Background: Despite the high frequency of PIK3CA mutations (mut) in BC, their role in tumor progression is uncertain. We have previously shown that PIK3CA mut status was highly concordant between Ps and matched Ms in ER+/HER2- BCs (89%). We sought to evaluate the levels of PI3K pathway activation concordance in Ps and matched Ms. Methods: For a series of 119 P ER+/HER2- BCs and 31 matched Ms with known PIK3CA mut status, the expression of 400 genes was obtained with the Nanostring technology. The expression of a PI3K pathway activation gene signature (PIK3CA-GS by Loi S PNAS 2010) and of single genes (ESR1 and AURKA) was derived. For 97 of the Ps and 27 of the Ms, the copy number data of 40 genes was obtained with an EvaGreen qPCR assay. Results: 43% of all samples had a PIK3CA mut. The PIK3CA-GS was able to predict moderately samples’ mut status (AUC 0.641, p 0.004). When considering only the Ps, 65% (36/55) of PIK3CA mut and 42% (27/64) of wild type (WT) samples had an expression of PIK3CA-GS higher than the median value, indicating PI3K activation status. The proportion of CCND1 amplified cases was moderately higher in WT compared to mut samples (p 0.06) while the proportion of FGFR1 (p 0.001) and ZNF703 (p<0.001) amplified cases was higher in GS low compared to GS high samples. When considering the 31 pairs, we observed a moderate correlation between PIK3CA-GS values in Ps and matched Ms (Spearman rho=0.50, p<0.01). In each pair, the expression level of the GS could change substantially: in 6 (19%) cases it went up, in 6 (19%) it went down and in 19 (61%) it remained the same. Compared to matched Ps, Ms looked biologically more aggressive with significantly higher levels of proliferation as measure by AURKA (p 0.04) and lower levels of ESR1 (p 0.01) despite maintaining an ER+ status at IHC. Conclusions: Despite the high concordance of PIK3CA genotype between Ps and matched Ms, activation of downstream signaling seems to vary. This suggests that, beside genotyping, additional investigations should be performed in each lesion to assess the level of pathway activation. Evaluation of downstream effectors using phosphorylated antibodies at IHC is ongoing (pAKT, pMTOR, pERK1/2, pS6).