Publications by authors named "Sheela Rao"

59 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

The Mutational Concordance of Fixed Formalin Paraffin Embedded and Fresh Frozen Gastro-Oesophageal Tumours Using Whole Exome Sequencing.

J Clin Med 2021 Jan 9;10(2). Epub 2021 Jan 9.

The Royal Marsden Hospital NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK.

1.

Background: The application of massively parallel sequencing has led to the identification of aberrant druggable pathways and somatic mutations within therapeutically relevant genes in gastro-oesophageal cancer. Given the widespread use of formalin-fixed paraffin-embedded (FFPE) samples in the study of this disease, it would be beneficial, especially for the purposes of biomarker evaluation, to assess the concordance between comprehensive exome-wide sequencing data from archival FFPE samples originating from a prospective clinical study and those derived from fresh-frozen material. 2.

Methods: We analysed whole-exome sequencing data to define the mutational concordance of 16 matched fresh-frozen and FFPE gastro-oesophageal tumours ( = 32) from a prospective clinical study. We assessed DNA integrity prior to sequencing and then identified coding mutations in genes that have previously been implicated in other cancers. In addition, we calculated the mutant-allele heterogeneity (MATH) for these samples. 3.

Results: Although there was increased degradation of DNA in FFPE samples compared with frozen samples, sequencing data from only two FFPE samples failed to reach an adequate mapping quality threshold. Using a filtering threshold of mutant read counts of at least ten and a minimum of 5% variant allele frequency (VAF) we found that there was a high median mutational concordance of 97% (range 80.1-98.68%) between fresh-frozen and FFPE gastro-oesophageal tumour-derived exomes. However, the majority of FFPE tumours had higher mutant-allele heterogeneity (MATH) scores when compared with corresponding frozen tumours ( < 0.001), suggesting that FFPE-based exome sequencing is likely to over-represent tumour heterogeneity in FFPE samples compared to fresh-frozen samples. Furthermore, we identified coding mutations in 120 cancer-related genes, including those associated with chromatin remodelling and Wnt/β-catenin and Receptor Tyrosine Kinase signalling. 4.

Conclusions: These data suggest that comprehensive genomic data can be generated from exome sequencing of selected DNA samples extracted from archival FFPE gastro-oesophageal tumour tissues within the context of prospective clinical trials.
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http://dx.doi.org/10.3390/jcm10020215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826535PMC
January 2021

EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers.

Gut 2021 Sep 16;70(9):1632-1641. Epub 2020 Nov 16.

Centre for Evolution and Cancer, The Institute of Cancer Research, Sutton, UK.

Objective: Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785).

Design: CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients.

Results: amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from -amplified aGEA.

Conclusion: CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.
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http://dx.doi.org/10.1136/gutjnl-2020-322658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355876PMC
September 2021

Reply to S. Kim et al.

Authors:
Sheela Rao

J Clin Oncol 2020 11 7;38(33):3974-3975. Epub 2020 Oct 7.

Sheela Rao, MBBS, Royal Marsden Hospital, Sutton, United Kingdom.

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http://dx.doi.org/10.1200/JCO.20.02643DOI Listing
November 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

Assessing the Quality of the Systems of Care for Children with Congenital Zika Virus Infection and Other Neurodevelopmental Disabilities in the United States Pacific Island Territories.

Hawaii J Health Soc Welf 2020 Sep;79(9):279-284

Keck School of Medicine of USC, Los Angeles, CA (PMY, SR, SI, DLV, AD-S).

