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Baseline clinico-pathological characteristics from patients included versus not included in the ctDNA analysis

Study protocol

Calculation of the neoadjuvant rectal (NAR) score.

Kaplan-Meier estimates of disease-free survival and overall survival according to paired CEA and ctDNA baseline and pre-surgery A. Disease-free survival according to baseline ctDNA and baseline CEA B. Overall survival according to baseline ctDNA and baseline CEA C. Disease-free survival according to pre-surgery ctDNA and pre-surgery CEA D. Overall survival according to pre-surgery ctDNA and pre-surgery CEA pos: positive; neg: negative

Kaplan-Meier estimates of disease-free survival and overall survival according to pCR and NAR score in the sub-study cohort A. Disease-free survival according to pCR B. Overall survival according pCR C. Disease-free survival according to NAR score D. Overall survival according NAR score

Supplementary Figures S1-S4; Supplementary Tables S1-S3.

Purpose: Preoperative chemoradiotherapy (CRT) is the treatment of choice for rectal cancer (RC), but half of the patients do not respond, suffer unnecessary toxicities, and surgery delays. We aimed to develop a model that could predict a clinically meaningful response to CRT by using formalin-fixed paraffin-embedded (FFPE) biopsies.Experimental Design: We first carried out an exploratory screening of candidate genes by using SAGE technology to evaluate dynamic changes in the RC transcriptome in selected refractory patients before and after CRT. Next, 53 genes (24 from SAGE and 29 from the literature) were analyzed by qPCR arrays in FFPE initial biopsies from 94 stage II/III RC patients who were preoperatively treated with CRT. Tumor response was defined by using Dworak's tumor regression grade (2–3–4 vs. 0–1). Multivariate Cox methods and stepwise algorithms were applied to generate an optimized predictor of response and outcome.Results: In the training cohort (57 patients), a 13-gene signature predicted tumor response with 86% accuracy, 87% sensitivity, and 82% specificity. In a testing cohort (37 patients), the model correctly classified 6 of 7 nonresponders, with an overall accuracy of 76%. A signature-based score identified patients with a higher risk of relapse in univariate (3-year disease-free survival 64% vs. 90%, P = 0.001) and multivariate analysis (HR = 4.35 95% CI: 1.2–15.75, P = 0.02), in which it remained the only statistically significant prognostic factor.Conclusions: A basal 13-gene signature efficiently predicted CRT response and outcome. Multicentric validation by the GEMCAD collaborative group is currently ongoing. If confirmed, the predictor could be used to improve patient selection in RC studies. Clin Cancer Res; 17(12); 4145–54. ©2011 AACR.

Metabolism; Resistance; Vaccines Metabolisme; Resistència; Vacunes Metabolismo; Resistencia; Vacunas Background Immune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects. Methods This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage. Results A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1–5.3 months] and overall survival was 12.2 months [3.2–23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways. Conclusions The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities. The study was funded by grants from the FIS PI17/00732 from Instituto de Salud Carlos III, Premi Fi de Residència Emili Letang from Hospital Clínic Barcelona, Plan Nacional de I + D (PID-107139RB-C21 to DB-R and PID2020-115051RB-I00 to MC) and Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD). The study was funded with Grants from Catalan Agency for Management of University and Research Grants (AGAUR) (2014-SGR-474, 2017-SGR-1174 and 2017-SGR-1033), Fundació la Marató de TV3 (201330.10), Instituto de Salud Carlos III (PI13/01728 and PI19/00740) and Fundacion Olga Torres (Modalitat A. 2019/2020) to JM. IMMETCOLS signature is under patent protection (EP21382772.8.) This research was financially supported by GEMCAD and (OR Avelumab was provided) by Merck, S.L.U., Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany, as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: https://doi.org/10.13039/100009945) and Pfizer.

Background: HER2 mutations define a subset of metastatic breast cancers (MBCs) with a unique mechanism of oncogenic addiction to HER2 signaling. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has been shown to have encouraging clinical activity when combined with fulvestrant in HER2-mutant, hormone receptor-positive (HR+) MBC [Smyth et al. SABCS 2018]. Genomic analyses suggest that acquired resistance to neratinib may occur by the acquisition of additional HER2 alterations, which may amplify HER2 pathway signaling [Won et al. AACR 2019]. We therefore explored whether dual HER2-targeted therapy may improve clinical benefit in this setting. Here we describe initial results from a cohort of patients with HER2-mutant, HR+ MBC treated with neratinib + trastuzumab + fulvestrant (N+T+F) from the phase 2 SUMMIT ‘basket’ trial (NCT01953926). Methods: Patients with HR+ MBC and known oncogenic driver HER2 mutations identified by genomic sequencing were eligible to receive combination treatment with oral neratinib 240 mg daily, intravenous trastuzumab 8 mg/kg initially followed by 6 mg/kg every 3 weeks, and intramuscular fulvestrant 500 mg on days 1 and 15 of month 1, then on day 1 every 4 weeks (N+T+F). Loperamide prophylaxis was mandatory during cycle 1. There was no restriction on the number of prior lines of systemic treatment for MBC. Efficacy endpoints included: confirmed objective response rate and clinical benefit rate - all defined according to RECIST v1.1 - as well as duration of response and progression-free survival. Genomic profiling from fresh/archival tumor tissues and/or plasma cfDNA was performed retrospectively by next-generation sequencing (MSK-IMPACT). Results: As of 01-May-2019, 19 patients were enrolled into the N+T+F cohort and received study treatment (safety population). 20 HER2 mutations were identified in the 19 patients: 14 kinase domain missense mutations, 3 extracellular domain missense mutations, and 3 exon-20 insertion mutations. Median number of prior systemic regimens for metastatic disease was 4 (range 0-10) and histologies were evenly split between lobular and ductal carcinomas. While the majority of patients remain on study treatment (n=15), only 13 of the 19 enrolled patients are efficacy evaluable at this time (having had ≥1 post-baseline tumor assessment). Clinical activity is summarized in the Table. Diarrhea was the most commonly reported adverse event (84.2% any grade) with 5 patients reporting Grade 3 diarrhea (there were no Grade 4 diarrhea events). Three patients (15.8%) reduced neratinib dose due to diarrhea but no patient discontinued treatment due to diarrhea. Conclusions: The combination of N+T+F resulted in an encouraging response rate and was a well-tolerated regimen in predominantly heavily pretreated HER2-mutant HR+ breast cancers. Based on a pre-planned interim analysis, the cohort has been expanded to enroll a total of 50 patients. Updated efficacy and safety data will be presented. Neratinib + trastuzumab + fulvestrant(n=13)Confirmed objective response rate, % (95% CI)39 (13.9-68.4)Complete response0Partial response5 (39)Duration of responses range, months4.2*-10.4*Median progression-free survivala,b, months (95% CI)NA (1.9-NA)*Response ongoing; aKaplan-Meier analysis; bincludes all patients enrolled (n=19); NA, not applicable. Citation Format: Hans Wildiers, Valentina Boni, Cristina Saura, Mafalda Oliveira, Komal Jhaveri, Helen Won, François-Clément Bidard, Adam M Brufsky, Mark E Burkard, Andrés Cervantes, Carlos Fernández-Martos, Barbara Haley, Sherene Loi, Iben Spanggaard, Stefano Panni, Janice Lu, Melanie E Dujka, Feng Xu, Sonia Macia, Lisa D Eli, Alshad S Lalani, Sarina Piha-Paul, Funda Meric-Bernstam, David B Solit, David M Hyman. Neratinib + trastuzumab + fulvestrant for HER2-mutant, hormone receptor-positive, metastatic breast cancer: Updated results from the phase 2 SUMMIT ‘basket’ trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-08.

