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Purpose: Reovirus is a wild-type oncolytic virus that is ubiquitous in the environment; most patients are therefore preimmune. Therapeutic administration leads to an increase in neutralizing antireovirus antibody (NARA) titer. We hypothesized that if NARA limited reovirus antitumor activity, the effect might be attenuated by coadministration of cyclophosphamide.Experimental design: In a phase I study, patients with advanced cancer received cyclophosphamide 3 days before intravenous reovirus serotype 3 Dearing (RT3D). The primary objective was to reduce the resulting rise in NARA titer. Cyclophosphamide dose was escalated from 25–1,000 mg/m2 through nine cohorts; we aimed to define a well-tolerated immunomodulatory dose.Results: The combination was well tolerated in 36 patients, with grade 3/4 toxicities only seen at or above the maximum tolerated dose of cyclophosphamide, which was 800 mg/m2 combined with reovirus. Immunosuppressive effect, defined as maintaining NARA titer rise below a predefined threshold, was observed in only one patient. Furthermore, despite expected myelosuppression seen at higher cyclophosphamide doses, no changes in T-cell subsets, including Tregs, occurred with dose escalation. Viable virus was detected in association with peripheral blood mononuclear cells (PBMC) from 14% of patients 10 days after the last RT3D injection, despite high plasma NARA titer, demonstrating a potential mechanism for prolonged evasion of neutralization by reovirus.Conclusions: Coadministration of cyclophosphamide with reovirus is safe, but does not attenuate host antiviral responses. Alternative immunomodulation approaches should be explored, but association with PBMCs may allow reovirus to persist and evade even high levels of neutralizing antibodies. Clin Cancer Res; 21(6); 1305–12. ©2014 AACR.

Supplementary Tables S1-S4 and Figures S1-S3. Tables S1/S2: % tumor response in mice with HCT116 and A2058 tumor xenografts following treatment; Table S3: Diagram showing dose-decision guidelines utilized in the MK-2206 clinical study based on observed toxicities; Table S4: number of patients with drug-related AEs in all courses of treatment; Figure S1/S2: Line graph showing the relative tumor volume and body weight observed in patients over time expressed in terms of days following treatment; Figure S3: Patient presenting with Grade III rash

Supplementary Figure 1. Total white blood cell numbers were reduced by higher doses of the cytotoxic CP in later cohorts

Purpose: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies.Experimental Design: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily.Results: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug–drug interactions. Clinical antitumor activity included RECIST 1.0–confirmed partial responses in non–small cell lung cancer and low-grade ovarian carcinoma.Conclusion: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). Clin Cancer Res; 21(4); 739–48. ©2014 AACR.

International audience; Simple Summary There have been huge improvements in both vaccination and the management of COVID-19 in patients with cancer. In addition, different variants may be associated with different presentations. Therefore, we examined whether indicators of the severity of COVID-19 in patients with cancer who present to hospital varied during different waves of the pandemic and we showed that these indicators remained predictive. We validated that the COVID-19 Risk in Oncology Evaluation Tool (CORONET), which predicts the severity of COVID-19 in cancer patients presenting to hospital, performed well in all waves. In addition, we examined patient outcomes and the factors that influence them and found that there was increased vaccination uptake and steroid use for patients requiring oxygen in later waves, which may be associated with improvements in outcome. Patients with cancer have been shown to have increased risk of COVID-19 severity. We previously built and validated the COVID-19 Risk in Oncology Evaluation Tool (CORONET) to predict the likely severity of COVID-19 in patients with active cancer who present to hospital. We assessed the differences in presentation and outcomes of patients with cancer and COVID-19, depending on the wave of the pandemic. We examined differences in features at presentation and outcomes in patients worldwide, depending on the waves of the pandemic: wave 1 D614G (n = 1430), wave 2 Alpha (n = 475), and wave 4 Omicron variant (n = 63, UK and Spain only). The performance of CORONET was evaluated on 258, 48, and 54 patients for each wave, respectively. We found that mortality rates were reduced in subsequent waves. The majority of patients were vaccinated in wave 4, and 94% were treated with steroids if they required oxygen. The stages of cancer and the median ages of patients significantly differed, but features associated with worse COVID-19 outcomes remained predictive and did not differ between waves. The CORONET tool performed well in all waves, with scores in an area under the curve (AUC) of >0.72. We concluded that patients with cancer who present to hospital with COVID-19 have similar features of severity, which remain discriminatory despite differences in variants and vaccination status. Survival improved following the first wave of the pandemic, which may be associated with vaccination and the increased steroid use in those patients requiring oxygen. The CORONET model demonstrated good performance, independent of the SARS-CoV-2 variants.

Background FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated. Methods We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III–IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method. Results We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III–IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX. Conclusions This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.

The use of BReast CAncer (BRCA) mutations as biomarkers for sensitivity to DNA damage response (DDR) targeted drugs and platinum agents is well documented in breast and gynaecological cancers. More recently the successful use DDR targeted therapies including poly (ADP-ribose) polymerases (PARP) inhibitors has been shown to extend to other germline and somatic deficiencies within the homologous recombination (HR) pathway (Farmer et al., 2005; Turner et al., 2019; Li and Heyer, 2008). Gastrointestinal (GI) cancers are lagging behind other tumour types when it comes to personalising treatment with targeted therapies. Current methods of identifying PARP-inhibitor sensitivity in gastrointestinal cancers are based on analogies from other cancer types despite there being a lack of uniformity in determining HR status between tumour types. There is an urgent clinical need to better understand the treatment implications of DDR alterations in gastrointestinal cancers. We have reviewed PARP-inhibitor use in pancreatic, gastroesophageal, hepatobiliary and colorectal cancers and explored HRD as a biomarker for sensitivity to PARP-inhibitors.

Background: Patients with cancer are at increased risk of severe COVID-19, but have heterogeneous presentations and outcomes. Decision-making tools for hospital admission, severity prediction and increased monitoring for early intervention are critical. We sought to identify features of COVID-19 in cancer patients predicting severe disease and build a decision-support online tool; COVID-19 Risk in Oncology Evaluation Tool (CORONET). Methods: Patients with active cancer (stage I-IV) and laboratory confirmed COVID-19 presenting to hospitals worldwide were included. Discharge (within 24hrs), admission (≥24hrs inpatient), oxygen requirement (O2) and death were combined in a 0-3 point severity scale. Association of features with outcome were investigated using Lasso regression and Random Forest (RF) combined with SHapley Additive exPlanations (SHAP). RF was further validated in 4 cohorts, split by geography. The CORONET model was then examined in the entire cohort to build an online CORONET decision-support tool. Admission and severe disease thresholds were established through pragmatically defined cost functions. Findings: The dataset comprised 920 patients; median age 70 (range 5-99), 56% males, 44% females, 81% solid vs. 19% haematological cancers. In derivation, RF demonstrated superior performance over Lasso with lower mean squared error (0.801 vs. 0.807) and was selected for development. During validation, RF achieved mean AUROC 0.77, 0.80 and 0.75 for prediction of admission, O 2 and death, respectively. Using the entire cohort, CORONET cut-offs for admission and mortality of 1.0 and 2.3 were established. The CORONET decision support tool recommended admission for 95% of patients eventually requiring oxygen and 97% of those who died. SHAP explanations revealed National-Early-Warning-Score-2, C-reactive protein and albumin were the most important features contributing to COVID-19 severity prediction in patients with cancer at time of hospital presentation. Interpretation: CORONET, a decision-support tool validated in healthcare systems worldwide can aid admission decisions and predict COVID-19 severity in patients with cancer. Funding Information: R. Lee and T. Robinson and J. Weaver are supported by the National Institute for Health Research as Clinical Lecturers. T. Bhogal is supported by the National Institute for Health Research as an academic clinical fellow. U. Khan is an MRC Clinical Training Fellow based at the University of Liverpool supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (Award Ref. MR/N025989/1). The Liverpool Experimental Cancer Medicine Centre for providing infrastructure support (Grant Reference: C18616/A25153) and The Clatterbridge Cancer charity (North West Cancer Research). C. Dive is funded by CRUK Core funding to Manchester Institute (C5757/A27412) and is supported by the CRUK Manchester Centre Award (C5759/A25254), and by the NIHR Manchester Biomedical Research Centre. C. Zhou is funded by the CRUK Manchester Centre Award (C5759/A25254), J. Stevenson and P. Fitzpatrick are funded by the CRUK Accelerator Award (29374). This research was funded in part, by the Wellcome Trust [205228/Z/16/Z]. LT is also supported by the National Institute for Health Research Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections (NIHR200907) at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. LT is based at University of Liverpool. MS is supported by a grant from the Ministry of Science and Higher Education of the Russian Federation for the state support for the creation and development of World Class Research Centers "Digital biodesign and personalized healthcare” N.075-15-2020-926. Declaration of Interests: R Lee research funding (institution) BMS and speaker fees Astrazeneca. A. Croitoru Consulting or Advisory Role: Lilly, Merck, Roche, Bayer, Novartis, Ipsen, Research Funding me and my hospital: Gilead Sciences, Pfizer, Canfite, NanoCarrier, Bristol-Myers Squibb, Merck, Amgen, Servier, Five Prime Therapeutics, Travel Accommodations: Pfizer, Genekor, and oz, Merck, Pfizer, Servier, Roche. O. Michielin reports personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Novartis, personal fees from Roche, personal fees from Amgen, personal fees from NeraCare GmbH, outside the submitted work. E. Romano institutional research grants from Amgen, Astra Zeneca, Bristol-Myers Squibb. G. Pentheroudakis advisory board for Amgen, Astra Zeneca, Bristol-Myers Squibb, Lilly, Merck, MSD, Roche, Abbvie, institutional research grants from Amgen, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Debbio, Enorasis, Genekor, Ipsen, Janssen, Lilly, Merck, MSD, Pfizer, Roche, Sanofi, Servier. Solange Peters reports consultation/advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F. Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody, talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda, receipt of grants/research supports: (Sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. M Rowe honoraria from Astellas Pharma, speaker fees MSD and Servier. C. Wilson consultancy and speaker fees Pfizer, Amgen, Novartis, A Armstrong conference fee Merck, spouse shares in Astrazeneca. T Robinson financial support to attend educational workshops from Amgen and Daiichi-Sankyo. C Dive, outside of this scope of work, has received research funding from AstraZeneca, Astex Pharmaceuticals, Bioven, Amgen, Carrick Therapeutics, Merck AG, Taiho Oncology, Clearbridge Biomedics, Angle PLC, Menarini Diagnostics, GSK, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Thermofisher. C Dive is on advisory boards for, and has received consultancy fees/honoraria from, AstraZeneca, Biocartis and Merck KGaA. No other authors have nothing to declare. Ethics Approval Statement: Approval (reference 20/WA/0269) was granted from the UK Research Ethics Committee for the study. Information regarding governance/regulatory approvals for each international cohort are available in the Supp. Methods.

ObjectiveColorectal cancer is a common cause of death and morbidity. A significant amount of data are routinely collected during patient treatment, but they are not generally available for research. The National Institute for Health Research Health Informatics Collaborative in the UK is developing infrastructure to enable routinely collected data to be used for collaborative, cross-centre research. This paper presents an overview of the process for collating colorectal cancer data and explores the potential of using this data source.MethodsClinical data were collected from three pilot Trusts, standardised and collated. Not all data were collected in a readily extractable format for research. Natural language processing (NLP) was used to extract relevant information from pseudonymised imaging and histopathology reports. Combining data from many sources allowed reconstruction of longitudinal histories for each patient that could be presented graphically.ResultsThree pilot Trusts submitted data, covering 12 903 patients with a diagnosis of colorectal cancer since 2012, with NLP implemented for 4150 patients. Timelines showing individual patient longitudinal history can be grouped into common treatment patterns, visually presenting clusters and outliers for analysis. Difficulties and gaps in data sources have been identified and addressed.DiscussionAlgorithms for analysing routinely collected data from a wide range of sites and sources have been developed and refined to provide a rich data set that will be used to better understand the natural history, treatment variation and optimal management of colorectal cancer.ConclusionThe data set has great potential to facilitate research into colorectal cancer.

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.

BackgroundImage guided tissue biopsies are critically important in diagnosis and management of cancer patients. High yield samples are also vital for biomarker and resistance mechanism discovery through molecular/genomic analyses.Patients and methodsAll consecutive patients who underwent plugged image-guided biopsy at Royal Marsden from June 2013 until September 2016 were included in the analysis. In second step, a second cohort of patients prospectively treated within two clinical trials (PROSPECT-C and R), were assessed for the DNA yield from biopsies assessed for complex genomic analysis.ResultsA total of 522 plugged core biopsies were performed in 457 patients [52% men; median age 63 years (range 17-93)]. Histological diagnosis was achieved in 501/522 (96%) of 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; 9, 3, 2, 1, 1,1 were admitted for grade I/II pain control, sepsis, vasovagal syncope, thrombosis, haematuria and deranged liver functions respectively; 2 patients with right upper quadrant pain after liver biopsy were found to have radiologically confirmed subcapsular haematoma requiring conservative treatment. One patient (0.2%) developed grade III haemorrhage following biopsy of a gastric GIST tumour. 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 >1microgram and tumour content of >20% respectively.ConclusionThe probability of diagnostic success for complex molecular analysis is increased with plugged large co-axial needle biopsy technique, which also minimises complications and reduces hospital stay. High yield DNA acquisition allows genomic molecular characterisation for personalised medicine.Statement of significanceCancer diagnosis and personalised management is largely dependent on safe acquisition of tumour tissue required for histological diagnosis, and sometimes genomic characterisation. This poses significant challenge to treating physicians, when deliberating risk-benefit ratio of invasive procedures, especially within the context of clinical trials. In this largest examination of safety and efficacy of biopsies in more than 500 patients, we show that diagnostic success for complex molecular analysis is increased with CNB technique that minimises complications and reduces hospital stay. Moreover, we provide validation of our findings with a group of patients treated within prospective clinical trials.

