PIK3CA mutation associates with improved outcome in breast cancer.
OBJECTIVE
In breast cancer, somatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have yielded variable outcomes. Our aim was to determine the prognostic implications of PIK3CA mutations in breast cancer.


METHODS
Archival formalin-fixed paraffin-embedded primary breast tumors, from 590 patients selected for known vital status with a median follow-up of 12.8 years and a tumor >1 cm, were genotyped for PIK3CA mutations. Mutation rates and associations between mutation site and clinicopathologic characteristics were assessed. Progression-free survival, overall survival, and breast cancer-specific survival were examined using Kaplan-Meier or competing risk methodology.


RESULTS
PIK3CA mutation is identified in 32.5% of breast cancers. PIK3CA mutation significantly associates with older age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. Patients with PIK3CA mutated tumors have significant improvement in overall survival (P = 0.03) and breast cancer-specific survival (P = 0.004). Analysis for PIK3CA mutation site-specific associations reveals that the H1047R kinase domain mutation highly associates with node negativity (P = 0.007), whereas helical domain hotspot mutations associate with older age at diagnosis (P = 0.004).


CONCLUSIONS
This study defines the positive prognostic significance of PIK3CA mutations. This work is clinically relevant, as it will significantly affect the design of clinical trials planned for phosphatidylinositol 3-kinase-targeted therapy. Future work may define a population of older age breast cancer patients in whom therapy can be minimized.
Kalinsky
Kevin
K
Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Jacks
Lindsay M
LM
Heguy
Adriana
A
Patil
Sujata
S
Drobnjak
Marija
M
Bhanot
Umeshkumar K
UK
Hedvat
Cyrus V
CV
Traina
Tiffany A
TA
Solit
David
D
Gerald
William
W
Moynahan
Mary Ellen
ME
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis / Q000379:methods; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D008040:Genetic Linkage; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D046888:Tissue Array Analysis; D016896:Treatment Outcome
D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C484760:PIK3CA protein, human