Subtype-specific KRAS mutations in advanced lung adenocarcinoma: a retrospective study of patients treated with platinum-based chemotherapy.
BACKGROUND
Platinum-based chemotherapy is the most common treatment in advanced-stage lung adenocarcinoma. Because the clinical significance of KRAS mutational status in this setting has not yet been clearly determined, a mutation subtype-specific analysis was performed in the so far largest cohort of Caucasian patients with KRAS mutant advanced-stage lung adenocarcinoma treated with platinum-based chemotherapy.


METHODS
505 Caucasian stage III-IV lung adenocarcinoma patients with known amino acid substitution-specific KRAS mutational status and treated with platinum-based chemotherapy were included. The correlations of subtype-specific KRAS mutations with smoking status, progression-free and overall survival (PFS and OS, respectively) and therapeutic response were analysed.


RESULTS
Among 338 KRAS wild-type, 147 codon 12 mutant and 20 codon 13 mutant patients, there were no mutation-related significant differences in PFS or OS (P values were 0.534 and 0.917, respectively). Eastern Cooperative Oncology Group (ECOG) status and clinical stage were significant independent prognostic factors. KRAS mutation showed a significant correlation with smoking status (P=0.018). Importantly, however, G12V KRAS mutant patients were significantly more frequent among never-smokers than all other codon 12 KRAS mutant (G12x) subtypes (P=0.016). Furthermore, this subgroup tended to have a higher response rate (66% versus 47%; P=0.077). A modestly longer median PFS was also found in the G12V mutant cohort (233days; versus 175days in the G12x group; P=0.145).


CONCLUSIONS
While KRAS mutation status per se is neither prognostic nor predictive in stage III-IV lung adenocarcinoma, subtype-specific analysis may indeed identify clinically relevant subgroups of patients that may ultimately influence treatment decisions.
Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary; Department of Pulmonology VIII, National Koranyi Institute of Pulmonology, Budapest, Hungary; Division of Thoracic Surgery, Medical University of Vienna, Austria.
Mihaly
M
Cserepes
Department of Pulmonology VIII, National Koranyi Institute of Pulmonology, Budapest, Hungary.
Gyula
G
Ostoros
Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary; Division of Thoracic Surgery, Medical University of Vienna, Austria.
Zoltan
Z
Lohinai
2nd Department of Pathology, Semmelweis University, Budapest, Hungary; Tumor Progression Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary.
Erzsebet
E
Raso
2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
Tamas
T
Barbai
2nd Department of Pathology, Semmelweis University, Budapest, Hungary; Tumor Progression Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary.
Jozsef
J
Timar
Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary; Division of Thoracic Surgery, Medical University of Vienna, Austria.
Anita
A
Rozsas
Department of Pulmonology, Semmelweis University, Budapest, Hungary.
Judit
J
Moldvay
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Ilona
I
Kovalszky
Department of Pulmonology, Semmelweis University, Budapest, Hungary.
Katalin
K
Fabian
County Hospital of Pulmonology, Torokbalint, Pest County, Hungary.
Marton
M
Gyulai
Division of Thoracic Surgery, Medical University of Vienna, Austria; Institute of Cancer Research and Comprehensive Cancer Center, Department of Internal Medicine I, Medical University of Vienna, Austria.
Bahil
B
Ghanim
Division of Thoracic Surgery, Medical University of Vienna, Austria.
Viktoria
V
Laszlo
Division of Thoracic Surgery, Medical University of Vienna, Austria.
Thomas
T
Klikovits
Division of Thoracic Surgery, Medical University of Vienna, Austria; Institute of Cancer Research and Comprehensive Cancer Center, Department of Internal Medicine I, Medical University of Vienna, Austria.
Mir Alireza
MA
Hoda
Institute of Cancer Research and Comprehensive Cancer Center, Department of Internal Medicine I, Medical University of Vienna, Austria.
Michael
M
Grusch
Institute of Cancer Research and Comprehensive Cancer Center, Department of Internal Medicine I, Medical University of Vienna, Austria.
Walter
W
Berger
Division of Thoracic Surgery, Medical University of Vienna, Austria.
Walter
W
Klepetko
Division of Thoracic Surgery, Medical University of Vienna, Austria; 2nd Department of Pathology, Semmelweis University, Budapest, Hungary; Tumor Progression Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary.
Balazs
B
Hegedus
Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary; Division of Thoracic Surgery, Medical University of Vienna, Austria; Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary. Electronic address: balazs.dome@meduniwien.ac.at.
Balazs
B
Dome
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D016009:Chi-Square Distribution; D002945:Cisplatin / Q000008:administration & dosage; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006814:Hungary / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009367:Neoplasm Staging; D018579:Patient Selection; D010641:Phenotype; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000208:ethnology; D013997:Time Factors; D016896:Treatment Outcome; D044465:White People / Q000235:genetics; D018631:ras Proteins / Q000235:genetics*
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016190:Carboplatin; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002945:Cisplatin
Advanced-stage lung adenocarcinoma; KRAS mutation; Non-small cell lung cancer; Platinum-based chemotherapy