This articles compares the capacity of several biomarkers (BRAF mutation, PIK3CA mutation/PTEN loss and DP phenotype) to predict 12‐month progression‐free survival and compares it with that of clinical variables, Background. RAS testing is used to select patients with anti‐epidermal growth factor receptor (EGFR) therapies sensitivity in metastatic colorectal cancer (mCRC). However, other biomarkers such as BRAF, PIK3CA/PTEN, and p‐IGF‐1R+/MMP7+ (double positive [DP] phenotype) have not been prospectively assessed to predict anti‐EGFR resistance. Materials and Methods. We designed a multicenter prospective trial (NCT01276379) to evaluate whether the biomarkers BRAF mutation, PIK3CA mutation/PTEN loss, and DP phenotype can improve the prediction for 12‐months progression‐free survival (PFS) over the use of clinical variables exclusively in patients with RAS wild‐type (WT) mCRC treated with standard chemotherapy plus biweekly cetuximab as first‐line therapy. The planned sample size was 170 RAS WT patients to detect a 20% difference in 12‐month PFS based on the analysis of clinical and selected biomarkers (α = .05, β = .2). The discriminatory capacity of the biomarkers was evaluated using receiver operating characteristic curves. Results. We included 181 RAS WT patients. The biomarker distribution was as follows: BRAF mutant, 20 patients (11%); PIK3CA mutated/PTEN loss, 98 patients (58%); DP, 23 patients (12.7%). The clinical variables in the clinical score were progression status >0, left‐sided tumor, and resectable liver metastasis as the only metastatic site. The area under the curve (AUC) of the score containing the clinical variables was 0.67 (95% confidence interval [CI], 0.60–0.75). The AUC of the score with clinical variables and BRAF mutational status was 0.68 (0.61–0.75, p = .37). The AUC of the score with clinical variables and PI3KCA mutation/PTEN status was 0.69 (0.61–0.76, p = .32). The AUC of the score with clinical variables and DP phenotype was 0.66 (0.58–0.73, p = .09). Conclusion. The addition of BRAF, PIK3CA/PTEN, and DP to a clinical score does not improve the discrimination of 12‐month PFS. Implications for Practice. This prospective biomarker design study has important clinical implications because many prospective clinical trials are designed with the hypothesis that BRAF mutation per se and MEK and PIK3CA downstream pathways are critical for colorectal tumor survival. The results lead to the question of whether these pathways should be considered as passengers instead of drivers.

Purpose: Total neoadjuvant treatment (TNT) is a valid strategy for patients with high-risk locally advanced rectal cancer (LARC). Biomarkers of response to TNT are an unmet clinical need. We aimed to determine the value of circulating tumor DNA (ctDNA) to predict tumor response, recurrence, and survival in patients with LARC treated with TNT. Experimental Design: The GEMCAD 1402 was a phase II randomized, multicentric clinical trial that randomized 180 patients with LARC to modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) +/− aflibercept, followed by chemoradiation and surgery. Plasma samples were collected at baseline and after TNT within 48 hours before surgery (presurgery). An ultrasensitive assay that integrates genomic and epigenomic cancer signatures was used to assess ctDNA status. ctDNA results were correlated with variables of local tumor response in the surgery sample, local/systemic recurrence, and survival. Results: A total of 144 paired plasma samples from 72 patients were included. ctDNA was detectable in 83% of patients at baseline and in 15% following TNT (presurgery). No association was found between ctDNA status and pathologic response. Detectable presurgery ctDNA was significantly associated with systemic recurrence, shorter disease-free survival (HR, 4; P = 0.033), and shorter overall survival (HR, 23; P < 0.0001). Conclusions: In patients with LARC treated with TNT, presurgery ctDNA detected minimal metastatic disease identifying patients at high risk of distant recurrence and death. This study sets the basis for prospective clinical trials that use liquid biopsy to personalize the therapeutic approach following TNT.

The potential of preoperative chemotherapy in rectal cancer is the subject of investigation in a number of global randomized trials. In this overview and expert discussion, Professor Cervantes summarizes the findings of numerous Phase II trials testing neoadjuvant chemotherapy. The crucial points in the next phase of trials include: patient selection, whether radiotherapy can be omitted altogether and whether chemotherapy can be used to augment the initial response to chemoradiotherapy. Finally, with the emergence of Magnetic Resonance Tumour Regression Grade a reliable method for assessing response after initial chemoradiotherapy, we ask if this can be used to drive the use of further selective chemotherapy to augment response.

New strategies for the treatment of cancer in the rectum should be directed towards the improvement of micrometastatic disease and the reduction of long-term sequelae, without prejudice to good local control. To achieve this, in the last decade, new strategies have been postulated. Treatment with preoperative chemotherapy (CT) alone or induction CT followed by chemoradiation CRT/short course radiation (CRT/SCPRT) or CRT/SCPRT and consolidative CT is being planned. We currently have data from phase II studies with results of stimulating efficacy and/or compliance. New single-arm and randomized trial is underway and will allow us to know the impact on survival outcomes and long-term sequelae of these strategies.

