Thorunn Helgason

Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses.

Clostridium novyi-NT targets aberrant tumor physiology and can produce a precise, robust, and reproducible antitumor response. Fighting Cancer with Clostridium Tumors are composed of necrotic, hypoxic, and well-oxygenated regions. Hypoxic tumor regions are more resistant to systemic anticancer agents and radiotherapy. However, they provide a fertile ground for the growth of anaerobic bacteria. Roberts et al. use an attenuated strain of the anaerobic, spore-forming bacterium Clostridium novyi (C. novyi-NT) and demonstrate precise, robust, and reproducible antitumor responses when C. novyi-NT spores were injected into tumors of rats, dogs, and one human patient. These results support the further development of intratumoral injections of C. novyi-NT spores as a therapeutic for patients with locally advanced, nonresectable cancers. Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted.

Phase I Study of the Antiangiogenic Antibody Bevacizumab and the mTOR/Hypoxia-Inducible Factor Inhibitor Temsirolimus Combined with Liposomal Doxorubicin: Tolerance and Biological Activity

Purpose: Preclinical data suggest that combining the mTOR/hypoxia-inducible factor (HIF) inhibitor temsirolimus and the antiangiogenesis antibody bevacizumab may augment antitumor activity as well as resensitize cells to anthracyclines. Experimental Design: We initiated a phase I study of bevacizumab and temsirolimus plus liposomal doxorubicin in patients with advanced malignancies. Patients (N = 136) were enrolled according to a modified 3 + 3 design plus dose expansion in responsive tumor types. Results: The most common cancers were breast (n = 29), epithelial ovarian (n = 23), and colorectal cancer (n = 17). The median number of prior chemotherapy regimens was four (range: 0–16). Grade 3 or higher adverse events (> 5%) included pancytopenia, mucositis, hand–foot syndrome, hypertension, and fistula. This regimen led to a 21% (n = 28) stable disease (SD) ≥ 6 months and 21% (n = 29) rate of partial or complete remission [PR/CR; (total SD ≥ 6 months/PR/CR = 42% (n = 57)]. PR/CR was most common in parotid gland adenocarcinoma (4/6, 67%), metaplastic breast cancer (5/12, 42%), endometrial endometrioid carcinoma (6/15, 40%), and in patients with a PIK3CA mutation and/or a PTEN mutation/loss (11/28, 39%). The maximum tolerated dose was liposomal doxorubicin 30 mg/m2 and bevacizumab 15 mg/kg every three weeks with temsirolimus 25 mg weekly. Conclusions: Patients tolerated bevacizumab and temsirolimus together with liposomal doxorubicin. Further evaluation, especially in patients with parotid, metaplastic breast, and endometrial endometrioid cancer, and in patients with PIK3CA and/or PTEN aberrations is warranted. Clin Cancer Res; 18(20); 5796–805. ©2012 AACR.

A Phase I Trial of Liposomal Doxorubicin, Bevacizumab and Temsirolimus in Patients with Advanced Gynecologic and Breast Malignancies

Purpose: Liposomal doxorubicin (D) and bevacizumab (A) are active single agents in gynecologic and breast malignancies which share a resistance mechanism: upregulation of hypoxia inducible factor (HIF-1α). We, therefore, added temsirolimus (T), which inhibits HIF-1α, to D and A (DAT). Trial objectives were assessment of safety, preliminary efficacy, and identification of biological response correlates. Patients and Methods: Cycle length was 21 days, with IV D, A, and T on day 1; T on days 8 and 15 (3+3 dose-escalation design with expansion cohorts). Mutational assays for PIK3CA, BRAF, KRAS, and immunhistochemistry for PTEN loss were conducted. Results: This article details 74 patients with gynecologic and breast malignancies who received at least one dose of drug on study. Median patient age: 52 (27–79); prior regimens: 4 (1–11). Responses: 1 (1.4%) complete response (CR), 14 (18.9%) partial responses (PR), and 13 (17.6%) with stable disease (SD) ≥ 6 months (total = 37.9%). The most common grade 1 toxicities were fatigue (27%) and anemia (20.2%). Notable grade 3/4 toxicities: thrombocytopenia (9.5%), mucositis (6.7%), and bowel perforation (2.7%). PIK3CA mutations or PTEN loss were identified in 25 of 59 (42.3%) of tested patients. Among these, nine (36%) achieved CR/PR and four (16%) had SD ≥ 6 months (CR+PR+SD ≥ 6 months = 52%). Conclusions: DAT is well tolerated with manageable side effects. Responses observed warrant further evaluation. Mutational analyses were notable for a high percentage of responders with phosphoinositide-3-kinase pathway aberrations. Clin Cancer Res; 17(21); 6840–6. ©2011 AACR.

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.

Weekly nab-Rapamycin in Patients with Advanced Nonhematologic Malignancies: Final Results of a Phase I Trial

Purpose: This dose-finding phase I study investigated the maximum-tolerated dose (MTD) and safety of weekly nanoparticle albumin-bound rapamycin (nab-rapamycin) in patients with untreatable advanced nonhematologic malignancies. Experimental Design: nab-Rapamycin was administered weekly for 3 weeks followed by 1 week of rest, with a starting dose of 45 mg/m2. Additional doses were 56.25, 100, 150, and 125 mg/m2. Results: Of 27 enrolled patients, 26 were treated. Two dose-limiting toxicities (DLT) occurred at 150 mg/m2 [grade 3 aspartate aminotransferase (AST) elevation and grade 4 thrombocytopenia], and two DLTs occurred at 125 mg/m2 (grade 3 suicidal ideation and grade 3 hypophosphatemia). Thus, the MTD was declared at 100 mg/m2. Most treatment-related adverse events (TRAE) were grade 1/2, including thrombocytopenia (58%), hypokalemia (23%), mucositis (38%), fatigue (27%), rash (23%), diarrhea (23%), nausea (19%), anemia (19%), hypophosphatemia (19%), neutropenia (15%), and hypertriglyceridemia (15%). Only one grade 3 nonhematologic TRAE (dyspnea) and one grade 3 hematologic event (anemia) occurred at the MTD. One patient with kidney cancer had a partial response and 2 patients remained on study for 365 days (patient with mesothelioma) and 238 days (patient with neuroendocrine tumor). The peak concentration (Cmax) and area under the concentration–time curve (AUC) of rapamycin increased with dose between 45 and 150 mg/m2, except for a relatively low AUC at 125 mg/m2. nab-Rapamycin significantly inhibited mTOR targets S6K and 4EBP1. Conclusions: The clinical dose of single-agent nab-rapamycin was established at 100 mg/m2 weekly (3 of 4 weeks) given intravenously, which was well tolerated with preliminary evidence of response and stable disease, and produced a fairly dose-proportional pharmacokinetic profile in patients with unresectable advanced nonhematologic malignancies. Clin Cancer Res; 19(19); 5474–84. ©2013 AACR.

Targeting the PI3K/AKT/mTOR pathway for the treatment of mesenchymal triple-negative breast cancer: Evidence from a phase 1 trial of mTOR inhibition in combination with liposomal doxorubicin and bevacizumab

Importance Triple-negative breast cancer (TNBC) classified by transcriptional profiling as the mesenchymal subtype frequently harbors aberrations in the phosphoinositide 3-kinase (PI3K) pathway, raising the possibility of targeting this pathway to enhance chemotherapy response. Up to 30% of mesenchymal TNBC can be classified histologically as metaplastic breast cancer, a chemorefractory group of tumors with a mixture of epithelial and mesenchymal components identifiable by light microscopy. While assays to identify mesenchymal TNBC are under development, metaplastic breast cancer serves as a clinically identifiable surrogate to evaluate potential regimens for mesenchymal TNBC. Objective To assess safety and efficacy of mammalian target of rapamycin (mTOR) inhibition in combination with liposomal doxorubicin and bevacizumab in patients with advanced metaplastic TNBC. Design, Setting, and Participants Phase 1 study with dose escalation and dose expansion at the University of Texas MD Anderson Cancer Center of patients with advanced metaplastic TNBC. Patients were enrolled from April 16, 2009, to November 4, 2014, and followed for outcomes with a cutoff date of November 1, 2015, for data analysis. Interventions Liposomal doxorubicin, bevacizumab, and the mTOR inhibitors temsirolimus or everolimus using 21-day cycles. Main Outcomes and Measures Safety and response. When available, archived tissue was evaluated for aberrations in the PI3K pathway. Results Fifty-two women with metaplastic TNBC (median age, 58 years; range, 37-79 years) were treated with liposomal doxorubicin, bevacizumab, and temsirolimus (DAT) (N = 39) or liposomal doxorubicin, bevacizumab, and everolimus (DAE) (N = 13). The objective response rate was 21% (complete response = 4 [8%]; partial response = 7 [13%]) and 10 (19%) patients had stable disease for at least 6 months, for a clinical benefit rate of 40%. Tissue was available for testing in 43 patients, and 32 (74%) had a PI3K pathway aberration. Presence of PI3K pathway aberration was associated with a significant improvement in objective response rate (31% vs 0%; P = .04) but not clinical benefit rate (44% vs 45%; P > .99). Conclusions and Relevance Using metaplastic TNBC as a surrogate for mesenchymal TNBC, DAT and DAE had notable activity in mesenchymal TNBC. Objective response was limited to patients with PI3K pathway aberration. A randomized trial should be performed to test DAT and DAE for metaplastic TNBC, as well as nonmetaplastic, mesenchymal TNBC, especially when PI3K pathway aberrations are identified.

