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Objectives Investigate the laboratory, imaging and procedural factors that are associated with a tumour-positive and/or NGS-feasible CT-guided sclerotic bone lesion biopsy result in cancer patients. Methods In total, 113 CT-guided bone biopsies performed in cancer patients by an interventional radiologist in one institution were retrospectively reviewed. Sixty-five sclerotic bone biopsies were eventually included and routine blood parameters and tumour marker levels were recorded. Non-contrast (NC) biopsy CTs (65), contrast-enhanced CTs (24), and PET/CTs (22) performed within four weeks of biopsy were reviewed; lesion location, diameter, lesion-to-cortex distance, and NC-CT appearance (dense-sclerosis versus mild-sclerosis) were noted. Mean NC-CT, CE-CT HU, and PET SUVmax were derived from biopsy tract and lesion segmentations. Needle diameter, tract length, and number of samples were noted. Comparisons between tumour-positive/negative and next-generation sequencing (NGS)-feasible/non-feasible biopsies determined significant (p < 0.05) laboratory, imaging, and procedural parameter differences. Results Seventy-four percent of biopsies were tumour-positive. NGS was feasible in 22/30 prostate cancer patients (73%). Neither laboratory blood parameters, PET/CT availability, size, nor lesion-to-cortex distance affected diagnostic yield or NGS feasibility (p > 0.298). Eighty-seven percent of mildly sclerotic bone (mean 244 HU) biopsies were positive compared with 56% in dense sclerosis (622 HU, p = 0.005) and NC-CT lesion HU was significantly lower in positive biopsies (p = 0.003). A 610 HU threshold yielded 89% PPV for tumour-positive biopsies and a 370 HU threshold 94% PPV for NGS-feasible biopsies. FDG-PET and procedural parameters were non-significant factors (each p > 0.055). Conclusion In cancer patients with sclerotic bone disease, targeting areas of predominantly mild sclerosis in lower CT-attenuation lesions can improve tumour tissue yield and NGS feasibility. Key Points • Areas of predominantly mild sclerosis should be preferred to areas of predominantly dense sclerosis for CT-guided bone biopsies in cancer patients. • Among sclerotic bone lesions in prostate cancer patients, lesions with a mean HU below 370 should be preferred as biopsy targets to improve NGS feasibility. • Laboratory parameters and procedure related factors may have little implications for CT-guided sclerotic bone biopsy success.

Supplementary Figures and Tables

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.

Objective A commercially available CT-guided robot offers enhanced abilities in planning, targeting, and confirming accurate needle placement. In this short communication, we describe our first UK experience of robotic interventional oncology procedures. Methods We describe the device, discuss installation, operation, and report upon needle insertion success, accuracy (path deviation; PD and tip deviation; TD), number of adjustments, complications, and procedural success. Results Nine patients (seven males), median age 66 years (range 43–79) were consented for biopsy or ablation between March and April 2021. Needle placement in biopsy was more accurate than ablation (median 1 vs 11 mm PD and 1 vs 20 mm TD) and required fewer adjustments (median 0 vs 5). No complications arose, and all procedures were successful (diagnostic material obtained or complete ablation at follow-up). Conclusion Short procedure times and very high levels of accuracy were readily achieved with biopsy procedures, although tumour ablation was less accurate which likely reflects higher procedural complexity. Advances in knowledge Achieving highly accurate robotic biopsy with is feasible within a very short time span. Further work is required to maximise the potential of robotic guidance in tumour ablation procedures, which is likely due to higher complexity giving a longer learning curve.

Objectives Percutaneous liver biopsy (PLB) poses specific challenges in oncological patients such as bleeding and tumour seeding. This study’s aim was to compare a coaxial (C-PLB) and non-coaxial (NC-PLB) biopsy technique in terms of diagnostic yield, safety and seeding risk of image-guided PLB techniques in an oncological setting. Methods Local research committee approval was obtained for this single-site retrospective study. Patients who underwent a PLB between November 2011 and December 2017 were consecutively included. Medical records were reviewed to determine diagnostic yield and complications. Follow-up imaging was re-reviewed for seeding, defined as visible tumour deposits along the PLB track. Mann-Whitney U and chi-squared tests were performed to investigate differences between biopsy techniques in sample number, complications and seeding rate. Results In total, 741 patients (62 ± 13 years, 378 women) underwent 932 PLB (C-PLB 72.9% (679/932); NC-PLB 27.1% (253/932)). More tissue cores (p p = 0.940). Complication rate (9.3%; 87/932) using C-PLB (8.2% (56/679)) was lower compared with NC-PLB (12.3% (31/253); p = 0.024). Major complications were uncommon (C-PLB 2.7% (18/679); NC-PLB 2.8% (7/253)); bleeding developed in 1.2% (11/932; C-PLB 1.2% (8/679); NC-PLB 1.2% (3/253)). Seeding was a rare event, occurring significantly less in C-PLB cases (C-PLB 1.3% (7/544); NC-PLB 3.1% (6/197); p = 0.021). Conclusions C-PLB allows for high diagnostic tissue yield with a lower complication and seeding rate than a NC-PLB and should be the preferred method in an oncological setting. Key Points • A coaxial percutaneous liver biopsy achieves a significant higher number of cores and fewer complications than a non-coaxial biopsy technique. • The risk of tumour seeding is very low and is significantly lower using the coaxial biopsy technique. • In this study, a larger number of cores (median = 4) could be safely acquired using the coaxial technique, providing sufficient material for advanced molecular analysis.

Background Initial grading of retroperitoneal leiomyosarcoma (LMS) is performed by core biopsy (CB) however, discrepancy between grade of tumour at initial CB and surgical excision is recognised, raising concerns about the accuracy of CB for directing neoadjuvant therapy. The histological grading system used for staging LMS consists of 3 components: tumour differentiation, mitotic index and proportion of necrosis. We postulate that assessment of necrosis by histopathology alone is inadequate, resulting in under-grading of LMS. We propose and assess a combined grading system that incorporates CT scan findings into pre-surgical grading. Methods Retrospective, blinded review of CT, CB histology and final surgical histology of patients with retroperitoneal LMS was undertaken. A modified grading system, CTH-Grade, was derived by replacing the CB necrosis score with a CT-derived necrosis score. The sensitivity and specificity of CTH-Grade, the standard histopathology scoring, H-grade were compared. Inter-observer variability in assessment of CT necrosis was also assessed. Results 53 patients fulfilled criteria for inclusion. CT was more sensitive at detection of necrosis than CB histology alone with sensitivity of 100% vs 53%. The use of CTHGrade resulted in increased detection of high-grade tumours with CTH-grade having sensitivities of 80% and 35% for Grade 2 and 3 tumours respectively vs 53% and 15% with H-Grade. Assessment of reader agreement demonstrated Kappa scores of 0.8. Conclusion Histology from CB under-grades LMS due to undersampling of tumour necrosis. CT is more sensitive in assessing necrosis and its incorporation into a modified CT-histopathology grading system (CTH-Grade) improves accuracy of grading with significant implications for patient management.

Objective: To analyze whether the route of preoperative biopsy influences oncological outcome in GIST patients. Summary of Background Data: Preoperative biopsies are widely used for diagnosing GIST. Little is known about the risk of tumor seeding after different routes of biopsy. Methods: Patients who underwent resection of a primary GIST between 1996 and 2014 were identified from 2 databases from 2 tertiary referral centers. Survival data were obtained using the Kaplan-Meier method. Possible confounders were identified using Cox regression analysis. The primary endpoint was local recurrence free survival (RFS) and the secondary endpoint was DSS. Results: A total of 228 patients were included, with a median age of 62 years (range 17-86) and a median follow-up time of 53 months (range 1-204). From these patients, 42 patients did not have a biopsy (18%), 70 underwent a transcutaneous biopsy (31%), and 116 a transluminal biopsy (51%). A total of 42 patients (19.0%) had a local and/or distant recurrence. From the 70 patients with a transcutaneous biopsy, only 1 patient developed a needle tract recurrence (1.4%). Local RFS and DSS were both significantly shorter in the transcutaneous biopsy group on univariate analysis compared to the other groups; however, in multivariate analysis the route of biopsy did not influence local RFS (P = 0.128) or DSS (P = 0.096). Conclusions: Transluminal or transcutaneous biopsies for diagnosing GIST do not significantly alter the risk of local recurrent disease or DSS in multivariate Cox regressions. The risk of needle tract seeding after transcutaneous biopsy was low.

Background/aim Distinguishing true oligometastatic disease from early polymetastatic disease is vital in patients with soft tissue sarcoma as contemporary treatment strategies differ significantly. Clinical factors such as tumour biology, organ involved, number of lesions, and patient fitness influence clinical decisions. Patients and methods A retrospective search of a prospective database identified patients with new distant relapse, treated between 2009 and 2012. Results A total of 223 patients were included, and oligometastases were diagnosed in 81 (36%) patients, which were pulmonary in just over half of cases. These were treated with local therapy in 66 of 89 cases, and 7 patients received subsequent treatment for additional oligometastases. Metastasectomy was the most common treatment modality. A total of 16/66 patients (24%) underwent active surveillance for >6 months prior to local therapy. Conclusion Patients with oligometastatic disease can experience durable disease control with timely multimodality treatment approaches for evolving metastatic disease, where disease biology allows.

Objectives To evaluate whether multiparametric bone MRI (mpBMRI) utilising a combination of DWI signal, ADC and relative fat-fraction (rFF) can identify bone metastases, which provide high diagnostic biopsy yield and next-generation genomic sequencing (NGS) feasibility. Methods A total of 150 CT-guided bone biopsies performed by interventional radiologists (3/2013 to 2/2021) at our centre were reviewed. In 43 patients, contemporaneous DWI and rFF images, calculated from 2-point T1w Dixon MRI, were available. For each biopsied lesion, a region of interest (ROI) was delineated on ADC and rFF images and the following MRI parameters were recorded: visual classification of DWI signal intensity (SI), mean, median, 10th and 90th centile ADC and rFF values. Non-parametric tests were used to compare values between tumour positive/negative biopsies and feasible/non-feasible NGS, with p-values Results The mpBMRI combination high DWI signal, mean ADC 2/s and mean rFF p = 0.001) and NGS feasibility with 91% sensitivity, 78% specificity and 91% PPV (p p > 0.082). In NGS feasible biopsies, mean and 90th centile rFF were significantly smaller (each p p > 0.292). Conclusions MpBMRI utilising the combination of DWI signal, ADC and rFF can identify active bone metastases, which provide biopsy tissue with high diagnostic yield and NGS feasibility. Key Points • Multiparametric bone MRI with diffusion-weighted and relative fat-fraction images helps to identify active bone metastases suitable for CT-guided biopsy. • Target lesions for CT-guided bone biopsies in cancer patients can be chosen with greater confidence. • CT-guided bone biopsy success rates, especially yielding sufficient viable tissue for advanced molecular tissue analyses, can be improved.