In colorectal cancer (CRC), imaging is important in determining tumor stage, selecting treatment strategies, and in assessing response to therapy. However, some challenges remain with established imaging techniques, such as computed tomography, and with some commonly used response criteria, such as Response Evaluation Criteria in Solid Tumors, which measures change in size of several target lesions instead of change in tumor morphology or metabolic function. In addition, these assessments are not typically conducted until after 8 weeks of treatment, meaning that potential non-responders are often not identified in a timely manner. Regorafenib, an oral tyrosine kinase inhibitor indicated for the treatment of metastatic CRC, blocks the activity of several protein kinases involved in angiogenesis, oncogenesis, metastasis, and tumor immunity. Timely differentiation of regorafenib responders from non-responders using appropriate imaging techniques that recognize not only changes in tumor size but also changes in tumor density or vasculature, may reduce unnecessary drug-related toxicity in patients who are unlikely to respond to treatment. This review discusses the latest developments in computed tomography, magnetic resonance imaging, and positron emission tomography tumor imaging modalities, and how these aid in identifying patients with metastatic CRC who are responders or non-responders to regorafenib treatment., SCOPUS: re.j, info:eu-repo/semantics/published

Background: Patients with cancer are hypothesised to be at increased risk of contracting COVID-19, leading to changes in treatment pathways in those treated with systemic anti-cancer treatments (SACT). We investigated the outcomes of patients receiving SACT to assess whether they were at greater risk of contracting COVID-19 or having more severe outcomes. Methods: We collected data on all patients receiving SACT in two cancer centres as part of CAPITOL (COVID-19 CAncer PatIenT Outcomes in North London). The primary outcome was the effect of clinical characteristics on the incidence and severity of COVID-19 infection in patients on SACT. We used univariable and multivariable models to analyse outcomes, adjusting for age, gender and comorbidities. Findings: We analysed 2871 patients receiving SACT from 2nd March to 31st May 2020; 68 (2.4%) were diagnosed with COVID-19. Cancer patients receiving SACT were more likely to die if they contracted COVID-19 than those who did not (adjusted (adj.) OR 9·84; 95% CI 5·73 – 16·9). Receiving chemotherapy increased the risk of developing COVID-19 (adj. OR 2·99; 95% CI = 1·72 - 5·21), with high dose chemotherapy significantly increasing risk (adj. OR 2·36, 95% CI 1·35 – 6·48), as did the presence of comorbidities (adjusted OR 2·29; 95% CI 1·19 - 4·38), and having a respiratory or intrathoracic neoplasm (adj. OR 2·12; 95% CI 1·04 - 4·36). Receiving targeted treatment had a protective effect (adj. OR 0·53; 95% CI 0·30 – 0·95). Treatment intent (curative versus palliative), hormonal- or immunotherapy and solid versus haematological cancers had no significant effect on risk. Interpretation: Patients on SACT are more likely to die if they contract COVID-19. Those on chemotherapy, particularly high dose chemotherapy, are more likely to contract COVID-19, while targeted treatment appears to be protective. Funding: None. Declaration of Interests: NJH reports grants from CRUK Clinical Trial Fellowship, outside the submitted work. VEC, WW, TAF, SD, JB KK, DH, KKS, RK, NC, MD, EB, JB, MF and DH have no conflicts of interest to disclose. Ethics Approval Statement: Research and development approval were sought from University College Hospital, which is where the study was primarily conducted, the ethical approval was granted by the ethics committee of University College London Hospital NHS Foundation Trust.

Cancer organoids to model therapy response Cancer organoids are miniature, three-dimensional cell culture models that can be made from primary patient tumors and studied in the laboratory. Vlachogiannis et al. asked whether such “tumor-in-a-dish” approaches can be used to predict drug responses in the clinic. They generated a live organoid biobank from patients with metastatic gastrointestinal cancer who had previously been enrolled in phase I or II clinical trials. This allowed the authors to compare organoid drug responses with how the patient actually responded in the clinic. Encouragingly, the organoids had similar molecular profiles to those of the patient tumor, reinforcing their value as a platform for drug screening and development. Science , this issue p. 920

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.

10567 Background: One of the major challenges with COVID-19 has been the changes to cancer services, including changes to the type of systemic anti-cancer treatment being delivered to patients. There needs to be a better understanding of which cancer patients are at the greatest amount of risk to make informed decisions on how cancer treatment can be altered to protect patients from COVID-19 infection. The CAPITOL (COVID-19 CAncer PatIenT Outcomes in North London) study investigated the outcomes of patients receiving systemic anti-cancer therapies (SACT) with regards to COVID-19 infection, as patients with cancer are hypothesised to be at higher risk. Methods: CAPITOL collected data from all patients receiving SACT at two cancer centres. The effect of clinical characteristics on the incidence and severity of COVID-19 infection in patients on SACT was the primary outcome, and we used univariable and multivariable models in our analysis, adjusting for age, gender and comorbidities. Results: 2871 patients were analysed from 2nd March to 31st May 2020, all of whom received SACT; during this time period 68 (2.4%) were diagnosed with COVID-19. Receiving SACT increased the risk of death when contracting COVID-19 (adjusted (adj.) OR 9.84; 95% CI 5.73 – 16.9). The risk of contracting COVID-19 was increased by receiving chemotherapy (adj. OR 2.99; 95% CI = 1.72 - 5.21), with the risk significantly increased by high dose chemotherapy (adj. OR 2.36, 95% CI 1.35 – 6.48). Patients with comorbidities (adjusted OR 2.29; 95% CI 1.19 - 4.38), or with a respiratory or intrathoracic neoplasm (adj. OR 2.12; 95% CI 1.04 - 4.36) were also at increased risk of contracting COVID-19. Cancer patients who received targeted treatment had a reduced risk of contracting COVID-19 (adj. OR 0.53; 95% CI 0.30 – 0.95), while there was no significant change in risk caused by treatment intent (curative versus palliative), hormonal- or immunotherapy and solid versus haematological cancers. Conclusions: To the best of our knowledge, this is one of the first investigations into the risk of contracting COVID-19 in a cohort of all cancer patients on SACT. We found that patients on SACT are more likely to die if they contract COVID-19. The type of SACT received by cancer patients can affect their likelihood of contacting COVID-19, with chemotherapy increasing risk, targeted therapy decreasing risk and a potential protective effect for hormonal and immunotherapy.

