Genetic modulation of the Let-7 microRNA binding to KRAS 3'-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab-irinotecan.
There is increasing evidence that the Let-7 microRNA (miRNA) exerts an effect as a tumor suppressor by targeting the KRAS mRNA. The Let-7 complementary site (LCS6) T>G variant in the KRAS 3'-untranslated region weakens Let-7 binding. We analyzed whether the LCS6 variant may be clinically relevant to patients with metastatic colorectal cancer (MCRC) treated with anti-epidermal growth factor receptor (EGFR) therapy. LCS6 genotypes and KRAS/BRAF mutations were determined in the tumor DNA of 134 patients with MCRC who underwent salvage cetuximab-irinotecan therapy. There were 34 G-allele (T/G+G/G) carriers (25%) and 100 T/T genotype carriers (75%). G-allele carriers were significantly more frequent in the KRAS mutation group than in patients with KRAS wild type (P=0.004). In the 121 patients without BRAF V600E mutation, overall survival (OS) and progression-free survival (PFS) times were compared between carriers of the LCS6 G-allele genotypes and carriers of the wild-type T/T genotype. LCS6 G-allele carriers showed worse OS (P=0.001) and PFS (P=0.004) than T/T genotype carriers (confirmed in the multivariate model including the KRAS status). In the exploratory analysis of the 55 unresponsive patients with KRAS mutation, LCS6 G-allele carriers showed adverse OS and PFS times. These findings deserve additional investigations as they may open novel perspectives for the treatment of patients with MCRC.
Graziano
F
F
Department of Onco-Hematology, Medical Oncology Unit, Azienda Ospedaliera Ospedale San Salvatore, Pesaro, Italy. frada@tin.it
Canestrari
E
E
Loupakis
F
F
Ruzzo
A
A
Galluccio
N
N
Santini
D
D
Rocchi
M
M
Vincenzi
B
B
Salvatore
L
L
Cremolini
C
C
Spoto
C
C
Catalano
V
V
D'Emidio
S
S
Giordani
P
P
Tonini
G
G
Falcone
A
A
Magnani
M
M
D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068818:Cetuximab; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D006801:Humans; D000077146:Irinotecan; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D016879:Salvage Therapy; D018631:ras Proteins / Q000235:genetics*
D020413:3' Untranslated Regions; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C487931:mirnlet7 microRNA, human; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002166:Camptothecin