Congenital Zika virus (ZIKV) infection can cause lifelong medical and developmental conditions and management needs. There is limited information on the strengths and weaknesses of the systems of care for addressing ZIKV and other neurodevelopmental disabilities (NRD) in the United States (US) Affiliated Pacific Island Territories. Therefore, the purpose of the study was to assess the quality of the chronic illness systems of care for children with congenital ZIKV and other NRD in the US Pacific Island Territories. A cross-sectional study was conducted among health professionals from American Samoa, Guam, and Commonwealth of the Northern Mariana Islands. Participants completed an adapted version of the Assessment of Chronic Illness Care 3.5 (ACIC), which is based on the Chronic Care Model. The median Total Program Score was calculated, which ranged from limited support (0-2), basic support (3-5), reasonably good support (6-8), to fully developed support for care (9-11). Among the 17 health professionals who completed the survey, 47% were Guamanian/Chamorro, 24% were Samoan, 12% were Filipino, and 6% were Other Pacific Islanders. The median (25th percentile, 75th percentile [interquartile range]) Total Program Score was 5 (3, 6 [3]), indicating basic support for ZIKV and other NRD care for children. As more is learned about the full spectrum of clinical findings related to ZIKV, it is critical to continue to build an interdisciplinary maternal and child health workforce with the capacity and preparation to adequately address the special needs of children with ZIKV and other NRD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477700PMC
September 2020

Racial/ethnic minority children recently placed in the child welfare system: the impact of sociodemographic, medical and mental health factors on overweight /obesity.

Soc Work Health Care 2020 08 7;59(7):499-512. Epub 2020 Aug 7.

Children's Hospital Los Angeles, Department of Pediatrics.

Children in the child welfare system have greater rates of obesity and are more prone to overweight/obesity as adults compared to other children. There is limited research on how ecological, biological and developmental factors impact the trajectory of overweight/obesity in this group. This retrospective study examined these factors among children entering the child welfare system. Overweight/obesity was highest among children 12-18 years. Children with diagnoses indicative of poor nutrition, and limiting exercise, were more likely to be overweight/obese. Ecological risks often were not disclosed. Barriers to obtaining information to address overweight/obesity reflect challenges to addressing chronic disease more broadly.
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http://dx.doi.org/10.1080/00981389.2020.1797978DOI Listing
August 2020

The FOCCUS study: a prospective evaluation of the frequency, severity and treatable causes of gastrointestinal symptoms during and after chemotherapy.

Support Care Cancer 2021 Mar 16;29(3):1443-1453. Epub 2020 Jul 16.

Royal Marsden Clinical Trials Unit Royal Marsden NHS Foundation Trust, Sutton, UK.

Background: The underlying mechanisms of chemotherapy-induced gastrointestinal (GI) symptoms are poorly researched. This study characterised the nature, frequency, severity and treatable causes for GI symptoms prospectively in patients undergoing chemotherapy for GI malignancy.

Methods: Patients receiving chemotherapy for a GI malignancy were assessed pre-chemotherapy, then monthly for 1 year using the Gastrointestinal Symptom Rating Scale, a validated patient-reported outcome measure. Patients with new, troublesome GI symptoms were offered investigations to diagnose the cause(s). Their oncologist was alerted when investigations were abnormal.

Results: A total of 241 patients, 60% male, median age 63 years (range 30-88), were enrolled; 122 patients were withdrawn, 93%, because of progressive disease or death. During the study, > 20% patients reported chronic faecal incontinence and > 10% reported moderate or severe problems with taste, dysphagia, belching, heartburn, early satiety, appetite, nausea, abdominal cramps, peri-rectal pain, rectal flatulence, borborygmi, urgency of defecation or tenesmus. Thirty percent reported continuing passage of hard stools and 30% on-going diarrhoea. Moderate or severe fatigue affected 40% participants at its peak and persisted in 15% at 1 year. Toxicity dictated change in chemotherapy for 13-29% patients/month. Common Terminology Criteria for Adverse Events underestimated gastrointestinal morbidity. Pre-chemotherapy screening identified previously undiagnosed pathology: exocrine pancreatic insufficiency (9%), vitamin B deficiency (12%) and thyroid dysfunction (20%). Patients often refused investigations to diagnose their chemotherapy-induced symptoms; however, for every three investigations performed, one treatable cause was diagnosed: particularly small intestinal bacterial overgrowth (54%), bile acid malabsorption (43%), previously not described after chemotherapy, and unsuspected urinary tract infection (17%).

