title: LKB1 Expression Correlates with Increased Survival in Patients with Advanced Non-Small Cell Lung Cancer Treated with Chemotherapy and Bevacizumab.
abstract: Purpose:LKB1 is a key sensor of metabolic stress, including hypoxia and glucose deprivation, two features of the tumor microenvironment exacerbated by antiangiogenic therapy. We investigated the role of LKB1 as a potential predictive marker of sensitivity to bevacizumab in advanced non-small cell lung cancer (aNSCLC).Experimental design:We retrospectively analyzed LKB1 expression by IHC in 98 samples from 125 patients with aNSCLC, including 59 patients treated with chemotherapy and 39 treated with chemotherapy plus bevacizumab. IHC intensity was recoded in two classes (negative/weak vs. moderate/intense) and correlated with outcome according to treatment arm. Patient-derived tumor xenografts (PDXs) were used to investigate mechanisms involved in preclinical models.Results:In the whole study population (125), median OS and PFS were 11.7 [95% confidence interval (CI), 9.1-15.3] and 6.7 (95% CI, 5.7-7.2) months, respectively. Differential impact of the marker on outcome of the 98 patients was highlighted according to the treatment. Patients with negative/weak LKB1 status did not have a statistically significant benefit from bevacizumab added to chemotherapy (HR for patients treated with bevacizumab: 0.89; 95% CI, 0.51-1.56;P= 0.6803), whereas patients expressing moderate/intense LKB1 and receiving bevacizumab had significant lower risk of death compared with those not receiving bevacizumab (HR, 0.26; 95% CI, 0.10-0.64;P= 0.0035). Loss of LKB1 was associated with reduced AMPK activation in PDXs and increased tumor necrosis following bevacizumab administration, highlighting impaired control of the metabolic stress caused by this antiangiogenic drug.Conclusions:Our data hint at a possible predictive impact of LKB1 expression in patients with aNSCLC treated with chemotherapy plus bevacizumab.Clin Cancer Res; 23(13); 3316-24. ©2017 AACR.
authors.affiliation: Medical Oncology 2, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bonanno
authors.affiliation: Clinical Trials and Biostatistics Unit, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: De Paoli
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Zulato
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.affiliation: Pathology Unit, Department of Cardiothoracic Siences, Università degli Studi di Padova, Padova, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Calabrese
authors.affiliation: Oncologia Medica, Ospedale Ca'Foncello, Treviso, Italy.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Favaretto
authors.affiliation: Oncologia Medica, Azienda Universitaria Integrata di Verona, Verona, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Santo
authors.affiliation: Oncologia Medica, Azienda Ospedaliera Santa Maria degli Angeli, Pordenone, Italy.
authors.forename: Alessandro Del
authors.initials: AD
authors.lastname: Conte
authors.affiliation: Pathology and Diagnostics, Università di Verona, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Chilosi
authors.affiliation: Oncologia Medica, Ospedale dell'Angelo, Mestre, Venezia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Oniga
authors.affiliation: Tumor Genomics Unit, Istituto Tumori Milano IRCCS, Milano, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sozzi
authors.affiliation: Tumor Genomics Unit, Istituto Tumori Milano IRCCS, Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Moro
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ciccarese
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Nardo
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bertorelle
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Candiotto
authors.affiliation: Clinical Trials and Biostatistics Unit, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: De Salvo
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Amadori
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: PierFranco
authors.initials: P
authors.lastname: Conte
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy. stefano.indraccolo@unipd.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000068258:Bevacizumab / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases