Background Dual blockade therapy encorafenib–cetuximab (EC) was recently established as the standard of care for second- or third-line treatment for BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients based on BEACON phase III study results. The CONFIDENCE study aims to provide insight about the real-world (RW) safety and effectiveness of EC in a Spanish cohort. Materials and methods This retrospective study included BRAFV600E-mutated mCRC patients treated in second line with EC in the RW setting. The primary endpoint (EC effectiveness) was measured by progression-free survival (PFS) and overall survival (OS). Key secondary endpoints were overall response rate (ORR), disease control rate (DCR), duration of response (DoR), potential factors affecting PFS and OS and safety. Results Eighty-one patients were included after at least 5 months of follow-up before study onset, 50.6% female with a median age of 66.1 years. Overall, 65% of patients debuted with synchronous metastatic disease. Patients received a median of six EC cycles. The median OS and PFS after 9.7 months of follow-up were 12.6 and 5.0 months, respectively. The median DoR was 5.8 months. ORR was 33.8% and DCR was 68.8%. Alkaline phosphatase, neutrophil/lymphocyte ratio and three or more metastatic lesions were accurate prognostic factors for OS. Additionally, the presence of liver metastases has prognostic value for PFS. The most reported adverse events (AEs) were skin-related toxicities (43.2%). Grade ≥3 AEs occurred in 13.5% of patients. Conclusions Our results align with the BEACON trial results, confirming the safety and efficacy of EC in the RW setting and additionally provide insight about survival prognostic factors.

Several molecular studies have explored different biomarkers to stratify gastric patients according to their relapse risk. Most of them are difficult to translate into routine practice because of expensive cost or required infrastructure. This study explores the prognosis impact of severe deficit of vitamin D (VD), nutritional, immune and clinical parameters in a score in local gastric cancer (LGC). Vitamin D function is related with carcinogenesis and tumoral progression through gene expression regulation. An ambispective, observational and multicentric study was conducted from 2015 to 2021 in eight university Spanish hospitals of the Galician Research Group on Digestive Tumors (GITuD). Seventy-seven patients with LGC treated with surgery (IQ) or perioperative chemotherapy (CT). Analytical levels and clinical features were measured prior to treatment. Severe deficit of vitamin D (< 1.0 mg/dL; nutritional markers: albumin 1 and severe deficit of vitamin D (assigning one point for each factor). Patients with score 0-1 were stratify as low risk, score 2-3 as moderate risk and score 4 as high risk. Levels of these data were related to time-to-relapse (TTR) and OS by Kaplan-Meier and compared by long-rank test and univariate analysis were carried out. Median age was 68.69 years old, 33.8% female, 60.9% had no comorbidity, 75.7% had PS ≤ 1, 40.3% pts were resected and 59.7% received CT, T3 were similar in CT and IQ groups (51.5% vs 48.5%, p=0.09), intestinal type (57.7% vs 42.3%, p=0.53). Median follow-up: 37.12 months, median DFS: 28.15months (1.05 -55.08), median OS: 41.26 months (26.87-55.64). Severe deficit of vitamin D was correlated with significantly shorter OS: 27.89 vs 54.63 months, p=0.043. Inflammatory, nutritional and clinical markers were correlated with significantly shorter OS: CRP > 1.0 mg/dL (25.88 vs 54.63 vs NA, p=0.014), albumin 1 (20.30 vs 50.04 p=0.004). Univariate analysis indicated that patients with high risk PALV score were associated with significant shorter median OS (8.67months vs 28.25 months moderate risk vs 59.01 months low risk, p Multivariate analysis showed that high risk PALV score was related with poor overall survival compared with moderated (HR: 0.45, 95% CI: 0.003 – 0.594, p= 0.019) and low risk (HR: 0.37, 95% CI: 0.004 – 0.356, p= 0.004) adjusted by sex, CEA level, vascular invasion and treatment (IQ vs CT). Severe deficit of vitamin D and Vitamin D-based score (PALV) were related with statistically significant shorter median OS. This classification system can be translated to routine clinical practice.

