Inhibition of the phosphoinositide 3-kinase pathway for the treatment of patients with metastatic metaplastic breast cancer

Background: Mesenchymal/ metaplastic breast cancers ( MpBCs) are often triple- negative ( TNBC), and chemo- refractory, and can harbor phosphoinositide 3- kinase ( PI3kinase) alterations; thus, therapy with mTor inhibitors may demonstrate activity. Patients and methods: Patients with mesenchymal/ MpBC treated with temsirolimus- based regimens were evaluated. Mutational analyses [ polymerase chain reaction ( PCR)- based DNA sequencing method, mass spectrometric detection ( Sequenom MassARRAY), or next- generation sequencing] as well as loss of phosphatase and tensin homolog ( PTEN) ( immunohistochemistry) were performed ( archived tissue when available). Results: Twenty- three patients ( one of whom was on two separate trials) were treated using temsirolimus- containing regimens: temsirolimus alone ( n = 1 patient) or combined with the following: liposomal doxorubicin and bevacizumab DAT, n = 18); liposomal doxorubicin (DT, n = 1); paclitaxel and bevacizumab (TAT, n = 2); paclitaxel (TT, n = 1); carboplatin and bevacizumab (CAT, n = 1). Response rate [complete response (CR) + partial response (PR)] was 25% across all regimens; 32% in the anthracycline- based regimens [DAT and DT (CR = 2, PR = 4; N = 19)]. An additional two patients achieved stable disease (SD) = 6 months [total SD = 6 months/ CR/ PR = 8 (33%)]. Molecular aberrations in the PI3K pathway were common: PIK3CA mutation = 6/ 15 (40%), PTEN mutation = 3/ 11 (27%), and PTEN loss = 2/ 11 (18%). A point mutation in the NF2 gene (K159fs* 16; NF2 alterations can activate mTor) was found in one patient who attained CR (3+ years). Of the eight patients who achieved SD = 6 months/ CR/ PR, all 4 patients with available tissue had a molecular aberration that activate the PIK3CA/ Akt/ mTOR axis: PIK3CA mutation = 2; PTEN loss = 1; NF2 aberration = 1. Conclusions: DAT has activity in MpBCs including complete CRs. Molecular aberrations that can activate the PI3 K/ Akt/ mTOR axis are common in MpBC.