14602-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989513PMC
January 2020

Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer.

Nat Commun 2020 01 16;11(1):139. Epub 2020 Jan 16.

Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.

Mismatch repair deficient (dMMR) gastro-oesophageal adenocarcinomas (GOAs) show better outcomes than their MMR-proficient counterparts and high immunotherapy sensitivity. The hypermutator-phenotype of dMMR tumours theoretically enables high evolvability but their evolution has not been investigated. Here we apply multi-region exome sequencing (MSeq) to four treatment-naive dMMR GOAs. This reveals extreme intratumour heterogeneity (ITH), exceeding ITH in other cancer types >20-fold, but also long phylogenetic trunks which may explain the exquisite immunotherapy sensitivity of dMMR tumours. Subclonal driver mutations are common and parallel evolution occurs in RAS, PIK3CA, SWI/SNF-complex genes and in immune evasion regulators. MSeq data and evolution analysis of single region-data from 64 MSI GOAs show that chromosome 8 gains are early genetic events and that the hypermutator-phenotype remains active during progression. MSeq may be necessary for biomarker development in these heterogeneous cancers. Comparison with other MSeq-analysed tumour types reveals mutation rates and their timing to determine phylogenetic tree morphologies.
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http://dx.doi.org/10.1038/s41467-019-13915-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965135PMC
January 2020

Targeted drugs ramp up cancer mutability.

Authors:
Marco Gerlinger

Science 2019 12;366(6472):1452-1453

Translational Oncogenomics Laboratory, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.

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http://dx.doi.org/10.1126/science.aaz9900DOI Listing
December 2019

Immunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment.

J Immunother Cancer 2019 11 18;7(1):309. Epub 2019 Nov 18.

Translational Oncogenomics Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.

Background: Patient derived organoids (PDOs) can be established from colorectal cancers (CRCs) as in vitro models to interrogate cancer biology and its clinical relevance. We applied mass spectrometry (MS) immunopeptidomics to investigate neoantigen presentation and whether this can be augmented through interferon gamma (IFNγ) or MEK-inhibitor treatment.

Methods: Four microsatellite stable PDOs from chemotherapy refractory and one from a treatment naïve CRC were expanded to replicates with 100 million cells each, and HLA class I and class II peptide ligands were analyzed by MS.

Results: We identified an average of 9936 unique peptides per PDO which compares favorably against published immunopeptidomics studies, suggesting high sensitivity. Loss of heterozygosity of the HLA locus was associated with low peptide diversity in one PDO. Peptides from genes without detectable expression by RNA-sequencing were rarely identified by MS. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detected by MS. In contrast, computational HLA binding prediction estimated that 304 mutations could generate neoantigens. One hundred ninety-six of these were located in expressed genes, still exceeding the number of MS-detected neoantigens 65-fold. Treatment of four PDOs with IFNγ upregulated HLA class I expression and qualitatively changed the immunopeptidome, with increased presentation of IFNγ-inducible genes. HLA class II presented peptides increased dramatically with IFNγ treatment. MEK-inhibitor treatment showed no consistent effect on HLA class I or II expression or the peptidome. Importantly, no additional HLA class I or II presented neoantigens became detectable with any treatment.

Conclusions: Only 3 out of 612 non-silent mutations encoded for neoantigens that were detectable by MS. Although MS has sensitivity limits and biases, and likely underestimated the true neoantigen burden, this established a lower bound of the percentage of non-silent mutations that encode for presented neoantigens, which may be as low as 0.5%. This could be a reason for the poor responses of non-hypermutated CRCs to immune checkpoint inhibitors. MEK-inhibitors recently failed to improve checkpoint-inhibitor efficacy in CRC and the observed lack of HLA upregulation or improved peptide presentation may explain this.
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http://dx.doi.org/10.1186/s40425-019-0769-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859637PMC
November 2019

Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer.

Cancer Cell 2019 07;36(1):35-50.e9

Tumour Microenvironment Lab, The Institute of Cancer Research, London SW3 6JB, UK.

Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.
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http://dx.doi.org/10.1016/j.ccell.2019.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617392PMC
July 2019

Detecting and Tracking Circulating Tumour DNA Copy Number Profiles during First Line Chemotherapy in Oesophagogastric Adenocarcinoma.

Cancers (Basel) 2019 May 27;11(5). Epub 2019 May 27.

Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK.

DNA somatic copy number aberrations (SCNAs) are key drivers in oesophagogastric adenocarcinoma (OGA). Whether minimally invasive SCNA analysis of circulating tumour (ct)DNA can predict treatment outcomes and reveal how SCNAs evolve during chemotherapy is unknown. We investigated this by low-coverage whole genome sequencing (lcWGS) of ctDNA from 30 patients with advanced OGA prior to first-line chemotherapy and on progression. SCNA profiles were detectable pretreatment in 23/30 (76.7%) patients. The presence of liver metastases, primary tumour in situ, or of oesophageal or junctional tumour location predicted for a high ctDNA fraction. A low ctDNA concentration associated with significantly longer overall survival. Neither chromosomal instability metrics nor ploidy correlated with chemotherapy outcome. Chromosome 2q and 8p gains before treatment were associated with chemotherapy responses. lcWGS identified all amplifications found by prior targeted tumour tissue sequencing in cases with detectable ctDNA as well as finding additional changes. SCNA profiles changed during chemotherapy, indicating that cancer cell populations evolved during treatment; however, no recurrent SCNA changes were acquired at progression. Tracking the evolution of OGA cancer cell populations in ctDNA is feasible during chemotherapy. The observation of genetic evolution warrants investigation in larger series and with higher resolution techniques to reveal potential genetic predictors of response and drivers of chemotherapy resistance. The presence of liver metastasis is a potential biomarker for the selection of patients with high ctDNA content for such studies.
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http://dx.doi.org/10.3390/cancers11050736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563045PMC
May 2019

CEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids.

J Immunother Cancer 2019 04 15;7(1):101. Epub 2019 Apr 15.

Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.

Background: The T cell bispecific antibody cibisatamab (CEA-TCB) binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells, which triggers T cell killing of cancer cell lines expressing moderate to high levels of CEA at the cell surface. Patient derived colorectal cancer organoids (PDOs) may more accurately represent patient tumors than established cell lines which potentially enables more detailed insights into mechanisms of cibisatamab resistance and sensitivity.

Methods: We established PDOs from multidrug-resistant metastatic CRCs. CEA expression of PDOs was determined by FACS and sensitivity to cibisatamab immunotherapy was assessed by co-culture of PDOs and allogeneic CD8 T cells.

Results: PDOs could be categorized into 3 groups based on CEA cell-surface expression: CEA (n = 3), CEA (n = 1) and CEA PDOs (n = 4), that stably maintained populations of CEA and CEA cells, which has not previously been described in CRC cell lines. CEA PDOs were sensitive whereas CEA PDOs showed resistance to cibisatamab. PDOs with mixed expression showed low sensitivity to cibisatamab, suggesting that CEA cells maintain cancer cell growth. Culture of FACS-sorted CEA and CEA cells from PDOs with mixed CEA expression demonstrated high plasticity of CEA expression, contributing to resistance acquisition through CEA antigen loss. RNA-sequencing revealed increased WNT/β-catenin pathway activity in CEA cells. Cell surface CEA expression was up-regulated by inhibitors of the WNT/β-catenin pathway.

Conclusions: Based on these preclinical findings, heterogeneity and plasticity of CEA expression appear to confer low cibisatamab sensitivity in PDOs, supporting further clinical evaluation of their predictive effect in CRC. Pharmacological inhibition of the WNT/β-catenin pathway may be a rational combination to sensitize CRCs to cibisatamab. Our novel PDO and T cell co-culture immunotherapy models enable pre-clinical discovery of candidate biomarkers and combination therapies that may inform and accelerate the development of immuno-oncology agents in the clinic.
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http://dx.doi.org/10.1186/s40425-019-0575-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463631PMC
April 2019

Efficacy and Cardiotoxic Safety Profile of Raltitrexed in Fluoropyrimidines-Pretreated or High-Risk Cardiac Patients With GI Malignancies: Large Single-Center Experience.