Colorectal cancer (CRC) is one of the commonest cancers in the world. During the last decade, the development of targeted therapies has given cancer treatment a novel direction in management of metastatic CRC (mCRC) and has enriched the therapeutic armamentarium in the management of this disease. In mCRC, targeting angiogenesis via the vascular endothelial growth factor (VEGF) pathway has been of particular interest based on the favourable survival benefit demonstrated by bevacizumab in clinical trials. More recently, large phase III studies have shown clinical efficacy for the new antiangiogenic agents aflibercept and regorafenib. However, the results of pre-clinical and clinical studies of other anti-angiogenic agents have been disappointing. Furthermore, the benefits from angiogenic inhibitors (AIs) in an unselected patient population are modest. Research into predictive biomarkers is therefore essential, but has, to date, been unsuccessful. Nevertheless, aflibercept and regorafenib have been shown to benefit both bevacizumab naive and refractory patients, suggesting that acquired resistance to AIs can be potentially reversed. This review describes the most recent advances in development of AIs in mCRC with particular focus on aflibercept and regorafenib, the existing challenges for the evaluation of these agents in clinical practice and potential strategies in designing clinical trials that could lead to the discovery of clinically meaningful biomarkers.

Dysregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is implicated in human cancer growth and progression. Agents targeting this pathway are associated with hyperglycemia due to interaction with the insulin-glucose regulatory axis. Identifying the predictive factors for hyperglycemia in patients treated with these agents may help direct future management.Clinical characteristics and outcomes of patients treated consecutively with PI3K, AKT, or mTOR inhibitors in the Drug Development Unit, The Royal Marsden (RM) National Health Service (NHS) Foundation Trust, between 2007 and 2012 were recorded. Baseline variables and their association with grade 3 hyperglycemia (Common Terminology Criteria for Adverse Events, version 3.0) were analyzed by using the chi-square test and Fisher exact test for categorical variables and binary logistic regression for continuous variables.A total of 341 patients were treated in 12 phase I trials of PI3K/AKT/mTOR inhibitors, and 298 patients (87.4%) developed hyperglycemia. Hyperglycemia was grade 1 in 217 (72.8%) and grade 2 in 61 (20.5%) patients, respectively. Grade ≥3 hyperglycemia was seen in 6.7% of patients (n = 20). According to the chi-square test, age65 years (p = .03), history of diabetes (p = .003), and treatment with AKT and dual PI3K/mTOR inhibitors (p.0005) predicted the occurrence of grade 3 hyperglycemia. Of 24 patients requiring intervention, 20 received metformin, 2 dietary advice, 1 insulin, and 1 both metformin and insulin. One patient required dose reduction. There were no permanent drug discontinuations, and no hyperglycemia-related dose-limiting toxicities were observed; thus, the recommended phase II dose was not affected by the hyperglycemia observed in our cohort.Hyperglycemia is common in patients treated with PI3K/AKT/mTOR inhibitors; however, it is manageable with conventional treatment. Predictive factors of age, history of diabetes, and administration of AKT and dual PI3K/mTOR inhibitors warrant prospective validation.This study reviewed the clinical data of 341 patients treated in 12 phase I trials of agents targeting phosphatidylinositol3-kinase (PI3), protein kinase B (AKT), and mammalian target of rapamycin (mTOR), as well as dual inhibitors. Hyperglycemia was evident in 87.4% of patients but was ≥grade 3 in just 6.7%. Age65 years, history of diabetes, and treatment with AKT and dual PI3K/mTOR inhibitors were each associated with grade 3 hyperglycemia. Management of patients was uncomplicated, and no permanent drug discontinuations were necessary. Despite the small study size, these findings support continued caution about enrolling patients with a history of diabetes into such trials. However, clinicians may be reassured, pending prospective validation of these results, that significant hyperglycemia is not frequent and, when it occurs, is manageable.

Background: This study had two aims: (a) to test the hypothesis that advanced age is associated with lower levels of tolerability and clinical benefit to experimental Phase I trial agents; (b) to assess the validity of the Royal Marsden Hospital (RMH) prognostic score as a patient selection tool in older patients. Methods: Clinico-pathological characteristics and treatment outcomes of all patients treated consecutively from 2005 to 2009 in phase I trials at the RMH were recorded. All toxicity and clinical outcome data were compared between patients aged below and above 65 years of age. Results: One thousand and four patients were treated in 30 Phase I trials, with 315 (31%) patients aged 65 years and older. Grade 3–5 toxicities (22.8% vs 24.8% (P=0.52)), trial discontinuation (6% vs 4% P=0.33), and dose interruptions (8.0% vs 8.0% (P=0.96)) were observed at similar rates in patients below and above 65 years of age, respectively. The overall response rate 5.2% vs 4.1%, progression-free survival (PFS) 1.9 vs 3.5 months and clinical benefit rate (CBR) at 6 months 15.2% vs 14.3% were comparable in both groups. To avoid bias due to the potential therapeutic benefit of abiraterone, comparisons were repeated excluding prostate cancer patients with similar results (ORR 4.6% vs 4%, PFS 1.8 vs 3.0 months, CBR at 6 months 13.5% vs 9.5%). Multivariate analysis indicated that the previously identified RMH score (including albumin and lactate dehydrogenase levels) was an accurate predictor of outcome. Conclusions: Phase I clinical trials should be considered in patients with advanced cancers regardless of age, as older patients who enter these have similar safety and efficacy outcomes as their younger counterparts. The RMH prognostic score can assist in the selection of suitable older patients.

Background: Despite notable advances in the management of metastatic colorectal cancer (mCRC) over the last two decades, treatment intent in the vast majority of patients remains palliative due to technically unresectable disease, extensive disease, or co-morbidities precluding major surgery. Up to 30% of individuals with mCRC are considered potentially suitable for primary or metastasis-directed multimodal therapy, including surgical resection, ablative techniques, or stereotactic radiotherapy (RT), with the aim of improving survival outcomes. We reviewed the potential benefits of multimodal therapy on the survival of patients with mCRC treated at the UCLH. Methods: Clinical data on baseline characteristics, multimodal treatments, and survival outcomes were retrospectively collected from all patients with mCRC receiving systemic chemotherapy between January 2013 and April 2017. Primary outcome was the impact of multimodal therapy on overall survival, compared to systemic therapy alone, and the effect of different types of multimodal therapy on survival outcome, and was assessed using the Kaplan&ndash, Meier approach. All analyses were adjusted for age, gender, and side of primary tumour. Results: One-hundred and twenty-five patients with mCRC were treated during the study period (median age: 62 years (range 19&ndash, 89). The liver was the most frequent metastatic site (78%, 97/125). A total of 52% (65/125) had &ge, 2 lines of systemic chemotherapy. Of the 125 patients having systemic chemotherapy, 74 (59%) underwent multimodal treatment to the primary tumour or metastasis. Median overall survival (OS) was 25.7 months [95% Confidence Interval (CI) 21.5&ndash, 29.0], and 3-year survival, 26%. Univariate analysis demonstrated that patients who had additional procedures (surgery/ablation/RT) were significantly less likely to die (Hazard Ratio (HR) 0.18, 95% CI 0.12&ndash, 0.29, p &lt, 0.0001) compared to those receiving systemic chemotherapy alone. Increasing number of multimodal procedures was associated with an incremental increase in survival&mdash, with median OS 28.4 m, 35.7 m, and 64.8 m, respectively, for 1, 2, or &ge, 3 procedures (log-rank p &lt, 0.0001). After exclusion of those who received systemic chemotherapy only (n = 51), metastatic resections were associated with improved survival (adjusted HR 0.36, 95% CI 0.20&ndash, 0.63, p &lt, 0.0001), confirmed in multivariate analysis. Multiple single-organ procedures did not improve survival. Conclusion: Multimodal therapy for metastatic bowel cancer is associated with significant survival benefit. Resection/radical RT of the primary and resection of metastatic disease should be considered to improve survival outcomes following multidisciplinary team (MDT) discussion and individual assessment of fitness.

Background: MicroRNAs (miRs) are small non-coding RNAs involved in cell homeostasis. miR dysregulation has been linked with activation of oncogenic pathways, cancer progression and clinical outcome in mCRC. Chemo-refractory mCRC patients are often treated with regorafenib, a multi-tyrosine kinase inhibitor with anti-angiogenic effect. Given the limited clinical benefits of regorafenib in unselected patient populations, there is an unmet need for better patient stratification and identification of mechanisms of resistance. Methods: Serial liquid biopsies were obtained at baseline (BL) and monthly until disease progression (PD) in 43 patients treated with regorafenib for chemo-refractory mCRC in the context of a phase II clinical trial (PROSPECT-R). Tissue biopsies were obtained at BL, after 2 months and at PD within the same trial and used to establish Patient-Derived Organoids (PDOs) and for molecular analyses. PDOs co-cultures and PDO-xenotransplants were generated to study primary and acquired resistance to regorafenib. Liquid biopsies were also obtained from an additional cohort (n=97) of mCRC patients treated with regorafenib. MiR profiling was performed on baseline seras using NanoString nCounter platform and significant miRs were validated with digital droplet (dd)PCR in serum, plasma, PDOs and by In Situ Hybridization (ISH) in matching tissue biopsies. Functional experiments were performed in PDOs, PDO co-cultures and PDO-xenotransplants. Results: MiR expression was tested in 43 BL in the PROSPECT-R trial. Up-regulation of miR-652-3p was associated with poor PFS and OS. These results were validated by ddPCR on the same serum samples, matching plasmas and organoids. ISH confirmed upregulation of this miR in sequential tissues biopsies, PDOs and PDO-xenotransplants of patients with primary and acquired resistance to regorafenib. The same findings were confirmed in the validation cohort. Functional experiments showed that miR-652-3p upregulation has significant effects on cancer cell migration. Up and down-regulation of miR-652-3p upon regorafenib treatment translated in a significant effect on cell viability in PDO co-cultures and liver PDO-xenotransplants. RNA-sequencing analysis of miR-652-3p over-expressing organoids showed downregulation of several components of the serine synthesis pathway. Among them, phosphoserine aminotransferase (PSAT1) was validated as a miR-652-3p direct target. Rescue experiments confirmed that PSAT1 over-expression and silencing lead to increase sensitivity and resistance to regorafenib respectively via cell and non-cell autonomous regulation of autophagy. Conclusions: Our data suggest that miR-652-3p may be uses as a prognostic/predictive biomarker for the selection of treatment and provide mechanics insight on regorafenib resistance. Citation Format: Somaieh Hedayat, Andrea Lampis, George Vlachogiannis, khurum Khan, Silvia Marchetti, Matteo Fassan, Michele Ghidini, Ruwaida Begum, Marta Schirripa, Rodolfo Passalacqua, David Cunningham, Fotios Loupakis, Nicola Valeri. MicroRNA deregulation of the serine synthesis pathway controls intrinsic and non-cell autonomous mechanism of resistance to Regorafenib in metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5720.

Gastric cancer is considered an age-related disease, with the majority of new cases in the UK diagnosed in individuals over the age of 75. At present most guidance related to the management of gastric cancer is based on trials undertaken in the fit, younger patient. Historically the elderly have been underrepresented in clinical trials, which frequently have a restricted inclusion to an upper age limit of 75. The European Society for Medical Oncology (ESMO) recommends use of a geriatric assessment to determine functional age when initiating treatment in elderly patients with gastric cancer, which has been shown to be a better predictor of treatment response than chronological age. The physiological changes that occur with age, including reduced organ function and pharmacokinetic and pharmacodynamic variability, together with impaired functional status, necessitate a more individualised approach to treatment decisions in the older patient to provide them with the same advantages from radical treatment and palliative chemotherapy as younger patients. This review summarises the current evidence extrapolated from trial data on how best to optimise treatment for elderly patients with gastric cancer.

Anti-epidermal growth factor receptor (EGFR) antibodies (anti-EGFR-Ab) are effective in a subgroup of patients with metastatic colorectal cancer (CRC). We applied genomic and transcriptomic analyses to biopsies from 35 RAS wild-type CRCs treated with the anti-EGFR-Ab cetuximab in a prospective trial to interrogate the molecular resistance landscape. This validated transcriptomic CRC-subtypes as predictors of cetuximab benefit; identified novel associations of NF1-inactivation and non-canonical RAS/RAF-aberrations with primary progression; and of FGF10- and non-canonical BRAF-aberrations with AR. No genetic resistance drivers were detected in 64% of AR biopsies. The majority of these had switched from the cetuximab-sensitive CMS2-subtype pretreatment to the fibroblast- and growth factor-rich CMS4-subtype at progression. Fibroblast supernatant conferred cetuximab resistance in vitro, together supporting subtype-switching as a novel mechanism of AR. Cytotoxic immune infiltrates and immune-checkpoint expression increased following cetuximab responses, potentially providing opportunities to treat CRCs with molecularly heterogeneous AR with immunotherapy.

Cancers of the gastrointestinal tract have limited available treatments and are often associated with a poor prognosis. Clinical trials and translational work associated with these trials provide the opportunity to increase understanding of the mechanisms of sensitivity and resistance to cytotoxic chemotherapy and targeted therapy in these diseases. In this review we discuss the rationale for intensive translational work within the context of academic clinical trials and the successes and challenges which have been associated with translational work at our institution over the past number of years. We reflect on tissue, plasma and radiological biomarker work including a novel patient derived organoid programme and discuss the iterative application of previous results to next generation trial design.

Item does not contain fulltext BACKGROUND: Adolescent and young adult (AYA) patients with advanced solid tumours are often considered for phase I clinical trials with novel agents. The outcome of AYAs in these trials have not been described before. AIM: To study the outcome of AYA patients in phase I clinical trials. METHODS: Clinical trial data of AYAs (defined as aged 15-39 years at diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, between 2002 and 2016, were analysed. RESULTS: From a prospectively maintained database of 2631 patients treated in phase I trials, 219 AYA patients (8%) were identified. Major tumour types included gynaecological cancer (25%) and sarcoma (18%). Twenty-five (11%) had a known hereditary cancer syndrome (most commonly BRCA). Molecular characterisation of tumours (n = 45) identified mutations most commonly in TP53 (33%), PI3KCA (18%) and KRAS (9%). Therapeutic targets of trials included DNA damage repair (16%), phosphoinositide 3-kinase (PI3K) (16%) and angiogenesis (16%). Grade 3/4 toxicities were experienced in 26% of patients. Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median overall survival (OS) was 7.5 months (95% confidence interval: 6.3-9.5), and 2-year OS was 11%. Of patients with responses, 36% were matched to phase I trials based on germline or somatic genetic aberrations. CONCLUSION: We describe the outcome of the largest cohort of AYA patients treated in phase I trials. A subgroup of these patients demonstrates benefit, with several durable responses beyond 2 years. A sizeable proportion of AYA patients have cancer syndromes, significant family history or somatic molecular aberrancies which may influence novel therapeutic treatment options.