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Venous thromboembolism (VTE) is a frequent complication in colorectal cancer (CRC) patients. In these patients, some molecular biomarkers, such as KRAS mutation, have been associated with an increased risk of thrombosis. However, little is known about the characteristics of VTE associated with less prevalent molecular biomarkers. The aim of this analysis is to describe the characteristics of VTE of a cohort of ambulatory CRC patients harboring BRAF mutation. We performed a retrospective review of consecutive patients with BRAF-mutated CRC attended in the Medical Oncology Department of 10 hospitals from the network of the Cancer & Thrombosis Section of the Spanish Society of Medical Oncology (SEOM). Between January 2014 and June 2018, 165 patients were identified and included in the analysis. Mean age was 63.47 years (standard deviation [SD] 11.50 years) and 46.7% (n=77) were men. With a median follow-up of 15 months (interquartile range [IQR] 9-25), forty patients (24.2%) developed a VTE (32.4% pulmonary embolism, 24.3% lower-extremity deep-vein thrombosis [DVT], 2.7% upper-extremity DVT, 16.2% visceral thrombosis, 18.9% catheter related-thrombosis, 5.4% others). Most patients had metastatic disease (90.0%) and was receiving systemic therapy (73.7%). Median time from CRC diagnosis to VTE was 5.06 months (IQR 2.85-10.81). 50.0% of events were diagnosed incidentally and 75.0% in the ambulatory setting. Most patients (87.5%) received anticoagulant treatment (low-molecular-weight heparins [LMWH] 33 patients, direct oral anticoagulants [DOACs] 1 patient, others 1 patient), 35.9% for more than 6 months. 6 patients (15.4%) experienced VTE recurrence and 7 patients (19.4%) bleeding (mayor or fatal bleeding 4 patients). Median survival was 20.86 months for non-VTE patients and 11.30 months for VTE patients (hazard-ratio [HR] 2.13; CI 95% 1.38-3.28; p=0.001). VTE is associated with increased morbidity and mortality in patients with BRAF-mutated CRC.

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Anaemia is defined by the presence of haemoglobin (Hb) levels < 13 g/dL in men and 12 g/dL in women. Up to 39% of cancer patients present it at the time of diagnosis and up to 40% have iron deficiency. Anaemia causes fatigue, functional deterioration and a reduction in the quality of life; it has also been associated with a poorer response to anti-tumour treatment and lower survival. Basic diagnostic tests for anaemia are simple and should be a routine part of clinical practice. These guidelines review the available evidence on the use of different therapies for treating anaemia: erythropoiesis-stimulating agents, iron supplements, and transfusion of blood products.

