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1. Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre

Author

Lau, David K., Fong, Caroline, Arouri, Faten, Cortez, Lillian, Katifi, Hannah, Gonzalez-Exposito, Reyes, Razzaq, Muhammad Bilal, Li, Su, Macklin-Doherty, Aislinn, Hernandez, Monica Arenas, Hubank, Michael, Fribbens, Charlotte, Watkins, David, Rao, Sheela, Chau, Ian, Cunningham, David, and Starling, Naureen

Published
2023
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2. Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage

Author

Carotenuto, Pietro, Amato, Francesco, Lampis, Andrea, Rae, Colin, Hedayat, Somaieh, Previdi, Maria C., Zito, Domenico, Raj, Maya, Guzzardo, Vincenza, Sclafani, Francesco, Lanese, Andrea, Parisi, Claudia, Vicentini, Caterina, Said-Huntingford, Ian, Hahne, Jens C., Hallsworth, Albert, Kirkin, Vladimir, Young, Kate, Begum, Ruwaida, Wotherspoon, Andrew, Kouvelakis, Kyriakos, Azevedo, Sergio Xavier, Michalarea, Vasiliki, Upstill-Goddard, Rosie, Rao, Sheela, Watkins, David, Starling, Naureen, Sadanandam, Anguraj, Chang, David K., Biankin, Andrew V., Jamieson, Nigel B., Scarpa, Aldo, Cunningham, David, Chau, Ian, Workman, Paul, Fassan, Matteo, Valeri, Nicola, and Braconi, Chiara

Published
2021
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4. MicroRNAs as biomarkers for trastuzumab-based therapy in HER2-positive advanced oesophago-gastric cancer patients

Author

Lote, Hazel, primary, Mousoullou, Florentia, additional, Vlachogiannis, George, additional, Lampis, Andrea, additional, Satchwell, Laura, additional, Peckitt, Clare, additional, Fong, Caroline, additional, Begum, Ruwaida, additional, Kidd, Shannon, additional, Cromarty, Susan, additional, Gordon, Anderley, additional, Fribbens, Charlotte, additional, Rao, Sheela, additional, Starling, Naureen, additional, Chau, Ian, additional, Cunningham, David, additional, and Valeri, Nicola, additional

Published
2023
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6. Immunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment

Author

Newey, Alice, Griffiths, Beatrice, Michaux, Justine, Pak, Hui Song, Stevenson, Brian J., Woolston, Andrew, Semiannikova, Maria, Spain, Georgia, Barber, Louise J., Matthews, Nik, Rao, Sheela, Watkins, David, Chau, Ian, Coukos, George, Racle, Julien, Gfeller, David, Starling, Naureen, Cunningham, David, Bassani-Sternberg, Michal, and Gerlinger, Marco

Published
2019
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7. CEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids

Author

Gonzalez-Exposito, Reyes, Semiannikova, Maria, Griffiths, Beatrice, Khan, Khurum, Barber, Louise J., Woolston, Andrew, Spain, Georgia, von Loga, Katharina, Challoner, Ben, Patel, Radhika, Ranes, Michael, Swain, Amanda, Thomas, Janet, Bryant, Annette, Saffery, Claire, Fotiadis, Nicos, Guettler, Sebastian, Mansfield, David, Melcher, Alan, Powles, Thomas, Rao, Sheela, Watkins, David, Chau, Ian, Matthews, Nik, Wallberg, Fredrik, Starling, Naureen, Cunningham, David, and Gerlinger, Marco

Published
2019
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8. SARS-CoV-2 Vaccine Immunogenicity in Patients with Gastrointestinal Cancer Receiving Systemic Anti-Cancer Therapy

Author

Lau, David K, primary, Aresu, Maria, additional, Planche, Timothy, additional, Tran, Amina, additional, Lazaro-Alcausi, Retchel, additional, Duncan, Julie, additional, Kidd, Shannon, additional, Cromarty, Susan, additional, Begum, Ruwaida, additional, Rana, Isma, additional, Li, Su, additional, Mohamed, Ali Abdulnabi, additional, Monahan, Irene, additional, Clark, David J, additional, Eckersley, Nicholas, additional, Staines, Henry M, additional, Groppelli, Elisabetta, additional, Krishna, Sanjeev, additional, Mayora-Neto, Martin, additional, Temperton, Nigel, additional, Fribbens, Charlotte, additional, Watkins, David, additional, Starling, Naureen, additional, Chau, Ian, additional, Cunningham, David, additional, and Rao, Sheela, additional

Published
2022
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12. SARS-CoV-2 Vaccine Immunogenicity in Patients with Gastrointestinal Cancer Receiving Systemic Anti-Cancer Therapy

Author

Lau, David K., Aresu, Maria, Planche, Timothy, Tran, Amina, Lazaro-Alcausi, Retchel, Duncan, Julie, Kidd, Shannon, Cromarty, Susan, Begum, Ruwaida, Rana, Isma, Li, Su, Mohamed, Ali Abdulnabi, Monahan, Irene, Clark, David J., Eckersley, Nicholas, Staines, Henry M., Groppelli, Elisabetta, Krishna, Sanjeev, Mayora-Neto, Martin, Temperton, Nigel J., Fribbens, Charlotte, Watkins, David, Starling, Naureen, Chau, Ian, Cunningham, David, Rao, Sheela, Lau, David K., Aresu, Maria, Planche, Timothy, Tran, Amina, Lazaro-Alcausi, Retchel, Duncan, Julie, Kidd, Shannon, Cromarty, Susan, Begum, Ruwaida, Rana, Isma, Li, Su, Mohamed, Ali Abdulnabi, Monahan, Irene, Clark, David J., Eckersley, Nicholas, Staines, Henry M., Groppelli, Elisabetta, Krishna, Sanjeev, Mayora-Neto, Martin, Temperton, Nigel J., Fribbens, Charlotte, Watkins, David, Starling, Naureen, Chau, Ian, Cunningham, David, and Rao, Sheela

Abstract

Introduction: Patients with gastrointestinal (GI) cancers have an increased risk of serious complications and death from SARS-CoV-2 infection. The immunogenicity of vaccines in patients with GI cancers receiving anti-cancer therapies is unclear. We conducted a prospective study to evaluate the prevalence of neutralizing antibodies in a cohort of GI cancer patients receiving chemotherapy following SARS-CoV-2 vaccination. Materials and methods: Between September 2020 and April 2021, patients with cancer undergoing chemotherapy were enrolled. At baseline (day 0), days 28, 56, and 84, we assessed serum antibodies to SARS-CoV-2 spike (anti-S) and anti-nucleocapsid (anti-NP) and concomitantly assessed virus neutralization using a pseudovirus neutralization assay. Patients received either the Pfizer/BioNTech BNT162b2, or the Oxford/AstraZeneca ChAdOx1 vaccine. Results: All 152 patients enrolled had a prior diagnosis of cancer; colorectal (n = 80, 52.6%), oesophagogastric (n = 38, 25.0%), and hepato pancreatic biliary (n = 22, 12.5%). Nearly all were receiving systemic anti-cancer therapy (99.3%). Of the 51 patients who did not receive a vaccination prior to, or during the study, 5 patients had detectable anti-NP antibodies. Ninety-nine patients received at least one dose of vaccine prior to, or during the study. Within 19 days following the first dose of vaccine, 30.0% had anti-S detected in serum which increased to 70.2% at days 20-39. In the 19 days following a second dose, anti-S positivity was 84.2% (32/38). However, pseudovirus neutralization titers (pVNT80) decreased from days 20 to 39. Conclusion: Despite the immunosuppressive effects of chemotherapy, 2 doses of SARS-CoV-2 vaccines are able to elicit a protective immune response in patients' ongoing treatment for gastrointestinal cancers. Decreases in pseudoviral neutralization were observed after 20-39 days, re-affirming the current recommendation for vaccine booster doses.

Published
2022

13. A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202)

Author

Rao, Sheela, Anandappa, Gayathri, Capdevila, Jaume, Dahan, Laëtitia, Evesque, Ludovic, Kim, Stefano, Saunders, Mark M.P., Gilbert, Duncan D.C., Jensen, Lars Henrik, Samalin, Emmanuelle, Spindler, Karen Lise Garm K.L., Tamberi, Stefano, Demols, Anne, Guren, Marianne M.G., Arnold, Dirk, Fakih, Marwan, Kayyal, T., Cornfeld, M., Tian, C., Catlett, M., Smith, M., Spano, Jean Philippe, Rao, Sheela, Anandappa, Gayathri, Capdevila, Jaume, Dahan, Laëtitia, Evesque, Ludovic, Kim, Stefano, Saunders, Mark M.P., Gilbert, Duncan D.C., Jensen, Lars Henrik, Samalin, Emmanuelle, Spindler, Karen Lise Garm K.L., Tamberi, Stefano, Demols, Anne, Guren, Marianne M.G., Arnold, Dirk, Fakih, Marwan, Kayyal, T., Cornfeld, M., Tian, C., Catlett, M., Smith, M., and Spano, Jean Philippe

Abstract

Background: Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC. Patients and methods: Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class. Conclusions: Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based che, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2022

14. A Machine-Learning-Based Bibliometric Analysis of the Scientific Literature on Anal Cancer

Author

Franco, Pierfrancesco, primary, Segelov, Eva, additional, Johnsson, Anders, additional, Riechelmann, Rachel, additional, Guren, Marianne G., additional, Das, Prajnan, additional, Rao, Sheela, additional, Arnold, Dirk, additional, Spindler, Karen-Lise Garm, additional, Deutsch, Eric, additional, Krengli, Marco, additional, Tombolini, Vincenzo, additional, Sebag-Montefiore, David, additional, and De Felice, Francesca, additional

Published
2022
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15. Ibrutinib in c-MYC and HER2 Amplified Oesophagogastric Carcinoma: Results of the Proof-of-Concept iMYC Study

Author

Turkes, Fiona, primary, Bryant, Annette, additional, Begum, Ruwaida, additional, Davidson, Michael, additional, Kalaitzaki, Eleftheria, additional, Aresu, Maria, additional, Lazaro-Alcausi, Retchel, additional, Bryant, Jane, additional, Rana, Isma, additional, Chua, Sue, additional, Aronson, Lauren, additional, Hulkki-Wilson, Sanna, additional, Fribbens, Charlotte, additional, Watkins, David, additional, Rao, Sheela, additional, Starling, Naureen, additional, Cunningham, David, additional, Chong, Irene Y., additional, and Chau, Ian, additional

Published
2022
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17. The Mutational Concordance of Fixed Formalin Paraffin Embedded and Fresh Frozen Gastro-Oesophageal Tumours Using Whole Exome Sequencing

Author

Chong, Irene Y., primary, Starling, Naureen, additional, Rust, Alistair, additional, Alexander, John, additional, Aronson, Lauren, additional, Llorca-Cardenosa, Marta, additional, Chauhan, Ritika, additional, Chaudry, Asif, additional, Kumar, Sacheen, additional, Fenwick, Kerry, additional, Assiotis, Ioannis, additional, Matthews, Nik, additional, Begum, Ruwaida, additional, Wotherspoon, Andrew, additional, Terlizzo, Monica, additional, Watkins, David, additional, Chau, Ian, additional, Lord, Christopher J., additional, Haider, Syed, additional, Rao, Sheela, additional, and Cunningham, David, additional

Published
2021
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18. Diagnostic Accuracy and Safety of Coaxial System in Oncology Patients Treated in a Specialist Cancer Center With Prospective Validation Within Clinical Trial Data

Author

Khan, Khurum, primary, Gonzalez-Exposito, Reyes, additional, Cunningham, David, additional, Koh, Dow-Mu, additional, Woolston, Andrew, additional, Barber, Louise, additional, Griffiths, Beatrice, additional, Kouvelakis, Kyriakos, additional, Calamai, Vanessa, additional, Bali, Monia, additional, Khan, Nasir, additional, Bryant, Annette, additional, Saffery, Claire, additional, Dearman, Charles, additional, Begum, Ruwaida, additional, Rao, Sheela, additional, Starling, Naureen, additional, Watkins, David, additional, Chau, Ian, additional, Braconi, Chiara, additional, Valeri, Nicola, additional, Gerlinger, Marco, additional, and Fotiadis, Nicos, additional

Published
2020
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19. Abstract 258: MicroRNAs as biomarkers of resistance to HER2 inhibition in combination with chemotherapy in gastro-esophageal cancer

Author

Lote, Hazel, primary, Lampis, Andrea, additional, Vlachogiannis, George, additional, Hahne, Jens, additional, Moorcraft, Sing-Yu, additional, Davidson, Michael, additional, Fong, Carolin, additional, Begum, Ruwaida, additional, Fassan, Matteo, additional, Rao, Sheela, additional, Watkins, David, additional, Starling, Naureen, additional, Chau, Ian, additional, Cunningham, David, additional, and Valeri, Nicola, additional

Published
2020
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21. Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study

Author

Khan, Khurum, Rata, Mihaela, Cunningham, David, Koh, Dow-Mu, Tunariu, Nina, Hahne, Jens C., Vlachogiannis, George, Hedayat, Somaieh, Marchetti, Silvia, Lampis, Andrea, Damavandi, Mahnaz Darvish, Lote, Hazel, Rana, Isma, Williams, Anja, Eccles, Suzanne A., Fontana, Elisa, Collins, David, Eltahir, Zakaria, Rao, Sheela, Watkins, David, Starling, Naureen, Thomas, Jan, Kalaitzaki, Eleftheria, Fotiadis, Nicos, Begum, Ruwaida, Bali, Maria, Rugge, Massimo, Temple, Eleanor, Fassan, Matteo, Chau, Ian, Braconi, Chiara, and Valeri, Nicola

Subjects
Adult, Male, liquid biopsy, Colon, anti-angiogenic treatment, DCE-MRI, Pyridines, Phenylurea Compounds, colorectal cancer, cancer therapeutics, regorafenib, Kaplan-Meier Estimate, Middle Aged, Magnetic Resonance Imaging, Treatment Outcome, Humans, Female, Prospective Studies, Colorectal Neoplasms, Biomarkers, Aged
Abstract

Objective: Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.\ud \ud Design: Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.\ud \ud Results: Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06).\ud \ud Conclusions: Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

Published
2017

22. Effect of perioperative FLOT versus ECF/ECX on short-term outcomes after surgery for resectable oesophagogastric adenocarcinoma: propensity score-matched study.

