Impact of Concurrent PIK3CA Mutations on Response to EGFR Tyrosine Kinase Inhibition in EGFR-Mutant Lung Cancers and on Prognosis in Oncogene-Driven Lung Adenocarcinomas.
BACKGROUND
In patients with epidermal growth factor receptor (EGFR)-mutant or KRAS-mutant lung adenocarcinomas, the prognostic impact of a concurrent PIK3CA mutation remains unclear. Although preclinical data suggest that sensitivity to EGFR tyrosine kinase inhibition (TKI) is decreased in EGFR-mutant lung cancers also harboring a PIK3CA mutation, this interaction has not been explored clinically.


METHODS
Patients with lung adenocarcinomas harboring a PIK3CA mutation concurrent with a separate driver mutation were identified through mutational hotspot testing, multiplex sizing assays, and fluorescence in situ hybridization. Overall survival and outcomes with EGFR TKI monotherapy (EGFR-mutant) were estimated using Kaplan-Meier methods and compared between double-mutant (EGFR-mutant or KRAS-mutant, concurrent PIK3CA-mutant) and single-mutant patients (EGFR-mutant or KRAS-mutant, PIK3CA wild-type) using log-rank tests.


RESULTS
In EGFR-mutant and KRAS-mutant lung cancers, a concurrent PIK3CA mutation was associated with a decrease in median overall survival: 18 versus 33 months (EGFR double mutant, n = 10 versus single mutant, n = 43, p = 0.006), and 9 versus 16 months (KRAS double mutant, n = 16 versus single mutant, n = 47, p = 0.020). In EGFR-mutant lung cancers, a concurrent PIK3CA mutation did not impact benefit from EGFR TKI monotherapy. Single versus double mutant: objective response rate, 83% (n = 29) versus 62% (n = 6, p = 0.80); median time to progression, 11 (n = 29) versus 8 months (n = 6, p = 0.84); and median duration of TKI therapy, 15 (n = 32) versus 15 months (n = 10, p = 0.65).


CONCLUSIONS
A concurrent PIK3CA mutation is a poor prognostic factor in patients with advanced EGFR-mutant or KRAS-mutant lung adenocarcinomas. There was no evidence that clinical benefit from EGFR TKI monotherapy is affected by a concurrent PIK3CA mutation in EGFR-mutant lung cancers.
*Thoracic Oncology Service, Department of Medicine, †Department of Epidemiology and Biostatistics, ‡Department of Radiology, and §Department of Pathology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.
Juliana
J
Eng
Kaitlin M
KM
Woo
Camelia S
CS
Sima
Andrew
A
Plodkowski
Matthew D
MD
Hellmann
Jamie E
JE
Chaft
Mark G
MG
Kris
Maria E
ME
Arcila
Marc
M
Ladanyi
Alexander
A
Drilon
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*
D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors