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Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAM, Background We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). Patients and methods VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and 1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. Results Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. Conclusions BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy, This work was supported by Roche Farma S.A (no grant number). Medical writing support was funded by Roche Farma S.A and provided by H. Lamb and L. Miller of Miller Medical Communications Ltd.

Aflibercept; Càncer colorectal; Perfil del pacient Aflibercept; Cáncer colorrectal; Perfil del paciente Aflibercept; Colorectal cancer; Patient profile Colorectal cancer is the second leading cause of cancer-related death worldwide. For metastatic colorectal cancer (mCRC) patients, it is recommended, as first-line treatment, chemotherapy (CT) based on doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX). In addition to CT, biological (targeted agents) are indicated in the first-line treatment, unless contraindicated. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. It is in this second line setting where Aflibercept offers an alternative and effective therapeutic option, thought its specific mechanism of action for different patient’s profile: RAS mutant, RAS wild-type (wt), BRAF mutant, potentially resectable and elderly patients. In this paper, a panel of experienced oncologists specialized in the management of mCRC experts have reviewed and selected scientific evidence focused on Aflibercept as an alternative treatment.

Background Genotyping of ctDNA characterizes the molecular profile and monitors tumor molecular dynamics, but the clinical applicability of next generation sequencing (NGS) DNA sequencing has not been assessed in a large prospective cohort of mCRC patients (pts). Methods mCRC pts with RAS wt tumors treated in first line with chemotherapy (CT) + cetuximab in 16 Spanish hospitals were included. Plasma samples were collected baseline (BL) and every 2 cycles until progression. ctDNA was isolated and sequenced with NGS platform Oncomine Colon cfDNA Assay which identifies hotspot mutations (mut) in AKT1, BRAF, CTNNB1, EGFR, ERBB2, FBXW7, GNAS, KRAS, MAP2K1, NRAS, PIK3CA, SMAD4, TP53 and APC. RAS ctDNA mut were also assessed by dPCR (BEAMing) at BL. Detection of any mut in plasma was considered as ctDNA+. Mut in BRAF/RAS/MAP2K1/PIK3CA were considered as anti-EGFR resistance. Results 101 pts were enrolled (65.3% male; median age 64.5y; 77.6% left colon). RAS mut were detected in 11 pts BL by BEAMing. After quality assessment, 84 samples were sequenced by NGS BL and at least one mut was detected in 65 samples (77.3%; median 1, range 0-5) and 10 RAS mut were detected. Plasma samples from 47 pts were also analyzed after 4 cycles of treatment (C4) and mut were detected in 30 pts (63.8%; median 1, range 0-3). Median mutant allele fraction for paired samples was 24.9 at BL and 0.56 at C4 (p = 0.0045). Treatment clinical benefit (CB: PR, CR and SD ≥ 16weeks) was observed in 72 out of 85 pts. BL ctDNA+ or C4 ctDNA change were not associated with CB (p = 0.722). Assessment of RAS BL mut was not associated with CB (p = 0.243 by NGS and p = 0.712 by BEAMing), while the absence of RAS mut at C4 predicted treatment CB (93.2% vs. 6.8% RAS mut p = 0.02). Median PFS for all pts was 10.13 month. ctDNA+ at BL or C4 were not correlated with PFS (HR 0.8; p = 0.73). No differences in PFS were found in ctDNA RAS mut vs RAS wt BL (BEAMing+ HR = 1.2 p = 0.79 and NGS+ HR = 2.6 p = 0.052). Among all anti-EGFR resistant mut, only ctDNA RAS mut were detected at C4 (N = 4). Persistence or emergence of RAS mut at C4 were strongly associated with PFS (12.9m vs. 4.2. HR 8.8 p = 0.0003). Conclusions Early RAS ctDNA dynamics predicts benefit to first line CT+cetuximab in mCRC pts. Legal entity responsible for the study Grupo de Tratamiento de los Tumores Digestivos (TTD), Spain. Funding Merck-Serono. Disclosure J. Vidal Barrull: Honoraria (self), Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Amgen; Honoraria (self): Sysmex-Inostics. E. Elez Fernandez: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Sanofi. F. Losa: Honoraria (self): Amgen; Honoraria (self): Merck-Serono. R. Salazar: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Guardant-Helth; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Ferrer; Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD. J. Tabernero: Honoraria (self), Advisory / Consultancy: Array Biopharma; Honoraria (self), Advisory / Consultancy: Merck-Serono; Honoraria (self), Advisory / Consultancy: Molecular Partners; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Foundation Medicine; Honoraria (self), Advisory / Consultancy: Halio DX SAS. E. Aranda Aguilar: Honoraria (self): Celgene; Honoraria (self): Merck-Serono; Honoraria (self): Roche; Honoraria (self): Sanofi. B. Bellosillo: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Biocartis; Advisory / Consultancy: Novartis; Advisory / Consultancy: Thermofisher. C. Montagut Viladot: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck-Serono; Advisory / Consultancy: Sysmex-Inostics; Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Biocartis; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Guardant-Helth; Advisory / Consultancy: Symphogen. All other authors have declared no conflicts of interest.