Clin Colorectal Cancer 2019 03 29;18(1):64-71.e1. Epub 2018 Sep 29.

Department of Medicine, GI and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, London and Surrey, UK. Electronic address:

Background: Gastrointestinal (GI) cancer patients may not be considered for therapy with fluoropyrimidines (FPs) because of previous cardiovascular (CV) toxicity or preexisting risk factors; such patients may benefit from raltitrexed-based therapy.

Patients And Methods: Patient, tumor, and treatment characteristics, as well as clinical outcomes of all consecutively treated patients with raltitrexed at the Royal Marsden Hospital between October 1998 and July 2011 were examined. GI cancer patients who developed CV toxicity as a result of FPs and those with significant CV risk factors receiving raltitrexed were included in this analysis.

Results: A total of 247 patients (155 and 92 with CV FP-related CV toxicities and significant CV risk factors, respectively) treated with raltitrexed alone or in combination were examined after a median follow-up of 47.1 months. CV toxicity profiles of patients receiving capecitabine (n = 110) and 5-fluorouracil (n = 45) were largely similar. Of raltitrexed-treated patients, 13 (5%) experienced CV toxicities and 1 (< 0.1%) died as a result of myocardial infarction. The median progression-free survival (PFS) and overall survival (OS) were 36.0 months (95% confidence interval [CI], 26.5-48.6) and 44.3 months (95% CI, 33.1-56.8), respectively. The 5-year survival for early stage GI malignancies (n = 140) was 62.0% (95% CI, 50.1-71.9). Median PFS and OS were not reached in this group (interquartile range = 38.4 months to NR); median PFS and OS for advanced GI malignancies (n = 107) were 18.8 (95% CI, 11.9-25.7) and 23.7 months (95% CI, 17.0-26.9), respectively.

Conclusion: A raltitrexed-based regimen is well-tolerated therapy with comparable efficacy to FPs in patients with GI malignancies with significant CV toxicities or risk factors.
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http://dx.doi.org/10.1016/j.clcc.2018.09.010DOI Listing
March 2019

Ultra-Sensitive Mutation Detection and Genome-Wide DNA Copy Number Reconstruction by Error-Corrected Circulating Tumor DNA Sequencing.

Clin Chem 2018 11 27;64(11):1626-1635. Epub 2018 Aug 27.

Centre for Evolution and Cancer, Division of Molecular Pathology, The Institute of Cancer Research, London, UK;

Background: Circulating free DNA sequencing (cfDNA-Seq) can portray cancer genome landscapes, but highly sensitive and specific technologies are necessary to accurately detect mutations with often low variant frequencies.

Methods: We developed a customizable hybrid-capture cfDNA-Seq technology using off-the-shelf molecular barcodes and a novel duplex DNA molecule identification tool for enhanced error correction.

Results: Modeling based on cfDNA yields from 58 patients showed that this technology, requiring 25 ng of cfDNA, could be applied to >95% of patients with metastatic colorectal cancer (mCRC). cfDNA-Seq of a 32-gene, 163.3-kbp target region detected 100% of single-nucleotide variants, with 0.15% variant frequency in spike-in experiments. Molecular barcode error correction reduced false-positive mutation calls by 97.5%. In 28 consecutively analyzed patients with mCRC, 80 out of 91 mutations previously detected by tumor tissue sequencing were called in the cfDNA. Call rates were similar for point mutations and indels. cfDNA-Seq identified typical mCRC driver mutations in patients in whom biopsy sequencing had failed or did not include key mCRC driver genes. Mutations only called in cfDNA but undetectable in matched biopsies included a subclonal resistance driver mutation to anti-EGFR antibodies in , parallel evolution of multiple mutations in 2 cases, and mutations originating from clonal hematopoiesis. Furthermore, cfDNA-Seq off-target read analysis allowed simultaneous genome-wide copy number profile reconstruction in 20 of 28 cases. Copy number profiles were validated by low-coverage whole-genome sequencing.