Author

Moussa, Osama, Bhogal, Ricky Harminder, Malietzis, George, Fribbens, Charlotte, Starling, Naureen, Gerlinger, Marco, Watkins, David, Chau, Ian, Rao, Sheela, Cunningham, David, Allum, William H., Chaudry, Asif, and Kumar, Sacheen

Subjects
TREATMENT effectiveness, ADENOCARCINOMA, GASTRECTOMY, SURGICAL complications, OXALIPLATIN, GASTRIC bypass
Abstract

Background Perioperative FLOT (fluorouracil plus leucovorin, oxaliplatin, and docetaxel) chemotherapy is a recent regimen used to treat resectable oesophagogastric (OG) adenocarcinoma, associated with improved overall survival versus earlier chemotherapy strategies. This study compared short-term perioperative morbidity in a large tertiary centre series of FLOT to a matched cohort receiving ECX/ECF (epirubicin, cisplatin, capecitabine (X) or 5-fluorouracil (F)). Methods Consecutive patients completing four perioperative cycles of FLOT and proceeding to surgery with resectable OG adenocarcinoma were included. This was matched to patients from a historic ECX/ECF cohort from the same institution. A propensity score was calculated, and a secondary analysis using a propensity-matched group performed. Results Cohorts were matched by tumour location and operations performed. In total there were 129 (64.5 per cent) oesophageal and 71 (35.5 per cent) gastric resections (FLOT 57 oesophageal, 43 gastric; ECF/ECX 64 oesophageal, 36 gastric). The median length of stay after surgery was 12 days in the FLOT group versus 15 in ECF/ECX (P  = 0.035). There were no significant differences in overall perioperative complications and, specifically, no difference in OG anastomotic leaks, analysed by site (gastric (FLOT 0/79 (0 per cent) versus ECX 2/79 (2.5 per cent); P  = 0.123), oesophageal (FLOT 4/121 (3.3 per cent) versus ECX 5/121 (4.1 per cent); P  = 0.868) or type of surgery (open FLOT 1/121 (0.8 per cent) versus ECX 3/121 (2.5 per cent); P  = 0.368; minimally invasive (FLOT 3/121 (2.5 per cent) versus ECX 2/121 (1.7 per cent); P  = 0.555)). There was no statistical difference in leak-related return to theatre, 30-day (FLOT 0 (0 per cent) versus ECX 3/100 (3.0 per cent); P  = 0.081), or 90-day (FLOT 0 (0 per cent) versus ECX 2/100 (2.0 per cent); P  = 0.155) mortality. Conclusion In terms of surgical complications, FLOT and ECX/ECF were equally safe in patients undergoing resection for OG adenocarcinoma. [ABSTRACT FROM AUTHOR]

Published
2022
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23. Detecting and Tracking Circulating Tumour DNA Copy Number Profiles during First Line Chemotherapy in Oesophagogastric Adenocarcinoma

Author

Davidson, Michael, Barber, Louise J., Woolston, Andrew, Cafferkey, Catherine, Mansukhani, Sonia, Griffiths, Beatrice, Moorcraft, Sing-Yu, Rana, Isma, Begum, Ruwaida, Assiotis, Ioannis, Matthews, Nik, Rao, Sheela, Watkins, David, Chau, Ian, Cunningham, David, Starling, Naureen, and Gerlinger, Marco

Subjects
somatic copy number aberration, liquid biopsy, circulating tumour DNA, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Article, oesophagogastric adenocarcinoma
Abstract

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.

Published
2019
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24. MicroRNA 31-3p expression and benefit from anti-EGFR inhibitors in metastatic colorectal cancer patients enrolled in the prospective phase II PROSPECT-C trial

Author

Anandappa, Gayathri, Lampis, Andrea, Cunningham, David, Khan, Khurum H., Kouvelakis, Kyriakos, Vlachogiannis, Georgios, Hedayat, Somaieh, Tunariu, Nina, Rao, Sheela, Watkins, David, Starling, Naureen, Braconi, Chiara, Darvish-Damavandi, Mahnaz, Lote, Hazel, Thomas, Janet, Peckitt, Clare, Kalaitzaki, Ria, Khan, Nasir, Fotiadis, Nicos, Rugge, Massimo, Begum, Ruwaida, Rana, Isma, Bryant, Annette, Hahne, Jens C., Chau, Ian, Fassan, Matteo, and Valeri, Nicola

Subjects
Male, Gene Expression, Middle Aged, Prognosis, Immunohistochemistry, ErbB Receptors, MicroRNAs, Antineoplastic Agents, Immunological, Treatment Outcome, Retreatment, Biomarkers, Tumor, Humans, Female, Molecular Targeted Therapy, Colorectal Neoplasms, Tomography, X-Ray Computed, In Situ Hybridization, Aged
Abstract

Purpose: Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. RAS 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 in situ 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 RAS 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.

Published
2019

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

Author

CRUK Cambridge Centre, The Institute of Cancer Research (UK), Sociedad Española de Oncología Médica, NIHR Biomedical Research Centre (UK), Wellcome Trust, Woolston, Andrew, Khan, Khurum, Spain, Georgia, Barber, Louise J., Griffiths, Beatrice, Gonzalez-Exposito, Reyes, Hornsteiner, Lisa, Punta, Marco, Patil, Yatish, Newey, Alice, Mansukhani, Sonia, Davies, Matthew N., Furness, Andrew, Sclafani, Francesco, Peckitt, Clare, Jiménez, Mirta, Kouvelakis, Kyriakos, Ranftl, Romana, Begum, Ruwaida, Rana, Isma, Thomas, Janet, Bryant, Annette, Quezada, Sergio, Wotherspoon, Andrew, Khan, Nasir, Fotiadis, Nikolaos, Marafioti, Teresa, Powles, Thomas, Lise, Stefano, Calvo, Fernando, Guettler, Sebastian, Von Loga, Katharina, Rao, Sheela, Watkins, David, Starling, Naureen, Chau, Ian, Sadanandam, Anguraj, Cunningham, David, Gerlinger, Marco, CRUK Cambridge Centre, The Institute of Cancer Research (UK), Sociedad Española de Oncología Médica, NIHR Biomedical Research Centre (UK), Wellcome Trust, Woolston, Andrew, Khan, Khurum, Spain, Georgia, Barber, Louise J., Griffiths, Beatrice, Gonzalez-Exposito, Reyes, Hornsteiner, Lisa, Punta, Marco, Patil, Yatish, Newey, Alice, Mansukhani, Sonia, Davies, Matthew N., Furness, Andrew, Sclafani, Francesco, Peckitt, Clare, Jiménez, Mirta, Kouvelakis, Kyriakos, Ranftl, Romana, Begum, Ruwaida, Rana, Isma, Thomas, Janet, Bryant, Annette, Quezada, Sergio, Wotherspoon, Andrew, Khan, Nasir, Fotiadis, Nikolaos, Marafioti, Teresa, Powles, Thomas, Lise, Stefano, Calvo, Fernando, Guettler, Sebastian, Von Loga, Katharina, Rao, Sheela, Watkins, David, Starling, Naureen, Chau, Ian, Sadanandam, Anguraj, Cunningham, David, and Gerlinger, Marco

Abstract

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.

Published
2019

28. Peri-operative chemotherapy in the management of resectable colorectal cancer pulmonary metastases

Author

Hawkes Eliza A, Ladas George, Cunningham David, Nicholson Andrew G, Wassilew Katharina, Barbachano Yolanda, Ratnayake Gihan, Rao Sheela, and Chau Ian

Subjects
Colorectal cancer, lung resection, peri-operative chemotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Surgery is often advocated in patients with resectable pulmonary metastases from colorectal cancer (CRC). Our study aims to evaluate peri-operative chemotherapy in patients with metastastic CRC undergoing pulmonary metastasectomy. Methods Patients treated for CRC who underwent pulmonary metastasectomy by a single surgeon were identified. Outcome measures included survival, peri-operative complications, radiological and histological evidence of chemotherapy-induced lung toxicities. Results Between 1997 and 2009, 51 eligible patients were identified undergoing a total of 72 pulmonary resections. Thirty-eight patients received peri-operative chemotherapy, of whom 9 received an additional biological agent. Five-year overall survival rate was 72% in the whole cohort - 74% and 68% in those who received peri-operative chemotherapy (CS) and those who underwent surgery alone (S) respectively. Five-year relapse free survival rate was 31% in the whole cohort - 38% and ≤18% in CS and S groups respectively. Only 8% had disease progression during neoadjuvant chemotherapy. There were no post-operative deaths. Surgical complications occurred in only 4% of patients who received pre-operative chemotherapy. There was neither radiological nor histological evidence of lung toxicity in resected surgical specimens. Conclusions Peri-operative chemotherapy can be safely delivered to CRC patients undergoing pulmonary metastasectomy. Survival in this selected group of patients was favourable.