Purpose: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. Experimental Design: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Results: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug–drug interactions. Clinical antitumor activity included RECIST 1.0–confirmed partial responses in non–small cell lung cancer and low-grade ovarian carcinoma. Conclusion: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). Clin Cancer Res; 21(4); 739–48. ©2014 AACR.

This study had two aims: (a) to evaluate the utility of fluorine 18-fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) in detecting occult disease recurrence with raised carcinoembryonic antigen (CEA) and (b) to establish the prognostic effects of early detection of disease recurrence in patients with colorectal cancer (CRC).Clinico-pathological data were obtained from all consecutive patients undergoing CRC surveillance from 2004 to 2010 who had an elevated CEA level (3 ng/mL in nonsmokers,5 ng/mL in smokers) but normal or equivocal conventional investigations. Histopathological confirmation or a minimum of 12 months' clinical and radiological follow-up were required to ascertain disease relapse.A total of 1,200 patients were screened; of those, 88 (59% men; mean age, 66 years [SD, 9.6]) eligible patients (67 with normal and 21 with equivocal results on conventional investigations) were identified. Recurrent disease was detected in 56 of 88 patients (64%). The sensitivity of FDG PET-CT to detect recurrence was 49 of 56 (88%; 95% confidence interval [CI], 76%-95%) and specificity was 28 of 32 (88%; 95% CI, 71%-97%). Twenty-seven of 49 (55%) patients with PET-CT-detected relapsed disease were deemed eligible for further curative therapy; 19 (70%) went on to receive potentially curative therapy. The median time to progression (8.8 months [interquartile range (IQR), 4.5-19.1 months] vs. 2.2 months [IQR, 0.7-5.6]), median overall survival (39.9 months [IQR, 23.6-65.4 months] vs. 15.6 months [IQR, 7.3-25.7 months]), and 5-year survival (36.8% [95% CI, 16.5%-57.5%] vs. 6.1% [95% CI, 1.1%-17.6%]; p ≤ .001) were higher in patients who received potentially curative therapy than in those who received noncurative therapy.FDG PET-CT is a highly sensitive and specific tool for the detection of occult CRC recurrence. In50% of patients, recurrent disease may still be potentially amenable to curative therapy. Long-term survival can be achieved in such patients.Colorectal cancer (CRC) patients who, on follow-up, have normal or equivocal results on clinical investigations but raised carcinoembryonic antigen (CEA) levels pose a significant challenge to treating physicians. This study supported the notion that the early use of fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) may have predictive and prognostic value in management of such patients. Long-term disease control and cure can be achieved in a subgroup of this patient population with low-volume disease relapse who are amenable to potentially curative treatment strategies. Reassuringly, the sensitivity and specificity for recurrence did not significantly vary as a function of the CEA level, suggesting that even with a minimal CEA rise, benefit can be attained by conducting FDG PET-CT in a timely manner.

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 RAS 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 RAS 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. Significance: 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. Cancer Discov; 8(10); 1270–85. ©2018 AACR. See related commentary by Siravegna and Corcoran, p. 1213. This article is highlighted in the In This Issue feature, p. 1195

Pancreatic ductal adenocarcinoma (PDA) has a very poor prognosis. Treatment with FOLFIRINOX has been shown to improve outcomes, but can be associated with significant toxicity.A retrospective review was performed of all patients with locally advanced or metastatic PDA treated with FOLFIRINOX at the Royal Marsden between November 2010 and November 2013. Efficacy, tolerability, and potential prognostic factors were evaluated.Twenty-seven patients with metastatic PDA and 22 patients with locally advanced PDA were treated with FOLFIRINOX. Patients received a median of 9 cycles (range, 1-26) of FOLFIRINOX. The overall response rate was 41% (20 patients), and a further 17 patients (35%) had stable disease. Thirty-five patients (71%) received FOLFIRINOX in the first-line setting, with a median progression-free survival and overall survival, respectively, of 12.9 months and 18.4 months for patients with locally advanced disease; and 8.4 months and 12.2 months for patients with metastatic disease. The most frequently occurring Grade 3/4 toxicities were neutropenia (29%), fatigue (18%), febrile neutropenia (14%), thromboembolism (12%), and thrombocytopenia (10%). In a univariate analysis, reduction in CA 19-9 of50% (P .001), normalization of CA19-9 (P .001), surgery after FOLFIRINOX (P = .004), and use of prophylactic pegfilgrastim (P = .005) were prognostic for overall survival.The efficacy and tolerability of FOLFIRINOX for PDA at our institution is similar to that reported in clinical trials. Careful selection of patients and monitoring of response (according to CA19-9) and toxicities can help maximize advantage in this patient population.

Conventional therapeutic options for patients with advanced upper gastrointestinal cancers (UGIC) are limited. Following first-line treatments, some patients are offered experimental therapies, including participation in Phase I trials. This study aims to describe the experience of UGIC patients treated in a dedicated Phase I unit.Patient, tumour and treatment characteristics, and clinical outcomes of UGIC patients treated consecutively at the Drug Development Unit, Royal Marsden Hospital, between 2005 and 2009, were recorded.Ninety-six patients who previously received a median of 2 (range 1-4) lines of chemotherapies were treated in 30 Phase I trials. Of 81 evaluable patients, 9 achieved RECIST-objective response (11 %) with a 6-month clinical benefit rate of 14 %. Median progression free and overall survival were 7.7 weeks [95 %CI 7.7 (6.4-9.0)] and 19.1 weeks (95 %CI 17.5-20.8), respectively. Grade 3 or 4 toxicities were observed in 37 patients (39 %) and led to trial discontinuation in 9 (9 %); no toxicity-related death was recorded. In the multivariate analysis, serum albumin (35 g/dl, HR2.0, p = 0.002) and lactate dehydrogenase (192 μmol/l, HR1.7, p = 0.016) were prognostic of overall survival.Phase I clinical trials can be considered a reasonable option in selected patients with relapsed UGIC. The use of objective prognosticators may improve selection and risk/benefit profile of patients.

