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Retrospective studies and meta-analyses suggest that upfront primary tumour resection (UPTR) confers a survival benefit in patients with asymptomatic unresectable metastatic colorectal cancer (mCRC) undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This retrospective study aimed to analyse the survival benefit of UPTR in terms of tumour location and mutational status, in patients with synchronous mCRC receiving chemotherapy and targeted therapy.Survival was analysed in a pooled cohort of synchronous mCRC patients treated with a first-line anti-VEGF or anti-EGFR inhibitor in seven trials of the Spanish TTD group, according to UPTR, tumour-sidedness and mutational profiling.Of 1334 eligible patients, 642 (48%) had undergone UPTR. UPTR was associated with significantly longer overall survival (OS; 25.0 vs 20.3 months; HR 1.30, 95%CI 1.15-1.48; p 0.0001). UPTR was associated with significant OS benefit in both left-sided (HR 1.38, 95%CI 1.13-1.69; p = 0.002) and right-sided (HR 1.39, 95%CI 1.00-1.94; p = 0.049) tumours, RASwt (HR 1.29, 95%CI 1.05-1.60; p = 0.016) and BRAFwt (HR 1.49, 95%CI 1.21-1.84; p = 0.0002) tumours, and treatment with anti-EGFRs (HR 1.47, 95%CI 1.13-1.92; p = 0.004) and anti-VEGFs (HR 1.25, 95%CI 1.08-1.44; p = 0.003). Multivariate analysis identified number of metastatic sites, RAS status, primary tumour location and UPTR as independent prognostic factors for OS.Considering the selection bias inherent to this study, our results support UPTR before first-line anti-EGFR or anti-VEGF targeted therapy in right and left-sided asymptomatic unresectable synchronous mCRC patients. RAS/BRAF mutational status may also influence UPTR function.

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

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment—panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA

Objectives The prevalence, clinical characteristics and prognosis of pleural effusions (PEs) associated with ovarian cancer (OC) have seldom been addressed systematically, as in the current investigation. Methods All records of consecutive women with a newly diagnosed OC in our institution over a 13-year period were retrospectively reviewed. Features of PEs on CT scans, pleural fluid analyses, need for definitive therapy of PEs, and the influence of PEs on the overall survival (OS) and progression-free survival (PFS) were evaluated. Results PEs were observed in 81 (43%) of 189 women with OC, either at presentation of cancer (55 patients) or during the course of the disease (26 patients). The causes of PEs were malignancy (55.5%), unknown (37%), or surgery-related (7.4%). The sensitivity of the cytologic diagnosis of malignant PEs was 79.1%. Sixty percent of malignant PEs required pleurodesis or indwelling pleural catheters for symptomatic relief. The presence of ascites strongly predicted PE development (odds ratio 43.2). Women with PEs fared much worse compared with those without PEs, in terms of OS (26.7 vs. 90.4 months), PFS (9.8 vs. 55.3 months) and tumor recurrences (86.4 vs. 43%). In multivariate analyses, PE remained as a relevant independent variable associated with poor outcome (hazard ratio 9.73 for OS, and 3.87 for PFS). Notably, PEs small enough to preclude tapping, and thus of unknown origin, had a similar bad prognosis as malignant PEs. Conclusions OC patients with PEs experience decreased survival, including those with trace effusions not amenable to tapping.

Breast cancer (BC) is the most diagnosed cancer worldwide and one of the main causes of cancer deaths. BC is a heterogeneous disease composed of different BC intrinsic subtypes such as triple-negative BC (TNBC), which is one of the most aggressive subtypes and which lacks a targeted therapy. Recent comprehensive analyses across cell types and cancer types have outlined a vast network of protein–protein associations between transcription factors (TFs). Not surprisingly, protein–protein networks central to oncogenesis and disease progression are highly altered during TNBC pathogenesis and are responsible for the activation of oncogenic programs, such as uncontrollable proliferation, epithelial-to-mesenchymal transition (EMT) and stemness. From the therapeutic viewpoint, inhibiting the interactions between TFs represents a very significant challenge, as the contact surfaces of TFs are relatively large and featureless. However, promising tools have emerged to offer a solution to the targeting problem. At the clinical level, some TF possess diagnostic and prognostic value in TNBC. In this review, we outline the recent advances in TFs relevant to TNBC growth and progression. Moreover, we highlight different targeting approaches to inhibit these TFs. Furthermore, the validity of such TFs as clinical biomarkers has been explored. Finally, we discuss how research is likely to evolve in the field. This work is funded by the Instituto de Salud Carlos III (Spanish Health Ministry) with a Miguel Servet fellowship (CP20/0039) and the project PI21/00438 which are co-funded by the European Social Fund (ESF) “Investing in your future” and the European Union, the Emergent Research Group Recognition Award from the University and Research Grants Management Agency of Catalonia (Spain) under Grant 2017SRG1620. The research was supported by CERCA Programme of Generalitat de Catalunya and the IRBLleida-Fundació Dr. Pifarré.

