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Next-generation sequencing (NGS) provides a molecular rationale to inform prognostic stratification and to guide personalized treatment in cancer patients. Here, we determined the prognostic and predictive value of actionable mutated genes in metastatic colorectal cancer (mCRC). Among a total of 294 mCRC tumors examined by targeted NGS, 200 of them derived from patients treated with first-line chemotherapy plus/minus monoclonal antibodies were included in prognostic analyses. Discriminative performance was assessed by time-dependent estimates of the area under the curve (AUC). The most recurrently mutated genes were

Central venous access devices (CVADs) including central venous catheters and peripherally inserted central catheters (PICCs) are essential in the treatment of cancer. Catheter-related thrombosis (CRT) is the most frequent non-infectious complication associated with the use of central lines. The development of CRT may cause to delays in oncologic treatment and increase morbidity leading to potentially life-threatening complications. Several local and systemic risk factors are associated with the development of CRT and should be taken into account to prevent CRT by standardizing appropriate catheter placement and maintenance. The use of primary pharmacological thromboprophylaxis in order to avoid CRT is not routinely recommended, although it can be considered in selected cases. Recommendations for the management of established CRT are based on the extrapolation of anticoagulation for lower limb venous thrombosis. The present review summarizes the current evidence and recommendations for the prevention and management of CRT and identifies areas that require further research.

4152 Background: Despite huge efforts patients (pts) with advanced PDAC, still have a dismal long-term prognosis. The lack of available good-quality tissue samples for next generation sequencing (NGS) prevents from finding actionable alterations that could guide personalized treatments. Circulating tumor DNA (ctDNA) provides a non-invasive method for obtaining molecular information with therapeutic potential. Here, we present prospective data of ctDNA sequencing in pts with PDAC. Methods: We collected a single blood sample from advanced PDAC pts at any line of treatment (Tx) and at least 10 days apart from their last therapy. The samples were analyzed by Guardant360 plasma-based NGS, a standardized assay which covers microsatellite instability [MSI] evaluation and analysis of all four types of somatic alterations in 74 genes. Alterations were reported either as pathogenic or non-pathogenic. We classified each gene alteration according to the different OncoKB therapeutic levels of evidence [LE]. Additionally, we gathered the dates of both blood collection and molecular report. In case the molecular report showed no tumor-related alterations, it was interpreted as either absence of detectable mutations or low ctDNA levels, which would translate low disease burden or pts responding to therapy. Demographic and clinical data have been accessed from the medical records. Results: From 08/2019 to 09/2021 we collected blood samples from 94 PDAC pts. 56% of them were male and 53% were >65 years old. At the time of sample collection, nearly all pts were metastatic (98%). Regarding previous lines of Tx, 57% pts were Tx naïve; 10% were receiving active systemic Tx and 33% had experienced disease progression. Molecular reports were available in an average of 9.1 days. A total of 243 gene alterations were detected, having 94% of pts at least 1 genomic alteration, which was pathogenic in 69% of the cases (see Table). There were no pathogenic alterations ranked as OncoKB LE 1-2 ( MSI or NTRK). Seventy alterations (30%) were ranked as OncoKB LE 3A and 4 ( ARID1A, BRAC2, CDKN2A, KRAS). Three of these pts were treated with PARP inhibitors due to the presence of BRCA2 mutations. No ctDNA was detected in 15 pts (16%), despite being the sample collected >10 days from receiving their last Tx. Of these, 11 had low tumor burden (only peritoneal or lung metastases) and 4 had documented response to the Tx by the time the samples were collected. Conclusions: Real-time and prospective genomic profiling of pts with advanced PDAC using ctDNA is feasible and conveniently fast, which would allow its role in identifying and developing therapeutic targets for approved Tx or clinical trial treatments. [Table: see text]

e15534 Background: The overall response rate following immune check-point blockade (ICB) is < 5% in microsatellite stable (MSS) advanced colorectal cancer (mCRC), and between 30-35% in MSI mCRC. We here evaluate the relationship between our immune-metabolic signature (IMMETCOLS) distribution (cluster (IMC) 1; mesenchymal glycolytic, IMC 2; epithelial-non glycolytic and IMC 3; epithelial mitochondrial oxidative) with immune phenotypes (inflamed (IF), immune-excluded (IE) and immune-desert (ID)) in MSS and MSI mCRC patients (pts). Methods: We have analyzed IMMETCOLS in a retrospective cohort of 128 mCRC pts enriched with MSI-H and BRAF genotype using the nCounter platform (Nanostring Technologies, US). Immune phenotypes were evaluated by immunohistochemistry using 7 immune markers (CD68, CD163, CD8, CD3, FOXP3, PD-L1 and PD1) in a subset of 47 mCRC pts (27 MSS and 20 MSI), in TMAs containing 4 cores from the center of the tumor (CT) and invasive front (IF). The number of stained immune cells was counted using a computerized image analysis system, and PD-L1 was evaluated using CPS score (< 1 vs > 1). Patients having a CD3 cell count below 572 cells/mm2 and a CD8 density below 175 cells/mm2 in IF or CT were considered as ID. (Halama Nils, 2011). CD3 density was also semi-quantitatively estimated in peritumoral stroma and intra-tumoral (range 1-4), defining as IE those cases with a difference > 1 between the two regions in both IF and CT (Brooks JM, 2019). Results: Cluster distribution was similar between MSI (IMC1-40%, IMC2-20% and IMC-40%) and MSS (IMC1-34%, IMC2-24%, IMC3-43%) pts. Patients with high LDH levels (> 1.5ULN) were enriched with IMC3 phenotype (p < 0.0001). MSI have increased CD3 (p = 0.002), CD68 (p = 0.002) and CD163 (p = 0.001) in CT than MSS patients. IMC1 pts had increased CD163/CD68 ratio in CT (p = 0.004). 75% of MSI pts were IE and 25% IF. 55% of MSS pts were IE, 38% ID and 7% IF. IMMETCOLS/ immune-phenotype distribution was: IMC1 (16% ID/ 84% IE), IMC2 (12% ID/ 63% IE/ 25% IF) and IMC3 (35%ID/ 47% IE/ 18% IF). PD1 immuno-expression > 1% (IF and CT) and PD-L1 positivity was observed in 38%, 30% and 28% of pts respectively. There were no differences in PD-L1 (CPS) and PD1 expression between MSS and MSI tumors. Inflamed tumors show higher PD-L1 expression compared with IE and ID immune-phenotypes (p = 0.014). PD1 > 1% expression at IF was significatively lower in IMC1 vs IMC2 and IMC3 tumors (p = 0.032). Conclusions: IMC1 subtype is associated with low PD1 expression, high CD163/CD68 ratio and IE phenotype even in MSI-H mCRC patients. Therefore, IMMETCOLS testing would be of value to identify MSI mCRC pts that do not benefit to ICB therapy.

The approval of a new drug for cancer treatment by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is based on positive, well-designed randomized phase III clinical trials (RCTs). However, not all of them are analyzed to support the recommendations. For this reason, there are different scales to quantify and evaluate the quality of RCTs and the magnitude of the clinical benefits of new drugs for treating solid tumors. In this review, we discuss the value of the progression-free survival (PFS) as an endpoint in RCTs and the concordance between it and the overall survival (OS) as a measure of the quality of clinical trial designs. We summarize and analyze the different scales to evaluate the clinical benefits of new drugs such as the The American Society of Clinical Oncology value framework (ASCO-VF-NHB16) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the concordance between them, focusing on metastatic colorectal cancer (mCRC). We propose several definitions that would help to evaluate the quality of RCT, the magnitude of clinical benefit and the appropriate approval of new drugs in oncology.