Background MicroRNAs (miRs) are small non-coding RNAs involved in cell homeostasis, carcinogenesis and control multiple oncogenic pathways. Numerous miRs deregulation is associated with clinical outcome. Chemo-refractory metastatic CRC (mCRC) patients are often treated with regorafenib. Given the limited clinical benefits of regorafenib in unselected patient populations, there is an unmet need for better patient selection and identification of mechanisms of resistance. Here we aimed to identify circulatory miRs that might be exploited for the upfront selection of patients’ to regorafenib treatment. Methods We ran a translational phase II trial of regorafenib in chemo-refractory mCRC patients. Serum, plasma and tissue biopsies were obtained at baseline (BL), every four weeks and at disease progression (PD). Patient Derived Organoids (PDOs) and PDO-xenotransplants were generated to study primary and acquired resistance to regorafenib. MiR profiling was performed by NanoString nCounter platform of 800 genes and validated with digital droplet (dd)PCR in serum, plasma, PDOs and by In Situ Hybridization (ISH) in matching tissue biopsies. Progression Free Survival (PFS) and Overall Survival (OS) was measured. Further validation was performed in 97 patients from an independent patient’s cohort. Results MiR expression was tested in 43 BL sera and dysregulation in 28 miRs was associated with PFS and OS. Up-regulation of miR-652-3p was associated with worse PFS and OS. These results were validated by ddPCR on the same serum samples, and matching plasmas. ISH confirmed upregulation of this miR in sequential tissues biopsies, PDOs and PDO-xenotransplants of patients with primary and acquired resistance to regorafenib. Validation in an independent patient’s cohort confirmed direct association of miR-652-3p dysregulation with OS. Functional experiments to define miR652-3p mediated resistance have shown that there is a decrease of tumour growth and migration in miR-652-3p inhibition in cell lines and PDOs. Conclusions We provided initial evidence suggesting that circulating miR-652-3p might work as a predictive biomarker for the upfront selection of patients’ candidate to regorafenib treatment. Legal entity responsible for the study Academic. Funding Royal Marsden. Disclosure All authors have declared no conflicts of interest.

MicroRNAs (miRs) are small non-coding RNAs involved in cell homeostasis and carcinogenesis and control multiple oncogenic pathways. Numerous miRs are aberrantly expressed in colorectal cancer (CRC) and their deregulation is associated with clinical outcome and cancer progression. Chemo-refractory metastatic CRC (mCRC) patients are often treated with regorafenib, a multi-tyrosine kinase inhibitor with anti-angiogenic effect. Given the limited clinical benefits of regorafenib in unselected patient populations, there is an unmet need for better patient selection and identification of mechanisms of resistance. miRs are highly stable and have shown encouraging value as potential biomarkers for CRC detection and prognosis. Here we aimed to identify circulatory miRs that might be exploited for the upfront selection of patients’ candidate to regorafenib treatment. We ran a translational phase II trial of regorafenib in chemo-refractory mCRC patients. Serum, plasma and tissue biopsies were obtained at baseline (BL), every four weeks and at disease progression (PD). Patient Derived Organoids (PDOs) and PDO-xenotransplants were generated to study primary and acquired resistance to regorafenib. MiR profiling was performed in baseline serum of all patients by NanoString nCounter platform of 800 genes and validated with digital droplet (dd)PCR in serum, plasma, PDOs and by In Situ Hybridization (ISH) in matching tissue biopsies. Progression Free Survival (PFS) was measured from date of registration to date of first progression/relapse or death from cancer progression. Overall Survival (OS) was measured from date of randomisation to death from cancer. Further validation was performed by ddPCR in 97 patients from an independent patient’s cohort. MiR expression was tested in 43 BL sera and dysregulation in 28 miRs was associated with PFS and OS. Up-regulation of miR-652-3p was associated with worse PFS and OS. These results were validated by ddPCR on the same serum samples, and matching plasmas. ISH confirmed upregulation of this miR in sequential tissues biopsies, PDOs and PDO-xenotransplants of patients with primary and acquired resistance to regorafenib. Validation in an independent patient’s cohort confirmed direct association of miR-652-3p dysregulation with PFS and OS. Functional experiments to define miR652-3p mediated resistance have shown that there is a decrease of tumour growth and migration in miR-652-3p inhibition in PDOs. We provide initial evidence suggesting that circulating miR-652-3p might work as a negative predictive biomarker for the upfront selection of patients’ candidate to regorafenib treatment. Citation Format: Somaieh Hedayat, Khurum Khan, David Cunningham, George Vlachogiannis, Andrea Lampis, Silvia Marchetti, Matteo Fassan, Ruwaida Begum, Marta Schirripa, Fotios Fotios Loupakis, Nicola Valeri. Circulating miR-652-3p as a biomarker of resistance to regorafenib in metastatic colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-305.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

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.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.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.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.

548 Background: RAS status in tissue and/or liquid biopsies and tumour location (sidedness) are predictive markers of patients’ response to anti-EGFR mABs. MiR-31-3p expression has been correlated with clinical benefit from anti-EGFR mABs with chemotherapy. We aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemo-refractory mCRC patients treated with single agent anti-EGFR mABs in the PROSPECT-C trial (NCT02994888). Methods: MiR-31-3p was tested by in-situ hybridization in 91 pre-treatment (PT) core biopsies from 45 mCRC patients. Sequential tissue biopsies obtained PT, at time of best response and at disease progression were tested to monitor changes in miR-31-3p expression over treatment. In 34 patients miR-31-3p, gender, sidedness, previous lines of treatment and RAS status in PT cell free (cf) DNA were evaluated in multivariate Cox and logistic regression models. Results: Patients with low miR-31-3p expression in PT biopsies showed better overall response rate (ORR: 58.3% vs 22.2%), median progression free survival (mPFS: 4.21 vs 2.27 months) and overall survival (mOS: 4.21 vs 2.27 mo) compared to those with high miR-31-3p expression (Hazard Ratio for PFS high vs low: 1.96; 95% CI: 0.98-3.88; p: 0.06 and HR for OS high vs low: 2.14; 95% CI: 1.04- 4.40; p: 0.04) adjusting for age, gender and sidedness. There was significant association between ORR and miR-31-3p expression (χ2 test p: 0.029). MiR-31-3p expression was an independent predictor of response, adjusting for gender, previous treatment lines and RAS (odds ratio: 0.14; 95% CI: 0.02-1.00, p: 0.048). A trend towards improved mPFS (5.10 vs 2.27 mo) and mOS (15.23 vs 4.67 mo) was noted in miR31-3p low vs high group in cfDNA RAS wild-type patients. No significant change in miR-31-3p expression were observed in archival tissue and sequential tissue biopsies. Conclusions: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mABs. Further studies are needed to test if miR-31-3p combined with cfDNA RAS test can identify best responders in specific clinical niches.