Conclusions: Patients undergoing chemotherapy for GI malignancy commonly have difficult GI symptoms requiring active management which does not occur routinely. The underlying causes for these symptoms are often treatable or curable. Randomised trials are urgently needed to show whether timely investigation and treatment of symptoms improve quality of life and survival.

Trial Registration: ClinicalTrials.gov Identifier: NCT02121626.
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http://dx.doi.org/10.1007/s00520-020-05610-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843552PMC
March 2021

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

International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct.

J Clin Oncol 2020 08 12;38(22):2510-2518. Epub 2020 Jun 12.

Royal Marsden Hospital, London, United Kingdom.

Purpose: To compare cisplatin plus fluorouracil (FU) versus carboplatin plus paclitaxel in chemotherapy-naïve advanced anal cancer to establish the optimal regimen.

Patients And Methods: Patients who had not received systemic therapy for advanced anal cancer were randomly assigned 1:1 to intravenous cisplatin 60 mg/m (day 1) plus FU 1,000 mg/m (days 1-4) every 21 days or carboplatin (area under the curve, 5; day 1) plus paclitaxel 80 mg/m (days 1, 8, and 15) every 28 days for 24 weeks, until disease progression, intolerable toxicity, or withdrawal of consent. Primary end point was objective response rate (ORR). Primary and secondary end points were assessed in a hierarchic model to compare the regimens and pick the winner.

Results: We conducted an international multicenter randomized phase II study in 60 centers between December 2013 and November 2017. Median follow-up was 28.6 months. A total of 91 patients were randomly assigned: 46 to cisplatin plus FU and 45 to carboplatin plus paclitaxel. ORR was 57% (95% CI, 39.4% to 73.7%) for cisplatin plus FU versus 59% (95% CI, 42.1% to 74.4%) for carboplatin plus paclitaxel. More serious adverse events were noted in the cisplatin plus FU arm (62%) compared with the carboplatin plus paclitaxel arm (36%; = .016). Median progression-free survival was 5.7 months (95% CI, 3.3 to 9.0 months) for cisplatin plus FU compared with 8.1 months (95% CI, 6.6 to 8.8 months) for carboplatin plus paclitaxel. Median overall survival was 12.3 months for cisplatin plus FU (95% CI, 9.2 to 17.7 months) compared with 20 months (95% CI, 12.7 months to not reached) for carboplatin plus paclitaxel (hazard ratio, 2.00; 95% CI, 1.15 to 3.47; = .014).

Conclusion: This is the first international randomized trial to our knowledge conducted in chemotherapy-naïve advanced anal cancer. Although there was no difference in ORR, the association with clinically relevant reduced toxicity and a trend toward longer survival suggest that carboplatin plus paclitaxel should be considered as a new standard of care.
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http://dx.doi.org/10.1200/JCO.19.03266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406334PMC
August 2020

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

Targeting EGFR pathway in metastatic colorectal cancer- tumour heterogeniety and convergent evolution.

Crit Rev Oncol Hematol 2019 Nov 7;143:153-163. Epub 2019 Sep 7.

Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Sutton SM2 5PT, UK. Electronic address:

Despite significant progress in management of metastatic colorectal cancer (mCRC) pertaining to better screening procedures and amelioration of the therapeutic armamentarium with targeted therapies, prognosis remains poor. Targeting epidermal growth factor receptor (EGFR) has been of particular interest owing to favourable efficacy benefits demonstrated by monoclonal antibodies (cetuximab and panitumumab) in various clinical settings and development of predictive biomarkers informing treatment decisions respectively. In spite of optimal patient selection based on RAS mutation status, primary and secondary resistance to monoclonal antibodies is higher than desired. Further research into predictive biomarkers is therefore essential, but has, to date, been conducted with considerable limitations. Whilst molecular heterogeneity has been demonstrated by several studies in mCRC, for incomprehensible reasons, multiple resistant genetic alterations that emerge under the selective pressure of EGFR-targeted therapies are somehow able to influence the biological and clinical behaviour of cancer cells, despite being detectable at extremely low frequencies. Intriguingly, these subclonal events largely seem to converge on RAS/RAF/MAPK pathway in patients treated with EGFR-targeted monoclonal antibodies. This review describes the clinical and biological evolution and development of EGFR targeted therapies in mCRC, the challenges in the presence of molecular complexities, the role of cell free (cf)-DNA and future strategies that could lead to further optimal discovery of clinically meaningful biomarkers and application of precision medicine.
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http://dx.doi.org/10.1016/j.critrevonc.2019.09.001DOI Listing
November 2019

Outcomes of Patients with Early Onset Colorectal Cancer Treated in a UK Specialist Cancer Center.

Cancers (Basel) 2019 Oct 14;11(10). Epub 2019 Oct 14.

Department of Medicine, The Royal Marsden Foundation Trust, London and Surrey SM2 5PT, UK.

The incidence of early onset colorectal cancer (EOCRC) is rapidly increasing, but there remains paucity of outcome data for young CRC patients. We reviewed the characteristics and outcomes of 241 adults, age <50, who were diagnosed with EOCRC between January 2009 and December 2014. Median age was 42, 56% were male, and 7% had hereditary etiology. Seventy percent had left-sided primaries. At diagnosis, 11%, 50%, and 39% had stage II, III, and IV CRC. Of the patients with stage II and III CRC who underwent curative surgery, 60% and 88% had adjuvant chemotherapy, with 5-year relapse free survival of 82% and 74% respectively. Of the 123 patients with metastatic (m) EOCRC, 93%, 63%, 33%, and 12% had 1st, 2nd, 3rd, and 4th line systemic anticancer therapy (SACT) respectively. For first line SACT, 99% had doublet chemotherapy, with bevacizumab or an anti-EGFR antibody in 57%. Median overall survival (mOS) of mEOCRC patients was 20.1 months (95% C.I: 15.9-23.2). Younger age and signet cells were associated with shorter mOS, whereas more lines of SACT and curative metastasectomy with longer mOS. Metastatic EOCRC patients had poorer outcomes than expected, despite optimal multimodality treatment. This suggests an aggressive disease biology that warrants further research and therapy development.
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http://dx.doi.org/10.3390/cancers11101558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826435PMC
October 2019

Clonal diversity of MYC amplification evaluated by fluorescent in situ hybridisation and digital droplet polymerase chain reaction in oesophagogastric cancer: Results from a prospective clinical trial screening programme.

Eur J Cancer 2019 11 10;122:12-21. Epub 2019 Oct 10.

Royal Marsden NHS Foundation Trust, Downs Road, Surrey, SM2 5PT, UK; Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK. Electronic address:

Introduction: The MYC proto-oncogene is among the most commonly dysregulated genes in human cancers. We report screening data from the iMYC trial, an ongoing phase II study assessing ibrutinib monotherapy in advanced pretreated MYC- and/or HER2-amplified oesophagogastric cancer, representing the first attempt to prospectively identify MYC amplifications in this tumour type for the purposes of therapeutic targeting.

Methods: Screening utilising a fluorescent in situ hybridisation (FISH) assay for assessment of tumour MYC amplification has been instituted. An experimental digital droplet polymerase chain reaction (ddPCR) assay to assess MYC amplification in both tumour and circulating-tumour (ct)DNA has been developed and investigated.