[Background] Aflibercept is an antiangiogenic drug against metastatic colorectal cancer (mCRC) combined with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI); however, no antiangiogenic biomarker has yet been validated. We assessed aflibercept plus FOLFIRI, investigating the biomarker role of baseline vascular endothelial growth factor A (VEGF-A) and angiotensin-converting enzyme (ACE)., [Methods] Phase II trial in oxaliplatin-treated mCRC patients who received aflibercept plus FOLFIRI. The reported 135 ng/mL ACE cut-off was used and ROC analysis was performed to assess the optimal VEGF-A cut-off for progression-free survival (PFS). Overall survival (OS), time to progression (TTP), time to treatment failure (TTF), overall response rate (ORR) and disease control rate (DCR) were also assessed., [Results] In total, 101 patients were followed for a median of 12 (6–17) months. The 1941 pg/mL VEGF-A was an optimal cut-off, with a longer median PFS when VEGF-A was, [Conclusions] This study supports aflibercept plus FOLFIRI benefits, suggesting VEGF-A as a potential biomarker to predict better outcomes., This work was supported by the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD) through an unrestricted grant provided by Sanofi (no grant number is applicable).

Simple Summary Colorectal cancer is a disease associated with a high mortality rate. During the tumorigenic process, several factors and signaling molecules produced by tumor cells and the cells that surround them (forming the tumor microenvironment) regulate and modify cancer proliferation and metastasis. These regulatory agents include reactive oxygen species (ROS), which are involved in different metabolic networks and in the maintenance of cell homeostasis. Their excess, however, can cause oxidative stress and be detrimental to the cell. In fact, oxidative stress has been linked to several processes related to colorectal cancer initiation and progression. The different activities where ROS are involved suggest that ROS level modulators could be used to benefit cancer patients. Abstract Colorectal cancer (CRC) is the fourth most common cause of cancer deaths worldwide. Although screening programs have reduced mortality rates, there is a need for research focused on finding the main factors that lead primary CRC to progress and metastasize. During tumor progression, malignant cells modify their habitat, corrupting or transforming cells of different origins and creating the tumor microenvironment (TME). Cells forming the TME like macrophages, neutrophils, and fibroblasts generate reactive oxygen species (ROS) that modify the cancer niche. The effects of ROS in cancer are very diverse: they promote cellular proliferation, epithelial-to-mesenchymal transition (EMT), evasion of cell death programs, migration, and angiogenesis. Due to the multifaceted role of ROS in cancer cell survival and function, ROS-modulating agents such as antioxidants or pro-oxidants could have therapeutic potential in cancer prevention and/or as a complement to systemic treatments. In this review, we will examine the main ROS producer cells and their effects on cancer progression and metastasis. Furthermore, we will enumerate the latest clinical trials where pro-oxidants and antioxidants have therapeutic uses in CRC.

Purpose The phase III ToGA trial established cisplatin, fluoropyrimidine and trastuzumab as the standard treatment in HER2-positive advanced gastric cancer (AGC). However, as demonstrated in HER2-negative AGC, oxaliplatin-based regimens could improve tolerance remaining effective. The aim of this trial was to explore the potential activity and safety of capecitabine, oxaliplatin (XELOX) and trastuzumab in patients with HER-2 positive advanced gastric cancer. Methods We conducted a multicentre, prospective, non-randomised, non-controlled, open-label and national (Spanish) phase II study. Patients with HER2-positive advanced gastric or gastro-oesophageal junction (EGJ) cancer received XELOX and trastuzumab as first-line treatment. Primary endpoint was objective tumour response rate (ORR). Results 45 patients from ten hospitals in Spain were included from September 2011 to December 2013. Median age was 65 years, 82.2% were male, 69% had gastric cancer and 31% had EGJ tumours. At a median follow-up of 13.7 months (7.1–20.9), the estimated median progression-free survival and overall survival were 7.1 (95% CI 5.5–8.7) and 13.8 months (95% CI 10.1–17.4), respectively, with 8.9%, 37.8% and 31.1% of patients achieving complete response, partial response and stable disease. Regarding safety, 44.4% of the patients had grade 3 or greater adverse events, being the most frequent diarrhoea (26.6%), fatigue (15.5%), nausea (20%) and vomiting (13.3%). Only two patients (4.4%) developed asymptomatic grade 2 left ventricle ejection fraction reduction. Conclusions XELOX-trastuzumab is a promising and effective therapy as first-line treatment for patients with HER2-positive AGC, with comparable results to the ones obtained with other “platinum-based” regimens. This scheme is feasible and tolerable with a low incidence of cardiac toxicity.

Simple Summary Malignant pleural effusion is a common complication arising as the natural progression of many tumors, such as lung cancer. When this occurs, the common protocol consists of analyzing the pleural fluid for the presence of malignant cells. However, on many occasions no malignant cells are found despite a clear suspicion of cancer. Thus, the current diagnostic methodology is imperfect and more precise methods for the identification of malignancy are needed. Nonetheless, these methods are often invasive, which may be counterproductive, especially for patients with poor health condition. These concerns have made clinicians consider alternative non-invasive strategies to diagnose cancer using the generally abundant pleural fluid (e.g., liquid biopsy). Thus, a liquid sample can be analyzed for the presence of cancer footprints, such as circulating malignant cells and tumor nucleic acids. Herein, we review the literature for studies considering pleural fluid as a successful source of liquid biopsy. Abstract Liquid biopsy is emerging as a promising non-invasive diagnostic tool for malignant pleural effusions (MPE) due to the low sensitivity of conventional pleural fluid (PF) cytological examination and the difficulty to obtain tissue biopsies, which are invasive and require procedural skills. Currently, liquid biopsy is increasingly being used for the detection of driver mutations in circulating tumor DNA (ctDNA) from plasma specimens to guide therapeutic interventions. Notably, malignant PF are richer than plasma in tumor-derived products with potential clinical usefulness, such as ctDNA, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), and circulating tumor cells (CTC). Tumor-educated cell types, such as platelets and macrophages, have also been added to this diagnostic armamentarium. Herein, we will present an overview of the role of the preceding biomarkers, collectively known as liquid biopsy, in PF samples, as well as the main technical approaches used for their detection and quantitation, including a proper sample processing. Technical limitations of current platforms and future perspectives in the field will also be addressed. Using PF as liquid biopsy shows promise for use in current practice to facilitate the diagnosis and management of metastatic MPE.

