Opposite Prognostic Impact of Single PTEN-loss and PIK3CA Mutations in Early High-risk Breast Cancer.

Lazaridis G1, Kotoula V2,3, Vrettou E2, Kostopoulos I2, Manousou K4, Papadopoulou K3, Giannoulatou E5,6, Bobos M3, Sotiropoulou M7, Pentheroudakis G8, Efstratiou I2, Papoudou-Bai A9, Psyrri A10, Christodoulou C11, Gogas H12, Koutras A13, Timotheadou E14, Pectasides D15, Zagouri F16, Fountzilas G3,17.

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Abstract

BACKGROUND/AIM:

PTEN-loss and PIK3CA mutations have been addressed as markers of PI3K activation in breast cancer. We evaluated these markers in early high-risk breast cancer (EBC) focusing on PTEN immunohistochemistry (IHC) issues, particularly in HER2-positive disease.

MATERIALS AND METHODS:

We examined PTEN-loss and PIK3CA mutations in 1265 EBC patients treated with adjuvant chemotherapy within two clinical trials. Two different methods for the evaluation of PTEN IHC were used, one upfront binary (loss; no-loss) and the other initially multi-scale allowing for the classification of "grey zone" tumors with low and very low PTEN protein expression.

RESULTS:

PTEN-loss (33.4% and 22.1%, depending on the IHC method) and PIK3CA mutations (29.6%) were associated with ER/PgR/HER2-negative and ER/PgR-positive disease, respectively. Concordance of the two IHC methods was moderate (Cohen's kappa 0.624). PTEN-loss discrepancy and intra-tumor heterogeneity concerned "grey zone" tumors that were prevalent among HER2-positive cancers. PTEN-loss independently conferred higher risk for relapse and death. Compared to single PIK3CA mutations,single PTEN-loss was independently associated with increased risk for relapse and death. Depending on the evaluation method, in HER2-positive cancer, PTEN-loss was without- or of marginal unfavorable prognostic significance.

CONCLUSION:

In EBC, PTEN-loss is an independent predictor of poor outcome. When occurring singly, PTEN-loss and PIK3CA mutations have opposite prognostic impact. In HER2-positive disease, assessment of PTEN-loss by IHC appears unreliable and the marker is without clear prognostic significance.