Published
2012
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29. Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer

Author

Woolston, Andrew, Khan, Khurum, Spain, Georgia, Barber, Louise J., Griffiths, Beatrice, Gonzalez-Exposito, Reyes, Hornsteiner, Lisa, Punta, Marco, Patil, Yatish, Newey, Alice, Mansukhani, Sonia, Davies, Matthew N., Furness, Andrew, Sclafani, Francesco, Peckitt, Clare, Jiménez, Mirta, Kouvelakis, Kyriakos, Ranftl, Romana, Begum, Ruwaida, Rana, Isma, Thomas, Janet, Bryant, Annette, Quezada, Sergio, Wotherspoon, Andrew, Khan, Nasir, Fotiadis, Nikolaos, Marafioti, Teresa, Powles, Thomas, Lise, Stefano, Calvo, Fernando, Guettler, Sebastian, Von Loga, Katharina, Rao, Sheela, Watkins, David, Starling, Naureen, Chau, Ian, Sadanandam, Anguraj, Cunningham, David, Gerlinger, Marco, CRUK Cambridge Centre, The Institute of Cancer Research (UK), Sociedad Española de Oncología Médica, NIHR Biomedical Research Centre (UK), and Wellcome Trust

Subjects
EGFR, Biopsy, DNA Mutational Analysis, Cetuximab, Kaplan-Meier Estimate, Cancer evolution, Molecular subtype, Antineoplastic Agents, Immunological, Cancer genomics, Biomarkers, Tumor, Humans, Molecular Targeted Therapy, neoplasms, Cancer-associated fibroblasts, Drug resistance mechanisms, Gene Expression Profiling, Immunity, Computational Biology, Prognosis, Colorectal cancer, digestive system diseases, ErbB Receptors, Gene Expression Regulation, Neoplastic, Predictive biomarker, Treatment Outcome, Drug Resistance, Neoplasm, Mutation, Immunotherapy, Colorectal Neoplasms, Transcriptome
Abstract

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., M.G., A.Woolston, L.J.B., and B.G. were supported by CRUK, a charitable donation from Tim Morgan, Cancer Genetics UK and the Constance Travis Trust. G.S. was funded by an Institute of Cancer PhD Studentship, R.G.E. by a Spanish Society of Medical Oncology (FSEOM) grant for Translational Research in Reference Centers. The study was also supported by the ICR/RMH NIHR Biomedical Research Center for Cancer, by the CRUK Immunotherapy Accelerator (ICR/RMH, UCL) and by a Wellcome Trust Strategic Grant (105104/Z/14/Z).

Published
2018

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

Author

Woolston, Andrew, primary, Khan, Khurum, additional, Spain, Georgia, additional, Barber, Louise J., additional, Griffiths, Beatrice, additional, Gonzalez-Exposito, Reyes, additional, Hornsteiner, Lisa, additional, Punta, Marco, additional, Patil, Yatish, additional, Newey, Alice, additional, Mansukhani, Sonia, additional, Davies, Matthew N., additional, Furness, Andrew, additional, Sclafani, Francesco, additional, Peckitt, Clare, additional, Jiménez, Mirta, additional, Kouvelakis, Kyriakos, additional, Ranftl, Romana, additional, Begum, Ruwaida, additional, Rana, Isma, additional, Thomas, Janet, additional, Bryant, Annette, additional, Quezada, Sergio, additional, Wotherspoon, Andrew, additional, Khan, Nasir, additional, Fotiadis, Nikolaos, additional, Marafioti, Teresa, additional, Powles, Thomas, additional, Lise, Stefano, additional, Calvo, Fernando, additional, Guettler, Sebastian, additional, von Loga, Katharina, additional, Rao, Sheela, additional, Watkins, David, additional, Starling, Naureen, additional, Chau, Ian, additional, Sadanandam, Anguraj, additional, Cunningham, David, additional, and Gerlinger, Marco, additional

Published
2019
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31. 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.

