Kyle G Mitchell1, Edwin R Parra2, Jiexin Zhang3, David B Nelson1, Erin M Corsini1, Pamela Villalobos2, Cesar A Moran4, Ferdinandos Skoulidis5, Ignacio I Wistuba2, Junya Fujimoto2, Jack A Roth1, Mara B Antonoff6. 1. Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas. 2. Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas. 3. Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas. 4. Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas. 5. Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. 6. Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: mbantonoff@mdanderson.org.
Abstract
BACKGROUND: Mutations in the serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) have been implicated in mediating resistance to checkpoint blockade among patients with advanced lung adenocarcinoma. We sought to examine the associations between clinicopathologic characteristics, tumor LKB1 expression, features of the immune microenvironment, and postoperative prognosis among patients with early stage lung adenocarcinoma undergoing surgical therapy. METHODS: Formalin-fixed, paraffin-embedded specimens of patients undergoing resection of stage I to III, chemotherapy-naïve adenocarcinomas (1997 to 2008) were analyzed using tissue microarray sectioning. Sublobar resections were excluded. Intratumoral LKB1/STK11 expression was quantified as H-score. In a subset, tumor-associated immune cell populations were quantified using whole tumor sections in peritumoral and intratumoral compartments. RESULTS: In all, 104 patients met inclusion criteria. Expression of LKB1/STK11 (median H-score 102.9) was higher in women (median 123.3) than in men (100, P = .004) and in never-smokers (median 145) than in former/current smokers (100, P = .002). Expression of LKB1/STK11 was positively correlated with intratumoral infiltration of cluster of differentiation (CD) 3+ (r = 0.351, P = .005), CD4+ (r = 0.436, P < .001), and CD8+ (r = 0.263, P = .049) cells. Patients with extrathoracic recurrence had lower tumor expression of LKB1/STK11 than did other patients with recurrent disease. On multivariate analysis, low LKB1/STK11 expression remained independently associated with poor disease-free survival and distant disease-free survival. CONCLUSIONS: Low LKB1/STK11 expression is associated with specific patient characteristics and poor postoperative prognosis in chemotherapy-naïve lung adenocarcinoma. Further investigation is warranted to delineate its clinical significance in the context of evaluating novel therapeutic agents in patients with resectable disease.
BACKGROUND: Mutations in the serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) have been implicated in mediating resistance to checkpoint blockade among patients with advanced lung adenocarcinoma. We sought to examine the associations between clinicopathologic characteristics, tumorLKB1 expression, features of the immune microenvironment, and postoperative prognosis among patients with early stage lung adenocarcinoma undergoing surgical therapy. METHODS:Formalin-fixed, paraffin-embedded specimens of patients undergoing resection of stage I to III, chemotherapy-naïve adenocarcinomas (1997 to 2008) were analyzed using tissue microarray sectioning. Sublobar resections were excluded. Intratumoral LKB1/STK11 expression was quantified as H-score. In a subset, tumor-associated immune cell populations were quantified using whole tumor sections in peritumoral and intratumoral compartments. RESULTS: In all, 104 patients met inclusion criteria. Expression of LKB1/STK11 (median H-score 102.9) was higher in women (median 123.3) than in men (100, P = .004) and in never-smokers (median 145) than in former/current smokers (100, P = .002). Expression of LKB1/STK11 was positively correlated with intratumoral infiltration of cluster of differentiation (CD) 3+ (r = 0.351, P = .005), CD4+ (r = 0.436, P < .001), and CD8+ (r = 0.263, P = .049) cells. Patients with extrathoracic recurrence had lower tumor expression of LKB1/STK11 than did other patients with recurrent disease. On multivariate analysis, low LKB1/STK11 expression remained independently associated with poor disease-free survival and distant disease-free survival. CONCLUSIONS: Low LKB1/STK11 expression is associated with specific patient characteristics and poor postoperative prognosis in chemotherapy-naïve lung adenocarcinoma. Further investigation is warranted to delineate its clinical significance in the context of evaluating novel therapeutic agents in patients with resectable disease.