Background: The treatment of luminal metastatic breast cancer is based on endocrine therapy and chemotherapy treatment is limited to the progression of this treatment. Materials & methods: We analyzed the efficacy of treatment with bevacizumab plus paclitaxel in 43 patients with hormone receptor-positive and HER2-negative metastatic breast cancer. Discussion: Paclitaxel plus bevacizumab combination is a useful treatment in metastatic luminal breast cancer with an impressive overall survival of 31 months, similar to combination to endocrine therapy and targeted therapy in first line. In patients with hormone resistance, endocrine therapy saw worse results thus the taxol plus bevacizumab combination could be a better option. This combination does not influence the results of subsequent treatments; therefore, it could provide a good option for patients., Lay abstract Luminal metastatic breast cancer often needs endocrine therapy. However, there is a subgroup with worse prognosis where endocrine therapy lacks benefit. This subgroup needs an optimal chemotherapy regimen. In our series we show a benefit in this subgroup with the bevacizumab plus taxol combination, with a good tolerability profile and improved overall survival.

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.

Simple Summary Metastasis is responsible for most of the deaths related to cancer patients. One of the hypotheses that explains the initiation of metastasis is a process called epithelial-to-mesenchymal transition (EMT), in which tumor cells change shape and acquire more aggressive properties that allows them to escape from the tumor and invade other organs. This also occurs in colorectal cancer (CRC), one of the most diagnosed types of cancer worldwide. During the past years, many scientists have discovered that certain molecules or biomarkers participating in this EMT process are able to predict the severity of the cancer and this is helping clinicians to manage treatments. Nevertheless, we think that all this information needs a detailed revision because a lot of biomarkers have been described but have not been analyzed whether they interact with each other in the same mechanism or not. Herein, we performed a bibliographic revision on this topic and identified a great number of biomarkers participating in oxidative stress, a cellular phenomenon that could have a role on the patient’s prognosis because its presence or absence on the patient’s tumor or blood had an influence on survival. Our findings suggest that oxidative stress deserves further study to understand metastasis better and to predict prognosis in a more efficient way. Abstract Epithelial-to-mesenchymal transition (EMT) is one of the most accepted mechanisms leading to metastasis, which is responsible for most of the cancer-related deaths. In order to identify EMT-related biomarkers able to predict clinical outcomes in colorectal cancer (CRC), a systematic review and meta-analysis of prognostic factors associated to overall survival (OS) and progression free survival (PFS) was conducted. The systematic literature search included studies from June 2014 to June 2019 available at PubMed and Scopus databases. Meta-analysis was performed for those markers appearing in minimum three works with a total number of 8656 participants. The rest were enlisted and subjected to functional enrichment. We identified nine clinical biomarkers and 73 EMT-related molecular biomarkers associated to OS and/or PFS in CRC. The significant enrichment of biomarkers found involved in cellular oxidoreductase activity suggests that ROS generation plays an active role in the EMT process. Clinical practice needs new biomarkers with a reliable prognostic value able to predict clinical outcomes in CRC. Our integrative work supports the role of oxidative stress in tumorigenesis and EMT progress highlighting the importance of deciphering this specific mechanism to get a better understanding of metastasis.

Neoadjuvant chemotherapy (NAC) is an optimal option in early breast cancer, but in ER-positive/HER2-negative (luminal) is still controversial, although a survival benefit has recently been observed when a histological response by Symmans’ method type 0 or I is achieved. The 21-gene Oncotype DX Breast Recurrence Score® assay (Oncotype DX®) is a validated test to assess the survival benefit of adjuvant chemotherapy in these patients but its role in the neoadjuvant setting is less established. We analyzed the results of the Oncotype DX® test in a cohort of 122 consecutive patients selected to receive NAC based on classical clinicopathological parameters and the correlation between the Oncotype DX® results and the pathological response assessed by Symmans’ method. Median age was 56.5 (range 31–84) years. Initial tumor size was T1 ( 25 in 43 (35.2%). Considering the Oncotype DX test results, neoadjuvant chemotherapy was administered to 60 patients (49%), 11 (9%) received adjuvant chemotherapy and 51 (42%) no chemotherapy. Testing with the assay has therefore led to 42% fewer chemotherapy treatments. Among 60 patients receiving NAC, pathologic response was achieved for 5 patients (8.3%) with RCB-0 and 15 RCB-1 (25%). We did not find any pathological response RCB-0 and RCB-I in the 20 patients who received NAC and had a Recurrence Score result 21 or 25 according to menopausal status) it was 12% (5/40) RCB-0 and 40% (16/40) RCB-I. Conclusions The Oncotype DX test could be a useful tool to select patients candidates for neoadjuvant chemotherapy in luminal breast cancer. Neoadjuvant chemotherapy could be avoided in 42% of patients. We found a correlation between Recurrence Score results and pathological response with 14% of RCB-0 and a total of 47% of significant pathological response type RCB-0 and RCB-I in patients with highest Recurrence Score results. Interestingly, patients with a Recurrence Score result inferior to 32 did not get any histological response type 0 and only 5% RCB-I., Highlights • All comments are reviewed in the main manuscript text. • We have introduced changes in tables and Figures according Editor′s comments. • It is an academic study and we don′t received any founding and we appreciate all patients who participated.

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 .

This is a post hoc analysis of biomarkers from a large cohort of patients with chemo-naive metastatic colorectal cancer. Both high baseline circulating tumor cell count and RAS mutated were associated with clinical or pathologic features classically associated with poor prognosis. Selection of high- and low-risk populations may help to individualize approaches in the future. Background: Clinicopathologic characteristics and prognostic and predictive factors offer valuable guidance when selecting optimal first-line treatment in patients with metastatic colorectal cancer (CRC). The association between baseline circulating tumor cell (bCTC) count, molecular tumor profile, and clinicopathologic features was analyzed in a chemo-naive metastatic CRC population. Patients and Methods: A total of 1202 patients from the Spanish VISNU-1 (FOLFIRINOX/bevacizumab vs. FOLFOX/bevacizumab) and VISNU-2 (FOLFIRI/bevacizumab vs. FOLFIRI/cetuximab; RAS-wildtype) studies were analyzed for mutational status and bCTC count. The association between clinicopathologic characteristics and bCTC count, mutational status, and microsatellite instability (MSI) was analyzed in 589 eligible patients. Results: Interestingly, 41% of the population studied presented >= 3 bCTC count. bCTC count >= 3 was associated with worse performance status (according Eastern Cooperative Oncology Group scale), stage IV at diagnosis, at least 3 metastatic sites, and elevated carcinoembryonic antigen (CEA) levels; but not with RAS or BRAF mutations or high MSI. BRAFmut (BRAF mutated) tumors were associated with right-sided primary tumors, peritoneum, distant lymph node metastasis, and less frequent liver involvement. RASmut (RAS mutated) was associated with worse performance status; stage IV at diagnosis; right-sided primary tumors; liver, lung, and bone metastases; at least 3 metastatic sites; and elevated CEA, whereas PIK3CAmut (PIK3CA mutated) tumors were associated with right-sided primary tumors, high CEA serum levels, and older age. High MSI was associated with right-sided primary tumors, distant lymph nodes metastasis, and lower CEA levels. Conclusions: In our study, elevated bCTCs and RASmut were associated with clinicopathologic features known to be associated with poor prognosis; whereas the poor prognosis of BRAFmut tumors in chemo-naive metastatic CRC is not explained by associations with poor clinicopathologic prognostic factors, except right-sided primary tumors. (C) 2020 Elsevier Inc. All rights reserved.

Malignant pleural effusions (MPE) may either coincide with or follow the diagnosis of a primary tumor. Whether this circumstance influences prognosis has not been well substantiated. Retrospective review of all consecutive patients who were cared for at a Spanish university hospital during an 11-year period and received a diagnosis of MPE. Of 401 patients, the MPE was the first evidence of cancer in 265 (66%), and it followed a previously diagnosed neoplasm in 136 (34%). Lung cancer predominated in the former group (131, 50%), and breast cancer in the latter (55, 40%). MPE that were the presenting manifestation of hematological and ovarian tumors had a statistically significant survival advantage as compared to those which developed in patients from a previously known cancer (respective absolute differences of 41 and 20 months; p

Resumen Objetivo Establecer la rentabilidad diagnostica de la medicion de CEA y CA 15-3 en el liquido pleural (LP) para identificar malignidad, asi como el valor adicional de estos marcadores en pacientes con derrame pleural maligno (DPM) y citologia pleural falsamente negativa. Metodo Se determinaron las concentraciones de CEA o CA 15-3 en el LP de 1.575 pacientes con exudados no purulentos, de los que 549 tenian DPM demostrados, 284 derrames probablemente malignos y 742 derrames benignos. Se buscaron puntos de corte 100% especificos para dichos marcadores, de forma que no pudieran ser superados por ningun derrame benigno. Resultados El 41, 40 y el 60% de los pacientes con DPM tenian concentraciones pleurales elevadas de CEA (>45 ng/mL), CA 15-3 (>77 UI/L), o de alguno de los anteriores, respectivamente. Estos porcentajes fueron del 30, 19 y 41% en los DPM con biopsia pleural positiva y estudios citologicos del LP negativos; y del 24, 13 y 35% en los derrames considerados clinicamente malignos, pero sin demostracion citohistologica. Los marcadores tumorales no tuvieron utilidad en linfomas ni mesoteliomas. El area bajo la curva de eficacia diagnostica (AUC) del CEA fue de 0,819 (IC 95%: 0,793-0,845) y la del CA 15-3 de 0,822 (IC 95%: 0,796-0,847). Globalmente, el uso adicional de los marcadores tumorales incremento el diagnostico de malignidad un 14% respecto a la citologia pleural de forma aislada. Conclusiones La determinacion de CEA y CA 15-3 en LP puede complementar a la citologia pleural en la identificacion de los DPM.