Author

Zai, Tiffany, Yasuda, Patrice M., Rao, Sheela, Iizumi, Staci, Vanderbilt, Douglas L., and Deavenport-Saman, Alexis

Subjects
ZIKA virus infections, CHILDREN with disabilities, CHILD care, MEDICAL personnel, CHRONIC care model, DISABILITIES
Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2020

32. Genomic loss of heterozygosity and survival in the REAL3 trial

Author

Smyth, Elizabeth C., primary, Cafferkey, Catherine, additional, Loehr, Andrea, additional, Waddell, Tom, additional, Begum, Ruwaida, additional, Peckitt, Clare, additional, Harding, Thomas C., additional, Nguyen, Minh, additional, Okines, Alicia F., additional, Raponi, Mitch, additional, Rao, Sheela, additional, Watkins, David, additional, Starling, Naureen, additional, Middleton, Gary W., additional, Wadsley, Jonathan, additional, Mansoor, Wasat, additional, Crosby, Tom, additional, Wotherspoon, Andrew, additional, Chau, Ian, additional, and Cunningham, David, additional

Published
2018
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34. Abstract 4339: Molecular subtypes and novel genetic mechanisms of primary and acquired anti-EGFR resistance in colorectal cancer in the Prospect C biomarker trial

Author

Khan, Khurum Hayat, primary, Woolston, Andrew, additional, Spain, Georgia, additional, Barber, Louise, additional, Patil, Yatish, additional, Griffiths, Beatrice, additional, GonzalezExposito, Reyes, additional, Mansukhani, Sonia, additional, Davies, Matthew, additional, Rao, Sheela, additional, Watkins, David, additional, Sclafani, Francesco, additional, Suntharanathan, Jana, additional, Peckitt, Clare, additional, Begum, Ruwaida, additional, Rana, Isma, additional, Thomas, Janet, additional, Oates, Jacqui, additional, Bryant, Annette, additional, Wotherspoon, Andrew, additional, Fotiadis, Nicos, additional, Khan, Nasir, additional, Guettler, Sebastian, additional, Loga, Katharina von, additional, Starling, Naureen, additional, Chau, Ian, additional, Sadanandam, Anguraj, additional, Cunningham, David, additional, and Gerlinger, Marco, additional

Published
2018
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37. A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial

Author

Battersby, Nick J., primary, Dattani, Mit, additional, Rao, Sheela, additional, Cunningham, David, additional, Tait, Diana, additional, Adams, Richard, additional, Moran, Brendan J., additional, Khakoo, Shelize, additional, Tekkis, Paris, additional, Rasheed, Shahnawaz, additional, Mirnezami, Alex, additional, Quirke, Philip, additional, West, Nicholas P., additional, Nagtegaal, Iris, additional, Chong, Irene, additional, Sadanandam, Anguraj, additional, Valeri, Nicola, additional, Thomas, Karen, additional, Frost, Michelle, additional, and Brown, Gina, additional

Published
2017
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38. In Reply

Author

Khan, Khurum, primary, Cunningham, David, additional, Aitken, Katharine, additional, and Rao, Sheela, additional

Published
2017
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39. Heterogeneity of MYC amplification in oesophagogastric (OG) carcinoma: Results from a prospective screening study

Author

Davidson, Michael, primary, Aronson, Lauren, additional, Howard-Reeves, Julie, additional, Bryant, Hanna, additional, Cunningham, David, additional, Watkins, David, additional, Rao, Sheela, additional, Starling, Naureen, additional, Cutts, Ros, additional, Begum, Ruwaida, additional, Hezelova, Blanka, additional, Kaur, Sarnjeet, additional, Cardenosa, Marta, additional, Keen, Jennifer, additional, Swansbury, John, additional, Wotherspoon, Andrew, additional, Chau, Ian, additional, and Chong, Irene, additional

Published
2017
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40. Systemic Chemotherapy as Salvage Treatment for Locally Advanced Rectal Cancer Patients Who Fail to Respond to Standard Neoadjuvant Chemoradiotherapy

Author

Sclafani, Francesco, primary, Brown, Gina, additional, Cunningham, David, additional, Rao, Sheela, additional, Tekkis, Paris, additional, Tait, Diana, additional, Morano, Federica, additional, Baratelli, Chiara, additional, Kalaitzaki, Eleftheria, additional, Rasheed, Shahnawaz, additional, Watkins, David, additional, Starling, Naureen, additional, Wotherspoon, Andrew, additional, and Chau, Ian, additional

Published
2017
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41. Molecular profiling of colorectal pulmonary metastases and primary tumours: implications for targeted treatment

Author

Moorcraft, Sing Y., primary, Jones, Thomas, additional, Walker, Brian A., additional, Ladas, George, additional, Kalaitzaki, Eleftheria, additional, Yuan, Lina, additional, Begum, Ruwaida, additional, Eltahir, Zakaria, additional, Wotherspoon, Andrew, additional, Montero-Fernandez, Angeles, additional, Teixeira Mendes, Larissa S., additional, Gonzalez de Castro, David, additional, Wilson, Sanna Hulkki, additional, Proszek, Paula, additional, To, Ye M., additional, Hawkes, Eliza, additional, Roy, Amitesh, additional, Cunningham, David, additional, Rao, Sheela, additional, Watkins, David, additional, Starling, Naureen, additional, Bowcock, Anne M., additional, and Chau, Ian, additional