Aims To prove if there is clinical inertia in the identification and treatment of episodes of breakthrough cancer pain (BTcP), comparing actual results from clinical practice with clinical oncologists’ prior perception. Design Observational and descriptive study, using information collected by practising medical oncologists, at three moments: (a) questionnaire regarding their professional judgement of the handling of patients with BTcP in their practice, (b) cross-sectional clinical screening, to detect possible existing cases of BTcP in a representative sample of their patients, (c) retrospective self-audit of clinical case histories of patients diagnosed with BTcP to find out about how it has been handled. Participants and study period A random sample on a state level of 108 specialists in medical oncology. 540 patients who suffer some type of cancer pain on the designated study date for each specialist (July–December 2016). Results The global prevalence of BTcP in the study sample covered 91.3% of the patients who were suffering some type of cancer pain. Barely 2% of the doctors surveyed suspected figures around this mark. 40.9% of the cases had not been previously detected as BTcP by their doctors. Although 90% of the patients who had previously been diagnosed with BTcP received a specific analgesic treatment for the symptoms, 42% of those patients with known BTcP were not able to control their episodes of pain. Conclusions Clinical inertia is a serious problem in the handling of BTcP in medical oncology services, where it is the subject of a significantly low level of detection and treatment, despite the contrasting perception of specialists. pre-print 339 KB

[Purpose]: Breakthrough cancer pain (BTcP) has been shown to be a prevalent and poor prognostic factor for oncologic patients, which remain under diagnosed and undertreated. In 2012, the Spanish Society of Medical Oncology (SEOM) published a clinical practice guideline (CPG) for the treatment of cancer pain which specifically addressed the management of BTcP., [Methods]: Fundación ECO designed a qualitative study using an Internet-based survey to investigate the attitudes toward, compliance with, and use of SEOM Guideline., [Results]: A total of 83 oncologists with a mean experience of 13 years responded. Overall, 82% were aware of different guidelines to manage BTcP. Notably, attitudes toward guidelines were highly positive and there was nearly unanimous agreement that CPG provided the best scientific evidence available (99%), on the minimum information to be gathered for the medical history (100%), on the need for a specific treatment for BTcP (100%), and fentanyl as the first-choice drug (99%). Interestingly, there were discrepancies between what oncologists agreed with and what they do in clinical practice. In fact, 87.6% declare full compliance with SEOM guideline, although adherence to registration of BTcP data in medical records ranged from 30.1 to 91.6% (mean 64.5%); therapeutic management compliance was higher ranging from 75.9 to 91.6%. Main barriers identified were time pressure together with vague statements and limited dissemination of the guidelines., [Conclusion]: Despite oncologist’s clinical practice is increasingly guided by GPC, it suffers from limited compliance, at least in part due to suboptimal statements. Improved dissemination and education are needed to enhance guideline implementation., This study was funded by Kyowa Kirin Farmacéutica S. L.U. through Fundación ECO.

Background So far, no biomarkers of response to anti-angiogenic drugs are available in colorectal cancer (CRC) treatment. Liquid biopsy technique identifies actionable targets in CRC patients (pts), tracking dynamic mutational changes. We and others described RAS mutant allele fraction in plasma (plMAF) as an independent prognostic marker in metastatic CRC (mCRC). Here, we explored the predictive value of plMAF in RAS mutant pts treated in first line with chemotherapy +/- bevacizumab (bev). Methods A multicentric prospective/retrospective analysis was conducted. We collected data from 226 mCRC pts and selected the subset not eligible for metastasis resection that had basal plMAF sample evaluable for RAS mutant MAF quantification using digital PCR (BEAMing). Pts were stratified as high (≥ 5.8%) or low ( Results From October 2017 to May 2019, BEAMing analysis from 62 basal plasma samples was performed. 42 pts (67.7%) were classified as high and 20 pts (32,3%) as low plMAF. Among high RAS plMAF, 24 pts received FOLFOX+bev (57%) and 20 pts FOLFOX alone (43%). In this high plMAF subgroup, a statistically significant longer PFS favouring FOLFOX+bev was observed when compared to FOLFOX alone (10.7 versus 6.9 months, respectively; HR: 0.30; p = 0.002). In the low RAS plMAF subgroup, no differences in terms of PFS were observed in either arm (8.9 versus 8.7 months, respectively; HR: 0.70; p = 0.6). Multivariate PFS model showed no association between RAS plMAF and clinicopathological variables, except for high RAS plMAF and treatment benefit with FOLFOX+bev. Conclusions Our results indicate that tumor-borne RAS plMAFs may constitute a potential predictive biomarker of efficacy for anti-angiogenic agents in mCRC. Confirmatory studies in randomized cohorts will be performed. Legal entity responsible for the study VHIO (Vall d’Hebron Institute of Oncology). Funding AECC (Asociacion Espanola Contra el Cancer). Disclosure G. Martini: Research grant / Funding (self), Research Project supported by ESMO with the aid of a grant from Amgen: ESMO-AMGEN. E. Elez: Honoraria (self): Merck Serono; Honoraria (self): Sanofi; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Servier; Honoraria (self): Amgen; Honoraria (self): Array. G. Argiles Martinez: Honoraria (self), Honoraria (institution), Research grant / Funding (self), Travel / Accommodation / Expenses: Hoffmann-LaRoche, Bristol-Myers Squibb, Bayer, Servier, Amgen, Merck Serono, Menarini; Honoraria (self): Menarini; Honoraria (institution): Boston Pharmaceuticals; Honoraria (institution): Genentech; Honoraria (institution): Boehringer Ingelheim. M.J. Ortiz Morales: Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert Testimony: Sanofi. P.G. Nuciforo: Honoraria (self): BAYER; Honoraria (self): MSD; Honoraria (self): Novartis. R. Dienstmann: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Symphogen, Ipsen, Amgen, Sanofi, MSD, Servier; Research grant / Funding (self): MERCK. J. Tabernero: Advisory / Consultancy: Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Part. E. Aranda Aguilar: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merck; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi. A. Vivancos: Advisory / Consultancy: sysmex; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck; Advisory / Consultancy: Bristol-Meyers Squidd; Advisory / Consultancy: Guardant Health. All other authors have declared no conflicts of interest.

