Correlation of PIK3CA
mutation-associated gene expression signature (PIK3CA-GS) with
deactivation of the PI3K pathway and with prognosis within the
luminal-B ER+ breast cancers
Loi S, Haibe-Kains B,
Lallemand F, Pusztai L, Bardelli A, Gillett C, Ellis P, Piccart-Gebhart
MJ, Phillips WA, McArthur GA and Sotiriou C
Background: The phosphathidylinositol-3-kinase (PI3K) signaling
pathway is frequently deregulated in tumor biology and is an attractive
target for cancer therapy. Our aim was to characterize the molecular
and clinical outcome effects of PIK3CA mutations in breast cancer (BC).
Methods: We analyzed 173 BC
samples for PIK3CA mutations. Corresponding gene expression profiles
were used to understand its effects on the PI3K pathway. We validated a
PIK3CA-GS in 2 independent BC cohorts (n = 183) with known PIK3CA
mutation status and evaluated its correlation with clinical outcome in
1748 BC samples stratified by treatment and subtype.
Results: 26% of BCs had a
PIK3CA mutation. Tumors with PIK3CA mutation demonstrated a distinct
gene expression signature (p = 0.03 after 1000 perm). In 2 datasets it
could discriminate PIK3CA mutation carriers from wild-type (ROC 0.68,
0.71, p = 0.001for both). However, the PIK3CA-GS was correlated with
deactivation of the PI3K pathway probably through a negative feedback
loop. This observation was supported by: 1) the PIK3CA-GS was
significantly correlated with gene expression changes induced by PI3K
inhibitors (Connectivity Map, Gene set enrichment analyses) and 2) the
PIK3CA-GS was anti-correlated with a GS of PTEN loss (R = -0.3; Saal et
al, 2007). Higher levels of the PIK3CA signature were observed in
HER-2+ and estrogen receptor positive (ER+), luminal BC subtypes.
Whilst there was no association with mutation status alone and
prognosis, increasing expression of the PIK3CA-GS (suggesting
deactivation) was significantly associated with better clinical outcome
in both untreated (p = 0.04) and particularly ER+, luminal-B, tamoxifen
only-treated (p = 0.004) BC. Multivariate analysis (HR: 0.4; 95%CI:
0.3–0.7; p = 0.002) confirmed that the PI3KCA-GS provided independent
prognostic information.
Conclusions: Paradoxically, the
PIK3CA-GS correlates with inhibition of the PI3K pathway in ER+ BC and
identifies a subgroup of luminal B BCs with a favorable outcome. The
PIK3CA-GS may be a better indicator of PI3K pathway dysfunction than
mutation status, potentially indicating patients who may benefit from
combined endocrine therapy and PI3K inhibition.