Background: Primary chemotherapy has been tested as a possible approach for patients with high risk features but predicted clear mesorectal margins on preoperative MRI assessment. This study investigates the prognostic relevance of baseline and post-treatment MRI and pathology staging in rectal cancer patients undergoing primary chemotherapy. Patients and methods: Forty-six patients with T3 tumour> = 2mm from the mesorectal fascia were prospectively treated with Neoadjuvant Capecitabine, Oxaliplatin and Bevacizumab prior to surgery between 2009 and 2011. The baseline and posttreatment MRI: T, Nodal and Extra-mural venous invasion (EMVI) status were recorded as well as post-treatment MRI Tumour regression grade (TRG) and modified-RECIST assessment of tumour length. The post-treatment pathology (yp) assessments of T3 substage, N, EMVI and TRG status were also recorded. Three-year disease-free survival (DFS) and cumulative incidence of recurrence were estimated by using the Kaplan-Meier product-limit method, and Cox proportional hazards models were used to determine associations between staging and response on MRI and pathology with survival outcomes. Results: About 46 patients underwent neoadjuvant chemotherapy alone for high risk margin safe primary rectal cancer. The median follow-up was 41 months, 5 patients died and 11 patients experienced relapse (2 local, 8 distant and 1 both). In total 23/ 46 patients were identified with MRI features of EMVI at baseline. mrEMVI positive status carried independent prognostic significance for DFS (P = 0.0097) with a hazard ratio of 31.33 (95% CI: 2.3-425.4). The histopathologic factor that was of independent prognostic importance was a final ypT downstage of ypT3a or less, hazard ratio: 14.0 (95% CI: 1.5-132.5). Conclusions: mrEMVI is an independent prognostic factor at baseline for poor outcomes in rectal cancer treated with neoadjuvant chemotherapy while

4102 Background: Neoadjuvant chemotherapy (CT) followed by CRT and TME is a treatment option for clinically staged HRRC. The goal of the GEMCAD 1402 trial was to evaluate the benefit of adding an antiangiogenic drug to the neoadjuvant CT. The analysis of primary endpoint showed a better response rate in the experimental arm (Fernandez-Martos et al. Jama Oncol 2019). Here we present 3-year disease-free survival (DFS) and a retrospective analysis of consensus molecular subtypes by Immunohistochemistry (CMSs-IHQ). Methods: Patients (p) with middle or distal third, mrT3/T4/N2 rectal adenocarcinoma were randomly assigned (2:1), to mFOLFOX6 with (arm 1, n=115) or without Aflibercept (arm 2, n=65) prior to CRT (capecitabine with 50.4 Gy in 28 fractions) and TME. Tissue microarrays from 90 (58 arm1, 32 arm 2) p were stained for nine markers (CDX2, FRMD6, HTR2B, ZEB1, KER, MSH2, MSH6, PMS2 and MLH1) by IHQ using both semiquantitative and quantitative approaches. Cases were classified as CMS1-IHQ1, CMS-IHQ2/3 or CMS-IHQ 4 (immune, epithelial or mesenchymal subtypes). Results: In the intention-to-treat population after a median follow-up time of 38 months, 29 p (25%) in arm 1 had a DFS-related event, as compared with 14 p (21%) in arm 2 (HR 1.2063, 95% confidence interval 0.6374 to 2.2829, P=0.5644. The rate of DFS at three years was 75.2% (95% confidence interval, 66.1% to 82.2%) in arm 1 and 81.5% (95% confidence interval, 69.8% to 89.1%) in arm 2 (P=0.5638 by the exact stratified log-rank test). Overall 0/80/10 p were classified as CMS-IHQ1, CMS-IHQ2/3 or CMS-IHQ4 respectively. The pathological complete response (pCR) rate (ypT0N0) was achieved in 27.5% and 0% in epithelial and mesenchymal subtypes respectively. A trend towards worse survival for the mesenchymal subtype was observed. Conclusions: Adding aflibercept to induction mFOLFOX6 is not associated with an improvement in DFS. Our findings suggest that CMSs-IHQ subtypes could be predictive for pCR with this treatment strategy. Clinical trial information: NCT02340949 .

3512 Background: Patients with advanced colorectal cancer with 4WT tumors achieve increased response rates with chemotherapy and anti-EGFR therapy as compared with chemotherapy alone. In clinically staged (c) T3 rectal cancer neoadjuvant oxaliplatin/fluoropyrimidine combination has shown to induce encouraging pathological complete response (pCR). We hypothesize that combining FOLFOX and P could improve outcomes in 4WT tumors. Methods: PIER was an investigator-initiated phase II, single-arm, multicentre clinical trial to evaluate the safety and efficacy of neoadjuvant mFOLFOX6 with P in pts < 75-y, with 4WT rectal cancer of the middle third staged as T3 by centrally-reviewed magnetic resonance imaging (MRI) and clear MRF, who were candidate for a R0 resection with sphincter preservation surgery. Pts received 6 cycles and underwent re-staging with MRI and sigmoidoscopy. Pts without progression underwent total mesorectal excision 4 weeks after the last cycle. Patients with progression were treated with pre-op chemoradiotherapy. The primary endpoint was pCR. The study followed a 2-Stage Simon’s MiniMax design (P0 of 16%, P1 of 35%, alpha and beta of 0.1). The target sample size was 35 patients and if 9 or more achieved a pCR, the results would be compatible with efficacy. We present primary and early secondary endpoints. Results: Between 9/2017 and 6/2020, 90 patients were screened (56 excluded; 42 were excluded due to mutations, 12 were excluded due to discrepancies with central review of radiology) of whom 34 were enrolled. In the ITT population a pCR was observed in 11 pts (32.3%; [95% CI 17.39-50.53]) and a near-complete pathological response (Mandard 1+2) was observed 17 pts (52.9%). Clinical complete or near complete response was achieved in 50% and there were no progressions. R0 resection rate and pathological circumferential resection margin neg- were 100%. Full compliance with induction was 88%. Neoadjuvant G3/4 toxicity occurred in 54% and was consistent with FOLFOX/P safety profile. G3/4 postoperative related toxicity was 19% with one reoperation. Conclusions: The study met the threshold for efficacy. mFOLFOX6 with P as neoadjuvant therapy can be effective and safe without unexpected toxicities in mrT3, clear MRF and 4WT rectal cancer and resulted in a higher rate of pCR compared with our previous series (GEMCAD 0801; The Oncologist 2014) in a similar molecular-unselected population. This study was funded by Amgen S.A. Clinical trial information: NCT03000374.