Background Biomarkers associated to antiangiogiogenic agents in metastatic colorectal cancer (mCRC) have not yet been validated Here we present the efficacy and safety results of FOLFIRI and aflibercept in second line therapy for mCRC and the analysis of biomarkers as predictive factors of efficacy. Methods POLAF is a multicenter, non comparative, phase II study conducted in patients with mCRC previously treated with oxaliplatin (NCT02970916) Plasma biomarkers were assayed using ELISA Vascular endothelial growth factor (VEGF A) and angiotensin-converting enzyme (ACE) biomarkers were statistically analyzed (Roc Curve) with respect to the primary endpoint (PE): progression free survival (PFS) (Kaplan Meier). Results Between November 2016 and December 2017, 101 patients for the PE were enrolled: male 59.4%, median age of 63.8 years and ECOG 0 in 46.5% of them The median of treatment duration was 5.7 months. Later antitumor therapies were received by 54.5% pts With a median follow up of 11.7 months, response rates were: PR 15.8%, SD 53.5% and PD 25.7%. The median OS, PFS, TTP and to TTF were 12.6, 7.4, 8.3 and 6.1 months, respectively Of note, both OS and PFS were significantly longer in pts with lower plasma VEGF A levels ( Table . 585P Cut off a PFS OS VEFG-A 9.2 (8.4-10) 18.9 (14.8-23) ≥1.941 4.2 (2.7-5.6) 7.6 (4.5-10.7) p ACE 8.8 (7.4-10.3) 15.2 (9.4-21.1) ≥135 6.8 (3.7-10) 11.7 (9.0-14.5) p = 0.103 p = 0.889 a Optimal point that maximizes sensitivity and specifity (ng/ml). Conclusions This study confirms the efficacy outcomes of FOLFIRI/aflibercept regimen in second line mCRC Our data shows that VEGF-A could be related to the survival of this population and its role as a potential predictive biomarker for efficacy should be considered. Legal entity responsible for the study The authors. Funding Sanofi. Disclosure M.E. Elez Fernandez: Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Sanofi; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self): Servier; Honoraria (self), Honoraria (institution): Array; Honoraria (institution): Novartis; Honoraria (institution): Boehringer Ingelheim; Honoraria (institution): MSD; Honoraria (institution): Servier; Honoraria (institution): Bayer; Honoraria (institution): GSK; Honoraria (institution): Pharmamar. B. Grana Suarez: Research grant / Funding (self): Sanofi; Research grant / Funding (self): Gilead; Research grant / Funding (self): Amgen. M. Valladares-Ayerbes: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AMGEN; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Servier; Honoraria (self), Speaker Bureau / Expert testimony: Bayer; Honoraria (self): BRISTOL; Advisory / Consultancy: Sanofi. M. Salgado Fernandez: Travel / Accommodation / Expenses: Sanofi. E. Martinez de Castro: Speaker Bureau / Expert testimony: Sanofi. A. Ruiz-Casado: Honoraria (self), Research grant / Funding (self): Sanofi; Honoraria (self): Amgen; Honoraria (self): Merck; Honoraria (self): Lilly; Honoraria (self): Servier; Honoraria (self): Roche; Honoraria (self): Medtronic; Honoraria (self): BTG; Honoraria (self): Bayer. E. Aranda Aguilar: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merck Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi. All other authors have declared no conflicts of interest.