Conclusions: This error-corrected, ultradeep cfDNA-Seq technology with a customizable target region and publicly available bioinformatics tools enables broad insights into cancer genomes and evolution.

Clinicaltrialsgov Identifier: NCT02112357.
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http://dx.doi.org/10.1373/clinchem.2018.289629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214522PMC
November 2018

Circulating tumour DNA, a promising biomarker for the management of colorectal cancer.

Crit Rev Oncol Hematol 2018 Feb 16;122:72-82. Epub 2017 Dec 16.

Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom. Electronic address:

Circulating cell free tumour DNA (ctDNA) maintains the same genomic alterations that are present in the corresponding tumour, thereby allowing for quantitative and qualitative real-time evaluation in body fluids as an alternative to onerous repeat biopsies. Improvements in the sensitivity of techniques used to identify ctDNA has led to a surge of research investigating its role in the detection of: early disease, relapse, response to therapy and emerging drug resistance mechanisms. Following curative surgery, ctDNA detection is a promising marker of minimal residual disease and could better select patients for adjuvant chemotherapy. Longitudinal monitoring could help identify early relapse. In metastatic disease, ctDNA can predict response to chemotherapy prior to evidence of disease progression on imaging and investigate novel primary and acquired resistance mechanisms to targeted therapies. More experience in detecting, analysing and interpreting ctDNA within prospective trials, will better define its role for implementation into routine clinical practice.
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http://dx.doi.org/10.1016/j.critrevonc.2017.12.002DOI Listing
February 2018

Metastasis Seeding Cells: Lone Invaders or Mass Migrators?

Authors:
Marco Gerlinger

Clin Cancer Res 2018 05 31;24(9):2032-2034. Epub 2018 Jan 31.

Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.

Lymph node metastases are among the best predictors of recurrence and of cancer-related death in early-stage colorectal cancers. Yet, despite their clinical and biological relevance, it remains elusive how lymph node metastases develop and whether metastatic seeding is a major bottleneck that restrains genetic heterogeneity of metastatic disease. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933519PMC
May 2018

Treatment and Survival Outcome of BRAF-Mutated Metastatic Colorectal Cancer: A Retrospective Matched Case-Control Study.

Clin Colorectal Cancer 2018 03 16;17(1):e69-e76. Epub 2017 Oct 16.

Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. Electronic address:

Background: Somatic v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation, present in approximately 10% of metastatic colorectal cancer (mCRC) cases, is associated with poor prognosis. Patient outcome outside of clinical trials has only been reported in small series. We report real-world data on treatment and survival for BRAF-mutated (MT) patients at a single tertiary center, compared with a matched BRAF wild type (WT) control group.

Patients And Methods: All colorectal cancer patients tested for BRAF mutation, from October 2010 to November 2014 were identified. BRAF-MT mCRC cases were compared with an age and sex-matched BRAF-WT control group. Clinicopathological data were collected and survival calculated using the Kaplan-Meier method and comparisons made using Cox regression.

Results: Forty-three of 503 patients (8.5%) tested had BRAF-MT mCRC and were compared with 88 BRAF-WT controls. Median overall survival (mOS) was 18.2 months for BRAF-MT and 41.1 months for BRAF-WT mCRC patients (hazard ratio, 2.74; 95% confidence interval, 1.60-4.70; P < .001). Progression-free survival for BRAF-MT and WT patients, respectively, was: 8.1 months versus 9.2 months (P = .571) first-line, 5.5 months versus 8.3 months (P = .074) second-line, and 1.8 months versus 5.6 months (P = .074) third-line. Treatment using sequential fluoropyrimidine-based doublet chemotherapy was similar between both groups. Anti-epidermal growth factor receptor (EGFR) therapy was mainly given third-line with progressive disease in 90% (n = 9 of 10) of BRAF-MT patients at first restaging.

Conclusion: In this case-control study, the poor mOS of BRAF-MT mCRC was associated with reduced treatment benefit beyond first-line. Sequential doublet chemotherapy remains a reasonable option in appropriately selected patients. BRAF-MT patients did not benefit from anti-EGFR therapy in this study. Recruitment to clinical trials is recommended to improve outcomes in BRAF-MT mCRC.
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http://dx.doi.org/10.1016/j.clcc.2017.10.006DOI Listing
March 2018

Cancer (r)evolution.

Nat Ecol Evol 2017 08;1(8):1051-1052

Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, The Institute of Cancer Research, London, SW3 6JB, UK.

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http://dx.doi.org/10.1038/s41559-017-0252-1DOI Listing
August 2017

Classifying the evolutionary and ecological features of neoplasms.

Nat Rev Cancer 2017 10 15;17(10):605-619. Epub 2017 Sep 15.

Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, NOR2424, Los Angeles, California 90033, USA.

Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus conference of experts in the fields of cancer evolution and cancer ecology, we propose a framework for classifying tumours that is based on four relevant components. These are the diversity of neoplastic cells (intratumoural heterogeneity) and changes over time in that diversity, which make up an evolutionary index (Evo-index), as well as the hazards to neoplastic cell survival and the resources available to neoplastic cells, which make up an ecological index (Eco-index). We review evidence demonstrating the importance of each of these factors and describe multiple methods that can be used to measure them. Development of this classification system holds promise for enabling clinicians to personalize optimal interventions based on the evolvability of the patient's tumour. The Evo- and Eco-indices provide a common lexicon for communicating about how neoplasms change in response to interventions, with potential implications for clinical trials, personalized medicine and basic cancer research.
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http://dx.doi.org/10.1038/nrc.2017.69DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811185PMC
October 2017

Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma.

BMC Med 2016 11 14;14(1):185. Epub 2016 Nov 14.

Centre for Evolution and Cancer, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.

Background: Molecular intratumour heterogeneity (ITH) is common in clear cell renal carcinomas (ccRCCs). However, it remains unknown whether this is mirrored by heterogeneity of drug responses between metastases in the same patient.

Methods: We performed a retrospective central radiological analysis of patients with treatment-naïve metastatic ccRCC receiving anti-angiogenic tyrosine kinase inhibitors (TKIs) (sunitinib or pazopanib) within three similar phase II trials. Treatment was briefly interrupted for cytoreductive nephrectomy. All patients had multiple metastases that were measured by regular computed tomography scans from baseline until Response Evaluation Criteria In Solid Tumours (RECIST)-defined progression. Each metastasis was categorised as responding, stable or progressing. Patients were classed as having a homogeneous response if all lesions were of the same response category and a heterogeneous response if they differed.

Results: A total of 115 metastases were assessed longitudinally in 27 patients. Of these patients, 56% had a heterogeneous response. Progression occurred through the appearance of new metastases in 67%, through progression of existing lesions in 11% and by both in 22% of patients. Despite RECIST-defined progression, 57% of existing metastases remained controlled. The sum of controlled lesions was greater than that of uncontrolled lesions in 47% of patients who progressed only with measurable new lesions.

Conclusions: We identified frequent ITH of anti-angiogenic TKI responses, with subsets of metastases responding and progressing within individual patients. This mirrors molecular ITH and may indicate that anti-angiogenic drug resistance is confined to subclones and not encoded on the trunk of the tumours' phylogenetic trees. This is clinically important, as patients with small-volume progression may benefit from drug continuation. Predominant progression with new rather than in existing metastases supports a change in disease biology through anti-angiogenics. The results highlight limitations of RECIST in heterogeneous cancers, which may influence clinical trial data validity. This analysis requires prospective confirmation.

Trial Registration: European Clinical Trials Database(EudraCT): 2009-016675-29 , registered 17 March 2010; EudraCT: 2006-004511-21 , registered 09 March 2007; EudraCT: 2006-006491-38 , registered 22 December 2006.
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http://dx.doi.org/10.1186/s12916-016-0729-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108081PMC
November 2016

Cancer Evolution and the Limits of Predictability in Precision Cancer Medicine.

Trends Cancer 2016 Jan 29;2(1):49-63. Epub 2016 Jan 29.

Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK; Gastrointestinal Cancer Unit, The Royal Marsden Hospital, London, UK. Electronic address:

The ability to predict the future behavior of an individual cancer is crucial for precision cancer medicine. The discovery of extensive intratumor heterogeneity and ongoing clonal adaptation in human tumors substantiated the notion of cancer as an evolutionary process. Random events are inherent in evolution and tumor spatial structures hinder the efficacy of selection, which is the only deterministic evolutionary force. This review outlines how the interaction of these stochastic and deterministic processes, which have been extensively studied in evolutionary biology, limits cancer predictability and develops evolutionary strategies to improve predictions. Understanding and advancing the cancer predictability horizon is crucial to improve precision medicine outcomes.
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http://dx.doi.org/10.1016/j.trecan.2015.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756277PMC
January 2016

Translating Seminoma Genomic Landscapes into Clinical Practice.

Authors:
Marco Gerlinger

Eur Urol 2015 Jul 2;68(1):84-5. Epub 2015 Feb 2.

Centre for Evolution and Cancer, The Institute of Cancer Research, and Department of Medicine, The Royal Marsden Hospital, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2015.01.020DOI Listing
July 2015

Dissecting cancer evolution at the macro-heterogeneity and micro-heterogeneity scale.

Curr Opin Genet Dev 2015 Feb 31;30:1-6. Epub 2014 Dec 31.

Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, Division of Molecular Pathology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Gastrointestinal Cancer Unit, The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK. Electronic address:

Intratumour heterogeneity complicates biomarker discovery and treatment personalization, and pervasive cancer evolution is a key mechanism leading to therapy failure and patient death. Thus, understanding subclonal heterogeneity architectures and cancer evolution processes is critical for the development of effective therapeutic approaches which can control or thwart cancer evolutionary plasticity. Current insights into heterogeneity are mainly limited to the macroheterogeneity level, established by cancer subclones that have undergone significant clonal expansion. Novel single cell sequencing and blood-based subclonal tracking technologies are enabling detailed insights into microheterogeneity and the dynamics of clonal evolution. We assess how this starts to delineate the rules governing cancer evolution and novel angles for more effective therapeutic intervention.
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http://dx.doi.org/10.1016/j.gde.2014.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728189PMC
February 2015

Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.

Science 2014 Oct;346(6206):251-6

Thermo Fisher Scientific, Carlsbad, CA 92008, USA.

Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.
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http://dx.doi.org/10.1126/science.1253462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636050PMC
October 2014

Cancer: evolution within a lifetime.

Annu Rev Genet 2014 1;48:215-36. Epub 2014 Oct 1.

Cancer Research UK London Research Institute, London, United Kingdom WC2A 3LY; email:

Subclonal cancer populations change spatially and temporally during the disease course. Studies are revealing branched evolutionary cancer growth with low-frequency driver events present in subpopulations of cells, providing escape mechanisms for targeted therapeutic approaches. Despite such complexity, evidence is emerging for parallel evolution of subclones, mediated through distinct somatic events converging on the same gene, signal transduction pathway, or protein complex in different subclones within the same tumor. Tumors may follow gradualist paths (microevolution) as well as major shifts in evolutionary trajectories (macroevolution). Although macroevolution has been subject to considerable controversy in post-Darwinian evolutionary theory, we review evidence that such nongradual, saltatory leaps, driven through chromosomal rearrangements or genome doubling, may be particularly relevant to tumor evolution. Adapting cancer care to the challenges imposed by tumor micro- and macroevolution and developing deeper insight into parallel evolutionary events may prove central to improving outcome and reducing drug development costs.
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http://dx.doi.org/10.1146/annurev-genet-120213-092314DOI Listing
July 2015

The promise of circulating tumor cell analysis in cancer management.

Genome Biol 2014 Aug 30;15(8):448. Epub 2014 Aug 30.

Enumeration and molecular characterization of circulating tumor cells isolated from peripheral blood of patients with cancer can aid selection of targeted therapy for patients, monitoring of response to therapies and optimization of drug development, while also providing valuable information about intratumoral heterogeneity.
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http://dx.doi.org/10.1186/s13059-014-0448-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281949PMC
August 2014
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