axl has a prognostic role in metastatic colorectal cancer mcrc and is a predictive biomarker of lack of efficacy of chemotherapy ct cetuximab in ras wild type wt patients pts

n/

Sequential HER2 blockade as effective therapy in chemorefractory, HER2 gene-amplified, RAS wild-type, metastatic colorectal cancer: learning from a clinical case

Background Constitutive activation of HER2-dependent intracellular signalling by HER2 gene amplification or by HER2 mutations has been demonstrated as a mechanism of primary and secondary cancer resistance to cetuximab or panitumumab in preclinical and clinical models of metastatic colorectal cancer (mCRC). Both HER2 Amplification for Colorectal Cancer Enhanced Stratification (HERACLES) cohort A and My Pathway clinical trials provided clinical evidence that anti-HER2 therapies could be active in these patients. Patient and methods HER2 gene amplification and HER2 protein overexpression analysis were performed in tumour tissue by fluorescence in situ hybridisation and immunohistochemistry. HER2 positivity was defined according to HERACLES CRC-specific HER2 scoring criteria. DNA analysis for multiple assessment of gene mutations or amplifications was carried out with the next-generation sequencing (NGS) Ion AmpliSeq Colon and Lung Cancer Panel and by using a more extensive targeted high-multiplex PCR-based NGS panel (OncoMine Comprehensive Assay). Results We report the clinical case of a patient with HER2 gene amplified and RAS/BRAF wild-type mCRC who experienced a long lasting and relevant clinical efficacy from sequential anti-HER2 therapies (trastuzumab plus lapatinib, pertuzumab plus trastuzumab, trastuzumab emtansine, trastuzumab plus capecitabine) achieving a cumulative clinical benefit of 29 months, after failure of the first three lines of standard treatments, which included all the potentially active drugs in mCRC, and which accounted for only 14 months of disease control. HER gene amplification was confirmed by NGS on two different metastatic lesions during the evolution of the disease. Conclusion The clinical case highlights the role of HER2 gene amplification as a key genetic driver of cancer development and progression in mCRC and suggests that sequential HER2 blockade could be a potential therapeutic strategy

The acquired resistance to the combination of the anti-EGFR cetuximab and the MEK-inhibitor refametinib in KRAS mutated colorectal cancer cell lines depends on PI3K-signalling

n/

A case report of a severe fluoropyrimidine-related toxicity due to an uncommon DPYD variant

Introduction: Fluoropyrimidines such as 5-fluorouracil (5-FU) and its orally active prodrug, capecitabine, are widely used in the treatment of gastrointestinal cancer, including colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) plays an important role in the 5-FU metabolism. Dihydropyrimidine dehydrogenase gene (DPYD) is a highly polymorphic gene with several hundreds of reported genetic variants and DPD activity levels vary considerably among individuals, with different 5-FU-related efficacy and toxicity. About 5% of the population is deficient in DPD enzyme activity. The most well studied DPYD variant is the IVS14+1G>A, also known as DPYD ∗2A. In this report, we present a case of a patient with a double heterozygote DPYD variant (DPYD activity score: 0,5 according to Clinical Pharmacogenetics Implementation Consortium) who experienced a severe fluoropyrimidine-related toxicity resolved without any consequence. Patient concerns: A 46-years-old Caucasian man with diagnosis of left colon adenocarcinoma underwent left hemicolectomy on July 2017: pT3 G3 N1c M0. According to the disease stage, he started an adjuvant therapy with XELOX using capecitabine at 50% of total dose, because of his DPYD IVS14+1G>A variant, detected before the treatment. DIAGNOSIS: After few days, despite of this dose reduction, he experienced life-threatening adverse events such as mucositis G3, diarrhea G3, neutropenia G4, thrombocytopenia G4, and hyperbilirubinemia G3 according to Common Terminology Criteria for Adverse Events v 5.0. Interventions: As first, we set up an intensive rehydration therapy, antibiotic and antifungal prophylaxis, Granulocyte-Colony Stimulating Factors, and supportive blood transfusions. Additional genetic tests revealed a double heterozygote variant of DPYD gene (DPYD IVS14+1G>A and 2846A>T) which is a very rare situation and only 3 cases are described in literature, all of them concluded with patient’s death. Outcomes: After 3 weeks of intensive therapy, the patient was fully recovered. Furthermore, all the whole-body CT scans performed since discharge from the hospital until now, have confirmed no evidence of disease. Conclusions: Recent studies demonstrated that screening strategy for the most common DPYD variants allowed for avoiding toxicities and saving money. This report underlines the importance of genotyping DPYD before treatment and emphasizes the role of genotype-guided dose individualization. Abbreviations: 5,10-MTHF = 5,10-Methylenetetrahydrofolate, 5-FU = 5-fluorouracil, AEs = Adverse events, CDA = cytidinedeaminase, CES = carboxylesterase, CPIC = Clinical Pharmacogenetics Implementation Consortium, CRC = colorectal cancer, CT = computed tomography, CTCAE = Common Terminology Criteria for Adverse Events, DPD = dihydropyrimidine dehydrogenase, DPYD = dihydropyrimidine dehydrogenase gene, DPYD-AS = DPYD activity score, ECOG = Eastern Cooperative Oncology Group, EDTA = ethylenediaminetetraacetic acid, FdUMP = 5-fluoro-20-deoxyuridine-50-monophosphate, HFS = hand-foot syndrome, HGB = hemoglobin, INB = incremental net benefit, INR = International Normalized Ratio, mCRC = metastatic colorectal cancer, MTHFR = Methylene Tetrahydrofolate Reductase, NEU = Neutrophils, PCR = polymerase chain reaction, PLT = Platelets, SNPs = single-nucleotide polymorphisms, TSER = thymidylate synthase enhancer region, TYMP = thymidine phosphorylase, TYMS = thymidylate synthase, VNTR = variable number of tandem repeat, WBC = white blood cells