Objective To establish the diagnostic accuracy of pleural fluid (PF) CEA and CA 15-3 in identifying malignancy, and to determine the additional value of these markers in patients with malignant pleural effusions (MPEs) with false negative results from cytological fluid examination. Methods PF concentrations of CEA and/or CA 15-3 were determined in 1575 patients with non-purulent exudates, 549 of whom had confirmed MPEs, 284 probable MPEs, and 742 benign effusions. Tumor marker cut-off points were set to ensure 100% specificity for malignant effusion. Results The 41%, 40% and 60% of MPE patients had high PF levels of CEA (>45 ng/mL), CA 15-3 (>77 UI/l) or both, respectively. These percentages were 30%, 19% and 41% in MPEs with positive pleural biopsy and negative PF cytology; and 24%, 13% and 35% in clinical MPEs without histocytological confirmation. Tumor markers were of no value in lymphomas and mesotheliomas. The area-under-the-curve for CEA was 0.819 (95% CI: 0.793–0.845) and for CA 15-3, it was 0.822 (95% CI: 0.796–0.847). The use of tumor markers compared to cytology alone, increased the diagnosis of malignancy by 14%. Conclusions Measurements of PF CEA and CA 15-3 may complement pleural cytology in the identification of MPEs.

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

BACKGROUND Indwelling pleural catheters (IPCs) offer ambulatory management of symptomatic persistent pleural effusions, but their widespread use is somewhat hampered by the risk of pleural infection and the inconvenience of carrying a catheter for a prolonged period of time. Factors associated with these 2 limitations were analyzed in this study. METHODS Retrospective review of consecutive patients who had undergone IPC placement over a 5 ½-year period. Time to IPC removal was analyzed with the Fine and Gray competing risks survival model, with competing risk being death. A binary logistic regression method was used to evaluate factors influencing IPC-related pleural infections. RESULTS A total of 336 IPCs were placed in 308 patients, mostly because of malignant effusions (83%). IPC removal secondary to pleurodesis was achieved in 170 (51%) procedures at a median time of 52 days. Higher rates of IPC removal were associated with an Eastern Cooperative Oncology Group (ECOG) grade of 0 to 2 [subhazard ratio (SHR)=2.22], an expandable lung (SHR=1.93), and development of a multiseptated pleural space (SHR=1.37). IPC-related pleural infections occurred in 8% of the cases, and were more often seen in hepatic hydrothoraces [odds ratio (OR)=4.75] and pleural fluids with a C-reactive protein

BackgroundTreatment of frail patients with advanced colorectal cancer (CRC) is controversial. This pilot phase II trial aimed to assess the efficacy and safety of regorafenib when administered in first-line to frail patients with advanced CRC.MethodsFrail patients without prior advanced colorectal cancer treatment were included in the study. Definition of frailty was defined per protocol based on dependency criteria, presence of chronic comorbid pathologies and/or geriatric features. Main objective: to assess progression-free survival (PFS) rate at 6months. Treatment consisted of 28-daycycles of orally administered regorafenib 160mg/day (3 weeks followed by 1 week rest).ResultsForty-seven patients were included in the study. Median age was 81years (range 63-89). Frailty criteria: dependency was observed in 26 patients (55%), comorbidities in 27 (57%) and geriatric features in 18 (38%). PFS rate at 6months was 45% (95% confidence interval [CI] 30-60]. Median PFS was 5.6months (95%CI 2.7-8.4). Median overall survival (OS) was 16months (95%CI 7.8-24). Complete response, partial response and stable disease were observed in one, two and 21 patients respectively (objective response rate 6.4%; disease control rate 51%). Thirty-nine patients (83%) experienced grade 3-4 adverse events (AEs). The most common grade 3-4 AEs were hypertension (15 patients; 32%), asthenia (14; 30%), hypophosphatemia (6; 13%); diarrhea (4; 8%), hand-foot-skin reaction (4; 8%). There were two toxic deaths (4.2%) (grade 5 rectal bleeding and death not further specified). Dose reduction was required in 26 patients (55%) and dose-delays in 13 patients (28%).ConclusionsThe study did not meet the pre-specified boundary of 55% PFS rate at 6months. Toxicity observed (83% patients experienced grade 3 and 4 AEs) preclude its current use in clinical practice on this setting. Disease control rate and overall survival results are interesting and might warrant further investigation to identify those who benefit from this approach.Trial registrationThis trial was prospectively registered at EudraCT (2013-000236-94). Date of trial registration: April 9th, 2013., Financial support for this research was provided by Bayer Hispania, which has no role in the design of the study; collection, analysis, and interpretation of data; and in writing the manuscript.

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.