Results: One hundred thirty-five archival tumour specimens have undergone successful FISH analysis with 23% displaying evidence of MYC amplification. Intertumour heterogeneity was observed, with the percentage of cancer cells harbouring MYC amplification ranging widely between samples (median 51%, range 11-94%). Intratumoural clonal diversity of MYC amplification was also observed, with a significant degree of variance in amplification ratios (Bartlett's test for equal variance p < 0.001), and an association between greater variance in MYC amplification and improved outcome with prior first-line chemotherapy. ddPCR was most accurate in quantifying MYC amplification in tumour-derived DNA from cases with a high proportion (>70%) of amplified cells within the tumour specimen but was not reliable in samples containing a low proportion of amplified cells or in ctDNA.

Conclusions: Our results illustrate the utility of FISH to assess MYC amplification prospectively for a biomarker-selected trial by providing reliable and reproducible results in real time, with a high degree of heterogeneity of MYC amplification observed. We show that ddPCR can potentially detect high-level MYC amplifications in tumour tissue.
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http://dx.doi.org/10.1016/j.ejca.2019.09.003DOI Listing
November 2019

Influence of sex on chemotherapy efficacy and toxicity in oesophagogastric cancer: A pooled analysis of four randomised trials.

Eur J Cancer 2019 11 19;121:40-47. Epub 2019 Sep 19.

Gastrointestinal Research Unit, Royal Marsden Hospitals NHS Foundation Trust, London, UK. Electronic address:

Background: Sex contributes to interpatient variability of chemotherapy metabolism and dose response, potentially influencing both efficacy and toxicity; however, comparative data on its effect on oesophagogastric cancer are lacking.

Patients And Methods: Data for patients with advanced oesophagogastric cancer randomised to comparable first-line chemotherapy regimens within four United Kingdom prospective trials were pooled, and key demographic and outcome measures were compared between males and females.

Results: A total of 1654 patients were included: 1328 (80.3%) males and 326 (19.7%) females. Female patients were younger, had a significantly higher proportion of gastric tumours as opposed to junctional or oesophageal tumours and experienced significantly higher rates of a number of toxicities including nausea and vomiting, diarrhoea, stomatitis and alopecia. When adjusting for potential confounding factors, the risk of female patients experiencing grade ≥III gastrointestinal toxicity was greater (adjusted odds ratio = 1.50; 95% confidence interval = 1.07-2.12). Females also had a significantly higher incidence of serious adverse events on treatment and received comparatively less cycles of chemotherapy overall than males.

Conclusions: This represents the largest pooled analysis of the effect of sex on chemotherapy outcome and toxicity in advanced oesophagogastric cancer. The differential toxicity and adverse event rates observed suggest that sex may be an important modulator of treatment tolerability and safety in this tumour type.
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http://dx.doi.org/10.1016/j.ejca.2019.08.010DOI Listing
November 2019

Safely surrendered infants in Los Angeles County: A medically vulnerable population.

Child Care Health Dev 2019 11 30;45(6):861-866. Epub 2019 Jul 30.

Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.

Background: As a means to provide safety for a population at great risk of harm through abandonment, every state in the United States now has laws and practices for the safe relinquishment of newborns and infants. However, there is no national database tracking the population of infants surrendered through such programmes, and few states monitor these numbers. The primary aim of this study was therefore to examine the descriptive characteristics of infants who have been safely surrendered in a large, socio-economically diverse urban area. The secondary aim was to compare them with local population norms to determine whether differences exist and to begin exploring what implications such differences may have for the treatment provided to these infants.

Methods: A retrospective cross-sectional study was conducted among safely surrendered infants.

Results: Over half of the infants had medical issues, and the majority of the infants were surrendered in communities characterized by low median income.

Conclusions: Preliminary information highlights potential economic, social, and medical risk factors, suggesting that these infants may require increased monitoring and/or specialized care.
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http://dx.doi.org/10.1111/cch.12711DOI Listing
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

miR-31-3p Expression and Benefit from Anti-EGFR Inhibitors in Metastatic Colorectal Cancer Patients Enrolled in the Prospective Phase II PROSPECT-C Trial.