RAMIS was an observational, retrospective, single-arm study, based on medical record review of patients with advanced gastric cancer (AGC) or gastro-esophageal junction (GEJ) adenocarcinoma treated with ramucirumab in real clinical practice. The observational study period was from December 2015 to December 2018. A total of 20 Spanish hospitals participated in the study, collecting data from 317 patients (297 treated with ramucirumab with paclitaxel and 20 patients treated with ramucirumab as monotherapy). The aim of this sub-analysis was to describe the effectiveness in a specific subgroup of patients (those treated with ramucirumab in combination with paclitaxel, ECOG 0/1), as well as effectiveness variables assessed by available imaging. In the RAINBOW study, a randomised, placebo-controlled, double-blind clinical trial, including ECOG 0/1 patients, ramucirumab showed a median progression-free survival (PFS) of 4.4 months (95% CI: 4.2 – 5.3) and a median overall survival (OS) of 9.6 (95% CI: 8.5 – 10.8) according to RECIST v1.1 criteria. A sub-analysis of patients treated with ramucirumab in a combination regimen, ECOG 0/1 and effectiveness variables evaluated by imaging available (according to RECIST v1.1 criteria) was performed. A descriptive analysis was carried out to present patients' sociodemographic and clinical characteristics, treatment patterns and ramucirumab effectiveness. Kaplan-Meier curves were used for time-to-event analysis (time on treatment, time to disease control, PFS and OS). A total of 173 patients fulfilled the criteria to be included in the sub-analysis. At time of analysis a total of 101 patients had died (72 patients had censored data). Main characteristics at baseline were: 72.3% male, mean (SD) of 61.9 (10.9) years, 74.0% with AGC diagnosis, mean (SD) time since metastatic disease 1.7 (2.2) years. Patients had ECOG-0 (26.6%), ECOG-1 (73.4%), primary tumour still present (60.7%), poorly differentiated tumours (40.5%) and diffuse histological subtype (23.7%). Prior surgery was performed in 49.7% of patients and previous treatments included chemotherapy (96.5%) [28.1% neoadjuvant, 23.4% adjuvant and 74.9% as first-line treatment], targeted therapy (12.1%) and radiotherapy (11.6%). 86.1% of patients received ramucirumab in combination with paclitaxel throughout the treatment, while 13.9% began receiving this combination and later switched to monotherapy with ramucirumab. The median (interquartile range) number of cycles received was 4.0 (3.0;6.0), with a median time on treatment of 3.8 (95% CI: 3.3-4.3) months. One hundred out of the total sample (57.8%) showed disease control (partial response/complete response/or stable disease) during the follow-up period, the median time to disease control being 3.2 months [95% CI 2.8–4.2] months. Median PFS and OS values were 4.9 (95% CI 3.9–5.4) and 10.3 (95% CI 8.5-12.3) months, respectively. PFS and OS rates at 3/6/9/12 months were 70.1%, 37%, 21.5% and 15.1% and 95.3%, 74.6%, 56.5% and 44.2%, respectively. Median PFS and OS values according to ECOG status, were 5.9 [95% CI 5.2–6.8] and 11.4 [95% CI 9.6–22.7] months in ECOG-0 patients and 3.8 [95% CI 3.3–4.9] and 9.7 [95% CI 7.6-12.3]) in ECOG-1 patients. In real-life conditions, patients with an ECOG status of 0/1 treated with ramucirumab plus paclitaxel showed effectiveness data consistent with the ramucirumab RAINBOW clinical trial.

The study of RAS status using circulating tumor DNA (ctDNA) provides a good alternative for the detection and monitoring of RAS mutations during therapy course. Liquid biopsy has the advantage of being less invasive than conventional tissue biopsy. Therefore, it is necessary to determine the degree of concordance of RAS status between plasma and tissue samples from metastatic colorectal cancer (mCRC) patients. We conducted a study to evaluate the concordance of RAS status between plasma and tissue samples of 301 patients from several hospitals in Galicia, Northwest of Spain. RAS genotyping in plasma was performed using the OncoBEAM RAS CRC kit (Sysmex) and compared to the standard of care technology for FFPE-tissue analysis. Clinical data were collected from electronic reports from each patient. We analyzed the clinical profiles of the mCRC patients to investigate the causes of discordance. The overall percent of RAS agreement was 84.4%, with a sensitivity of 81.3% and a specificity of 88.5%. Evaluating the clinical features of the patients, the absence of liver metastasis was a significant factor of discordance of RAS status (71% vs 28%, p<0.0001). Patients with peritoneal disease alone showed the lowest level of agreement (71.4%), followed by those with lung metastasis alone (72%), as compared with patients with liver metastasis alone (88.9%). Taking into account the diagnosis timing of stage IV, the concordance (75.9% vs 88.4%) and the sensitivity (68.1 vs 86.3) were significantly lower in metachronous than synchronous patients. The overall concordance between plasma and tissue RAS mutation supports liquid biopsy technology as an alternative to tissue testing for RAS characterization in mCRC patients, especially in patients with liver metastasis. The RAS status obtained from plasma of patients with peritoneal or lung diseases, and particularly with those of metachronous stage IV, should be considered cautiously. These results reinforce the use of liquid biopsy as a non-invasive tool for guiding targeted therapy in selected patients.