Background and objective The discovery of highly accurate pleural fluid (PF) biomarkers of malignancy remains elusive. We assessed the operating characteristics of the PF epithelial cell adhesion molecule (EpCAM), claudin 4 (CL4) and human epididymis protein 4 (HE4) as potential markers of epithelial malignancies. Methods The three markers were quantified by immunoassays in the supernatants (s) and cell lysates (cl) of 175 PF samples. The cut-off values with 100% specificity were selected for malignant-benign discrimination. An immunocytochemical staining index score for each marker was also evaluated on PF cell blocks. The resulting best biomarker was further validated in two independent populations of 73 and 48 patients with pleural effusions (PE). Results An EpCAM(cl) >98 pg/g total lysate protein yielded 75% sensitivity, 100% specificity, negative likelihood ratio of 0.25 and area under the curve of 0.94 for labelling adenocarcinomatous effusions. Sensitivity reached 88% if EpCAM(cl) was combined with EpCAM immunostaining. One-third or more of the malignant effusions exhibiting a false-negative cytological fluid examination were correctly classified by EpCAM(cl) concentrations. Immunoassays for CL4 and HE4 were diagnostically useless. Conclusion EpCAM(cl) is a new biomarker of adenocarcinomatous PE with meaningful discriminating properties.

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

e17534 Background: The presence of pleural effusion in the evolution of patients with ovarian cancer is not uncommon. In one series of 123 patients, malignant pleural effusion at the diagnoses was observed in 29%, and 70% during the course of the disease. Methods: This observational, retrospective study included patients with ovarian cancer and pleural effusion between July 2007 and December 2019 in Lleida, province of Catalonia, Spain. Data were collected from electronic medical reports. This study analyzed the clinical features of ovarian cancer patients with pleural effusion and its impact on their survival. Results: Data from 189 patients with ovarian cancer were collected. The median age was 63 years old. Pleural effusion was observed in 81 patients, 55 at the diagnosis and 26 in the disease evolution. Fifty five percent were confirmed as malignant etiology. Most of the patients were diagnosed with an advanced stage (38.3% stage IIIC, 12.3% stage IVA, 40.7% stage IVB), and 74.1% were high-grade serous carcinoma. When the pleural effusion was observed at the diagnosis, the median overall survival was 20.8 vs 69.3 months in the absence of it (p < 0.001). When the pleural effusion was observed at any time of the disease, the median overall survival was 26.7 vs 90.4 months without it (p < 0.001). Conclusions: In this study, patients with ovarian cancer and pleural effusion, at diagnosis or in the course of the disease, experienced reduced survival compared with the absence of it.

e12609 Background: Endocrine sensitivity (ES) determined by response to the Ki67 index to short-term preoperative endocrine therapy (ET) is accepted but not included in adjuvant treatment decision. However, genomic platforms have been incorporated into decision guides. Therefore, it would be interesting to analyze the correlation between both tools to improve the determination of endocrine sensitivity. Methods: A prospective series of 129 patients with early N0/N1 ES breast cancer was analyzed and Oncotype Dx platform was performed. Clinicopathological variables, and changes in ki67 index less than 10% (ES) were correlated with Oncotype Dx Recurrence Score (RS). Results: Median age was of 58 (23-84), 32% were premenopausal, median tumor size was of 22mm (7-90), nodal involvement was of 31%, 20% were progesterone receptor negative and initial median ki67 index of 24% (5-70). RS distribution: 27% RS 0-11, 29% RS 11-18, 23% RS 18-25, 21% RS > 26. All premenopausal patients received Tamoxifeno as preoperative ET and letrozole for postmenopausal. Globally, 62% of patients had ES with a decrease < 10% of ki67 after preoperative ET: 24/41 in premenopausal and 56/87 in postmenopausal. In all series ES according to RS was distributed: 80% in RS < 11, 61% RS 11-18, 55% RS 18-25 and 50% RS > 26. In premenopausal patients, ES and RS distribution was: 75% RS < 11, 62% RS 11-18, 57% RS 18-25 and 33% RS > 26. In postmenopausal patients, ES and RS distribution was: 83% RS < 11, 61% RS 11-18, 55% RS 18-25 and 58% RS > 26. ES results were not conditioned by tumor size or nodal involvement. RS > 26 was strongly associated with less ES with an OD of 4 (p = 0.014) and RS 18-25 with an OD of 3.25 (p = 0.037). The sensitivity and specificity for ES and RS < 11, was of 80% and 44%, respectively. Conclusions: We have found an ES of 62% in the whole population with the following distribution according RS: 80% in RS < 11, 61% RS 11-18, 55% RS 18-25 and 50% RS > 26. Of note, in premenopausal patients, ES rate in RS > 26 is only of 33%. Determination of ES by response of ki67 is feasible and correlates with data of genomic platforms. Both tools could help to predict ES in this setting.