Authors: Patrick M Forde; Jamie E Chaft; Kellie N Smith; Valsamo Anagnostou; Tricia R Cottrell; Matthew D Hellmann; Marianna Zahurak; Stephen C Yang; David R Jones; Stephen Broderick; Richard J Battafarano; Moises J Velez; Natasha Rekhtman; Zachary Olah; Jarushka Naidoo; Kristen A Marrone; Franco Verde; Haidan Guo; Jiajia Zhang; Justina X Caushi; Hok Yee Chan; John-William Sidhom; Robert B Scharpf; James White; Edward Gabrielson; Hao Wang; Gary L Rosner; Valerie Rusch; Jedd D Wolchok; Taha Merghoub; Janis M Taube; Victor E Velculescu; Suzanne L Topalian; Julie R Brahmer; Drew M Pardoll Journal: N Engl J Med Date: 2018-04-16 Impact factor: 91.245
Authors: Ferdinandos Skoulidis; Lauren A Byers; Lixia Diao; Vassiliki A Papadimitrakopoulou; Pan Tong; Julie Izzo; Carmen Behrens; Humam Kadara; Edwin R Parra; Jaime Rodriguez Canales; Jianjun Zhang; Uma Giri; Jayanthi Gudikote; Maria A Cortez; Chao Yang; Youhong Fan; Michael Peyton; Luc Girard; Kevin R Coombes; Carlo Toniatti; Timothy P Heffernan; Murim Choi; Garrett M Frampton; Vincent Miller; John N Weinstein; Roy S Herbst; Kwok-Kin Wong; Jianhua Zhang; Padmanee Sharma; Gordon B Mills; Waun K Hong; John D Minna; James P Allison; Andrew Futreal; Jing Wang; Ignacio I Wistuba; John V Heymach Journal: Cancer Discov Date: 2015-06-11 Impact factor: 39.397
Authors: S Matsumoto; R Iwakawa; K Takahashi; T Kohno; Y Nakanishi; Y Matsuno; K Suzuki; M Nakamoto; E Shimizu; J D Minna; J Yokota Journal: Oncogene Date: 2007-03-26 Impact factor: 9.867
Authors: Monique B Nilsson; Huiying Sun; Lixia Diao; Pan Tong; Diane Liu; Lerong Li; Youhong Fan; Alissa Poteete; Seung-Oe Lim; Kathryn Howells; Vincent Haddad; Daniel Gomez; Hai Tran; Guillermo Armaiz Pena; Lecia V Sequist; James C Yang; Jing Wang; Edward S Kim; Roy Herbst; J Jack Lee; Waun Ki Hong; Ignacio Wistuba; Mien-Chie Hung; Anil K Sood; John V Heymach Journal: Sci Transl Med Date: 2017-11-08 Impact factor: 17.956
Authors: Hassan Ghaffar; Fikret Sahin; Montserrat Sanchez-Cepedes; Gloria H Su; Marianna Zahurak; David Sidransky; William H Westra Journal: Clin Cancer Res Date: 2003-08-01 Impact factor: 12.531
Authors: Hao Tang; Guanghua Xiao; Carmen Behrens; Joan Schiller; Jeffrey Allen; Chi-Wan Chow; Milind Suraokar; Alejandro Corvalan; Jianhua Mao; Michael A White; Ignacio I Wistuba; John D Minna; Yang Xie Journal: Clin Cancer Res Date: 2013-01-28 Impact factor: 12.531
Authors: Shohei Koyama; Esra A Akbay; Yvonne Y Li; Amir R Aref; Ferdinandos Skoulidis; Grit S Herter-Sprie; Kevin A Buczkowski; Yan Liu; Mark M Awad; Warren L Denning; Lixia Diao; Jing Wang; Edwin R Parra-Cuentas; Ignacio I Wistuba; Margaret Soucheray; Tran Thai; Hajime Asahina; Shunsuke Kitajima; Abigail Altabef; Jillian D Cavanaugh; Kevin Rhee; Peng Gao; Haikuo Zhang; Peter E Fecci; Takeshi Shimamura; Matthew D Hellmann; John V Heymach; F Stephen Hodi; Gordon J Freeman; David A Barbie; Glenn Dranoff; Peter S Hammerman; Kwok-Kin Wong Journal: Cancer Res Date: 2016-02-01 Impact factor: 12.701
Authors: Jiyeon Kim; Zeping Hu; Ling Cai; Kailong Li; Eunhee Choi; Brandon Faubert; Divya Bezwada; Jaime Rodriguez-Canales; Pamela Villalobos; Yu-Fen Lin; Min Ni; Kenneth E Huffman; Luc Girard; Lauren A Byers; Keziban Unsal-Kacmaz; Christopher G Peña; John V Heymach; Els Wauters; Johan Vansteenkiste; Diego H Castrillon; Benjamin P C Chen; Ignacio Wistuba; Diether Lambrechts; Jian Xu; John D Minna; Ralph J DeBerardinis Journal: Nature Date: 2017-05-24 Impact factor: 49.962