par Sonnenblick, Amir;Desmedt, Christine ;Neven, Patrick;Loibl, Sibylle;Denkert, Carsten;Joensuu, Heikki;Loi, Sherene ;Sirtaine, Nicolas;Kellokumpu-Lehtinen, Pirkko-Liisa;Piccart-Gebhart, Martine ;Sotiriou, Christos ;Brohée, Sylvain ;Fumagalli, Debora ;Vincent, Delphine;Venet, David ;Ignatiadis, Michail ;Salgado, Roberto;Van den Eynden, Gert;Rothé, Françoise
Référence BMC medicine, 13, 1, 177
Publication Publié, 2015-08
Référence BMC medicine, 13, 1, 177
Publication Publié, 2015-08
Article révisé par les pairs
Résumé : | Background: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance. Methods: We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting. Results: We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation. Conclusions: This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2-positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive breast cancer. |