Colorectal cancer (CRC) is a commonly diagnosed malignancy. The prognosis of patients with unresectable, metastatic colorectal cancer (mCRC) is dismal and medical treatment is mainly palliative in nature. Although chemotherapy remains the backbone of treatment, the landscape is changing with the understanding of its heterogeneity and molecular biology. First-line therapy relies on a combination of chemotherapy and targeted therapies, according to clinical patient characteristics and tumor molecular profile. Here we review current evidence from randomized clinical trials for using chemotherapy doublets or triplets, and for the addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) agents. Novel therapies developed for small, selected populations are also discussed.

© 2019 by the authors., The current standard-of-care for metastatic colorectal cancer (mCRC) includes chemotherapy and anti-angiogenic or anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, even though the addition of anti-angiogenic agents to backbone chemotherapy provides little benefit for overall survival. Since the approval of anti-angiogenic monoclonal antibodies bevacizumab and aflibercept, for the management of mCRC over a decade ago, extensive efforts have been devoted to discovering predictive factors of the anti-angiogenic response, unsuccessfully. Recent evidence has suggested a potential correlation between angiogenesis and immune phenotypes associated with colorectal cancer. Here, we review evidence of interactions between tumor angiogenesis, the immune microenvironment, and metabolic reprogramming. More specifically, we will highlight such interactions as inferred from our novel immune-metabolic (IM) signature, which groups mCRC into three distinct clusters, namely inflamed-stromal-dependent (IM Cluster 1), inflamed-non stromal-dependent (IM Cluster 2), and non-inflamed or cold (IM Cluster 3), and discuss the merits of the IM classification as a guide to new immune-metabolic combinatorial therapeutic strategies in mCRC., This work was funded by MINECO European Commission FEDER funds, “Una manera de hacer Europa” (SAF2015-66984-C2-1-R), Instituto de Salud Carlos III and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD CB17/04/00023), to T.M.T, and by Instituto de Salud Carlos III (PI13/01728 and PI19/00740) and Agencia de Gestió de Ajuts de Recerca (AGAUR) 2017 SGR 1174, to J.M.

3060 Background: Genetic profiling (GP) is essential not only for understanding tumor biology but also helps to identify potential genes for targeted therapies. At the same time, selected CT provide an individual genomic profile panel during the pre-screening phase. Here, we demonstrate our experience using these panels. Methods: We selected 14 CT from our Early Drug Development Clinical Trial Unit at Hospital Clinic of Barcelona that included analysis of gene panels in tumor (Foundation One, ArcherDX, Therascreen and Sophia Genetics) or plasma (Resolution Bioscience ctDx). These panels analyzed mutations, fusions, amplifications, microsatellite instability (MSI) and tumor mutational burden (TMB), among others. We collected information about types of cancers, molecular alterations and therapies chosen according to the results of GP. The platform OncoKB (Chakravarty JCO PO, 2017) was used to define genes with potential target therapies and levels of evidence (LE) for those targets (from LE 1 –FDA-recognized biomarker predictive of response to an FDA-approved drug- to LE 4 –Compelling biological evidence supports the biomarker as being predictive of response to a drug). Descriptive statistics were used. Results: From March 2017 to January 2021 we analyzed samples from 410 patients (pts) with CNS (19.3%), urothelial (18.3%), prostate (17.6%), breast (15.4%), ovarian (9.3%), esophageal and gastric (5.4%), colorectal (4.4%), pancreas (2.7%), endometrial (2.4%), cholangiocarcinoma (1.2%), cervix (1%), HNSCC (1%), renal (1%), lung (0.5%), liver (0.2%) fallopian tube (0.2%) and paraganglioma (0.2%). 352 pts (85.8%) had at least 1 genetic alteration. The most frequently altered genes were TP53 (153 pts, 46.2%), INSR (19 pts, 22.8%), TERT (76 pts, 22%), CDKN2A (65 pts, 19.9%), FAM175A (11 pts, 19.3%), CDKN2B (54 pts, 18.1%), MLL2 (53 pts, 17.7%), PTEN (52 pts, 16%), MTAP (45 pts, 15.7%), PIK3CA (52 pts, 15%) and ATM (55 pts, 14.4%). TMB ranged from 0 to 76.9 mut/Mb (median 2.5 mut/Mb). MSI was found in 3 pts (1.5%). 196 pts (47.1%) had an OncoKB LE 1 alteration, 105 pts (25.6%) if we restrict the options to their specific cancer type. 16 pts (3.9%) received a matched therapy: 6 pts received an off-label drug, 6 pts were included in the same CT for which the pre-screening was performed and 4 pts were included in a different CT. Additionally, 13 pts (3.2%) received a matched therapy either with OncoKB LE 4 (5 pts received an off-label drug and 3 were included in a different CT) or not included in OncoKB (8 pts included in the same CT of the pre-screening). As a whole, 29 pts (7.1%) received a matched drug according to their genomic results. Conclusions: Comprehensive gene panel testing offered through CT allows the identification of targets to enroll pts, although the recruitment was 1.5%. However, 7.1% of the pts received a matched therapy due to the molecular information of these gene panels.

