Abstract 2273: Targeting the PI3K/AKT/mTOR pathway for the treatment of metaplastic breast cancer: Does location of PIK3CA mutation or histology affect response
Authors: Basho Reva K. , Gilcrease Michael , Murthy Rashmi K. , Helgason Thorunn , Booser Daniel J. , Karp Daniel D. , Meric-Bernstam Funda , Hess Kenneth R. , Herbrich Shelley M. , Valero Vicente , Albarracin Constance , Litton Jennifer , Chavez-MacGregor Mariana , Ibrahim Nuhad K. , Murray James L. , Koenig Kimberly B. , Hong David , Subbiah Vivek , Kurzrock Razelle , Janku Filip , Moulder Stacy 
Published: July 2016

Abstract
Background: Metaplastic breast cancers (MpBCs) are a chemo-refractory group of tumors that contain a component of squamous and/or mesenchymal differentiation identifiable by light microscopy. MpBCs contain a high frequency of aberrations in the PI3K/AKT/mTOR pathway, making this pathway a potential target for therapy.
Methods: Patients with advanced MpBC (N = 52) were treated with liposomal doxorubicin (D), bevacizumab (A) and the mTOR inhibitors temsirolimus (T) or everolimus (E). D and A were administered IV on day 1 with T (IV on days 1, 8 and 15) or E (continuous daily oral administration) using 21 day cycles. All tumors were evaluated to assess histology of metaplasia (spindle, mixed spindle vs non-spindle cell). Response was assessed every 6 weeks using RECIST. When available, archived tissue was evaluated for aberrations in the PI3K pathway using standard assays.
Results: Fifty-two MpBC patients were treated with DAT (N = 39) or DAE (N = 13). Median age was 58 (range 37-79); median number of prior regimens for metastatic disease was 1 (range 0-5). The objective response rate (ORR) was 21% [complete response (CR) = 4 (8%); partial response (PR) = 7 (13%)] and 10 (19%) pts had stable disease (SD)≥6 months for a clinical benefit rate (CBR) of 40%. Tissue was available in 43 pts and 32 (74%) had a PI3K pathway activating aberrations. PI3K pathway aberration was associated with a significant improvement in ORR (31 vs 0%; P = 0.04) but not CBR (44 vs 45%; P = 1.00) or progression-free survival (median 5 vs 3 months; P = 0.35). The most frequent PI3K pathway aberration was mutation in PIK3CA, occurring in 19 patients. Outcomes were similar if mutations of PIK3CA were located in the helical or kinase domain (ORR 25% vs 27%; P = 1.00 and CBR 38% vs 47%; P = 1.00, respectively). Spindle cell was the most frequent metaplastic histology seen, occurring in 18 tumors and mixed with other metaplastic histologies including squamous, chondroid and osseous in 14 additional tumors, while 20 tumors had non-spindle cell morphologies. The incidence of PI3K pathway aberration was similar across histologies (61% in spindle vs 67% in mixed spindle vs 60% in non-spindle cell). Tumors with mixed histology had lower ORR, CBR and PFS, but this was not statistically significant, likely due to small numbers in each cohort: ORR 22% in spindle vs 7% in mixed spindle vs 30% in non-spindle cell, P = 0.27; CBR 50% in spindle vs 21% in mixed spindle vs 40% in non-spindle cell, P = 0.25; and PFS median 4 months in spindle vs 2 months in mixed spindle vs 5 months in non-spindle cell, P = 0.68.
Conclusions: Response to mTOR inhibition is enhanced in MpBCs with PI3K pathway aberrations. However, specific aberrations in PIK3CA do not lead to differential response to mTOR inhibition. PI3K pathway aberrations and response to mTOR inhibition are seen across all histologies of MpBC, and the response is not enhanced in particular histologies.
Citation Format: Reva K. Basho, Michael Gilcrease, Rashmi K. Murthy, Thorunn Helgason, Daniel J. Booser, Daniel D. Karp, Funda Meric-Bernstam, Kenneth R. Hess, Shelley M. Herbrich, Vicente Valero, Constance Albarracin, Jennifer Litton, Mariana Chavez-MacGregor, Nuhad K. Ibrahim, James L. Murray, Kimberly B. Koenig, David Hong, Vivek Subbiah, Razelle Kurzrock, Filip Janku, Stacy Moulder. Targeting the PI3K/AKT/mTOR pathway for the treatment of metaplastic breast cancer: Does location of PIK3CA mutation or histology affect response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2273.