Background In 2017, the ECO Foundation (Excellence and Quality in Oncology) completed the EIO-50 project to learn about the diagnostic and treatment criteria of opioid-induced constipation (OIC) in cancer patients. The EIO-Praxis project was designed as a continuation of EIO-50, to learn about the current clinical practice of oncology professionals for the management of patients with OIC (process, follow-up and results). Methods 77 health care professionals (HCP) from oncology units participated in the study. Each investigator collected information from 10 medical records of cancer patients who received OIC treatment, with a total of 770 records. In each center, 6 indicators of its structure were collected and the completion of a questionnaire with 15 questions regarding patient’s follow-up and treatment process was conducted. Results According to healthcare professionals (HCP), an average proportion of 47.5% of cancer patients received treatment with opioids. From these, an average of 44.9% developed OIC. 51.9% of the investigators didn’t follow any guidelines for the management of patients with OIC. The mean age of the patients of the study was 61.6 years old. The mean duration of opioid treatment was 4.9 months, with an average time of 16.5 days from the start of opioid treatment to the appearance of the first symptoms of OIC. Only in 55.1% of the patients, the presence of functional constipation before starting opioid treatment was assessed. Patients of the study presented the following Rome IV criteria symptoms: 82.6% reduced bowel frequency, 52.9% fewer than three spontaneous bowel movements per week, 54.4% development or worsening of straining and stool consistency (54.2%). The majority of the patients were treated with laxatives (76.0%). Oral Peripherally Active µ-Opioid Receptor Antagonist (PAMORA) was also used in 54.8% of the patients. Conclusions Despite new guidelines for the management of constipation in cancer patients were published in 2018, the management of OIC is still insufficient. After laxative failures, the use of PAMORA drugs should be taken into consideration for the management of OIC. Legal entity responsible for the study ECO Foundation. Funding Kyowa Kirin. Disclosure E. Aranda Aguilar: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merck; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi. J. Garcia Foncillas: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Research grant / Funding (institution): Merck. E. Diaz Rubio: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Genomica; Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Speaker Bureau / Expert testimony: MSD; Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Sysmex. R. Lopez: Shareholder / Stockholder / Stock options, Licensing / Royalties: Nasasbiotech; Shareholder / Stockholder / Stock options: Mtrap Inc; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: Janssen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Pierre Fabre. All other authors have declared no conflicts of interest.

Background The AVANT study did not demonstrate disease-free survival (DFS) benefit of the addition of bevacizumab to oxaliplatin-based chemotherapy in stage III resected CC and suggested a potential detrimental effect on overall survival (OS) (A. de Gramont et al. Lancet Oncol. 2012). Here, we present the results of the AVANT study for stage II CC patients. Methods The primary endpoint of AVANT was DFS for stage III disease. As an exploratory measure, AVANT also included high-risk stage II CC defined by T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age Results 573 patients had stage II CC (arm A: FOLFOX4, n = 192; arm B: FOLFOX4-bevacizumab, n = 194; arm C: XELOX-bevacizumab, n = 187), of whom 38 (19.8%) in arm A, 36 (18.6%) in arm B, and 40 (21.4%) in arm C had relapsed, developed a new CC, or died after a median follow-up of 6.86 years (IQR: 6.13-11.34). The DFS hazard-ratio was 0.94 (95% CI 0.59-1.48; P = 0.78) for arm B vs arm A and 1.07 (95% CI 0.69-1.67; P = 0.76) for arm C vs arm A. The OS hazard ratio was 0.92 (95% CI 0.55-1.55; P = 0.76) for arm B vs arm A and 0.85 (95% CI 0·50-1.44; P = 0.55) for arm C vs arm A. Safety data of stage II and stage III CC have been reported previously. In multivariable analysis, T4 vs T3-1 (P = 0.041), number of examined nodes (P = 0.005), and age (P = 0.0008) were prognostic for DFS. The 3-year DFS and 5-year OS rates of stage II were 88.2% (95% CI 83.7%-93.0%) and 89.7% (95% CI 85.4%-94.2%) in arm A, 86.6% (95% CI 81.8%-91.6%) and 89.7% (95% CI 85.4%-94.2%) in arm B, 86.7% (95% CI 81.8%-91.8%) and 93.2% (95% CI 89.6%-97.0%) in arm C, respectively. Conclusions In this exploratory analysis, bevacizumab did not prolong DFS and OS when added to adjuvant oxaliplatin-based chemotherapy in resected high-risk stage II patients with CC. Clinical trial identification NCT00112918. Editorial acknowledgement Magdalena Benetkiewicz (GERCOR). Legal entity responsible for the study GERCOR. Funding Roche. Disclosure A. De Gramont: Honoraria (self): Yakult; Honoraria (self): Chugai Pharma. T.W. Kim: Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Pfizer; Research grant / Funding (self): AstraZeneca. J. Gallego-Plazas: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: Lilly; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Novartis; Leadership role, Study Coordinator of Agamenon study in advanced gastric cancer: Agamenon study. A. Cervantes: Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Servier; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Roche Beigene; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Foundation Medicine; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Fibrogen; Research grant / Funding (institution): Amcure; Research grant / Funding (institution): Sierra Oncology; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MSD; Leadership role, Executive Board member of ESMO: not remunerated Chair of Education of ESMO: not remunerated General and Scientific Director of INCLIVA: not remunerated Associate Editor of ESMO Open: not remunerated Associate Editor of Annals of Oncology: remunerated Editor in Chief of Cancer Treatment Reviews: remunerated: Executive Board member of ESMO: not remunerated Chair of Education of ESMO: not remunerated General and Scientific Director of INCLIVA: not remunerated Associate Editor of ESMO Open: not remunerated Associate Editor of Annals of Oncology: remunerated. D.J. Jonker: Research grant / Funding (institution): Hoffman-La Roche; Non-remunerated activity/ies, Chair of the GI Disease Site Committee of the Canadian Cancer Trials Group: Canadian Cancer Trials Group. A. Dewdney: Honoraria (self), Chairing evening meetings: Servier; Honoraria (self): Roche. T. (Sirisingha) Dejthevaporn: Honoraria (self): Roche; Honoraria (self): Eisai; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Leadership role: Thai Society of Clinical Oncology (TSCO). M. Moehler: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. T. Andre: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD Oncology; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Ventana; Honoraria (self): Sanofi; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self): Chugai; Honoraria (self): Yakult; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: HalioDx. All other authors have declared no conflicts of interest.