Published
2017
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43. Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative

Author

Bogaerts, Jan, Sydes, Matthew R., Keat, Nicola, McConnell, Andrea, Benson, Al, Ho, Alan, Roth, Arnaud, Fortpied, Catherine, Eng, Cathy, Peckitt, Clare, Coens, Corneel, Pettaway, Curtis, Arnold, Dirk, Hall, Emma, Marshall, Ernie, Sclafani, Francesco, Hatcher, Helen, Earl, Helena, Ray-Coquard, Isabelle, Paul, James, Blay, Jean-Yves, Whelan, Jeremy, Panageas, Kathy, Wheatley, Keith, Harrington, Kevin, Licitra, Lisa, Billingham, Lucinda, Hensley, Martee, McCabe, Martin, Patel, Poulam M., Carvajal, Richard, Wilson, Richard, Glynne-Jones, Rob, McWilliams, Rob, Leyvraz, Serge, Rao, Sheela, Nicholson, Steve, Filiaci, Virginia, Negrouk, Anastassia, Lacombe, Denis, Dupont, Elisabeth, Pauporté, Iris, Welch, John J., Law, Kate, Trimble, Ted, and Seymour, Matthew

Subjects
Cancer Research, International Cooperation, Methodology, Randomised controlled trials, Review, Bayesian, Public-Private Sector Partnerships, Clinical trials, Rare Diseases, Oncology, Research Design, Neoplasms, Rare cancers, Humans, Frequentist, Multi-arm, Randomized Controlled Trials as Topic
Abstract

Background\ud The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.\ud \ud Settings\ud The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional – usually randomised – clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.\ud \ud Results\ud The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.\ud \ud Interpretation\ud Trials can be designed using a wide array of possibilities. There is no ‘one size fits all’ solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

Published
2014

44. Survival Outcomes in Asymptomatic Patients With Normal Conventional Imaging but Raised Carcinoembryonic Antigen Levels in Colorectal Cancer Following Positron Emission Tomography-Computed Tomography Imaging

Author

Khan, Khurum, primary, Athauda, Avani, additional, Aitken, Katharine, additional, Cunningham, David, additional, Watkins, David, additional, Starling, Naureen, additional, Cook, Gary J., additional, Kalaitzaki, Eleftheria, additional, Chau, Ian, additional, and Rao, Sheela, additional

Published
2016
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45. Characterising timing and pattern of relapse following surgery for localised oesophagogastric adenocarcinoma: a retrospective study

Author

Moorcraft, Sing Yu, primary, Fontana, Elisa, additional, Cunningham, David, additional, Peckitt, Clare, additional, Waddell, Tom, additional, Smyth, Elizabeth C., additional, Allum, William, additional, Thompson, Jeremy, additional, Rao, Sheela, additional, Watkins, David, additional, Starling, Naureen, additional, and Chau, Ian, additional

Published
2016
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47. miR-21 expression and clinical outcome in locally advanced pancreatic cancer: exploratory analysis of the pancreatic cancer Erbitux, radiotherapy and UFT (PERU) trial

Author

Khan, Khurum, primary, Cunningham, David, additional, Peckitt, Clare, additional, Barton, Sarah, additional, Tait, Diana, additional, Hawkins, Maria, additional, Watkins, David, additional, Starling, Naureen, additional, Rao, Sheela, additional, Begum, Ruwaida, additional, Thomas, Janet, additional, Oates, Jacqui, additional, Guzzardo, Vincenza, additional, Fassan, Matteo, additional, Braconi, Chiara, additional, and Chau, Ian, additional

Published
2016
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49. Metastatic Squamous Cell Carcinoma of the Anus: Time for a Shift in the Treatment Paradigm?

Author

Dewdney, Alice and Rao, Sheela

Subjects
Article Subject
Abstract

Anal cancers are rare tumours; however, the incidence is increasing in both men and women. Changing trends in sexual behaviour, smoking, and infection with the human papillomavirus are thought to be responsible for the increase. Patients with metastatic disease have a poor prognosis, with 5-year median overall survival rates of 10% in men and 20% in women. The standard systemic treatment of metastatic disease remains cisplatin and 5-fluorouracil, and aside from several non-randomised small phase II trials there has been no real progress over the past two decades. Based on the efficacy of cetuximab in squamous cell carcinomas from other primary sites, there appears to be clinical rationale for evaluation of anti-epidermal growth factor inhibitors in anal squamous cell carcinoma. In order to facilitate research and implement more effective treatment strategies international collaboration in clinical trials incorporating tissue collection for biomarkers is essential.

Published
2012
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