Despite the fact that the prognostic relevance of the derived neutrophil to lymphocyte ratio (dNLR) in the metastatic colorectal cancer (mCRC) setting has been examined by several groups, there is a lack of homogeneity in the cut-off threshold applied. In this study, we aimed to validate the dNLR as a prognostic biomarker in the mCRC setting by using a previously established cut-off threshold. 70 patients from the Onco-CHUS mCRC cohort treated with oxaliplatin-based first-line therapy were studied. The dNLR was calculated from the pre-first-line therapy initiation blood count and categorized as high (≥2.2) or low (< 2.2). The Cox proportional hazards model, adjusting for known prognostic factors in mCRC, was used to assess the prognostic value of the dNLR. The population distribution by the dNLR was 48.6% (34) patients in the high dNLR group and 47.2% (36) in the low dNLR group. A high dNLR was independently associated with poor overall survival [HR = 2.71 (95% CI, 1.3512 - 5.4402; p = 0.0050)]. The only other statistically significant factor in multivariate analysis was carcinoembryonic antigen (>5 vs. ≤5) [HR = 3.23 (95% CI, 1.252 – 8.309; p = 0.0153)]. We validate for the first time, to the best of our knowledge, the prognostic value of the dNLR (2.2) in a population-based cohort of mCRC patients treated with oxaliplatin-based therapy in the first-line setting.

Venous thromboembolic disease (VTED) is a common and clinically important complication in patients with cancer, contributing to its mortality and morbidity. Direct oral anticoagulant agents (DOACs), including direct thrombin inhibitors and direct factor Xa inhibitors, are as effective as vitamin K antagonists for the treatment of VTED and are associated with less frequent and severe bleeding. They have advantages over low-molecular-weight heparin, but comparative long-term efficacy and safety data are lacking for these compounds. Recent randomized clinical trials suggest a role for DOACs in the treatment of VTED in patients with cancer. This review will discuss the existing evidence and future perspectives on the role of DOACs in the treatment of VTE based on the current evidence about their overall efficacy and safety and the limited information in patients with cancer; in addition, we will briefly review their pharmacokinetic properties with special reference to potential interactions.

The study of RAS status using circulating tumor DNA (ctDNA) provides a good alternative for the detection and monitoring of RAS mutations during therapy course. Liquid biopsy has the advantage of being less invasive than conventional tissue biopsy. Therefore, it is necessary to determine the degree of concordance of RAS status between plasma and tissue samples from metastatic Colorectal Cancer (mCRC) patients. We already know that sidedness (right or left) is related with different molecular biology, conditioned predictive and prognostic factors along the course of the disease. We conducted a study to evaluate the concordance of RAS status between plasma and tissue samples of 301 patients from several hospitals in Galicia, Northwest of Spain. RAS genotyping in plasma was performed using OncoBEAM RAS CRC kit (Sysmex) and compared to the standard of care technology for FFPE-tissue analysis. Clinical data were collected from electronical reports from each patient. We analyzed the clinical profiles of the mCRC patients to investigate the causes of discordance, such as origin side of the primary tumour and the site of metastasis. Tumours from left-side were more concordant in the RAS status between tissue and blood analysis (91.3%), following by rectum (83.5%) and right-side (76.9%) (table). The mCRC subpopulation diagnosed of right-side primary tumours presented more frequently spread to peritoneal lesions and patients with rectum primary presented higher frequency of lung metastatis. Both peritoneal and lung metastasis had less concordance than liver.Table: 437PConcordance between analysis of the RAS locus in solid tissue and blood liquid biopsyPrimary OriginConcordance%Sensitivity%Specificity%Left-sided91.387.195.3Right-sided76.973.385Rectum83.582.585 Open table in a new tab Variations in the anatomical location of metastases (lung and peritoneal disease) and primary sidedness (right-side and rectum) were associated with the lack of concordance, conditioned by the absence of liver metastasis in discordant cases.

After regorafenib (REG) was approved due to a survival benefit in refractory metastatic colorectal cancer (mCRC), some predictive markers such as the FAS and FAS-CORRECT scores have been proposed to improve patient selection. We have explored the survival and safety outcomes of REG in a real-life setting and tried to find and validate predictive markers. We conducted a retrospective, multicentre, observational study of pts with mCRC treated with REG after failure to standard therapies as part of routine clinical practice at seven hospitals from the Galician Research Group on Digestive Tumors (GITuD). We recorded 130 pts treated with REG between September 2013 to December 2019. Median age was 63 years (range 27-79 years), 65.4% male, ECOG PS0/1/2 19.2/75.4/4.6%, 45.4% left-sided location, 78.5% low grade, 55.4% RASmt and 1.5% BRAFmt, 58.5% synchronous presentation, 76.2% primary tumor resection, 32.3% >3 metastatic locations and 75% liver metastases. Median prior lines of treatment were 3 (range 2-8) including TAS-102 in 29.2% of pts. Initial dose: 53.1% pts full standard dose, 14.6% dose level -1, 16.9% dose level -2. 15.4% pts used a dose-escalation strategy (ReDOS strategy). Dose selection 60 (OS 5.2 vs 9.1; p 85 (OS 6.4 vs 9.0; p= 0.016) achieved prognostic significance. Median of weeks until reimbursement approval was 3.1 weeks. Patients who had to wait longer to start treatment had lower OS (5.2 vs 7.8; p=0.006) despite having similar clinical characteristics. The results of our series corroborate that REG offers and modest survival benefit in all patients with refractory mCRC, which can be significant in selected patients. Although we have not been able to validate the FAS and FAS-correct algorithms, our results suggest that they could be useful and some important parameters that reflect disease burden are confirmed to be predictors of poor prognosis. Finally, we have identified for the first time in our study, that delay of treatment due to reimbursement reasons is an independent prognostic factor.

The association between venous thromboembolism (VTE) and cancer has been recognized for more than 100 years. Numerous studies have been performed to investigate strategies to decrease VTE incidence and to establish whether treating VTE impacts cancer progression and overall survival. Accordingly, it is important to understand the role of the hemostatic system in tumorigenesis and progression, as there is abundant evidence associating it with cell survival and proliferation, tumor angiogenesis, invasion, and dissemination, and metastasis formation. In attempts to further the scientific evidence, several studies examine survival benefits in cancer patients treated with anticoagulant therapy, specifically treatment with vitamin K antagonists, unfractionated heparin, and low-molecular-weight heparin. Several studies and meta-analyses have been conducted with a special focus on brain tumors. However, no definitive conclusions have been obtained, and more well-designed clinical trials are needed.

Glioblastoma multiforme (GBM) is the most common brain tumor in adults. The role of high in normal-1 (HIN-1) as a potential biomarker in combating this disease is being described for the first time in this study. A combination of O6-methylguanine DNA methyltransferase (MGMT) and HIN-1 methylation could be a possible biomarker in therapy choice. Interestingly, survival data shows a similar trend for the methylation of MGMT and for unmethylation of HIN-1 and vice versa. Eighty-eight paraffin-embedded brain tumors were analyzed to screen methylation rates of different genes and evaluate the association between genes methylation and clinicopathologic variables. Our study is the first of its kind to indicate that MGMT and HIN-1 methylation status are inverted (97.7% of methylated ones) and could be new markers in the study of GBM prognosis, especially in the therapy selection.