Abstract P5-20-09: Tumor mutational analysis and therapy outcomes for patients (pts) with metastatic/unresectable locally advanced myoepithelial/metaplastic breast cancer treated with PI3K targeted therapy
Authors: Moulder S , Wheler J , Albarracin C , Gilcrease M , Falchook G , Naing A , Hong D , Fu S , Piha-Paul S , Tsimberidou A , Janku F , Kurzrock R 
Published: August 2014

Abstract
Background: Metaplastic breast cancers are considered a chemorefractory subset of triple negative breast cancers. Molecular profiling has demonstrated that metaplastic tumors are enriched for epithelial-to-mesenchymal transition (EMT), frequently express myoepithelial differentiation, make up a component of the ‘claudin-low’ subtype, and harbor relatively high rates of mutations/activation of the PI3kinase pathway (Hennessy, Cancer Research, 2009; Prat, Breast Cancer Res, 2010).
Methods: Data from pts with myoepithelial/metaplastic breast cancer treated within the Center for Targeted Therapy using regimens with known inhibitors of the PI3K pathway were evaluated to determine response to therapy. Mutational analyses were performed in archived tumor samples when available.
Results: 23 pts have been treated using 6 different therapy regimens and one pt was treated on two separate clinical trials for a total of 24 analyzable outcomes. Patients were treated with liposomal doxorubicin, bevacizumab and the mTOR inhibitor, temsirolimus (DAT, n=17); liposomal doxorubicin and temsirolimus (DT, n=1); paclitaxel, bevacizumab and temsirolimus (TAT, n=3); paclitaxel and temsirolimus (TT, n=1), paclitaxel in combination with an experimental PI3K inhibitor (TEx, n=1), or temsirolimus alone (tem, n=1). Response was measured every two cycles using RECIST criteria. Most pts had received prior chemotherapy, median of 2 prior regimens (range 0–7). Three patients were not evaluated for response, one who died of pneumonia during cycle 2 (DAT) and two who have not yet completed 2 cycles of therapy (DAT, TEx). Response rate (CR+PR) was 35% (CR = 2, PR=4, SD≥6 months=2, SD&lt;6 months=2, PD/death=7) with the anthracycline based regimens, DAT and DT; whereas, stable disease was the best response seen thus far with the paclitaxel based regimens or temsirolimus alone: TAT (SD&lt;6months=2, PD=1), TT (SD&lt;6months=1), tem (SD&lt;6months=1). 8 of 9 tumors tested (89%) were found to have mutations that would lead to activation of the PI3K pathway: PIK3CA=5 (62%), PTEN=2 (25%) and NF2=1(13%). The two patients with CR from DAT had mutations in NF2 and PIK3CA, respectively. Both patients remain in CR (2+ years and 1+ year respectively) after discontinuing protocol therapy, and both continue maintenance everolimus.
Conclusion: Activating mutations in the PI3K pathway are common in metaplastic breast cancers, a tumor subtype that shares molecular features with claudin-low and mesenchymal/mesenchymal-stem cell like triple negative breast cancers. DAT has demonstrated activity in myoepithelial/metaplastic breast cancer including two durable CRs to therapy. This regimen should be explored in larger, randomized trials to test superiority to chemotherapy alone.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-09.