4112 Background: BRAF V600 mt mCRC is an aggressive disease with poor OS under standard chemotherapy. Treatment with doublet and triplet targeted combinations, such as BRAF inhibitor+ antiEGFR+/- MEK inhibitor, has been shown to improve outcomes. Prognostic factors in this targeted treated population remain to be studied. Methods: Prospective international cohort of patients who received doublet or triplet anti-BRAF combinations in clinical trials or as compassionate use. Univariate Cox models for OS were constructed and the strongest predictors in stepwise variable selection were used to develop a prognostic score. The final multivariate model with selected predictors was stratified by prior lines. Results: In total, 42 patients were enrolled. Median age 60.7 y (33-83), 61% female, 61% right-sided tumors, 26% received 2 or more prior chemotherapy lines. One patient (2.6%) achieved complete response and 36% had partial response with median follow-up of 14.3 months. Median progression-free survival was 5.5 months (CI95% 4.4-10.4) and median OS (mOS) was 10.7 months (CI95% 8.4-22.1). In univariate models, ECOG performance status (1 vs 0), CEA levels (high - > 3.5 ng/mL- vs low - < 3.5 ng/mL), CA 19.9 (high vs. low), LDH (high vs. low), number of metastatic sites and presence of liver metastasis were significant prognostic factors. On the other hand, MSI status and peritoneal or nodal metastasis did not associate with outcome. In multivariable model, strongest determinants of OS were ECOG and baseline CEA levels. If high-risk for both factors (ECOG 1 and CEA high, 46% of the patients), mOS was 5.6 months (CI95% 4.2-NA); if intermediate-risk (either ECOG 1 or CEA high, 33%), mOS was 13.5 months (CI95% 10.6-NA); if low-risk (ECOG 0 and CEA low, 21%), mOS not reached (CI95% 16.5-NA). Differences between intermediate- and high-risk prognostic groups compared to low-risk were significant (HR = 5.9, p = 0.03; and HR = 25.9, p < 0.001, respectively). Conclusions: Patients characteristics such as ECOG and surrogates of tumor burden like CEA levels remain important OS determinants in BRAF V600 mt mCRC treated with doublet or triplet targeted therapy. In fact, there are not prognostic scores regarding BRAF mt mCRC treated with targeted therapies. Our study suggests that these prognostic factors may be considered as stratification factors in future clinical trials.

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.

Background and objective The clinical relevance of pleural effusions in lung cancer has seldom been approached systematically. The aim of this study was to determine the prevalence, causes and natural history of lung cancer-associated pleural effusions, as well as their influence on survival. Methods Retrospective review of clinical records and imaging of 556 consecutive patients with a newly diagnosed lung cancer over a 4-year period at our institution. Results Lung cancer comprised 490 non-small cell and 66 small cell types. About 40% of patients with lung cancer developed pleural effusions at some time during the course of their disease. In half the patients, the effusions were too small to be tapped. These effusions did not progress to require a pleural intervention. Patients with minimal effusions had a worse prognosis compared to patients without pleural effusions (median survival of 7.49 vs 12.65 months, P Conclusions Malignant pleural effusions are a poor prognostic factor in the setting of lung cancer, which includes minimal effusions not amenable to tapping.

BACKGROUND The role of fluorodeoxyglucose (FDG)-PET imaging for diagnosing malignant pleural effusions is not well defined. The aim of this study was to summarize the evidence for its use in ruling in or out the malignant origin of a pleural effusion or thickening. METHODS A meta-analysis was conducted of diagnostic accuracy studies published in the Cochrane Library, PubMed, and Embase (inception to June 2013) without language restrictions. Two investigators selected studies that had evaluated the performance of FDG-PET imaging in patients with pleural effusions or thickening, using pleural cytopathology or histopathology as the reference standard for malignancy. Subgroup analyses were conducted according to FDG-PET imaging interpretation (qualitative or semiquantitative), PET imaging equipment (PET vs integrated PET-CT imaging), and/or target population (known lung cancer or malignant pleural mesothelioma). Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2. We used a bivariate random-effects model for the analysis and pooling of diagnostic performance measures across studies. RESULTS Fourteen non-high risk of bias studies, comprising 407 patients with malignant and 232 with benign pleural conditions, met the inclusion criteria. Semiquantitative PET imaging readings had a significantly lower sensitivity for diagnosing malignant effusions than visual assessments (82% vs 91%; P = .026). The pooled test characteristics of integrated PET-CT imaging systems using semiquantitative interpretations for identifying malignant effusions were: sensitivity, 81%; specificity, 74%; positive likelihood ratio (LR), 3.22; negative LR, 0.26; and area under the curve, 0.838. Resultant data were heterogeneous, and spectrum bias should be considered when appraising FDG-PET imaging operating characteristics. CONCLUSIONS The moderate accuracy of PET-CT imaging using semiquantitative readings precludes its routine recommendation for discriminating malignant from benign pleural effusions.

Background HER2-positive gastric cancer (GC) affects 7%–34% of patients with GC. Trastuzumab-based first-line treatment has become the standard of care for HER2-positive advanced gastric cancer (AGC). However, there are no clinically validated biomarkers for resistance to HER2-targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2-positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2-positive AGC treated with trastuzumab. Patients and Methods Forty-two HER2-positive GC samples from patients treated with trastuzumab-based first-line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed. Results Concurrent genetic alterations were detected in 97.1% of HER2-positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression-free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab-based chemotherapy in terms of OS and PFS. Conclusion Our results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2-positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab. Implications for Practice This article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2-positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression-free survival in AGC treated with trastuzumab-based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2-positive AGC.

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.

Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-ca catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast-enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by independent radiologist from previous determination were associated with responses compared with 1.38-fold increase by investigator assessment and 1.59 by independent radiologist in non-responders (p= 0.0009 and p = 0.03, respectively). Responders had a 3.36-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A from previous determination by investigator assessment and 3.66-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A by independent radiologist compared with 1.43-fold increase by investigator assessment and 1.53 by independent radiologist for non-responders (p = 0.002 and 0.003, respectively). In conclusion, a decrease in vascular endothelial growth factor-A and an increase in soluble vascular endothelial growth factor receptor 1 during chemotherapy and bevacizumab exposure can contribute to both chemotherapy (due to c- MET/b-catenin activation) and bevacizumab (due to low vascular endothelial growth factor requirements) resistance. Because hepatocyte growth factor levels decrease also during acquired resistance, alternative strategies to hepatocyte growth factor–ligand inhibition should be investigated, This work was supported by “beca SEOM a Jóvenes Investigadores 2009” and by the Emili Letang fellowship to Estela Pineda.