SummaryAntigen recognition and T-cell mediated cytotoxicity in clear-cell renal cell carcinoma (ccRCC) remains incompletely understood. To address this knowledge gap, we analysed 115 multiregion tumour samples collected from 15 treatment-naïve patients pre- and post-nivolumab therapy, and at autopsy in three patients. We performed whole-exome sequencing, RNAseq, TCRseq, multiplex immunofluorescence and flow cytometry analyses and correlated with clinical response. We observed pre-treatment intratumoural TCR clonal expansions suggesting pre-existing immunity. Nivolumab maintained pre-treatment expanded, clustered TCR clones in responders, suggesting ongoing antigen-driven stimulation of T-cells. T-cells in responders were enriched for expanded TCF7+CD8+T-cells and upregulated GZMK/B upon nivolumab-binding. By contrast, nivolumab promoted accumulation of new TCR clones in non-responders, replacing pre-treatment expanded clonotypes. In this dataset, mutational features did not correlate with response to nivolumab and human endogenous retrovirus expression correlated indirectly. Our data suggests that nivolumab potentiates clinical responses in ccRCC by binding pre-existing expanded CD8+T-cells to enhance cytotoxicity.

Antigen recognition and T-cell mediated cytotoxicity in clear-cell renal cell carcinoma (ccRCC) remains incompletely understood. To address this knowledge gap, we analysed 115 multiregion tumour samples collected from 15 treatment-naive patients pre- and post-nivolumab therapy, and at autopsy in three patients. We performed whole-exome sequencing, RNAseq, TCRseq, multiplex immunofluorescence and flow cytometry analyses and correlated with clinical response. We observed pre-treatment intratumoural TCR clonal expansions suggesting pre-existing immunity. Nivolumab maintained pre-treatment expanded, clustered TCR clones in responders, suggesting ongoing antigen-driven stimulation of T-cells. T-cells in responders were enriched for expanded TCF7+CD8+ T-cells and upregulated GZMK/B upon nivolumab-binding. By contrast, nivolumab promoted accumulation of new TCR clones in non-responders, replacing pre-treatment expanded clonotypes. In this dataset, mutational features did not correlate with response to nivolumab and human endogenous retrovirus expression correlated indirectly. Our data suggests that nivolumab potentiates clinical responses in ccRCC by binding pre-existing expanded CD8+ T-cells to enhance cytotoxicity.

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

Objectives: Myxoid liposarcomas (MLS) show enhanced response to radiotherapy due to their distinctive vascular pattern and therefore could be effectively treated with lower radiation doses. This is a descriptive study to explore the use of functional MRI to identify response in a uniform cohort of MLS patients treated with reduced dose radiotherapy Methods: 10 patients with MLS were imaged pre-, during, and post-radiotherapy receiving reduced dose radiotherapy and the response to treatment was histopathologically assessed post-radiotherapy. Apparent diffusion coefficient (ADC), T2* relaxation time, volume transfer constant (Ktrans), initial area under the gadolinium curve over 60 s (IAUGC60) and (Gd) were estimated for a central tumour volume. Results: All parameters showed large inter- and intrasubject variabilities. Pre-treatment (Gd), IAUGC60 and Ktrans were significantly different between responders and non-responders. Post-radiotherapy reductions from baseline were demonstrated for T2*, (Gd), IAUGC60 and Ktrans for responders. No statistically significant ADC differences were demonstrated between the two response groups. Significantly greater early tumour volume reductions were observed for responders. Conclusions: MLS are heterogenous lesions, characterised by a slow gradual contrast-agent uptake. Pre-treatment vascular parameters, early changes to tumour volume, vascular parameters and T2* have potential in identifying response to treatment. The delayed (Gd) is a suitable descriptive parameter, relying simply on T1 measurements. Volume changes precede changes in MLS functionality and could be used to identify early response. Advances in knowledge: MLS are are characterised by slow gradual contrast-agent uptake. Measurement of the delayed contrast-agent uptake (Gd) is simple to implement and able to discriminate response.

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.

Opinion statementThe treatment of advanced GIST is rapidly evolving with the development of novel molecular compounds such as avapritinib and ripretinib, but also promising results have been achieved with cabozantinib in a phase II trial. The availability of over five lines of treatment for patients with advanced GIST is likely to completely shift the current second-line and third-line treatment options, and will also potentially enable a personalised approach to treatment. Imatinib will most likely remain as the first-line treatment of choice for the vast majority of GIST patients. However, for GIST patients with tumours harbouring a D842V mutation in PDGFRA exon 18, avapritinib has shown efficacy and will become first-line therapy for this molecular subgroup. For second- and third-line treatment, results are awaited of a number of clinical trials. However, second-line and further treatment could potentially be tailored depending on secondary mutations found in imatinib-resistant GISTs. As secondary resistance to TKIs remains the biggest challenge in the treatment of GIST and despite negative results with alternating regimens in phase II, combination treatments should be further evaluated to tackle this issue. Moreover, the favourable safety profiles observed with avapritinib and ripretinib suggest that combination treatments are feasible, for instance, combining two TKIs or a TKI with drugs targeting downstream signalling pathways, such as PI3K inhibitors or MEK inhibitors. Finally, in line with further personalisation of treatment in GIST, a multidisciplinary approach is essential, and local treatment options, such as RFA, resection in case of unifocal progression, and radiotherapy, should be considered.

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.

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

TPS471 Background: Oesophagogastric (OG) cancers represent a significant health burden and leading cause of cancer related death. Prognosis in advanced disease is poor and novel therapies are needed to improve outcomes. Molecular features of advanced OG cancer suggest that assessment of DDR (DNA damage repair) targeted agents is warranted. Specifically, ATM and ARID1A defects and mutational scars indicative of homologous recombination defects are present in a subset of OG cancers and are associated with polyadenosine 5’diphosphoribose polymerase inhibitor (PARPi) sensitivity. Methods: SOlar is a multi-centre, open-label, single arm, phase II study of olaparib, a PARPi, in patients with advanced oesophageal, gastro-oesophageal junction and gastric adenocarcinoma. The trial will use a single-arm Simon two-stage design to evaluate the anti-tumour activity of olaparib in advanced OG cancers. The primary endpoint is disease control rate (DCR) at 8 weeks by RECIST v1.1. To rule out a DCR of ≤15% while aiming for DCR ≥30% (alpha = 0.09, power = 89%), 54 patients must be recruited it total. An interim analysis will take place when 27 patients have been accrued, dosed and followed until the 8-week disease evaluation. If 4 or fewer patients have disease control (DC) the study will be terminated. If 5 or more patients have DC, an additional 27 patients will be enrolled to a total of 54 patients. If ≥12/54 have DC in the final analysis then it will be concluded that the treatment has shown anti-tumour activity compatible with 30% and an investigation of potential biomarkers of response will be carried out. Secondary endpoints are ORR, DoR, OS, PFS, time to radiological progression and safety. This highly translational study incorporating serial tumour biopsies will investigate candidate predictive biomarkers of PARPi sensitivity with the aim of identifying responder/non-responder subpopulations. Further exploratory objectives will investigate the predictive role of early FDG-PET/CT in assessing tumour response and the creation of an organoid biobank. The trial opened to recruitment in July 2019 and will recruit up to 54 patients over 3 years. Clinical trial information: NCT03829345.

Summary Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5′ UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor’s most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention., Graphical Abstract, Highlights • Novel hotspot of driver mutations in 5′-UTR repressor of TERT, expanding telomeres • Most common cause of 3p loss is a chromothripsis event, generating concurrent 5q gain • t(3;5) event occurs in childhood or adolescence, decades before tumor diagnosed • Initial clonal expansion after 3p loss starts from only a few hundred cells, Combination of whole-genome sequencing analysis and a multi-region sampling approach provides insights into the nature and timing of key oncogenic events in clear cell renal cell carcinoma, depicts the evolutionary trajectories of tumors in patients and highlights the opportunity for early intervention.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with > 10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance. We thank Aida Murra, Naheed Shaikh, Justine Korteweg, Jeremy Tai, Eleanor Carlyle, Leonora Conneely, KimEdmonds, Karla Lingard, Karen O'Meara, Helen Breeze, Sarah Sarker, Lesley Cooper, Linda Shephard, Susie Slater, and Catherine Rogers for study support. We thank the patients and their families. S.T. and H.X. are funded by Cancer Research UK (CRUK) (C50947/A18176). S.T., T.C., J.L., and M.G. are funded by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at the Royal Marsden Hospital and Institute of Cancer Research (A109). J.I.L. is funded by the Ministerio de Economia y Competitividad (MINECO, SAF2016-79847-R). M.S., A.S., J. Lynch, R.F., L.A., and L.S. are funded by the Royal Marsden Cancer Charity. K.L. is funded by UK Medical Research Council (MR/P014712/1). T.B.K.W. is funded by the European Union Seventh Framework Programme (FP7-People-2013-ITN). M.J.-H. is funded by the NIHR. N.M.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support towards the establishment of The Francis Crick Institute. N.M.L. is additionally funded by a Wellcome Trust Joint Investigator Award (103760/Z/14/Z) and the MRC eMedLab Medical Bioinformatics Infrastructure Award (MR/L016311/1). M.K. is funded by the Danish Cancer Society grant (R90-A6213). P.C. is funded by the Wellcome Trust (WT088340MA). N.M. receives funding from CRUK, Rosetrees, and the NIHR BRC at University College London Hospitals. C.S. is a Royal Society Napier Research Professor. C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees and Stoneygate Trusts, NovoNordisk Foundation (THESEUS), Marie Curie Network PloidyNet, the NIHR BRC at University College London Hospitals, and the CRUK University College London Experimental Cancer Medicine Centre. C.S., O.P., D.R., I.C., and Z.S. are funded by NovoNordisk Foundation (16584). O.P., D.R., and I.C. are funded by the National Research, Development and Innovation Office of Hungary (NVKP_16-1-20160004). This work was supported by CRUK (Clinical Scientist Fellowship to S.T., C50947/A18176), The Francis Crick Institute, which receives its core funding from Cancer Reseach UK (FC010110), the UK Medical Research Council (FC010110), the Wellcome Trust (FC010110), and NIHR BRC at the Royal Marsden Hospital and Institute of Cancer Research (A109). High-performance computing was supported by eMedLab. The results published here are in whole or part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.

Introduction In the era of biomarker-driven systemic therapy for advanced NSCLC, the role of routine repeated biopsies for decision making outside EGFR-mutant disease remains unproven. We report our center's experience of safety and adequacy for molecular retesting of tumor material obtained from image-guided lung rebiopsies in NSCLC. Methods We performed a retrospective case note analysis of patients undergoing image-guided lung rebiopsies at a single cancer center between 2011 and 2014. The primary objective was to determine the pathological success rate. Secondary and exploratory objectives were to determine technical success rate, histological concordance, molecular adequacy, genotypes identified, and complication rate. Results In all, 103 patients underwent transthoracic image-guided procedures. A total of 66 rebiopsies in NSCLC were identified and analyzed. The pathological success rate was 87.1%. A high histological discordance rate was observed (12 of 52 evaluable cases [23.1%]). Pretest molecular adequacy as determined by the lung pathologist was 78.8% (52 of 66). Of 52 adequate samples 51 were sent for molecular analysis, with a total of 209 genes analyzed (including EGFR, ALK receptor tyrosine kinase gene [ALK], KRAS, BRAF, dicoidin domain receptor tyrosine kinase 2 gene [DDR2], NRAS, ROS1, and rearranged during transfection proto-oncogene gene [RET]). The rate of postgenotyping molecular adequacy was 87.1% (182 of 209). Overall, 20 new potentially actionable mutations were identified, with 13 of 66 patients (19.7%) starting to receive new targeted treatment as a result. Overall, rebiopsies informed clinical decision making in 63.6% of cases. The rates of complications were 15% for pneumothorax, 3% for pneumothorax requiring chest drain, and 8% for hemoptysis. Conclusions We have validated the pathological and molecular adequacy rates of rebiopsies and demonstrated clinical utility in routine decision making.

Small cell transformation is a rare but well recognised mechanism of acquired resistance to EGFR-TKI therapy in EGFR-mutated NSCLC, but optimal drug therapy thereof is unknown. Nivolumab has demonstrated activity in relapsed de novo small cell lung cancer in early phase trials. Here, we report a case of transformed EGFR-mutant SCLC treated with nivolumab with no benefit.

Background Retroperitoneal tumours often require a preoperative core needle biopsy to establish a histological diagnosis. Literature is scarce regarding the risk of biopsies in retroperitoneal sarcomas, so the aim of this study is to identify the potential risks of core needle biopsies causing needle tract recurrences or local recurrences. Method Patients who underwent resection of a primary retroperitoneal sarcoma between 1990 and 2014 were identified from a prospectively maintained database from two tertiary referral centres. Patient demographics, tumour characteristics and biopsy techniques were examined. The primary endpoint was needle tract recurrence and local intra-abdominal recurrence. Results 498 patients were included in the analysis. The most common histological subtypes were liposarcoma (66%) and leiomyosarcoma (18%). Of the 498 patients that underwent resection, 255 patients were diagnosed with a preoperative biopsy. Five patients (2%) developed a biopsy site recurrence: 3 patients with leiomyosarcomas and 2 patients with dedifferentiated liposarcomas. All biopsy site recurrences occurred after trans-abdominal biopsies and were not performed with a co-axial technique. There was no significant difference in local recurrence rate between the patients with or without a biopsy (=0.30) or for the biopsy route (trans-abdominal or trans-retroperitoneal (p = 0.72)). Conclusion The risk of a needle tract metastasis after core needle biopsy for retroperitoneal sarcoma is very low but not zero. The safest method seems a trans-retroperitoneal approach with a co-axial technique. Local recurrence rate is not altered after doing a core needle biopsy.

Background ADATPeR is the first prospective study evaluating the role of anti-PD1 agents in the neoadjuvant setting prior to cytoreductive nephrectomy in treatment-naive patients with metastatic clear cell renal cell carcinoma (mccRCC). We performed multi-omic analyses to resolve spatial heterogeneity and temporal dynamics in putative biomarkers of response to anti-PD1 blockade. Methods In a single center study, patients received nivolumab (3mg/kg every 2 weeks) pre- and post-operatively until progressive disease (PD). Primary endpoint was safety, secondary endpoints were response evaluation and exploratory biomarker analysis. Multiregion tumour biopsies were obtained at baseline, on-treatment (week 9) and at PD. Whole-exome sequencing was performed to infer somatic mutations and predict candidate neoantigens (NAs). Tumour immune microenvironment was evaluated using a RNA-seq-derived immune signature and by stromal and intraepithelial tumour infiltrating lymphocytes (TILs) assessments. Results 15 patients were treated. At median follow-up of 12.5 months(m), nivolumab had an acceptable side-effect profile. Overall response rate was 37%. Preliminary transcriptome analyses of pre-treatment biopsies (33 samples from 14 patients; up to 4 regions per case) revealed enrichment for primary-resistance (defined as PD within 2m; n = 4) with immune ‘cold’ tumours, distinct from ’hot’ tumours. Histologic TILs scoring showed concordant immune phenotypic clusters. Primary-resistant cases demonstrated 0% on-treatment stromal- and IE-TILs (2 evaluable patients). In contrast, we observed heavy on-treatment stromal TILs (70-90%) and intraepithelial TILs (30-90%) across 7 regions at nephrectomy in an exceptional responder receiving ongoing treatment (>24 cycles). Conclusions ADATPeR is the first neoadjuvant immune checkpoint inhibitor study pre-cytoreductive nephrectomy, and incorporated multi-omic analyses of putative biomarkers. Baseline immune gene expression signature is distinct in responders compared with non-responders. On-treatment intraepithelial TILs were prominent in those deriving durable clinical benefit. Integrative analyses are ongoing. Clinical trial identification NCT02446860. Legal entity responsible for the study The authors. Funding Bristol-Myers Squibb; The National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research; Cancer Research UK (CRUK). Disclosure All authors have declared no conflicts of interest.

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.

Hemophilic arthropathy (HA) contributes the greatest morbidity and cost in the hemophilic population. Imaging plays a crucial role in accurately monitoring the disease process in all phases and evaluating treatment. It has been shown that prophylactic factor VIII replacement therapy, if given early in life, can prevent or delay the progression of HA and reduce the frequency of hemarthroses. This review evaluates the role of the different imaging modalities used in the staging of HA. It is noteworthy that a new refined consensus magnetic resonance imaging scale for assessment of HA has recently been published which together with introduction of semiquantitative scoring systems in ultrasound will help to provide a more tailored approach to the management of HA in the future.

Aim Repeated needle punctures of arteriovenous hemodialysis grafts can lead to the development of pseudoaneurysms. As they enlarge, graft pseudoaneurysms are associated with significant morbidity and require treatment. We present our single-center experience using stent grafts in selected patients to exclude symptomatic hemodialysis graft pseudoaneurysms. Materials and Methods Between March 2007 and December 2010, 11 consecutive patients (7 men and 4 women, mean age 57 years) underwent percutaneous endovascular repair of symptomatic hemodialysis access graft pseudoaneurysms. Indications for treatment were rapidly enlarging pseudoaneurysm in 5 patients, high venous pressures, limb edema and pseudoaneurysm in 3, skin breakdown over the pseudoaneurysm site in 2 and acute rupture and bleeding in 1 patient. No patient was lost to follow-up. Results Technical success across the 11 patients was 90.9%. The patient who presented with rupture required ligation of the access due to continuous bleeding after stent graft insertion. Balloon angioplasty of a separate hemodynamically significant stenosis at the time of stent graft insertion was performed in 7 of 11 (63.6%) patients. The primary access patency rates were 72.7% (95% CI of 0.390-0.939) at 3 months and 36.4% (95% CI 0.109-0.692) at 6 months. Secondary access patency rates were 72.7% at 6 months (95% CI 0.233-0.832). There were no procedure-related complications. Mean follow-up was 9 months (range 2-29 months). Conclusions Endovascular treatment of symptomatic hemodialysis graft pseudoaneurysms is safe and effective with similar patency rates to surgical approaches. Importantly, this approach allows aggressive management of associated access circuit stenoses at the same time and avoids interval tunneled dialysis line insertion.

Despite stratification of only RAS wt CRCs for anti-EGFR antibody (aEa) therapy, many patients (pts) do not benefit and the molecular resistance (res) landscape remains incompletely understood. In order to decipher novel res mechanisms, we treated 40 RAS wt CRCs with single-agent aEa in a prospective trial and applied exome- and RNA-Seq to biopsies (bx) taken at baseline (BL) and at progression (PD). Among 20 BL bx from tumors with primary progression, 7 showed BRAF V600E mutations (mut), 3 harbored noncanonical BRAF D594K and/or KRAS L19F/A18D mut or KRAS amplifications (amp), 1 had a MEK1 mut and 1 was ERBB2 amp. Inactivating mut of the NF1 gene, a negative regulator of RAS, were found as novel mechanisms of primary res in 2 pts. No genetic drivers of primary res could be identified in 6/20 bx. Using transcriptomic analysis, 78% of pts with prolonged clinical benefit (≥16wks) displayed the Transit-Amplifying (TA) molecular subtype (Sadanandam et al., 2013). Stem-like (SL), goblet and inflammatory subtypes predominated (75%) among primary progressors. This significant enrichment in aEa sensitive CRCs (p=0.017) validates the TA subtype as a predictive biomarker. Exome- and deep Seq of PD bx from 13 pts who acquired res after prolonged clinical benefit detected KRAS mut or amp in only 2 cases. The FGFR2 ligand FGF10 was amplified in 1 PD bx and was validated in vitro as a novel mechanism of acquired res. No mut/amp of genes to which aEa res is usually attributed (RAS/RAF, EGFR, MET, ERBB2, MEK1) were found in the remaining 10 PD bx. Ultra-sensitive circulating tumor DNA-Seq at PD in 7 of these pts detected EGFR exodomain and RAS mut, including parallel evolution of multiple mut, in 3 cases. However, comparison to truncal TP53/APC mut showed that these res drivers were confined to small subclones and could therefore not explain the bulk of res. Overall, aberrations of RAS/RAF-pathway members and regulators were less abundant as drivers of acquired aEa res in this prospective trial than in reported retrospective series. Hence, we suspected additional novel mechanisms of acquired res. Molecular subtype switching from the aEa sensitive TA subtype to the comparatively insensitive SL subtype occurred in paired BL/PD bx from 3/7 pts who progressed after prolonged aEa benefit without detectable genetic res drivers in PD bx. Subtype switching was not observed in any of 6 analyzed BL/PD pairs from primary progressors. Considering the strong association of aEa sensitivity with TA subtype at BL, these data suggest subtype switching from TA to SL as a novel mechanism of acquired aEa res. This prospective trial revealed novel genetic (NF1 mut, FGF10 amp) and likely transcriptomic (TA to SL subtype switching) mechanisms of aEa resistance in CRC. These results should enable more precise aEa therapy stratification and may open opportunities to prevent res through SL subtype targeting strategies. Citation Format: Khurum Hayat Khan, Andrew Woolston, Georgia Spain, Louise Barber, Yatish Patil, Beatrice Griffiths, Reyes GonzalezExposito, Sonia Mansukhani, Matthew Davies, Sheela Rao, David Watkins, Francesco Sclafani, Jana Suntharanathan, Clare Peckitt, Ruwaida Begum, Isma Rana, Janet Thomas, Jacqui Oates, Annette Bryant, Andrew Wotherspoon, Nicos Fotiadis, Nasir Khan, Sebastian Guettler, Katharina von Loga, Naureen Starling, Ian Chau, Anguraj Sadanandam, David Cunningham, Marco Gerlinger. Molecular subtypes and novel genetic mechanisms of primary and acquired anti-EGFR resistance in colorectal cancer in the Prospect C biomarker trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4339.

401 Background: Microwave (MWA) and radiofrequency (RFA) ablation are commonly used for the treatment of unresectable liver metastases from colorectal cancer (CRC). MWA has a few theoretical advantages over RFA (active heating, less affected by heat sink effect, larger ablation zones, faster) however limited data exists on this field. Our aim was to analyse the safety and efficacy of MWA and RFA in the treatment of CRC liver metastases. Methods: All patients with unresectable CRC liver metastasis who were treated with RFA or MWA in a single center between March 2006 and December 2016 were included. Medical records and imaging studies were reviewed retrospectively for demographic data, to assess for local tumour recurrence and overall survival and to evaluate ablation-related adverse events. Results: 456 ablations were performed in 193 patients (123 men) with a median age of 66 (range 32-91). The majority of patients had a history of surgery of the primary tumour (n=170, 88,1%) and systemic chemotherapy (n=183, 94,8%). 68 patients had a history of liver surgery (35,2%). RFA was used in 343 procedures (75,2%) and MWA in 113 (24,8%). Median number of procedures per patient was 2 (range 1-10). Median lesion size was 17mm (range 3-80mm). Mean follow-up per lesion was 2.0 years in the RFA group and 1.3 years in the MWA group. Local tumour recurrence rate was 45% for RFA and 28% for MWA, with a hazard ratio of 0.6 in favour of MWA (95% CI 0.4-0.9). Two and five year overall survival rates from diagnosis of liver metastasis were 88% and 35% for RFA and 89% and 66% for MWA, respectively. Complications were reported in 43 of 456 procedures (9,4%); In 8,2% of RFAs (n=28) and 13,3% of MWAs (n=15). Complications classified as CTCAE grade 3 or higher were: haemothorax requiring surgery (n=1 for RFA), biloma (n=2 for RFA & MWA), biliary stricture (n=2 for RFA and n=1 MWA), liver failure (n=2 for RFA), liver abscess (n=1 RFA), pneumonia (n=2 for RFA) and pulmonary embolism (n=1 RFA). Segmental portal vein occlusion was only seen with MWA (n=2; 1,8%). One patient died due to multi-organ failure post RFA. Conclusions: MWA could achieve better local tumour control compared with RFA in the treatment of CRC liver metastasis, with slightly higher complication rate.

246 Background: Percutaneous biopsy of suspected liver metastases is a common practice for diagnostic purposes. Particularly, in the setting of oncological clinical trials, it is a relatively non-invasive method to obtain sufficient tissue for molecular analyses at regular set time points. However, various complications may occur, including seeding of the tumour along the biopsy tract. Only few reports exist on the actual incidence of seeding, on a limited number of tumor types. The aim of this study was to evaluate the technique’s safety and risk of seeding. Methods: All patients with an ultrasound or CT-guided liver biopsy between 2012-2016 were included. Medical records were reviewed retrospectively for post-biopsy complications and all follow-up imaging was re-assessed for the presence of seeding, defined as tumoral deposits in the biopsy needle tract. Results: In total 782 biopsies were performed in 550 patients (282 women, 268 men; mean age of 61 years), 43.9% (343/782) for trials and 56.1% (439/782) for diagnostic/molecular purposes, 93.7% (733/782) were diagnostic, revealing malignancy in 96.9% (710/733). Number of biopsies per patient ranged between 1 (n=387) to 7 (n=1), a co-axial system was used in 70.6% (552/782) and multiple passes in 29.4% (230/782). Complications were reported in 8.8% (69/782), more often pain (4.7%) and hypotension/vasovagal (2.3%). Admission and/or re-intervention were needed for more severe complications as bleeding (1.0%), sepsis/fever (1.1%), pulmonary embolism (0.3%) and pneumothorax (0.4%). Seeding was seen in 1.1% (8/782) of cases (2/44 melanoma, 1/11 GIST, 1/39 cholangiocarcinoma, 1/247 colorectal, 1/14 oesophagus, 1/97 breast, 1/31 prostate). Mean time for seeding was 208 days (range 43-469 d); mean post-biopsy survival time was 495 days in the seeding and 349 days in the non-seeding group. Conclusions: Percutaneous liver biopsy is a highly effective and safe method for tissue collection, with only a minimal risk of seeding.

Covered or uncovered self-expanding metal stents are currently used for the palliative treatment of neoplastic esophageal obstructions or compressions and malignant esophageal leaks or fistulas. This small series, from three different European hospitals, highlights the unusual but significant complication of esophageal stent perforation followed by erosion and prolapse of the endoprosthesis into the tracheobronchial tree causing acute airway compromise or aspiration. Possible causal mechanisms and means of treatment are discussed to raise physician awareness of this life-threatening complication.

Radiofrequency ablation (RFA) is an increasingly used minimally invasive treatment option for patients with pulmonary metastatic disease or inoperable non-small-cell lung cancer. We describe a case of RFA in a female patient who underwent multiple ablation sessions for pulmonary metastatic disease. The case highlights some of the issues regarding lesion suitability for RFA, technical considerations, and potential complications. In our experience RFA is an effective treatment option when applied to appropriately selected patients. Careful follow-up is critical for early detection of incomplete treatment or recurrence.

