title: KRAS mutation in lung metastases from colorectal cancer: prognostic implications.
abstract: KRAS mutant colorectal cancer (CRC) patients develop lung and brain metastases more frequently than KRAS wild-type (WT) counterpart. We retrospectively investigated the prognostic role of KRAS, BRAF, and PIK3CA (exon 20) mutations and loss of phosphatase and tensin homolog (PTEN) in surgically resected lung metastases. Lung specimens from 75 metastatic CRC (mCRC) patients treated with one or more metastasectomies with curative intent were analyzed. Sixty-four percent of patients had KRAS WT lung metastases. PTEN loss-of-function was found in 75%. BRAF and PIK3CA exon 20 mutations were not found. Seven patients subsequently developed brain metastases and 43% of them had KRAS mutation. In univariate analysis, median overall survival (OS) for KRAS WT patients was longer, compared to KRAS mutant patients (median 60.9 vs. 36.6 months, P = 0.035). In addition, both progression-free survival (PFS) and lung disease-free survival (LDFS) between lung surgery and relapse were not associated with KRAS and PTEN status. In multivariate analysis, the risk of death was significantly increased by KRAS mutational status (OS Hazard ratio (HR) 2.17, 95% IC 1.19-3.96, P = 0.012) and lack of adjuvant chemotherapy (OS HR 0.10, 95% IC 0.01-0.74, P = 0.024). The proportion of KRAS mutations in lung metastases was similar to the expected proportion in primary tumors. Patients harboring KRAS mutation had a poorer survival rate compared to WT group both in univariate and multivariate analysis. Moreover, administration of adjuvant chemotherapy after lung metastasectomy (LM) significantly improved both PFS and OS. KRAS mutation is a negative prognostic factor in mCRC patients undergoing LM. Further larger and prospective studies are necessary to confirm these findings.
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Michele
authors.identifier: http://orcid.org/0000-0002-7630-4479
authors.initials: M
authors.lastname: Ghidini
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.|Department of Medical Biotechnology and Translational Medicine, University of Milan, Via Vanvitelli 32, 20129, Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Personeni
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bozzarelli
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Baretti
authors.affiliation: Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Basso
authors.affiliation: Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bianchi
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Tronconi
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pressiani
authors.affiliation: Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grizzi
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Giordano
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, Via Vanvitelli 32, 20129, Milan, Italy.|Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Malesci
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Alloisio
authors.affiliation: Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.|Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Laghi
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.|Humanitas University, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Rimassa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012189:Retrospective Studies; D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018631:ras Proteins
keywords: BRAF; KRAS; brain metastases; cancer; colorectal; lung metastases