TPS4122 Background: In clinical stages II and III (cT3-4 and/or N+), preoperative chemoradiotherapy (CRT) or short-course radiation followed by total mesorectal escision (TME) have been the standard of care for the last 15 years. Induction chemotherapy (CT) before CRT (strategy known as TNT) results in fewer toxic effects and improved compliance. TNT may release tumor-neoantigens with platinum-based induction CT, and radiotherapy has the potential ability to induce an immunogenic cell death and counteract an immune-suppressive tumor microenvironment that provides the rationale for combining with immunotherapies. In addition, the presence of tumor infiltrating lymphocytes has been demonstrated in patients with rectal cancer treated with neoadjuvant CRT, reinforcing the rational for immune check-point inhibitors in this setting. We hypothesize that combining TNT with durvalumab (an optimized monoclonal antibody directed against programmed cell death-1 ligand 1) would improve outcome. Methods: DUREC is a multicenter, single-arm, open-label, phase Ib/II study for patients with magnetic resonance (mr) image middle or distal third, mrT3c-d/T4/N2 rectal adenocarcinoma. Treatment: Patients will receive 6 cycles of modified FOLFOX6 prior to CRT (capecitabine with 50.4 Gy in 28 fractions) and TME, combined with durvalumab 1500 mg every 4 weeks during induction CT, CRT and waiting period until surgery. To assess the tolerability and toxicity profile we plan to perform a run-in treatment phase including the first 6 patients in the study, holding recruitment until all of them will be operated and 30-days post-surgery period completed. If ≤ 2 durvalumab-related dose-limiting toxicities (DLTs) are observed, recruitment will continue. The primary objective is pathological complete response (pCR) rate. Secondary endpoints include toxicity, tumor regression grade, R0 resections, clear circumferential margins, surgical complications, NAR score, disease-free survival and a biomarker program on tumor tissue, blood samples and stool microbiota. Statistical design: 58 evaluable patients (assuming a P0 of 16% and a P1 of 30%, with 0.1 alpha and 0.1 beta); Study started recruitment on December 2019. Clinical trial information: 2018-004835-56 .

This study evaluated safety and quality of life in patients with metastatic colorectal cancer undergoing treatment with aflibercept and FOLFIRI (fluorouracil, leucovorin, irinotecan). Most patients treated with this combination experienced either improvement or stability in quality of life scores. Aflibercept plus FOLFIRI is tolerable in the treatment of patients with metastatic colorectal cancer with a safety profile similar to that seen in previous studies of these individual medications. Background: The objectives of this study were to evaluate the safety profile of aflibercept and health-related quality of life (HRQL) in patients with metastatic colorectal cancer (mCRC) provided with aflibercept access before marketing authorization. Patients and Methods: Patients received aflibercept followed by FOLFIRI (fluorouracil, leucovorin, irinotecan) on day 1 of a 2-week cycle until disease progression, unacceptable toxicity, death, or patient/investigator decision to discontinue. Treatment-emergent adverse events (TEAEs) were evaluated, and HRQL was assessed at baseline, cycle 3, and every other cycle using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-CR29, and EuroQol 5-Dimensions 3-Levels questionnaires (NCT01571284). Results: Overall, 779 adult patients with mCRC, who received >= 1 prior oxaliplatin-based regimen and had disease progression during or following their last administration of oxaliplatin-based chemotherapy, were enrolled. At data cutoff, all patients had discontinued treatment, mainly owing to disease progression (51.7%). The most common TEAEs of any grade were diarrhea (61.6%), hypertension (48.4%), and nausea (43.3%). The most common grade 3/4 TEAEs were hypertension (24.1%), neutropenia (23.1%), and diarrhea (15.3%). Clinically meaningful changes in HRQL were reported for all measures. Most patients either had an improvement in their HRQL scores or remained stable during the treatment period based on patient-reported outcomes. Conclusion: The data from this study support the tolerability of the combination of aflibercept and FOLFIRI in a setting that more closely approximates real life in patients with mCRC who failed to respond to oxaliplatin-based chemotherapy, and also suggest an improvement in HRQL.

PURPOSE RAS and BRAF mutations can be detected as a mechanism of acquired resistance in circulating tumor (ct) DNA in patients with metastatic colorectal cancer treated with anti–epidermal growth factor receptor therapy. METHODS RAS and BRAF mutational status was assessed in ctDNA in a baseline plasma sample and a serum sample collected at the time of the last available determination (named secondary extraction) from patients with KRAS exon 2 wild-type metastatic colorectal cancer treated in two first-line prospective biomarker-designed clinical trials (PULSE, ClinicalTrials.gov identifier: NCT01288339; and POSIBA, ClincialTrials.gov identifier: NCT01276379). RESULTS Analysis of extended RAS and BRAF in tissue and plasma from 178 patients with KRAS exon 2 wild-type metastatic colorectal cancer showed a sensitivity of 64.1% and a specificity of 90%. The median overall survival (OS) of baseline patients with RAS and BRAF mutations in ctDNA was 22.3 months (95% CI, 15.6 to 29 months) and 8.9 months (95% CI, 6.3 to 11.4 months), respectively, which was significantly inferior to the median OS of 40.4 months (95% CI, 35.9 to 44.9 months) in two patients with wild-type disease ( P < .001). Acquisition of RAS/BRAF mutations occurred in nine of 63 patients (14%) with progressive disease (PD; ie, blood draw within 1 month before PD or after PD) compared with six of 73 patients (8%) with no PD or blood extraction for ctDNA analysis before 1 month of PD ( P = .47). Median OS in patients with RAS/BRAF acquisition was 23.9 months (95% CI, 19.7 to 27.9 months) compared with 40.6 months (95% CI, not reached to not reached) in patients who remained free of mutations ( P = .016). CONCLUSION Our results confirm that baseline RAS and BRAF testing in ctDNA discriminates survival. The emergence of RAS/BRAF mutations has limited relevance for the time to progression to anti–epidermal growth factor receptor therapy.

IMPORTANCE: Preclinical studies suggest that a vascular endothelial growth factor (VEGF) blockade may play a role in the preoperative treatment of rectal adenocarcinoma; however, how to combine anti-VEGF drugs with neoadjuvant chemotherapy (CT) and/or chemoradiotherapy (CRT) remains controversial. OBJECTIVE: To study the effect of aflibercept plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) induction CT prior to standard CRT and total mesorectal excision (TME) surgery in patients with high-risk rectal adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTS: In the Grupo Español Multidisciplinar En Cancer Digestivo (GEMCAD) 1402 phase 2 randomized clinical trial, 180 patients aged 18 to 75 years, identified by centrally reviewed magnetic resonance imaging to have mrT3c-d/T4/N2 rectal adenocarcinoma, were enrolled from 20 treatment centers in Spain between January 2015 and March 2017. Patients were randomized in a 2:1 treatment to control arm ratio. The primary end point was evaluated at 2 interim and 1 final analyses. The study was designed to perform hypothesis testing at α = .2 and β = .2. A 2-sided P value of

Introduction Endoscopic resection is the common treatment in pT1 colorectal adenocarcinoma whenever possible. The presence of adverse histological factors requires subsequent lymph node evaluation. Materials and methods We selected 29 colorectal pT1 adenocarcinoma including endoscopic polypectomies and the corresponding surgical specimens. All histologic parameters associated with N+ were evaluated by 2 pathologists, including: tumour differentiation grade, depth of invasion in the submucosa, angiolymphatic invasion (ALI), perineural invasion, chronic inflammation, tumour budding, poorly differentiated cluster, pre-existing adenoma, tumour border, and endoscopic resection margin. Univariate and multivariate logistic regression analysis was performed to assess the individual capacity of each variable to predict N+. Results In the univariate analysis, rectal tumour localization, ALI and poorly differentiated cluster were significantly associated with N+. Among the significant parameters, ALI had the highest area under the ROC curve (0.875). Multivariate analysis showed no independent variables associated with N+. Conclusions We confirm that ALI and the presence of poorly differentiated cluster are frequently associated with N+ in early colorectal cancer. Consequently, these parameters should be routinely evaluated by pathologists.

Resumen Introduccion El tratamiento habitual del adenocarcinoma colorrectal pT1 consiste en la reseccion endoscopica siempre que sea posible. Se requiere la evaluacion de los ganglios linfaticos locorregionales cuando se detectan factores histologicos adversos en las polipectomias endoscopicas. Materiales y metodos Se seleccionaron 29 adenocarcinomas colorrectales pT1 incluyendo las polipectomias endoscopicas y piezas quirurgicas correspondientes. Se evaluaron por 2 patologos todos los parametros histologicos asociados a N+, incluyendo: grado de diferenciacion tumoral, profundidad de invasion en submucosa, invasion angiolinfatica (IAL), invasion perineural, inflamacion cronica, gemaciones tumorales, grupos de tumor pobremente diferenciados, adenoma preexistente, borde tumoral y margen de reseccion endoscopico. Se realizo un analisis de regresion logistica univariante y multivariante para evaluar la capacidad individual de cada variable para predecir N+. Resultados En el analisis univariante, la localizacion rectal, la presencia de IAL y la presencia de grupos de tumor pobremente diferenciados se asociaron significativamente con metastasis ganglionares. De todas estas variables, la presencia de IAL presento la mayor area bajo la curva ROC (0,875). El analisis multivariante no encontro ninguna variable independiente asociada a N+. Conclusiones La IAL y la presencia de grupos de tumor pobremente diferenciados se asocia frecuentemente con N+ en cancer colorrectal precoz, por lo que se debe implementar rutinariamente la evaluacion de estos parametros histologicos.

Background Since the publication of the German trial by Sauer et al. a standard strategy of care for locally advanced rectal (LAR) cancer is the preoperative infusional 5-fluorouracil (5-FU) and concurrent radiation therapy (RT) followed by total mesorectal surgery, because it is associated with significantly lower rates of local relapse and less toxic than postoperative treatment [1]. Capecitabine is an oral prodrug that is converted into 5-FU by intracellular thymidine phosphorylases at the tumor site, which results in avoiding extensive systemic exposure and higher intratumoral concentrations of 5-FU [2]. Substitution of infusional 5-FU with capecitabine is an attractive option that provides a more c onvenient administration schedule. The present editorial, mainly focus on recent data and discusses the incorporation of capecitabine into the standard and new strategies in the treatment of LAR.

Background The primary results of our phase II randomized trial suggested that compared with conventional preoperative chemoradiation (CRT), the addition of chemotherapy (CT) before CRT and surgery allows most patients receive their planned treatment with a better toxicity profile without compromising the pathological complete response and complete resection rates. We now report the 5-year outcomes. Patients and methods Patients with distal or middle third, T3–T4 and/or N+ rectal adenocarcinoma selected by magnetic resonance imaging, were randomly assigned to arm A—preoperative CRT followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)—or arm B—four cycles of CAPOX followed by CRT and surgery. The following 5-year actuarial outcomes were assessed: the cumulative incidence of local relapse (LR) and distant metastases (DM), disease-free (DFS) and overall survival (OS). Results A total of 108 eligible patients were randomly assigned to arm A (n = 52) or arm B (n = 56). With a median follow-up of 69.5 months, 5-year DFS was 64% in arm A and 62% in arm B (P = 0.85) and 5-year OS was 78% in arm A and 75% in arm B (P = 0.64). The 5-year cumulative incidence of LR was 2% and 5% (P = 0.61) and 5-year cumulative incidence of DM was 21% and 23%; (P = 0.79) in arms A and B, respectively. Conclusion Both treatment approaches yield similar outcomes. Given the lower acute toxicity and improved compliance with induction CT compared with adjuvant CT, integrating effective systemic therapy before CRT and surgery is a promising strategy and should be examined in phase III trials.

This is an open-access article distributed under the terms of the Creative Commons Attribution License., This is a collaborative study between the Molecular Oncology Unit of The Institute of Advanced Studies of Madrid IMDEAFood and the Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD).-- et al., Lipid metabolism plays an essential role in carcinogenesis due to the requirements of tumoral cells to sustain increased structural, energetic and biosynthetic precursor demands for cell proliferation. We investigated the association between expression of lipid metabolism-related genes and clinical outcome in intermediate-stage colon cancer patients with the aim of identifying a metabolic profile associated with greater malignancy and increased risk of relapse. Expression profile of 70 lipid metabolism-related genes was determined in 77 patients with stage II colon cancer. Cox regression analyses using c-index methodology was applied to identify a metabolic-related signature associated to prognosis. The metabolic signature was further confirmed in two independent validation sets of 120 patients and additionally, in a group of 264 patients from a public database. The combined analysis of these 4 genes, ABCA1, ACSL1, AGPAT1 and SCD, constitutes a metabolic-signature (ColoLipidGene) able to accurately stratify stage II colon cancer patients with 5-fold higher risk of relapse with strong statistical power in the four independent groups of patients. The identification of a group of 4 genes that predict survival in intermediate-stage colon cancer patients allows delineation of a high-risk group that may benefit from adjuvant therapy, and avoids the toxic and unnecessary chemotherapy in patients classified as low-risk group., This work was supported by Ministerio de Ciencia e Innovación del Gobierno de España (Plan Nacional I + D + i AGL2013–48943-C2–2-R and IPT-2011–1248-060000), Comunidad de Madrid (P2013/ABI-2728. ALIBIRDCM) and European Union Structural Funds. CIBEREHD is funded by the Instituto de Salud Carlos III.

INTRODUCTION: The coexpression of pIGF-1R and MMP-7 (double-positive phenotype, DP) correlates with poor overall survival (OS) in KRAS wild-type (WT) (exon 2) metastatic colorectal cancer (mCRC) patients treated with irinotecan-cetuximab in second/third line. METHODS: We analyzed two prospective biomarker design trials of newly diagnosed RAS-WT mCRC patients treated with panitumumab-FOLFOX6 (PULSE trial; NCT01288339) or cetuximab plus either FOLFOX6/FOLFIRI (POSIBA trial; NCT01276379). The main exposure was DP phenotype (DP/ non-DP), as assessed by two independent pathologists. DP cases were defined by immunohistochemistry as N70% expression of moderate or strong intensity for both MMP-7 and pIGF-1R. Primary endpoint: progression-free survival (PFS); secondary endpoints: OS and response rate. PFS and OS were adjusted by baseline characteristics using multivariate Cox models. RESULTS: We analyzed 67 patients (30 non-DP, 37 DP) in the PULSE trial and 181 patients in the POSIBA trial (158 non-DP, 23 DP). Response rates and PFS were similar between groups in both studies. DP was associated with prolonged OS in PULSE (adjusted HR: 0.23; 95% CI: 0.11-0.52; P =. 0004) and with shorter OS in POSIBA (adjusted HR: 1 .67; 95% CI: 0.96-2.90; P =. 07). CONCLUSION: A differential effect of anti-EGFRs on survival by DP phenotype was observed. Panitumumab might be more beneficial for RAS-WT mCRC patients with DP phenotype, whereas cetuximab might improve OS in non-DP., Amgen supported the PULSE trial and Merck supported the POSIBA trial. Neither Amgen nor Merck had any role in the present analysis design, analysis and interpretation of data, writing the report, and the decision to submit the report for publication.

Treatment of micrometastasis should now be the focus of major interest in the treatment of locally advanced rectal cancer because distant metastases remain the leading cause of mortality in this population. In stage II and III rectal cancer, even in modern series, after preoperative treatment with short-course radiotherapy (SCRT) or chemoradiation (CRT) and total mesorectal excision (TME) with or without adjuvant chemotherapy (CT), 5-year distant relapse is about 35%, and local relapses are about 8% [1]. However, the role of adjuvant CT after CRT is still controversial.

Altres ajuts: Mutua Madrileña (AP75002010); Porgrama CERCA; CIBERehd Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation. Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R. Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.

[Purpose]: Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance. [Methods]: This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival. [Results]: Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis. [Conclusion]: Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target. © 2012 Elsevier Inc. All rights reserved., Funded by Fondo de Investigaciones SanitariasPI021094 and Fundación Mutua Madrileña. P. Cejas is supported by Asociación Española Contra el Cáncer programa PAO 2010, and V. M. García is supported by Fundación Para la Investigación Biomédica del Hospital La Paz grant REX 09.

Preoperative infusional 5-fluorouracil (5-FU) and concurrent radiation therapy (RT) followed by total mesorectal surgery is the current standard of care for locally advanced rectal cancer (LAR). When compared with postoperative 5-FU-based chemoradiation, this strategy is associated with significantly lower rates of local relapse, lower toxicity and better compliance. Capecitabine is a rationally designed oral prodrug that is converted into 5-FU by intracellular thymidine phosphorylase. Substitution of infusional 5-FU with capecitabine is an attractive option that provides a more convenient administration schedule and, possibly, increased efficacy. Indeed, incorporation of capecitabine in combined modality neoadjuvant therapy for LAR has been under intense investigation during the last 10 years. Phase I and II clinical trials showed that a regimen consisting of capecitabine 825mg/m2 twice daily for 7 days/week continuous oral administration in combination with RT is an active and well tolerated regimen, thereby being the preferred concurrent regimen. The definitive demonstration that efficacy of capecitabine/RT is similar to 5-FU/RT has been provided by the NSABP-R-04 and the German Margit trials. One approach to improve outcomes in rectal cancer is to deliver a second RT-sensitizing drug with effective systemic activity. Oxaliplatin and irinotecan are therefore good candidates. However, two phase III trials demonstrated that incorporation of oxaliplatin to capecitabine with RT did not improve early outcomes and, by contrast, increased toxicity. Capecitabine has also been combined with irinotecan. This regimen showed encouraging results in phase I and II clinical trials, which led to an ongoing phase III clinical trial. New strategies with induction chemotherapy with or without chemo-radiation prior to surgery are currently under investigation. Whether or not capecitabine has a role in this setting is being investigated in ongoing trials. Incorporation of agents directed towards new targets, such as anti-epidermal growth factor receptor (EGFR) antibodies or antiangiogenic agents, in combination preoperative regimens, is being hampered by results of early trials in which efficacy outcomes with cetuximab were poor and an excessive rate of surgical complications with bevacizumab was observed. The lack of improvements in efficacy with the addition of cetuximab or bevacizumab in the adjuvant treatment of colon cancer led to concerns about further devel-opment of these agents in rectal cancer. The role of capecitabine in the postoperative adjuvant setting is the aim of the ongoing Dutch SCRIPT trial. The prediction of response associated with capecitabine has been based on expression of thymidylate synthase and dihydropyrimidine dehydrogenase, as well as on gene expression arrays. All these procedures require further validation and should be considered as investigational. In conclusion, capecitabine can safely and effectively replace intravenous continuous infusion of 5-FU in the preoperative chemoradiation setting for rectal cancer management. The addition of other new antineoplastic agents to a fluoropy-rimidine-based regimen remains investigational.

The purpose of this study was (a) to evaluate the association between cigarette smoking and the prevalence of distal colorectal polyps and adenocarcinoma and (b) to analyse genetic alterations representing different molecular pathways of the colorectal carcinogenesis. A total of 623 asymptomatic male (mean age: 53 years; 50-65) car factory workers were included. Information on smoking habits and other lifestyle factors were collected followed by a 60 cm colonoscopy. APC and KRAS mutations and microsatellite status were determined in colorectal lesions (colorectal carcinoma (CRC), hyperplastic (HP) and adenomatous polyps (AP)). Data were analysed using unconditional multiple logistic regression models. Smokers had a higher prevalence of AP (OR 2.1; 95% CI 1.2-3.6; p < 0.05) and HP (OR 5.4; 95% CI 2.6-11.1; p < 0.05). No differences in CRC were observed. There was a dose-response relationship with the number of cigarettes smoked. The risk of developing AP or HP decreased after smoking cessation, even among heavy smokers (a parts per thousand yen20 packs/year). KRAS mutations were more prevalent among smokers AP (OR 5.6; 95% CI 1.6-20.4; p=0.007). There was a trend of positive association with APC mutations (OR 3.5; 95% CI 0.9-4.4; p=0.096). APC and KRAS mutations were found in 36% and 61% of the HP of smokers, but were absent in non-smokers (p=0.89 and 0.78, respectively). There were no differences in MSI between smokers and non-smokers. Cigarette smoking is associated with a higher risk of developing both HP and AP and a higher prevalence of mutations in APC and KRAS.

Purpose: Preoperative chemoradiotherapy (CRT) is the treatment of choice for rectal cancer (RC), but half of the patients do not respond, suffer unnecessary toxicities, and surgery delays. We aimed to develop a model that could predict a clinically meaningful response to CRT by using formalin-fixed paraffin-embedded (FFPE) biopsies. Experimental Design: We first carried out an exploratory screening of candidate genes by using SAGE technology to evaluate dynamic changes in the RC transcriptome in selected refractory patients before and after CRT. Next, 53 genes (24 from SAGE and 29 from the literature) were analyzed by qPCR arrays in FFPE initial biopsies from 94 stage II/III RC patients who were preoperatively treated with CRT. Tumor response was defined by using Dworak's tumor regression grade (2–3–4 vs. 0–1). Multivariate Cox methods and stepwise algorithms were applied to generate an optimized predictor of response and outcome. Results: In the training cohort (57 patients), a 13-gene signature predicted tumor response with 86% accuracy, 87% sensitivity, and 82% specificity. In a testing cohort (37 patients), the model correctly classified 6 of 7 nonresponders, with an overall accuracy of 76%. A signature-based score identified patients with a higher risk of relapse in univariate (3-year disease-free survival 64% vs. 90%, P = 0.001) and multivariate analysis (HR = 4.35 95% CI: 1.2–15.75, P = 0.02), in which it remained the only statistically significant prognostic factor. Conclusions: A basal 13-gene signature efficiently predicted CRT response and outcome. Multicentric validation by the GEMCAD collaborative group is currently ongoing. If confirmed, the predictor could be used to improve patient selection in RC studies. Clin Cancer Res; 17(12); 4145–54. ©2011 AACR.

3518Background: Preclinical studies suggest that VEGF blockade can have a role in the preoperative treatment of rectal cancer but how to combine it with chemotherapy (CT) and/or CRT remains controv...

TPS875 Background: Retrospective data suggest that patients with advanced colorectal carcinoma wild-type (WT) for RAS, BRAF or Pi3K achieve increased response rates from anti-EGFR therapy as compared with mutated tumors. Neoadjuvant chemotherapy with oxaliplatin/fluoropyrimidine combination has shown to induce encouraging pathological complete response (pCR) in clinically staged T3 rectal cancer tumours (Schragg et al, JCO 2014 and Fernandez-Martos et al, The Oncologist 2014). We hypothesize this efficacy could be improved in a selected population (quadruple WT [4WT]) combining chemotherapy and anti-EGFR therapy. The objective is to assess the feasibility, efficacy and safety of neoadjuvant therapy with mFOLFOX-6 + P in rectal adenocarcinoma patients of intermediate risk and 4WT. Methods: PIER is a prospective, phase II, single-arm, multicentre, open-label clinical trial (NCT03000374). Key eligibility criteria include patients < 75 years with rectal adenocarcinoma in the middle third , clear mesorectal fascia, candidate for R0 resection with sphincter preservation surgery and absence of mutations in KRAS (exon 2 [codons 12/13], exon 3 [codons 59/61] and exon 4 [codon 117/146]), NRAS ( exon 2 [codons 12/13], exon 3 [codons 59/61] and exon 4 [codons 117/146]), BRAF (exon 15 [codon 600]) and PI3KCA in exons 9 and 20. All pre- and post-treatment MRI scans are centrally reviewed. Treatment: 6 induction cycles of mFOLFOX6 + P every 14 days. After the last cycle, a CT-scan, MRI and rectal endoscopy will be performed and patients will undergo TME surgery within 4 weeks +/- 1 week after the last dose. In case of progression patients will receive standard preoperative chemoradiation. The primary end point is pCR; key secondary end points include R0 resection rate, and clinical complete response. Statistical design: 42 evaluable patients (assuming a P0 of 16% and a P1 35%, with 0.1 alfa and 0.1 beta); 2-stage Simon’s optimal design. Enrolment in PIER is ongoing. Clinical trial information: NCT03000374.

583 Background: Matrilysin can activate phospho-insulin growth factor receptor-1 (pIGF-1R) through IGFBP-3 degradation, releasing IGF-1. Matrilysin per se has shown poor prognosis in mCRC and the co-expression of matrilysin and pIGF-1R (double positivity, DP) correlates with poor prognosis in WT KRAS refractory patients (pts) treated with anti-EGFR in retrospective analyses. We performed a prospective clinical trial in WT KRAS (exon 2) pts, treated with FOLFOX plus panitumumab in first-line therapy to validate those findings. Methods: Positive cases were defined by immunohistochemistry as those with moderate or strong intensity (++/+++) and > 70% expression for both matrilysin and p-IGF-1R (antibody anti-pY1316). The primary end-point was progression-free survival (PFS). Seventy-eight pts and 56 events were required to have an 80% power to detect a difference in median PFS of 6 months (two-sided p< 0.05). Results: We screened 196 mCRC pts in 24 centers between Nov/2010 and Apr/2013 and 78 pts met inclusion criteria (42 non-DP and 36 DP). Median follow-up was 23 months. There were no differences in baseline characteristics [age, sex, liver metastases, lactate dehydrogenase (LDH) levels, performance status and BRAF mutational status] between both groups. There were no differences in the number of FOLFOX-6 and panitumumab cycles received. Cutaneous toxicity was more frequent in DP pts (p = 0.035). Response rate was 80.5% in non-DP and 72.2% in DP patients (p = 0.37). Median PFS (95% CI) was 7.4 months (95%CI 5.2-13.3) in non-DP and 9.6 months (95% CI 6.7-17.5, p = 0.15) in DP patients. Median overall survival was 19.8 months (11.5-26.3) in non-DP pts and 39.1 months (26-NE, p = 0.071) in DP pts. Adjusted HR for PFS was 0.68 (95% CI 0.41-1.12). Adjusted analysis for OS was 0.50 (95% CI 0.27-0.90). Conclusions: We found that co-expression of matrilysin and pIGF-1R is a novel strong prognostic biomarker of survival benefit in mCRC KRAS WT pts treated in first-line with FOLFOX-6 plus panitumumab. Clinical trial information: NCT01288339.

Background: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. Methods: Patients were randomised (2 : 1) to IMM-101 (10 mg ml−l intradermally)+GEM (1000 mg m−2 intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. Results: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44–1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33–0.87, P=0.01). Conclusions: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.

A multi-centred, open-labelled, phase II study containing 46 patients was conducted to evaluate the clinical benefit of gemcitabine (1,400 mg/m2) combined with 5-FU (3 g/m2) in a 48 h continuous infusion (CI). Both drugs were administered on days 1,8 and 15 of every 4 week cycle in chemotherapy-naive patients with locally advanced un-resectable metastatic pancreatic carcinoma. The minimum follow-up was 6 months. Clinical benefit response was the primary endopint and this was achieved by 24.4% of the patients. Quality of life (QoL) improved in 16.6% of patients. Objective response was observed in 7% of the patients. The median progression-free survival (PFS) was 14.4 weeks and the median overall survival (OS) time was 22.7 weeks. One-year survival was 25%. The most frequent grade 3–4 toxicities were neutropenia (4.5%), mucositis (7.5%) and hyperbilirubinaemia (10.5%). This schedule was not superior in terms of clinical benefit, response rate, PFS and OS than standard gemcitabine treatment.

Background 5-fluorouracil (5-FU), irinotecan, and oxaliplatin are the most active drugs in advanced colorectal cancer (CRC), and survival is improved with patient exposure to all of them. The efficacy and safety of an alternating schedule of continuous-infusion 5-FU with leucovorin (LV) plus oxaliplatin (ie, FOLFOX regimen) or irinotecan (ie, FOLFIRI regimen) was assessed in the first-line setting. Patients and Methods Seventy-nine patients with previously untreated, unresectable CRC were included. Treatment consisted of 5-FU/LV (de Gramont schedule) plus oxaliplatin (85 mg/m2) alternated biweekly with the same 5-FU/LV regimen plus irinotecan (180 mg/m2). Treatment was maintained until tumor progression or unacceptable toxicity was noted. Results Median age was 62 years. Performance status was 0/1 in 91% of patients, 63% had 1 organ involved, and 80% had liver metastases. A median of 6 courses per patient (range, 1–9) and a total of 952 infusions were given. The most frequent grade 3/4 toxic events were neutropenia (32%), diarrhea (26%), and asthenia (7%). Grade ½ neurotoxicity was seen in 59% of cases, but no grade 3/4 neurotoxicity was observed. There were no toxic deaths. An objective response rate of 54% (4 complete responses plus 39 partial responses) was attained. Median time to progression and overall survival were 13 months and 18 months, respectively. Conclusion This alternating schedule is active, with efficacy results similar to those seen with sequential protocols, the advantages of less toxicity, and 100% patient exposure to irinotecan and oxaliplatin.

751 Background: In the VELOUR trial, adding Z to FOLFIRI improves OS, PFS and RR in mCRC pts progressing after oxaliplatin ±biologic agents. The ASQoP trial (NCT01571284) was designed to gather safety and QoL data from mCRC in real-life setting. We report data collected by the Spanish investigators. Methods: ASQoP is single-arm, open-label trial evaluating safety and QoL of Z in mCRC pts as 2nd line. Eligible pts received Z (4mg/kg) q2wks on day 1/cycle, followed by FOLFIRI (dosing was at physician’s discretion) until disease progression, unacceptable toxicity, death, or investigator/pt decision. The EQ-5D was used for utility index (UI) measure and the EORTC QLQ-C30 as generic cancer instrument. QoL population consisted of pts completing the questionnaire at baseline and ≥1 assessment post-baseline and received ≥1 part of 1 dose of study treatment. Results: The safety population comprised 77 pts with ≥1 completed cycle of treatment. Grade (G)3/4 AEs were reported in 72.7% of pts (vs 83.5% in VELOUR), being G3 most commonly reported. There was no G4 hypertension, stomatitis, or proteinuria. G4 Diarrhea was found in 1.3% of pts. Mean baseline UI was 0.7 (95% CI, 0.63-0.78) in 51 pts, and remained relatively stable at cycles 3 (n=39) and 7 (n=24), with a mean (±SD) change from baseline of 0.03 (±0.26) and -0.06 (±0.35), respectively. Mean baseline global health status score was 63.1 (95% CI, 55.8-70.4) in 54 pts, and remained stable up to cycle 9 with a mean (±SD) change from baseline of 4.17 (±38). Conclusions: Thisanalysis has identified no new safety signals and suggests an acceptable toxicity profile with a relatively stable UI and QoL in Spanish mCRC pts in the real-life setting. [Table: see text]

Anal carcinoma is an uncommon disorder accounting for less than 2% of large bowel malignancies and 1-6% of anorectal tumours. Its incidence ranges between 0.5 and 1% per 100,000. Local staging should be done with MR imaging using an external pelvic phased-array coil. Treatment strategy should be optimally discussed in a multidisciplinary team. HIV-positive patients seem to achieve similar response rate and overall survival to HIV-negative patients but with increased toxicity and higher local recurrences. Combined modality treatment with irradiation and chemotherapy has resulted in complete response over 90% and local control over 85%. This guide gives recommendations for diagnosis, staging and treatment.