Contains fulltext : 165965.pdf (Publisher’s version ) (Closed access) Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.

Background: LEA Study (GEICAM/2006-11/GBG51), is a randomized clinical trial comparing bevacizumab in combination with endocrine therapy (ET + B) with endocrine therapy (ET) in postmenopausal women with advanced or metastatic HR-positive/HER2-negative breast cancer (BC) with indication of hormonotherapy as first-line treatment. Patients with secondary hypertension had better progression-free survival (PFS) and overall survival (OS). We have evaluated the role of two hypertension-related biomarkers, Angiotensin-Converting Enzyme (ACE) and Small-Inducible Cytokine B10 (CXCL10) as prognostic and/or predictive biomarkers of benefit to bevacizumab in the first line metastatic disease. Methods: From 380 patients, 266 were included in 33 Spanish sites. Median age was 64 years, 63.5% had measurable disease, 97.4% were metastatic at randomization, 51.5% had visceral disease and 52.6% received previous chemotherapy. PFS was 14.3 months (range 0.8-61.1), OS was 34 months (range 0.8-71.6) and 93 patients had Objective Response (OR). We analyzed 124 plasma samples collected before treatment (52 from ET and 72 from ET + B arms). Circulating levels of ACE and CXCL10 were determined by ELISA. ACE levels of 115ng/ml and 135ng/ml were pre-defined as cutoff values. CXCL10 was explored as a quantitative variable. Results: PFS was 15.1 months (range 1.4-61.1), OS was 31.1 months (range 2.8-61.1) and 40.3% had OR. OR was significantly different between treatment arms (p < 0.001) but not PFS or OS. Median ACE concentration was 130.9ng/ml (range 35.3-315.4). Low ACE (

592 Background: Accurate detection of RAS mutations in metastatic colorectal cancer (mCRC) patients is of high clinical importance for therapy selection as RAS detection methods lacking sensitivity may lead to poor patient outcomes. Liquid biopsy has emerged as a viable alternative to individualize the management and treatment of mCRC patients. However, there is a current need to cross-compare the performance of liquid biopsy platforms. The OncoBEAM RAS dPCR assay offers highly sensitive RAS mutation detection in clinical practice, achieving > 90% concordance when compared to results obtained by tumor mutation testing. The Idylla platform offers a highly-automated qPCR platform for RAS mutation testing of tissue samples, and has shown potential for liquid biopsy. The objective of this study was to provide a head-to-head comparison of the sensitivity of OncoBEAM and Idylla for KRAS mutation detection in plasma from mCRC patients. Methods: Plasma samples from 92 mCRC patients determined to be KRAS-positive using OncoBEAM were re-tested using Idylla. Samples with mutant allelic fractions (MAF) below 5% were selected for analysis. The positive percent agreement (PPA) of KRAS mutation results was compared for replicate samples analyzed by OncoBEAM and Idylla. Results: So far, Idylla detected KRAS mutations in 63 out of 92 (68.4%) OncoBEAM KRAS-positive plasma samples. Categorization of results based on MAF% revealed distinct differences in sensitivity between the two technologies. Conclusions: OncoBEAM demonstrated significantly greater sensitivity for plasma detection of RAS mutations than Idylla. Moreover, these data identify a “gray zone” below 1% MAF where Idylla fails to identify RAS-positivity in patient plasma samples. These findings serve as a reminder that liquid biopsy assays with diminished sensitivity may lack the dynamic range to provide accurate and timely RAS mutational status information to properly guide highly individualized anti-EGFR therapy and chemotherapy treatment decisions that may benefit patient outcomes. [Table: see text]

