Evaluation of six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon therapy in the He13A/98 multicenter trial

<p>ABSTRACT</p> <p>Purpose</p> <p>Interferon is approved for adjuvant treatment of patients with stage IIb/III melanoma. The toxicity and uncertainty regarding survival benefits of interferon have qualified its acceptance, despite significant durable relapse prevention in a fraction of patients. Predictive biomarkers that would enable selection of patients for therapy would have a large impact upon clinical practice. Specific CTLA-4 polymorphisms have previously shown an association with response to CTLA-4 blockade in patients with metastatic melanoma and the development of autoimmunity.</p> <p>Experimental design</p> <p>286 melanoma patients and 288 healthy controls were genotyped for six CTLA-4 polymorphisms previously suggested to be important (AG 49, CT 318, CT 60, JO 27, JO30 and JO 31). Specific allele frequencies were compared between the healthy and patient populations, as well as presence or absence of these in relation to recurrence. Alleles related to autoimmune disease were also investigated.</p> <p>Results</p> <p>No significant differences were found between the distributions of CTLA-4 polymorphisms in the melanoma population compared with healthy controls. Relapse free survival (RFS) and overall survival (OS) did not differ significantly between patients with the alleles represented by these polymorphisms. No correlation between autoimmunity and specific alleles was shown. The six polymorphisms evaluated where strongly associated (Fisher's exact p-values < 0.001 for all associations) and significant linkage disequilibrium among these was indicated.</p> <p>Conclusion</p> <p>No polymorphisms of CTLA-4 defined by the SNPs studied were correlated with improved RFS, OS, or autoimmunity in this high-risk group of melanoma patients.</p

Evaluation of six CTLA-4 polymorphisms in high risk melanoma patients

Purpose: Interferon is approved for adjuvant treatment of patients with stage llb/lll melanoma. The toxicity and uncertainty regarding survival benefits of interferon have qualified its acceptance, despite significant durable relapse prevention in a fraction of patients. Predictive biomarkers that would enable selection of patients for therapy would have a large impact upon clinical practice. Specific CTLA-4 polymorphisms have previously shown an association with response to CTLA-4 blockade in patients with metastatic melanoma and the development of autoimmunity. Experimental design: 286 melanoma patients and 288 healthy controls were genotyped for six CTLA-4 polymorphisms previously suggested to be important (AG 49, CT 318, CT 60, JO 27, JO 30 and JO 31). Specific allele frequencies were compared between the healthy and patient populations, as well as presence or absence of these in relation to recurrence. Alleles related to autoimmune disease were also investigated. Results: No significant differences were found between the distributions of CTLA-4 polymorphisms in the melanoma population compared with healthy controls. Relapse free survival (RFS) and overall survival (OS) did not differ significantly between patients with the alleles represented by these polymorphisms. No correlation between autoimmunity and specific alleles was shown. The six polymorphisms evaluated where strongly associated (Fisher’s exact p-values<0.001 for all associations) and significant linkage disequilibrium among these was indicated. Conclusion: No polymorphisms of CTLA-4 defined by the SNPs studied were correlated with improved RFS, OS, or autoimmunity in this high-risk group of melanoma patients.Σκοπός: Η ιντερφερόνη θεωρείται καθιερωμένη επικουρική θεραπεία σε ασθενείς με κακοήθες μελάνωμα σταδίων IIB, IIC και III. Είναι όμως περιορισμένης αποδοχής λόγω της τοξικότητας και της αβεβαιότητας όσον αφορά το όφελος της επιβίωσης, καίτοι βελτιώνει σημαντικά την ελεύθερη υποτροπής επιβίωση σε μία υποομάδα ασθενών με κακοήθες μελάνωμα. Επομένως, θα ήταν χρήσιμο να κατανοήσουμε καλύτερα τους μηχανισμούς δράσης της ιντερφερόνης άλφα-2b και να αναγνωρίσουμε προγνωστικούς δείκτες που θα μας επιτρέψουν να ξεχωρίσουμε τους ασθενείς που είναι πιθανότερο να ωφεληθούν από τη θεραπεία με IFN-a2b. Ο σκοπός αυτής της μελέτης είναι η αναζήτηση 6 πολυμορφισμών του CTLA-4 και η εκτίμηση της επίδρασης της έκφρασής τους στην επιβίωση ασθενών με μελάνωμα υψηλού κινδύνου οι οποίοι λαμβάνουν επικουρική θεραπεία με ιντερφερόνη υψηλής δόσης (HDI). Μεθοδολογία και ασθενείς: Στη μελέτη περιλήφθηκαν διακόσιοι ογδόντα τέσσερις (284) ασθενείς με μελάνωμα σταδίου IIB, IIC και III και 246 υγιείς μάρτυρες. Περιφερικό αίμα ελήφθη πριν από την έναρξη της επικουρικής ανοσοθεραπείας με ιντερφερόνη. To DNA απομονώθηκε χρησιμοποιώντας το σύστημα εξαγωγής GenoPrep και για την ανίχνευση των πολυμορφισμών (SNP-PCR) του CTLA-4 (AG 49, CT 60, CT 318, JO 27, JO 30, JO 31 και του HLA-Cw*06) χρησιμοποιήθηκε η αλυσιδωτή αντίδραση της πολυμεράσης. Όλες οι αντιδράσεις ανάγνωσης αλληλουχίας πραγματοποιήθηκαν με τον PyroMark™ ID pyrosequencer και η ανάλυση έγινε με το πρόγραμμα PyroMark™ ID 1.0. Το θεραπευτικό σχήμα που χρησιμοποιήθηκε αποτελεί μια τροποποίηση του σχήματος Ε1684 από τη μελέτη της ECOG του 1996. Οι ασθενείς της ομάδας Α, έλαβαν IFN-α2b (15 ΜIU/m²/ημέρα ενδοφλέβια για 5 ημέρες την εβδομάδα επί 4 εβδομάδες) και στη συνέχεια ετέθησαν σε παρακολούθηση. Οι ασθενείς της ομάδας Β έλαβαν την ίδια δόση εφόδου για 4 εβδομάδες και στη συνέχεια έλαβαν υποδόρια θεραπεία (10 MIU)/ημέρα, τρεις φορές την εβδομάδα) για επιπλέον 48 εβδομάδες. Ο πρωταρχικός τελικός στόχος της μελέτης ήταν η επιβίωση δίχως υποτροπή και η συνολική επιβίωση της κάθε θεραπευτικής ομάδας. Παράλληλα, η συσχέτιση των πολυμορφισμών του CTLA-4 που συνδυάζεται με την ανάπτυξη αυτοάνοσων παθήσεων καθώς και το αλλήλιο HLA Cw*06 το οποίο προδιαθέτει στην ανάπτυξη ψωρίασης, συσχετίσθηκαν με το αποτέλεσμα και την εμφάνιση αυτοανοσίας σε ασθενείς με μελάνωμα υψηλού κινδύνου οι οποίοι λαμβάνουν επικουρική θεραπεία με HDI. Αποτέλεσμα: Δεν υπήρξαν σημαντικές διαφορές στην κατανομή των πολυμορφισμών του CTLA-4 στους ασθενείς με μελάνωμα με τους υγιείς μάρτυρες. Η ελεύθερη υποτροπής επιβίωση (RFS) και η συνολική επιβίωση (OS) δεν διέφεραν σημαντικά μεταξύ των ασθενών με τα αλλήλια που αντιπροσωπεύουν αυτούς τους πολυμορφισμούς. Δεν υπήρξε συσχέτιση μεταξύ της εμφάνισης αυτοανοσίας και συγκεκριμένων αλληλίων. Παρατηρήθηκε ισχυρή συσχέτιση μεταξύ των έξι πολυμορφισμών (Fisher’s exact τεστ, p<0,001 για όλες τις συσχετίσεις) καθώς και σημαντική αστάθεια σύνδεσης μεταξύ τους. Συμπεράσματα: Κανένας πολυμορφισμός, όπως αυτός ορίζεται από συγκεκριμένο SNP, δεν σχετίστηκε με βελτίωση των RFS και OS, ή με την εμφάνιση αυτοανοσίας σε αυτή την ομάδα ασθενών με μελάνωμα υψηλού κινδύνου