Clin Cancer Res 2019 07 5;25(13):3830-3838. Epub 2019 Apr 5.

Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom.

Purpose: Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. status and tumor location (sidedness) are predictive markers of patients' response to anti-EGFR mAbs. Recently, low miR-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here, we aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemorefractory mCRC patients treated with single-agent anti-EGFR mAbs.

Experimental Design: miR-31-3p was tested by hybridization (ISH) in 91 pretreatment core biopsies from metastatic deposits of 45 patients with mCRC. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in miR-31-3p expression overtreatment. miR-31-3p expression, sidedness, and status in pretreatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination.

Results: Patients with low miR-31-3p expression in pretreatment biopsies showed better overall response rate, as well as better progression-free survival and overall survival, compared to those with high miR-31-3p expression. The prognostic effect of miR-31-3p was independent from age, gender, and sidedness. No significant changes in the expression of miR-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mAbs. miR-31-3p scores were similar when pretreatment biopsies were compared with treatment-naïve archival tissues (often primary colorectal cancer).

Conclusions: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mAbs.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3769DOI Listing
July 2019

Pseudoprogression on treatment with immune-checkpoint inhibitors in patients with gastrointestinal malignancies: Case series and short literature review.

Curr Probl Cancer 2019 10 21;43(5):487-494. Epub 2019 Feb 21.

Clinical Radiology Deaprtment, The Royal Marsden NHS Foundation Trust.

Gastrointestinal cancers are very common cancers with colorectal being the fourth most common type, gastric the sixth, and esophageal the tenth. Although recent advances have been made in management including incorporation of antiangiogenic, anti-EGFR, and anti-HER2 directed therapies, overall their prognosis remains poor. Anti-PD-1 therapy with nivolumab and pembrolizumab are licensed for advanced chemorefractory gastroesophageal cancer and many other checkpoint inhibitor therapies are being assessed alone and in combination in these diseases. One of the challenges posed in assessing response to immunotherapy treatment is the phenomenon of pseudoprogression. This phenomenon, which is well described in patients with malignant melanoma is most frequently described as a size increase of contrast enhancing lesions or appearance of new lesions that stabilize or reduce in size with time. Most other solid tumors have a low incidence of pseudoprogression although cases have been reported for lung, head, and neck cancer and a range of gliomas. Herein we present 6 cases of patients with gastrointestinal cancers who were treated with anti-PD1 (programmed cell death) and anti-PD-L1 (programmed cell death ligand-1) antibodies, and experience pseudoprogression.
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http://dx.doi.org/10.1016/j.currproblcancer.2019.01.008DOI Listing
October 2019

Multimodality treatment of oligometastatic anal squamous cell carcinoma: A case series and literature review.

J Surg Oncol 2019 Mar 12;119(4):489-496. Epub 2019 Jan 12.

Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.

Background And Objectives: There is limited evidence to guide the management of patients with oligometastatic anal squamous cell carcinoma (SCC). We aimed to address this question by reporting the outcome of SCC patients who were treated with organ-directed therapies at two large cancer centers.

Methods: Patients with advanced anal SCC who were treated with surgery, stereotactic radiotherapy, or radiofrequency ablation (RFA) with a curative intent from 2008 to 2017 were retrospectively identified from the institutional electronic patient records.

Results: Eight patients with liver or lung metastases met the study inclusion criteria. Seven were treated with surgery while one received RFA and radiotherapy. Median progression-free survival was 5 months (range, 4-39). Three patients underwent repeat organ-directed treatment upon failure of the initial surgery with no evidence of further recurrent disease at the last follow-up. Median overall survival from the time of the first organ-directed therapy was 31 months (range, 11-96) with two out of eight patients being alive and disease-free at 5 years.