PUNTOS CLAVE Epidemiologia. El cancer colorrectal es la segunda causa de muerte por cancer en paises desarrollados. Su incidencia aumenta con la edad y es un importante problema de salud. Factores pronosticos. El estadio es el factor pronostico mas importante para la supervivencia. Existen otros factores clinico-patologicos que nos ayudan a establecer el pronostico. Las alteraciones moleculares se encuentran en investigacion. Clinica. Dependiendo de la localizacion tumoral y de la metastasis en el caso de que existan. Las mas frecuentes son sangrado, alteraciones del ritmo intestinal y dolor, entre otras. Diagnostico. Es importante realizar una buena anamnesis y exploracion fisica. La prueba diagnostica por excelencia en el cancer colorrectal es la colonoscopia. Es fundamental un buen estudio de extension para un correcto estadiaje. Tratamiento. La cirugia debe ser llevada a cabo por cirujanos con amplia experiencia en cirugia oncologica. Existen numerosos farmacos activos frente al cancer colorrectal que han conseguido aumentar la supervivencia y mejorar la calidad de vida. De todos ellos, el mas utilizado sigue siendo el 5-FU.

PUNTOS CLAVE Epidemiologia. El cancer de pancreas es un tumor frecuente en los paises desarrollados, que tiene muy mal pronostico * Supervivencia de 2%-5% a los 5 anos. Clinica. La presentacion clinica mas frecuente es dolor abdominal, ictericia y perdida de peso. Anatomia patologica. El 90% de los tumores exocrinos de pancreas son adenocarcinomas. Diagnostico. El estudio va dirigido a la identificacion del tumor pancreatico para lo que habitualmente se emplean tecnicas de imagen. La tomografia computarizada o la resonancia magnetica son las de mayor rentabilidad * El diagnostico histologico se realiza por puncion aspiracion o por CPRE * Es necesario en el proceso diagnostico evaluar la resecabilidad tumoral como primer paso. Tratamiento. La cirugia, cuando es posible, es el tratamiento de eleccion * La radioterapia y quimioterapia son un tratamiento local activo que mejora la supervivencia y el intervalo libre de recurrencia en determinados subgrupos de pacientes * La quimioterapia es un buen tratamiento paliativo que ha demostrado ser superior al mejor de los tratamiento de soporte * Existen otras medidas paliativas analgesicas, protesis biliares, o derivaciones quirurgicas, que mejoran la calidad de vida de los pacientes.

PUNTOS CLAVE Epidemiologia. El carcinoma gastrico es la segunda causa de mortalidad por cancer en el mundo * Es mas frecuente en paises subdesarrollados * El control de la infeccion por Helicobacter pylori ha favorecido un descenso en el numero de carcinomas gastricos distales. Factores etiologicos. El consumo de nitratos y conservas con salazon y ahumados se relaciona con una mayor incidencia de carcinoma gastrico, asi como la infeccion por H. pylori. Anatomia patologica. El 95% de los tumores del estomago son adenocarcinomas * El adenocarcinoma tipo difuso tiene una tendencia a diseminacion y metastatizacion precoz. Clinica. Los sintomas mas precoces son dolor abdominal y perdida de peso * La presencia de una ulcera gastrica que no cura con tratamiento medico debe hacernos sospechar un carcinoma gastrico. Diagnostico. La esofagogastroscopia con toma de biopsia es la principal exploracion complementaria para el diagnostico del carcinoma gastrico * La estadificacion prequirurgica se realiza con la TC toracoabdominal. Factores pronosticos. El carcinoma gastrico proximal tiene peor pronostico que el distal * El carcinoma gastrico tiene hasta un 80%-95% de recaidas locales y un 75% de recaidas a distancia * Los factores pronosticos con valor independiente son: estadio TNM y la afectacion de margenes quirurgicos. Prevencion. No fumar y cambios en la dieta ayudarian a una disminucion en la incidencia del carcinoma gastrico * El cribado con radiologia de doble contraste y esofagogastroscopia con toma de biopsia no esta indicado en Espana. Tratamiento. La cirugia con intencion curativa implica una linfadenectomia a nivel de D1 (D2 tiene un mayor indice de complicaciones y no mejora la supervivencia global) * Para una correcta estadificacion es necesario examinar = 15 ganglios * La radioquimioterapia adyuvante ha demostrado beneficio en pacientes de alto riesgo de recaida.

Aims: Combinations of surgery and chemotherapy have a favourable impact on survival in the treatment of disseminated neoplastic disease isolated to the lung. Sample and technical factors have made the reproduction of the published results difficult. Methods: In this study we report experience over 10 years. Results: From 1989 to 1999 40 patients underwent metastasectomy. Thirty received chemotherapy. The median survival is 51 months, similar to other published series. Conclusion: Survival benefit can be observed in small series of such cases.

The TTD Group is a Spanish Cooperative Group with 28 years of history investigating and developing protocols in the digestive tumor field to improve healthcare quality. In the last decade, it research has been focused on the identification of biomarkers to improve and predict treatment outcomes. The MACRO (Maintenance in Colorectal Cancer) study was a phase III study to assess maintenance therapy with single-agent bevacizumab (B) versus B plus chemotherapy (QT) in patients (p) with metastatic colorectal cancer (mCRC). A post hoc analysis of the trial investigated the prognostic value of the circulating tumor cell (CTC) count and KRAS mutation status on patient outcomes and showed that both factors were independent prognostic factors for outcomes. Based on these results, the ongoing VISNU study will screen 750 p previously untreated with mCRC according to CTC count and gene status (RAS, BRAF y PI3K). In VISNU-1 trial (NCT01640405), 350 p with ≥ 3 CTC, will be randomized to receive FOLFOX-6 + B or FOLFOXIRI + B. In VISNU-2 trial (NCT01640444), 240 p with Disclosure: E. Aranda Aguilar: Honoraria or consultation fees: Roche and Merck.

Introduction and objective Vascular development is critical in tumor biology and targeted therapies against angiogenesis process have proven their therapeutic efficacy. Neuropilin-1 (NPR1), a membrane glycoprotein that works as a receptor for semaphorins, is also a co-receptor for VEGF-A165 and it is expressed in endothelial cells and in many other tumors. Very few studies about this protein in primary and secondary tumors have been reported with contradictory conclusions1,2. The aim of this study is to analyze the relationship between the expression of NRP1 in colorectal cancer patients in primary tumor and metastases and clinical and pathologic features, treatment response, progression-free interval and overall survival. Patients and methods From 1995 to 2010, 70 patients with available biological material in paraffin of primary tumor and metastases (liver and/or lung) have been selected. NRP1 expression was performed using immunohistochemistry with neuropilin-1 Rabbit Monoclonal Antibody Catalog # 2621-1 (ATOM) at 1:75 dilution. Vascular endothelium was used as positive control and tumor sample without antibody as negative control. Clinical and pathological data of patients, treatments administered, toxicity, response, progression-free interval and overall survival were registered. Results The mean age of patients was 63 years. 51 patients (85%) were adenocarcinoma and 46 patients (76%) were moderately differentiated. 34 patients (56.7%) presented metastatic disease at the moment of primary tumor diagnosis. NRP1 expression exists in 100% (120) of samples analyzed. Conclusions In our study, in contrast to latest published data2, no differences about intensity and frequency of expression of NRP1 were found between primary and metastatic samples. It is not possible to establish any relationship between tumor response to treatment and evolution. References: 1. Parikh AA, Fan F, Liu WB, et al. Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis. Am J Pathol 2004;164:2139-51. 2. Jubb AM, Strickland LA, Liu SD, Mak J, Schmidt M, Koeppen H. Neuropilin-1 expression in cancer and development. J Pathol 2012;226:50-60. Disclosure All authors have declared no conflicts of interest.

Purpose We report the clinical results of adding bevacizumab (BEV) to preoperative chemoradiation (CRT), in patients (pts) with locally advanced rectal cancer (LARC). This pre-planned sub-study was aimed to evaluate the evolution of several biomarkers and their correlation with downstaging. Methods Patients with LARC were randomized to radiotherapy 45Gy/25f/5 weeks + capecitabine (CAP: 825mg/m/bid) + BEV every 2 weeks (5 mg/kg for 3 doses) (arm A) or the same schedule without BEV (arm B): surgery was scheduled 6-8 weeks after completing CRT. Plasma levels of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2) and angiopoietin-2 (Ang-2) were measured at baseline (d1), day 15 (d15) and day 57 (d57). Tissue samples (baseline and at surgery) were assessed for microvessel density (MVD). Comparisons between concentrations at different time points were assessed by using appropriate statistical paired tests. Logistic regression model was adopted to estimate and test the biomarkers for their association with downstaging. Results Samples for biomarker analyses were obtained for 50 out of 90 randomized pts (arm A/B: 22/28): paired plasma samples were available for 18/23 pts at d1 and d15, and for 14/17 pts at d57; paired tumor samples were obtained from 12/18 pts. Eleven pts in each arm were downstaged (lower pT compared with the pretreatment cT). No differences were observed in baseline levels of any biomarker between both arms. Ang-2 levels were significantly higher in arm B than in arm A at d15 and d57 (p = 0.0056 and p = 0.0133, respectively). Ang-2 levels significantly decreased at d15 only in arm A (p Conclusions Additional larger tailored studies are needed to corroborate the observed association between decreasing Ang-2 levels, tumoral downstaging and the role of Bevacizumab in this effect. Disclosure E. Aranda Aguilar: Consultant or Advisory Role: Roche and Merck Serono. All other authors have declared no conflicts of interest.

