The exact role of the dysregulation of the PI3K/AKT/mTOR pathway components is not clearly understood. In this study, we aimed to clarify the correlations between each of the pathway components with the presentation and outcome of estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer.
Immunohistochemistry (IHC) was performed on TMA blocks prepared from samples of 352 luminal breast cancer patients (ER + /HER2-) who presented for adjuvant treatment to CLB between January 2001 to December 2003. Another validation cohort of 160 patients (from 1999 to 2000) was used to confirm the findings. Patients were followed for a median of 9.2 years (Range: 0.2-13.7 years).
Median age at diagnosis was 58.3y. Tumors were larger than 2 cm in 36.4% of the cases and 58.5% had axillary LN deposits. Among the whole cohort, 329 patients were assessable for Nuclear LKB1, 331 for cytoplasmic LKB1, 329 for nuclear pAKT, 330 for cytoplasmic pAKT, 335 for p70-pS6RP, 335 for p4E-BP1, 319 for p85-pS6K, 339 for p70-pS6K and 332 for cytoplasmic IGF1. Nuclear LKB1, cytoplasmic LKB1, nuclear pAKT, cytoplasmic pAKT, p4EBP1, p70-S6RP, p70-pS6K, p85-pS6K and cytoplasmic IGF1 expression was high in 48%, 36%, 55.9%, 19.1%, 43.9%, 22.7%, 71.4%, 27.3 and 55.1% respectively.
Nuclear pAKT high expression, but not cytoplasmic pAKT expression, was associated with better disease free survival (DFS) (HR = 0.53; 95%CI:0.36-0.79; p = 0.002), OS (HR = 0.48; 95%CI: 0.31-0.75; p = 0.001), smaller tumors (p = 0.002), lower lymph node involvement (p = 0.007) and lower pathological grade. This was confirmed in an independent patient cohort. In contrast, p85-pS6K was associated with poorer DFS (HR = 1.65; 95%CI: 1.08-2.50; p = 0.02) and OS (HR = 1.85; 95%CI: 1.09-3.13; p = 0.022). Neither p4E-BP1 nor p70-pS6K expression showed any prognostic significance. In the multivariate analysis, p85-pS6K was the only independent for poorer DFS (HR = 1.81; 95%CI: 1.18-2.97; p = 0.007) & OS (HR = 2.07; 95%CI: 1.20-3.38; p = 0.009).
Higher nuclear pAKT is associated with better prognosis while the downstream markers of mTOR activation as p85-pS6K are associated with poorer prognosis.
Clinical trial identification
Legal entity responsible for the study
Centre Leon Berard
Centre Leon Berard
All authors have declared no conflicts of interest.