Conclusions: Our study confirms that consideration should be given to the adoption of a multidisciplinary treatment approach in carefully selected, oligometastatic anal SCC patients as organ-directed therapies may offer the chance of achieving a relatively long disease control.
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http://dx.doi.org/10.1002/jso.25320DOI Listing
March 2019

Genomic loss of heterozygosity and survival in the REAL3 trial.

Oncotarget 2018 Nov 30;9(94):36654-36665. Epub 2018 Nov 30.

Department of Gastrointestinal Oncology and Lymphoma, Royal Marsden Hospital, London & Sutton, United Kingdom.

Background: Homologous recombination deficiency (HRD) measured using a genomic signature for loss of heterozygosity (LOH) predicts benefit from rucaparib in ovarian cancer. We hypothesized that some oesophagogastric cancers will have high-LOH which would be prognostic in patients treated with platinum chemotherapy.

Methods: Diagnostic biopsy DNA from patients treated in the REAL3 trial was sequenced using the Foundation Medicine T5 next-generation sequencing (NGS) assay. An algorithm quantified the percentage of interrogable genome with LOH. Multidimensional optimization was performed to identify a cut-off dichotomizing the population into LOH-high and low groups associated with differential survival outcomes.

Results: Of 158 available samples, 117 were successfully sequenced; LOH was derived for 74 of these. A cut-off of 21% genomic LOH defined an LOH-high subgroup (n=10, 14% of population) who had median overall survival (OS) of 18.3 months (m) versus 11m for the LOH-low group (HR 0.55 95% CI 0.19-0.97, p= 0.10). Progression free survival (PFS) for LOH-high and LOH-low groups was 10.7m and 7.3m (HR 0.61 (95% CI 0.21 - 1.09, p=0.09). Sensitivity analysis censoring operated patients (n=4), demonstrated OS of 18.3m vs. 10.2m (HR 0.43, 95% CI (0.20-0.92), p=0.02; PFS was 10.5m vs. 7.2m (HR 0.55, (95% CI 0.26-1.17), p=0.09 for LOH-high and LOH-low.

Conclusion: HRD assessment using an algorithmically derived LOH signature on a standard NGS panel identifies oesophagogastric cancer patients with high LOH who have prolonged survival when treated with platinum chemotherapy. Validation work will determine the signature's predictive value in patients treated with a PARP inhibitor and with platinum chemotherapy.
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http://dx.doi.org/10.18632/oncotarget.26336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291175PMC
November 2018

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

Cisplatin Substitution with Carboplatin During Radical Chemoradiotherapy for Oesophagogastric Carcinoma: Outcomes from a Tertiary Centre.

Anticancer Res 2018 Oct;38(10):5943-5949

Gastrointestinal Unit, Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey, U.K.

Background/aim: Cisplatin-based radical chemoradiotherapy (CRT) is utilised in oesophagogastric (OG) cancer but the toxicity profile of cisplatin limits its use. This study aimed to evaluate the clinical characteristics and outcomes of patients treated with either cisplatin or carboplatin based CRT at our institution.

Materials And Methods: This is a retrospective analysis of patients with localised OG cancer undergoing CRT with cisplatin/fluoropyrimidine (CX/F) or carboplatin/fluoropyrimidine (CarboX/F) between January 2001 and December 2014.

Results: A total of 91 eligible patients were included. Median age was 65 years (IQR=57-75) for CX/F and 77 years (IQR=69-80) for CarboX/F. Adenocarcinoma histology and Charlson comorbidity index were higher in the CarboX/F group. Endoscopic complete response (CR) was achieved in 64% of CX/F group and 48% of CarboX/F group (p=0.19). The median PFS for CX/F was 31.0 months (95%CI=18.2-NE) vs. 18.7 months for CarboX/F (95%CI=13.5-30.4; HR=1.49, p=0.21).

Conclusion: Despite significant differences in baseline clinical characteristics, patients treated with carboplatin CRT demonstrated no significant difference in PFS or endoscopic CR rate, compared to those treated with cisplatin.
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http://dx.doi.org/10.21873/anticanres.12940DOI Listing
October 2018

Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial.