Interventional radiology uses image guidance to perform minimally invasive therapeutic and diagnostic procedures. It is an integral part of the multidisciplinary team managing patients with cancer. Interventional radiology is involved in all stages of the cancer patient’s journey starting from performing image-guided biopsies for the diagnosis of cancer, venous access procedures, and therapeutic procedures, and focuses on the palliation of symptoms and improvement in the quality of life. All interventional procedures carry some risk, which is related to the underlying condition, the nature of the procedure, and the experience of the radiologist. Therefore, it is important in patients with advanced malignant disease receiving palliative care to contemplate only those procedures that will alleviate symptoms, and in which the potential benefits outweigh the risks. This chapter presents the drainage, stenting, feeding, embolization, ablation, and supportive interventional radiology procedures which could potentially benefit patients undergoing palliative care. The focus will be on the indications, contraindications, and likely outcomes, rather than on detailed technical descriptions.

613 Background: REG demonstrated efficacy in pre-treated mCRC pts. Lack of predictive biomarkers, potential toxicities and cost/effectiveness concerns highlight the unmet need for better patient selection. Methods: RAS mutant mCRC pts with biopsiable metastases were enrolled in this phase II trial. Tissue biopsies (6-12 cores) were obtained at baseline (BL), after 2 months if stable disease (SD) and at disease progression (PD). Dynamic contrast enhanced (DCE) MRI was acquired pre and at day 15 post-treatment. Median values of volume transfer constant (Ktrans) and enhancing fraction (EF) [K-trans*EF/100] were generated. Circulating tumour (ct)DNA was collected monthly until PD and tested for clonal RAS mutations by digital droplet PCR. PDOs derived from responders and non-responders pts were implanted orthotopically in the liver of mice and treated with REG for 5 days. Changes in tumour and fractional blood volume (fBV) were monitored by oxygen-enhanced MRI. Results: mCRC pts (n = 27) with paired MRI scans were analysed; a single target lesion per pt was chosen (25 liver and 2 pelvic metastases). Median K-trans*EF/100 product decrease was 58.2%. In the 23 analysable pts (4 received < 1 cycle of treatment due to toxicities), > 70% drop in K-trans*EF/100 (8/23) was associated with higher disease control rate (6/6 vs. 0/6, p = 0.048) measured by RECIST 1.1 at 2 months, improved progression free survival (PFS) [HR = 0.24 (0.07-0.86), p = 0.03], and 4-month PFS (58.3% VS 21.2%). Sequential tissue biopsies analysis confirmed reduction in CD31 in pts with K-trans*EF/100 drop. RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS [HR = 0.25 (0.08 - 0.83), p = 0.02] independently of K-trans*EF/100 drop. PDOs xeno-transplants treated with REG compared to controls had significant lower tumour fBV (4.5 VS 10.6, p = 0.03) and lower microvascular density measured by CD31 staining (4.3 VS 8.9, p = 0.02). Conclusions: Combining DCE MRI and ctDNA predicts depth and duration of anti-angiogenic response to REG monotherapy and may improve pt selection with potential health/economic implications. Clinical trial information: 201400357951.

TPS4583Background: Cytoreductive nephrectomy may be beneficial in patients with metastatic clear cell renal cell carcinoma (mccRCC). However, there are currently no standard pre-operative systemic ...

580 Background: REG that has single agent efficacy in patients (pts) with refractory mCRC, is known to have anti-angiogenic activities. The benefit of REG in unselected pts is modest. Thus, the identification of predictive biomarkers is critical for treatment stratification. PROSPECT-R study aims to identify genetic and radiological mechanisms of primary and acquired REG resistance in RAS mt mCRC patients. Methods: Multiparametric MRI studies including dynamic contrast enhancement (DCE)-MRI and diffusion weighted imaging (DWI) were acquired pre- and at day 15 post-treatment on a 1.5T Siemens Avanto MR scanner. Regions of interest of the entire chosen target metastatic lesion were drawn by a senior radiologist and the following imaging parameters were generated: volume transfer constant (Ktrans) derived from a pharmacokinetic analysis based on the extended Kety model and apparent diffusion coefficient (ADC) calculated using a mono-exponential fitting algorithm; median values of ADC and Ktrans were reported. Results: The first seven enrolled pts were analysed; a single target lesion per patient was chosen (5 liver and 2 pelvic metastases). At day 15 post treatment, a marked decrease (68-81%) of median tumour Ktrans was observed in 4 out of 7 pts; the remaining 3 patients showed no significant median Ktrans change (-36 to + 17%). Overall, the cohort average Ktrans decreased from 0.17 to 0.07 min-1(58%). No significant ADC changes were observed at day 15. Of the 4 pts with Ktrans reduction on day 15, 1 achieved RECIST 1.1 partial response (38% reduction in target lesions), 2 had stable disease and 1 progressed, based on CT assessments performed at 8 weeks of REG therapy; 3/7 pts with no Ktrans change progressed within 2 months of initiating REG. When modified Choi criteria were applied, 3/4 pts with Ktrans reduction were classified as responders. Conclusions: REG may have early anti-angiogenic affects; DCE-MRI could be a potential predicting biomarker in pts treated with REG. Further analysis within PROSPECT-R may elucidate genetic biomarkers to validate these findings. Clinical trial information: EUDRACT No: 2014- 003579-51.