EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers.

Funder: FP7 People: Marie-Curie Actions; FundRef: http://dx.doi.org/10.13039/100011264; Grant(s): CIG 334261OBJECTIVE: Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and EGFR copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785). DESIGN: EGFR CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients. RESULTS: EGFR amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant EGFR CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from EGFR-amplified aGEA. CONCLUSION: EGFR CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials

Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage

FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome

Εκτίμηση θνησιμότητας σε ασθενείς με HIV λοίμωξη μετά την έναρξη αντιρετροϊκής θεραπείας

Υπόβαθρο και σκοπός: O σκοπός αυτής της μελέτης ήταν η εκτίμηση του ρυθμού θνησιμότητας σε ασθενείς με HIV λοίμωξη μετά την έναρξη αντιρετροικής θεραπείας (ΑRT) στην Ευρώπη. Tα χαρακτηριστικά των οποίων η επίδραση στο ρυθμό θνησιμότητας αξιολογήθηκε ήταν ο αριθμός των CD4 λεμφοκυττάρων κατά την έναρξη της θεραπείας, το φύλο, η ηλικία και η διάρκεια της θεραπείας. Μέθοδοι: Δημογραφικά και κλινικά δεδομένα που συλλέχθηκαν διαχρονικά από 4.941 ασθενείς που συμμετέχουν στην κοορτή Eurosida και έχουν πρόσβαση σε κέντρα υγείας/ νοσοκομεία της Ανατολικής και Δυτικής Ευρώπης στάλθηκαν από τον οργανισμό COHERE. H επεξεργασία αυτών των δεδομένων έγινε με σκοπό τη διενέργεια ανάλυσης επιβίωσης με σημείο έναρξης παρακολούθησης για κάθε ασθενή την παλαιότερη ημερομηνία έναρξης φαρμακολογικής θεραπείας και καταληκτικό σημείο την τελευταία ημερομηνία στην οποίο ο/η ασθενής είχε καταγραφεί ζωντανός ή ζωντανή. Δύο διαφορετικά μοντέλα Poisson εφαρμόσθηκαν στα δεδομένα τα οποία περιείχαν τις ανεξάρτητες κατηγορικές μεταβλητές: αριθμός CD4 λεμφοκυττάρων κατά την έναρξη της θεραπείας, φύλο, ηλικία και διάρκεια θεραπείας. Το πρώτο μοντέλο εξέτασε την επίδραση αυτών των μεταβλητών στον κίνδυνο θνησιμότητας κατά τους 6 πρώτους μήνες της θεραπείας ενώ το δεύτερο μοντέλο την επίδραση αυτών των μεταβλητών από τον 7ο μήνα κι έπειτα. Αποτελέσματα: Ένα μεγάλο ποσοστό ασθενών (38,96%) άρχισε ΑRT με χαμηλά επίπεδα CD4 λεμφοκυττάρων (<200 κύτταρα το μικρόλιτρο). Ο μεγαλύτερος μέσος ρυθμός θνησιμότητας εκτιμήθηκε για τους ασθενείς που ξεκίνησαν θεραπεία με χαμηλό αριθμό CD4 λεμφοκυττάρων καθ’όλη τη διάρκεια της παρακολούθησης, κυρίως κατά τους 6 πρώτους μήνες της θεραπείας. Χαρακτηριστικά όπως το ανδρικό φύλο και ηλικία μεγαλύτερη των 35 ετών φαίνεται ότι αυξάνουν τον κίνδυνο θνησιμότητας. Συζήτηση και συμπεράσματα: Ο αριθμός των CD4 λεμφοκυττάρων κατά την έναρξη της θεραπείας διαδραματίζει σημαντικό ρόλο στην επιβίωση των ασθενών όπως φάνηκε από αυτή τη μελέτη. Ασθενείς που αρχίζουν θεραπεία με χαμηλό αριθμό λεμφοκυττάρων διατρέχουν το μεγαλύτερο κίνδυνο θνησιμότητας και είναι φανερά ανησυχητικό το γεγονός ότι μεγάλο ποσοστό οροθετικών ασθενών αρχίζουν θεραπεία με χαμηλό αριθμό λεμφοκυττάρων στην Ευρώπη.Background and Objectives: The aim was to produce mortality rate estimates in HIV-infected patients in Europe after initiation of antiretroviral therapy (ART). Mortality estimates were analyzed by gender, age category, CD4 count at initiation of ART and months on ART in order to evaluate the effect of these covariates on the hazard of death. Methods: Demographic and longitudinal clinical data from 4,941 patients from the Eurosida cohort with access to HIV care in clinical centers from Western and Eastern Europe were sent by the COHERE organization. Data were subsequently processed for the conduction of survival analysis with time of origin for every patient the earliest date of initiation of ART and the last date known alive as the last date of follow-up. Two separate Poisson regression models containing the factors CD4 category at ART start, gender, age category and duration of therapy were fitted to the observed data; the first for the first 6 months of therapy and the second from 7 months onwards. Results: A large proportion of patients (38.96%) entered ART with low CD4 lymphocyte counts (<200 cells/μl). Mortality was estimated to be highest in patients with the highest degree of immunosupression at the start of treatment, as indicated by a low CD4 count, particularly during the first 6 months of therapy. Male gender and age over than 45 years seem also to be associated with an increased risk of death. Discussion and Conclusions: The role of the CD4 count at initiation of ART as a prognostic factor was highlighted in this analysis. Patients with low CD4 count die at a higher rate than patients with higher CD4 counts and it is worrying that a large number of HIV-infected patients still enter therapy with low CD4 counts in the European setting

MicroRNA 31-3p expression and benefit from anti-EGFR inhibitors in metastatic colorectal cancer patients enrolled in the prospective phase II PROSPECT-C trial

PURPOSE: Anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibodies (mABs) are effective in the treatment of metastatic colorectal cancer (mCRC) patients. RAS status and tumour location (sidedness) are predictive markers of patients' response to anti-EGFR mABs. Recently, low microRNA-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here we aimed to validate the predictive power of microRNA-31-3p in a prospective cohort of chemo-refractory mCRC patients treated with single agent anti-EGFR mABs. EXPERIMENTAL DESIGN: microRNA-31-3p was tested by in-situ hybridization in ninety-one pre-treatment core biopsies from metastatic deposits of forty-five mCRC patients. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in microRNA-31-3p expression over treatment. MicroRNA-31-3p expression, sidedness, and RAS status in pre-treatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination. RESULTS: Patients with low microRNA-31-3p expression in pre-treatment biopsies showed better overall response rate, as well as better progression free and overall survival, compared to those with high microRNA-31-3p expression. The prognostic effect of microRNA-31-3p was independent from age, gender and sidedness. No significant changes in the expression of microRNA-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mABs. MicroRNA-31-3p scores were similar when pre-treatment biopsies were compared with treatment-na\uefve archival tissues (often primary CRC).Conclusions: Our study validates the role of microRNA-31-3p as potential predictive biomarker of selection for anti-EGF mABs

Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer

Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.M.G., A.Woolston, L.J.B., and B.G. were supported by CRUK, a charitable donation from Tim Morgan, Cancer Genetics UK and the Constance Travis Trust. G.S. was funded by an Institute of Cancer PhD Studentship, R.G.E. by a Spanish Society of Medical Oncology (FSEOM) grant for Translational Research in Reference Centers. The study was also supported by the ICR/RMH NIHR Biomedical Research Center for Cancer, by the CRUK Immunotherapy Accelerator (ICR/RMH, UCL) and by a Wellcome Trust Strategic Grant (105104/Z/14/Z)