Cancer Discov 2018 10 30;8(10):1270-1285. Epub 2018 Aug 30.

Clinical Genomics, The Centre for Molecular Pathology, The Royal Marsden NHS Trust, London and Sutton, United Kingdom.

Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies. Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380469PMC
October 2018

Survival in Advanced Esophagogastric Adenocarcinoma Improves With Use of Multiple Lines of Therapy: Results From an Analysis of More Than 500 Patients.

Clin Colorectal Cancer 2018 09 8;17(3):223-230. Epub 2018 Jun 8.

Department of Medicine, Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom. Electronic address:

Background: Although progress has been made in the molecular stratification of esophagogastric adenocarcinoma, the outlook for advanced disease remains poor. The present evaluation of over 500 patients treated at a single European high-volume tertiary center during a 6-year period gives important information on current and developing "real-world" treatment patterns and outcomes.

Results: The overall survival for the whole cohort was 11.5 months, with a range of treatments used in first-, second-, and third-line settings. Treatment with sequential lines of therapy was associated with better outcomes, although only 39% and 14% of patients subsequently received treatment in the second- and third-line setting, respectively. Treatment within a therapeutic clinical trial was associated with significantly improved survival.

Conclusion: At present, a substantial proportion of patients with advanced esophagogastric adenocarcinoma will not proceed beyond first-line therapy, and for this group refinement of initial systemic therapies are required to improve outcomes. Although a number of established first- and second-line treatment options are now available, the therapeutic landscape of the disease continues to change, most notably in the application of immunotherapy and increasing interest in establishing evidence-based interventions in the third-line setting and beyond. A small but growing proportion of patients will benefit from sequential treatment approaches incorporating multiple lines of therapy, and improved selection of such patients will be a key challenge for clinicians moving forwards. Data such as these provide an overview of current treatment patterns and outcomes which can be used to inform planning of future research effectively within existing treatment frameworks.
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http://dx.doi.org/10.1016/j.clcc.2018.05.014DOI Listing
September 2018

Systemic Therapies for Advanced Squamous Cell Anal Cancer.

Curr Oncol Rep 2018 05 4;20(7):53. Epub 2018 May 4.

Department of Medicine, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, SM2 5PT, UK.

Purpose Of Review: We aim to summarise the available evidence on systemic therapies for advanced anal cancer.

Recent Findings: There is no universal consensus on the management of this condition and the prognosis remains poor. Nevertheless, significant progress has been recently made including completion of the first, ever-conducted, randomised trial in the first-line setting, investigation of immunotherapy in the refractory setting and use of comprehensive genomic profiling for a better molecular characterisation of this disease and the identification of novel potential targets. The combination of a platinum agent and a fluoropyrimidine is generally considered the standard first-line treatment. Other cytotoxic agents, especially docetaxel and paclitaxel, have shown activity in both the chemotherapy-naive and chemo-refractory setting and are currently being investigated in clinical trials. Finally, further to the promising results of early clinical trials, immunotherapy with checkpoint inhibitors (i.e. nivolumab and pembrolizumab) is likely to become a standard second-line treatment option.
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http://dx.doi.org/10.1007/s11912-018-0698-6DOI Listing
May 2018

Patient-derived organoids model treatment response of metastatic gastrointestinal cancers.

Science 2018 02;359(6378):920-926

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

Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living biobank of PDOs from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients recruited in phase 1/2 clinical trials. Phenotypic and genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors. Molecular profiling of tumor organoids was matched to drug-screening results, suggesting that PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses. We compared responses to anticancer agents ex vivo in organoids and PDO-based orthotopic mouse tumor xenograft models with the responses of the patients in clinical trials. Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs.
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http://dx.doi.org/10.1126/science.aao2774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112415PMC
February 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
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