164 Background: Cancer cells may metabolize glutamine to fulfill their metabolic needs. In prostate cancer it has been shown that androgen receptor signaling promotes glutamine metabolism by increasing the expression of the glutamine transporters, and that stromal glutamine may promote tumor growth. Methods: We retrospectively tested glutamine levels in frozen plasma samples from mCRPC patients treated with taxanes, which were included in a prospective biomarker study in our institution. Glutamine levels were determined by a bioluminescent assay. Optimal cut-offs for glutamine levels were assessed using maximally selected log-rank statistics to determine low and high level groups. Pre-treatment glutamine level was correlated with taxanes response and clinical outcome. Independent association with survival was evaluated by multivariate Cox modeling. Results: Seventy eight mCRPC patients treated with taxanes were included. Median age was 70.3 (55.8-83.5) years and median follow-up was 13.1 (0.2-53.9) months. Glutamine was tested in 88 plasma samples: 69 from pre-docetaxel and 19 pre-cabazitaxel treatment (10 patients had both samples). High glutamine levels significantly correlated with worst PSA-progression-free survival (PFS) (median 2.8 vs 4.7 months, hazard ratio [HR] 1.8, 95%CI 1.1-2.7, P= 0.012) and overall survival (OS) (median 12.4 vs 20.4, HR 2, 95%CI 1.2-3.3, P= 0.006). In a multivariate analysis, high plasma glutamine levels were independently associated with shorter PSA-PFS (HR 2.3, 95%CI 1.4-3.7, P< 0.001) and OS (HR 2.2, 95%CI 1.3-3.7, P= 0.003). Patients with high glutamine levels were more likely to present PSA progression to taxanes than those with low levels (odds ratio [OR] 3, 95%CI 1.2-7.7, P= 0.016). Moreover, samples from patients treated with abiraterone or enzalutamide before taxanes (51 samples from 43 patients) had significantly higher glutamine levels (T-test, P= 0.014) than those without these prior therapies. Conclusions: Glutamine can be detected in plasma of mCRPC patients and higher levels are associated with adverse clinical outcome, supporting the relevance of metabolism in prostate cancer progression.

3553Background: Several prognostic clinical scores for metastatic colorectal cancer (mCRC) GEMCAD (Ann Oncol 25 (Supp 4)), 2014; GERCOR (Oncologist 16, 2011); Kohne (Ann Oncol 13, 2002) are useful ...

Gastrointestinal stromal tumors (GIST) are the most common sarcomas of the gastrointestinal tract and are characterized by constitutive activation of the KIT or PDGFRA receptor tyrosine kinase (1,2). According the Surveillance, Epidemiology and End Results (SEER) database, the incidence of GIST was 0.32 per 100,000 persons in the United States. The median age was 62 years and primary tumors are located mainly in the stomach (58.7%) and small bowel (31.2%). Up-front surgery is still standard therapy for located GIST (except for located GIST tumors of