Developments in the systemic treatment of metastatic cervical cancer

Despite the available prevention and early detection strategies, advanced squamous-cell carcinoma of the uterine cervix remains a major concern for public health. Systemic treatment with cisplatin, either in combination with external beam irradiation for locally advanced disease, or as monotherapy for recurrent/metastatic disease has been the cornerstone of treatment for more than two decades. Cisplatin has been also combined with a number of agents including paclitaxel, topotecan, gemcitabine, vinorelbine and ifosfamide, leading to encouraging response rates and increases in progression-free survival in a series of randomized phase III trials. Platinum-based triplets have been also tested, albeit at the cost of substantial toxicity. More recently, combinations with molecular agents targeting critical pathways in cervical malignant transformation are being assessed in clinical trials. In the current review, we discuss all recent advances in the systemic treatment of metastatic cervical cancer with emphasis on the results of large randomized phase III trials. Concerns regarding treatment-related toxicity in the context of co-morbidities and the need for potent predictive biomarkers for individualized treatment are also addressed. (c) 2012 Elsevier Ltd. All rights reserved

Developments in the systemic treatment of endometrial cancer

Systemic treatment represents the cornerstone of endometrial cancer management in advanced, relapsed and metastatic disease, which is still characterized by poor prognosis. Progestins remain an effective option for patients with low grade, estrogen and/or progesterone receptor positive disease, with some of them achieving prolonged survival. Platinum compounds, anthracyclines and more recently taxanes have been implemented in combination regimens achieving response rates more than 50% and resulting in overall survival above 1 year in randomized trials. Adjuvant chemotherapy with the same agents may be useful for patients with early stage disease and high-risk features, such as high grade or non-endometrioid histology. Combination of chemotherapeutic agents with radiotherapy remains investigational. Hematologic, cardiac toxicity and neurotoxicity represent the main concern of chemotherapy and increase the risk for treatment-related morbidity and death, especially in pretreated patients bearing substantial co-morbidities. The gradual elucidation of the molecular aspects of endometrial carcinogenesis has led to the development of novel, selective antineoplastic agents, targeting specific molecular pathways and mediators of signal transduction implemented in cell proliferation, survival and angiogenesis. In the current review, we report on the recent advances regarding systemic therapy of endometrial carcinoma with special emphasis on results of large, randomized phase III clinical trials. Biomarkers with potent prognostic significance or predictive value for response to treatment are presented and novel molecular agents showing promising results in early clinical trials are discussed. © 2010 Elsevier Ireland Ltd

Markers of epithelial to mesenchymal transition in association with survival in head and neck squamous cell carcinoma (HNSCC).

BACKGROUND:Elucidating the molecular phenotype of cancers with high metastatic potential will facilitate the development of novel therapeutic approaches to the disease. Gene expression profiles link epithelial to mesenchymal transition (EMT) phenotype with high-risk HNSCC. We sought to determine the role of protein biomarkers of EMT in head and neck squamous carcinoma (HNSC) prognosis. METHODS:Protein expression analysis of EGFR, β-catenin and E-cadherin was performed on a cohort of 102 patients with HNSCC recruited between 1992 and 2005 using automated quantitative protein analysis (AQUA). We evaluated associations with clinicopathological parameters and prognosis. RESULTS:There were 67 patients with primary squamous cell carcinoma of the head and neck in this cohort who met inclusion criteria and for whom we had complete E-cadherin, beta-catenin and EGFR expression data. High E-cadherin expressers had longer 5-year progression-free survival (PFS) compared to those with low E-cadherin (59.7% versus 40.6%, p = 0.04) and overall survival (OS) (69.6% versus 44.3%, p  = 0.05). Kaplan-Meier analysis showed that patients with low beta-catenin-expressing tumors trended toward worse 5-year PFS (p = 0.057). High EGFR expressers had inferior OS compared to low EGFR expressers (27.7% vs. 54%, p = 0.029). In the multivariable analysis context, E-cadherin remained an independent predictor of improved OS (HR = 0.204, 95% CI 0.043 to 0.972, p = 0.046) while EGFR trended towards significance for OS. CONCLUSIONS:The putative markers of EMT defined within a panel of HNSCC using AQUA are associated with tumors of poor prognosis

Kaplan-Meier survival curve comparing progression-free survival estimation between low- and high-expressing E-cadherin, beta-catenin and EGFR groups.

<p>a) Patients with high tumor E-cadherin expression exhibit a higher probability of PFS (59.7% vs. 40.6%, p = 0.04). b) Patients with low expression of beta-catenin trended towards worse PFS (p = 0.057). c) There was no association between EGFR expression and PFS (p = 0.49).</p