535 Background: The bispecific antibody CEA-TCB binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells. This triggers T cell killing of colorectal cancer cell lines expressing moderate to high levels of CEA at the cell surface (Bacac, Clin Cancer Res 2016). Patient derived organoids (PDOs) may more accurately represent patient tumors than established cell lines. Yet, determinants of CEA-TCB resistance have not been studied in PDOs. Methods: PDOs were established from biopsies of eight multidrug-resistant metastatic CRCs, GFP labelled and adapted to 2D culture. Allogenic CD8 T cells and CEA-TCB or a non-targeting control antibody were added and cancer cell killing and growth were monitored for 10 days. CEA expression of PDOs was determined by FACS. Results: CRC PDOs could be categorized into three groups based on CEA cell-surface expression: CEAhigh (n = 3), CEAlow (n = 2), and CEA heterogeneous PDOs (n = 3) that stably maintained populations of both CEAhigh and CEAlow cells, which has not previously been described in CRC cell lines. Heterogeneity of cell-surface CEA expression is common in CRC cells in patients, supporting that PDOs may better represent these tumors than established cell lines. CEAhigh cells were sensitive whereas CEAlow cells showed resistance to CEA-TCB. All PDOs with heterogeneous CEA expression were resistant to CEA-TCB, suggesting that CEA-negative cells maintain cancer cell growth. Culture of FACS sorted CEAhigh and CEAlow cells from PDOs with heterogeneous CEA expression demonstrated high plasticity of CEA expression which may contribute to rapid resistance acquisition through CEA antigen loss. Conclusions: These results suggest that cell-surface CEA expression is a major determinant of CEA-TCB sensitivity and resistance in PDOs. In addition, we identified heterogeneous CEA expression in several PDOs and demonstrated that this could confer CEA-TCB resistance in vitro. These PDO models are likely to provide insights into the mechanism of CEA loss and may inform therapeutic opportunities to counter CEA-TCB resistance. RNA-sequencing and functional experiments are ongoing to investigate this and will be presented.

Despite recent improvements to current therapies and the emergence of novel agents to manage advanced non-small cell lung cancer (NSCLC), the patients' overall survival remains poor. Re-challenging with first-line chemotherapy upon relapse is common in the management of small cell lung cancer but is not well reported for advanced NSCLC. NSCLC relapse has been attributed to acquired drug resistance, but the repopulation of sensitive clones may also play a role, in which case re-challenge may be appropriate. Here, we report the results of re-challenge with gemcitabine plus carboplatin in 22 patients from a single institution who had previously received gemcitabine plus platinum in the first-line setting and had either partial response or a progression-free interval of longer than 6 months. In this retrospective study, the charts of patients who underwent second-line chemotherapy for NSCLC in our cancer center between January 2005 and April 2010 were reviewed. All the patients who received a combination of gemcitabine and carboplatin for re-challenge were included in the study. These patients were offered second-line treatment on confirmation of clear radiological disease progression. The overall response rate was 15% and disease control rate was 75%. The median survival time was 10.4 months, with 46% of patients alive at 1 year. These results suggest that re-challenge chemotherapy should be considered in selected patients with radiological partial response or a progression-free survival of longer than 6 months to the initial therapy.

Background. This study had two aims: (a) to evaluate the utility of fluorine 18-fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) in detecting occult disease recurrence with raised carcinoembryonic antigen (CEA) and (b) to establish the prognostic effects of early detection of disease recurrence in patients with colorectal cancer (CRC). Patients and Methods. Clinico-pathological data were obtained from all consecutive patients undergoing CRC surveillance from 2004 to 2010 who had an elevated CEA level (>3 ng/mL in nonsmokers, >5 ng/mL in smokers) but normal or equivocal conventional investigations. Histopathological confirmation or a minimum of 12 months’ clinical and radiological follow-up were required to ascertain disease relapse. Results. A total of 1,200 patients were screened; of those, 88 (59% men; mean age, 66 years [SD, 9.6]) eligible patients (67 with normal and 21 with equivocal results on conventional investigations) were identified. Recurrent disease was detected in 56 of 88 patients (64%). The sensitivity of FDG PET-CT to detect recurrence was 49 of 56 (88%; 95% confidence interval [CI], 76%–95%) and specificity was 28 of 32 (88%; 95% CI, 71%–97%). Twenty-seven of 49 (55%) patients with PET-CT-detected relapsed disease were deemed eligible for further curative therapy; 19 (70%) went on to receive potentially curative therapy. The median time to progression (8.8 months [interquartile range (IQR), 4.5–19.1 months] vs. 2.2 months [IQR, 0.7–5.6]), median overall survival (39.9 months [IQR, 23.6–65.4 months] vs. 15.6 months [IQR, 7.3–25.7 months]), and 5-year survival (36.8% [95% CI, 16.5%–57.5%] vs. 6.1% [95% CI, 1.1%–17.6%]; p ≤ .001) were higher in patients who received potentially curative therapy than in those who received noncurative therapy. Conclusion. FDG PET-CT is a highly sensitive and specific tool for the detection of occult CRC recurrence. In >50% of patients, recurrent disease may still be potentially amenable to curative therapy. Long-term survival can be achieved in such patients.

// Khurum Khan 1 , David Cunningham 1 , Clare Peckitt 1 , Sarah Barton 1 , Diana Tait 1 , Maria Hawkins 1,2 , David Watkins 1 , Naureen Starling 1 , Sheela Rao 1 , Ruwaida Begum 1 , Janet Thomas 1 , Jacqui Oates 1 , Vincenza Guzzardo 3 , Matteo Fassan 3 , Chiara Braconi 1,4 and Ian Chau 1 1 Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK 2 CRUK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Oxford, UK 3 Department of Medicine, University of Padua, Padua, IT 4 Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK Correspondence to: Chiara Braconi, email: // Ian Chau, email: // Keywords : pancreatic cancer, microRNA, miR-21, chemo-radiotherapy, cetuximab Received : November 27, 2015 Accepted : January 25, 2016 Published : February 05, 2016 Abstract Background: Locally advanced pancreatic cancer (LAPC) is associated with high mortality, and biomarker-driven treatment approach is currently lacking. This study evaluated safety and efficacy of a combination approach of chemotherapy followed by chemo-radiotherapy (CRT) +/- cetuximab, and the prognostic role of miR-21 in patients with LAPC treated with a multimodality approach. Patients and Methods: This was a randomised phase II trial in which patients with inoperable LAPC were offered gemcitabine and capecitabine (GEM-CAP) for 16 weeks. Patients with stable disease or response after GEM-CAP were randomised to capecitabine or UFT plus radiotherapy (RT) (A), or capecitabine or UFT plus cetuximab plus RT (B). The primary outcome of the study was overall survival (OS). Clinical outcome was compared according to baseline circulating miR-21 levels. Results: 17 patients were enrolled and treated with GEM-CAP, with 13 patients achieving disease control and being randomised to arms A (n:7) and B (n:6). After a median follow-up of 61.2 months, median progression free survival (PFS) was 10.4 months and 12.7 months, median OS was 15.8 months and 22.0 months in arms A and B respectively ( p > 0.05). Patients with high baseline plasma miR-21 had worse PFS (3.5 vs . 12.7 months; p:0.032) and OS (5.1 vs 15.3 months; p:0.5) compared to patients with low miR-21. Circulating miR-21 levels reflected miR-21 expression within the tissues. Conclusions: Addition of Cetuximab to CRT following induction chemotherapy did not improve survival. High miR-21 baseline plasma expression was associated with poor clinical outcome in LAPC patients treated with induction chemotherapy followed by chemo-radiotherapy.