4137 Background: Cetuximab is an IgG1 anti-EGFR monoclonal antibody, active alone and in combination with irinotecan in mCRC patients (pts) who have failed prior irinotecan therapy. In previous studies with cetuximab, IRRs were observed in a small proportion of pts especially at the first infusion. Methods: MABEL investigated cetuximab plus irinotecan in pts with EGFR-detectable mCRC whose last treatment regimen contained irinotecan. A secondary objective of MABEL was to further study cetuximab-related adverse events. Study treatment was cetuximab, initial dose 400 mg/m2, weekly 250 mg/m2, plus irinotecan with dose and schedule as pre-study. Data analyzed included prophylactic pre-medication, IRRs and medication for IRRs. Prophylactic medication given before the first cetuximab infusion was categorized as chlorphenamine antihistamines, antihistamines other than chlorphenamine, and any antihistamines plus corticosteroids. Results: Overall, 1147 pts were treated in this study: median age was 62 years [25–84], Karnofsky performance status was =70% and 64% pts were male. 1,122 patients were pre-treated with antihistamines. The frequency of IRRs was lower in pts who received antihistamines plus corticosteroids than in pts who received antihistamines alone (9.6% vs 25.6% any grade, 1% vs 4.7% grade 3/4 IRRs). The primary efficacy variable of MABEL was the 12-weeks progression-free survival (PFS) status. Efficacy results by pre-medication groups for PFS (see table ) and overall survival do not suggest differences related to prophylactic pre-medication. Conclusions: The data suggest that the type of pre-medication impacts on the occurrence of IRRs, and that the addition of corticosteroids to antihistamines reduces IRRs without altering antitumor efficacy in the analyzed pre-medication groups. [Table: see text] No significant financial relationships to disclose.

3549 Background: Cetuximab is an IgG1 anti-EGFR monoclonal antibody, active alone and in combination with irinotecan in metastatic colorectal cancer (mCRC) patients (pts) who failed irinotecan (Cunningham et al, NEJM 2004). MABEL investigated cetuximab plus irinotecan in an uncontrolled, multicenter study in pts with EGFR-detectable mCRC whose last treatment regimen contained irinotecan. MABEL is to date the largest cetuximab study published in this setting. Methods: Primary endpoint was the progression-free survival (PFS) rate at 12 weeks (wks), (expected rate 50% ± 3%). Study treatment was cetuximab, initial dose 400 mg/m2, weekly 250 mg/m2, plus irinotecan with dose and schedule as pre-study: Regimen A: 125 mg/m2 weekly for 4/6 wks, B: 180 mg/m2 q 2 wks, or C: 350 mg/m2 q 3 wks. Results: 197 centers from 7 countries screened tumors of 1681 pts for EGFR expression: 1461 (87%) pts had EGFR-detectable tumors. 1123 pts are currently evaluable: median age is 62 years (25–84), Karnofsky status ≥70% in all pts, and 64% pts were male. 64% pts had ≥ 2 prior therapy lines. 76% pts were also pretreated with oxaliplatin. On-study distribution of pts to irinotecan regimens was A: 92, B: 674, C: 357. 12-week PFS rates were: A: 60% (50–71%); B: 60% (56–64%); C: 63% (58–68%); overall: 61% (58–64%), and at 24 wks: A: 29% (19–39%); B: 32% (28–36%); C: 39% (34–45%); overall 34% (31–37%). The current estimate of median survival, based on 717 deaths, is 9.2 (8.7–9.9) months. Treatment was generally well tolerated with grade 3/4 adverse events >5%: diarrhea 20%, skin and subcutaneous tissue disorders incl. acne-like rash 19%, neutropenia 9%, asthenia 8%. Grade 3/4 immune system disorders incl. hypersensitivity reactions occurred in 1.5%, hypomagnesemia in 0.4% pts. Conclusions: The PFS rates observed in this heavily pretreated population fully met the primary endpoint of this study. Similar PFS rates were seen at 12 weeks (overall 61%) and 24 weeks (overall 34%) for all irinotecan regimens. Estimated survival time is in line with previously published results. MABEL clearly confirmed in a wider setting the efficacy and safety of cetuximab plus irinotecan seen in previous studies. [Table: see text]

3630 Background: EGFR is commonly expressed in CRC (72–82%) and is therefore a target for anticancer therapies, such as the anti-EGFR monoclonal antibody cetuximab (Erbitux). There appears to be no...