Highlights d NF1 and non-canonical KRAS and BRAF aberrations associate with cetuximab resistance d Genetic resistance drivers are absent in most biopsies that acquired resistance d Stromal remodeling is an alternative non-genetic mechanism of cetuximab resistance d Cetuximab-mediated immune modulation may sensitize CRCs to immunotherapy

Background The T cell bispecific antibody cibisatamab (CEA-TCB) binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells, which triggers T cell killing of cancer cell lines expressing moderate to high levels of CEA at the cell surface. Patient derived colorectal cancer organoids (PDOs) may more accurately represent patient tumors than established cell lines which potentially enables more detailed insights into mechanisms of cibisatamab resistance and sensitivity. Methods We established PDOs from multidrug-resistant metastatic CRCs. CEA expression of PDOs was determined by FACS and sensitivity to cibisatamab immunotherapy was assessed by co-culture of PDOs and allogeneic CD8 T cells. Results PDOs could be categorized into 3 groups based on CEA cell-surface expression: CEA hi ( n = 3), CEA lo ( n = 1) and CEA mixed PDOs ( n = 4), that stably maintained populations of CEA hi and CEA lo cells, which has not previously been described in CRC cell lines. CEA hi PDOs were sensitive whereas CEA lo PDOs showed resistance to cibisatamab. PDOs with mixed expression showed low sensitivity to cibisatamab, suggesting that CEA lo cells maintain cancer cell growth. Culture of FACS-sorted CEA hi and CEA lo cells from PDOs with mixed CEA expression demonstrated high plasticity of CEA expression, contributing to resistance acquisition through CEA antigen loss. RNA-sequencing revealed increased WNT/β-catenin pathway activity in CEA lo cells. Cell surface CEA expression was up-regulated by inhibitors of the WNT/β-catenin pathway. Conclusions Based on these preclinical findings, heterogeneity and plasticity of CEA expression appear to confer low cibisatamab sensitivity in PDOs, supporting further clinical evaluation of their predictive effect in CRC. Pharmacological inhibition of the WNT/β-catenin pathway may be a rational combination to sensitize CRCs to cibisatamab. Our novel PDO and T cell co-culture immunotherapy models enable pre-clinical discovery of candidate biomarkers and combination therapies that may inform and accelerate the development of immuno-oncology agents in the clinic. Electronic supplementary material The online version of this article (10.1186/s40425-019-0575-3) contains supplementary material, which is available to authorized users.

Testicular germ cell tumors (TGCTs) are the most common solid tumors in young adult men. They constitute a unique pathology because of their embryonic and germ origin and their special behavior. Genetic predisposition, environmental factors involved in their development and genetic aberrations have been under study in many works throughout the last years trying to explain the susceptibility and the transformation mechanism of TGCTs. Despite the high rate of cure in this type of tumors because its particular sensitivity to cisplatin, there are tumors resistant to chemotherapy for which it is needed to find new therapies. In the present work, it has been carried out a literature review on the most important molecular aspects involved in the onset and development of such tumors, as well as a review of the major developments regarding prognostic factors, new prognostic biomarkers and the possibility of new targeted therapies.

Background Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encoding DPYD gene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementing DPYD variant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom. Methods Patients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation of DPYD testing were identified retrospectively. After November 2018, patients were tested for DPYD variants c.1905+1G>A (DPYD*2A), c.2846A>T (DPYD rs67376798), c.1679T>G (DPYD*13), c.1236G>A (DPYD rs56038477), c.1601G>A (DPYD*4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a DPYD heterozygous variant received an initial dose reduction of 25–50%. Toxicity by CTCAE v4.03 criteria was compared between DPYD heterozygous variant and wild type carriers. Results Between 1st December 2018 and 31st July 2019, 370 patients who were fluoropyrimidine naïve underwent a DPYD genotyping test prior to receiving a capecitabine (n = 236, 63.8%) or 5FU (n = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygous DPYD variant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G > A (n = 16) and c.1236G > A (n = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5–75%) for DPYD heterozygous carriers and 93.2% (42.9–100%) for DPYD wild type carriers. Overall grade 3 or worse toxicity was similar in DPYD variant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%; P = 0.0924). Conclusions Our study demonstrates successful routine DPYD mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients with DPYD heterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routine DPYD genotype testing prior to commencement of fluoropyrimidine chemotherapy.

Methods: 76 consecutive mCRC patients treated with first-line bevacizumab were retrospectively selected. Immunohistochemistry analysis of tissue microarrays assessed NICD, JAG1, CD44, CD3, CD4, CD8, CD20, DLL3 and DLL4 expression. Abdominal CT scans were imported into a dedicated software for tumor segmentation and extraction of 852 radiomic features (RFs), which were included into machine learning-based predictive models. Pre-processing of RFs included redundant features elimination and standardization; L2 penalized logistic regression with Monte-Carlo cross-validation were implemented for wrapper-based feature selection and model training/test. Three models were developed: clinical/genomic (C/G), radiomic (R) and the comprehensive integrated model (I), which were compared based on ROC-AUC and accuracy metrics.Results: NICD and JAG1 expression was associated with response to bevacizumab (p<0.05). Using likelihood-ratio test as inclusion criteria, the selected variables were 5 for both C/G and R models, then aggregated into the I model. C/G features included NICD expression, number of involved sites, primitive location, resection of metastases and performance status, while selected RFs belonged to both firstand higher-orders classes. ROC-AUC and accuracy were 0.724 (95%CI:0.722-0.727) and 0.669 (95%

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Ramucirumab (IMC-1121B, LY3009806) is a fully human G1 monoclonal antibody that specifically targets vascular endotelial growth factor receptor 2 (VEGFR-2) with a substantially greater binding affinity than that of its natural ligands. Early clinical trials in patients with advanced solid tumors demonstrated that biologically relevant blood target concentrations are achievable with tolerable doses, and also showed some preliminary evidence of clinical activity. Several pivotal phase III trials have now been concluded and have led regulatory agencies to grant marketing authorization to ramucirumab for use as second line therapy in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma (as single agent or in combination with paclitaxel), in patients with advanced colorectal carcinoma (CRC) (in combination with infusional fluorouracil and irinotecan (FOLFIRI regimen)) and in patients with advanced non-small cell lung cancer (NSCLC) (in combination with docetaxel). In contrast, ramucirumab failed to significantly improve survival versus placebo as second line therapy in patients with advanced hepatocellular carcinoma (HCC). The aim of this review is to summarize the clinical development and emerging role of ramucirumab in gastrointestinal (GI) tumors, including relevant aspects of its mechanism of action, pharmacology, safety profile, and antitumor activity in gastric, HCC, and CRC carcinomas.

Background: Image-guided tissue biopsies are critically important in the diagnosis and management of cancer patients. High-yield samples are also vital for biomarker and resistance mechanism discovery through molecular/genomic analyses.