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

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. 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. 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. 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.

Lazaridis G ，Kotoula V ，Vrettou E ，Kostopoulos I ，Manousou K ，Papadopoulou K ，Giannoulatou E ，Bobos M ，Sotiropoulou M ，Pentheroudakis G ，Efstratiou I ，Papoudou-Bai A ，Psyrri A ，Christodoulou C ，Gogas H ，Koutras A ，Timotheadou E ，Pectasides D ，Zagouri F ，Fountzilas G ... -  《-》

Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer.

Razis E ，Bobos M ，Kotoula V ，Eleftheraki AG ，Kalofonos HP ，Pavlakis K ，Papakostas P ，Aravantinos G ，Rigakos G ，Efstratiou I ，Petraki K ，Bafaloukos D ，Kostopoulos I ，Pectasides D ，Kalogeras KT ，Skarlos D ，Fountzilas G ... -  《-》

Frequent mutational activation of the PI3K-AKT pathway in trastuzumab-resistant breast cancer.

HER2-amplified breast cancer is sometimes clinically insensitive to HER2-targeted treatment with trastuzumab. Laboratory models of resistance have causally implicated changes in HER2 expression and activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway. We conducted a prospective tissue acquisition study to determine if there is evidence for these lesions in metastatic tumors that have progressed on trastuzumab-containing therapy. From 2/2007 to 11/2011, 63 patients with HER2-amplified breast cancer with recurrence of disease after adjuvant trastuzumab therapy or World Health Organization-defined progression of metastatic disease on a trastuzumab-containing regimen were prospectively enrolled and underwent tumor biopsy. Specimens were analyzed for activating mutations in PIK3CA and HER2 by Sequenom and analyzed for HER2 and PTEN status by immunohistochemistry. In 53/60 cases (88%, 3 cases not evaluable for HER2), HER2 overexpression persisted in the metastatic tumor following trastuzumab exposure. Among the 7 cases lacking HER2 overexpression, repeat analysis of the pretreatment tumor failed to confirm HER2 overexpression in five cases. Among cases evaluable for PTEN (56) or PI3K mutation (45), absent or significantly diminished PTEN expression was noted in 33 (59%) and activating mutations in PIK3CA in 13 (29%). The combined rate of PTEN loss and PIK3CA mutation in the trastuzumab-refractory tumors was 71% compared with 44% (P = 0.007) in an unexposed cohort of 73 HER2-amplified tumors. In this series of prospectively collected trastuzumab-refractory human breast cancers, loss of HER2 overexpression was rare, whereas activation of the PI3K-AKT pathway through loss of PTEN or PIK3CA mutation was frequently observed.

Chandarlapaty S ，Sakr RA ，Giri D ，Patil S ，Heguy A ，Morrow M ，Modi S ，Norton L ，Rosen N ，Hudis C ，King TA ... -  《-》

Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer.

Rimawi MF ，De Angelis C ，Contreras A ，Pareja F ，Geyer FC ，Burke KA ，Herrera S ，Wang T ，Mayer IA ，Forero A ，Nanda R ，Goetz MP ，Chang JC ，Krop IE ，Wolff AC ，Pavlick AC ，Fuqua SAW ，Gutierrez C ，Hilsenbeck SG ，Li MM ，Weigelt B ，Reis-Filho JS ，Kent Osborne C ，Schiff R ... -  《-》

PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer.

Esteva FJ ，Guo H ，Zhang S ，Santa-Maria C ，Stone S ，Lanchbury JS ，Sahin AA ，Hortobagyi GN ，Yu D ... -  《-》