This phase II trial investigated the efficacy of an induction regimen of bevacizumab, capecitabine plus oxaliplatin (XELOX) followed by maintenance therapy with bevacizumab plus erlotinib as first-line therapy in patients with metastatic colorectal cancer. Patients with metastatic colorectal cancer received intravenous bevacizumab 7.5 mg/kg plus oxaliplatin 130 mg/m2 on day 1 followed by oral capecitabine 1,000 mg/m2 twice daily on days 1‐14 every 3 weeks for six cycles. In the absence of disease progression, patients then received bevacizumab 7.5 mg/kg every 3 weeks plus oral erlotinib 150 mg once daily. The primary study endpoint was progression-free survival. In the intention-to-treat population (n = 90), the median progression-free survival was 9.2 [95% confidence interval (CI): 7.9‐11.9] months, and the median overall survival was 25.8 (95% CI: 18.0‐30.9) months. In the patient subpopulation who received both induction and maintenance therapy (n = 52), median progression-free survival was 11.1 (95% CI: 9.0‐15.7) months, and the median overall survival was 29.5 (95% CI: 23.7‐36.7) months. KRAS status did not predict efficacy. The most common grade 3/4 adverse events were diarrhea, asthenia, and neutropenia. XELOX‐bevacizumab for 6 cycles followed by bevacizumab‐erlotinib maintenance therapy has been shown to be a highly active and well-tolerated first-line regimen in patients with metastatic colorectal cancer.

Locally advanced rectal cancer (LARC) is associated with a 25 % rate of metastases. The prognostic and predictive relevances of the expression of five proteins (c-FLIPL/s, HIF-1α, β-catenin, p65, and p105/p50 NF-κβ) were assessed. This is a retrospective study. From 1998 to 2009, 152 patients with stage II/III rectal cancer were treated with radio-chemotherapy. TMAs constructed with tumor and normal tissue from the diagnostic endoscopic biopsy and the surgical specimen after chemoradiotherapy were subjected to immunohistochemical (IHC) analysis. Results were correlated with clinical and pathological data, including progression-free survival (PFS). Four different IHC conditions were independent prognostic parameters for PFS: (1) cytoplasmic c-FLIPL/s (p = 0.007), (2) nuclear HIF-1α (p = 0.020), (3) a change in the cytoplasmic p65 between the diagnostic biopsy and the post-treatment specimen (p = 0.004), and (4) a change in the cytoplasmic c-FLIPL/s between the diagnostic biopsy and the post-treatment specimen (p = 0.021). Three different protein expression profiles, combining biomarkers, showed prognostic significance. IHC evaluation of these biomarkers in our three protein expression profiles may help to identify patients with worse prognosis and design more effective therapeutic strategies to personalize the treatment of rectal cancer.

Resumen Objetivo Conocer la prevalencia, las caracteristicas epidemiologicas y la calidad del registro relativos a la sedacion paliativa (SP) en un hospital universitario. Establecer areas de mejora. Material y metodo Analisis descriptivo retrospectivo de los registros clinicos de pacientes oncologicos fallecidos en nuestro centro entre octubre y diciembre de 2010. Las variables analizadas incluyeron: datos epidemiologicos y ubicacion de los pacientes, presencia de SP, sintoma que la motivo, grado de participacion del paciente y la familia en la toma de decisiones, farmacos y dosis utilizados. El analisis cualitativo se desarrollo mediante 2 rondas Delphi en las que cada participante recibio los resultados globales del grupo. Fueron seleccionados aquellos items en los que existia un consenso completo o elevado. Resultados Identificamos 53 defunciones por cancer, el 51% recibieron SP. La edad media fue de 67 anos, y el 64% fueron varones. El cancer de pulmon supuso el 32%. Quince pacientes dependian de Oncologia, 7 de Hematologia y 4 del Servicio de Urgencias. En el 53,85% existio intervencion de cuidados paliativos. Los sintomas que motivaron la SP fueron: disnea en 11 casos y delirium en 5. El tiempo medio ingreso-SP fue de 9,5 dias (duracion media, 1,2 dias). La media de farmacos utilizados fue de 2,6, con empleo de morfina en el 100% y midazolam en el 98%. En 20 casos constatamos el registro de consentimiento para su inicio (100% verbal). Doce profesionales participaron en el analisis cualitativo fruto del cual consensuamos una plantilla para mejorar los registros de seleccion, toma de decisiones y evolucion en los casos de SP. Conclusiones La SP fue motivada por disnea o delirium y se aplico en la mitad de los pacientes fallecidos. Las areas de mejora detectadas afectaban al registro de los criterios de seleccion, al tipo de sedacion y a la participacion del paciente en la toma de decisiones. Por ello hemos consensuado un conjunto minimo de datos que facilitara la recogida de informacion de los profesionales.