Abstract C120: Genomic landscape in advanced metaplastic breast cancer and outcomes with mTOR targeted therapy.

Background: Metaplastic breast cancer (BC) is a treatment-refractory rare type of BC with characteristics similar to claudin-low tumors. Understanding the genomic landscape of metaplastic BC can lead to identification of new therapies. Methods: Patients with metastatic metaplastic BC referred for experimental therapies, who had adequate archival tumor tissue for DNA extraction, had targeted next-generation sequencing (NGS) for 3,769 exons of 236 cancer-related genes and 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform (Foundation One, Foundation Medicine, MA). Results: NGS results were obtained for 10 women with metaplastic BC (median age 60 years [39-73], median prior therapies for metastatic BC 0 [0-1]). NGS revealed a total of 41 aberrations in 25 genes and all 10 patients had at least 1 molecular aberration (range 1-7, median 4). Of 41 detected molecular aberrations, 17 (41%) included putative activation of the PI3K/mTOR and/or MAPK pathways (PIK3CA [6], PTEN [3], PIK3R1 [1], NF1 [1], EGFR [1], EPHB1 [1], FGF23 [1], FGFR2 [1], HRAS [1], PTPN11 [1]), 13 (32%) loss of cell cycle control (CCND2 [1], CCND3 [1], CCNE1 [1], CDK2 [1], CDKN2A [2], MYC [6], RB1 [1]), 6 (15%) loss of apoptosis (MCL1 [1], NFKBIA [1], TP53 [4]), 2 (5%) aberrant DNA repair (BRCA2 [1], FANCA [1]), 2 (5%) aberrant methylation (KDM6A [1], MLL2 [1]) and 1 (2.5%) aberrant SWI/SNF chromatin remodeling (ARID1A [1]). Of the 10 patients, 9 (90%) received an experimental mTOR targeting therapy combination with temsirolimus, bevacizumab, and liposomal doxorubicin and at the median follow up of 5.8 months, 2 (22%) patients attained a partial response and 3 (33%) had stable disease >/= 4 months. The median progression-free survival was 6.2 months (95% confidence Interval 3.4 - 9.0) Conclusion: Genomic alterations putatively activating PI3K/mTOR and MAPK pathways are common in metastatic metaplastic BC. A combination therapy targeting mTOR demonstrated encouraging activity. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C120. Citation Format: Filip Janku, Razelle Kurzrock, Thorunn Helgason, Vicente Valero, Francisco Esteva, Jennifer J. Wheler, Daniel D. Karp, Funda Meric-Bernstam, Stacy L. Moulder. Genomic landscape in advanced metaplastic breast cancer and outcomes with mTOR targeted therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C120.

Abstract OT2-01-14: Triple-negative first-line study: Neoadjuvant trial of nab-paclitaxel and atezolizumab, a PD-L1 inhibitor, in patients with triple negative breast cancer (TNBC) (NCT02530489)

BACKGROUND: TNBC has an especially poor prognosis in patients (pts) whose tumor does not respond to anthracycline and taxane-based chemotherapy. Approximately 50% will have chemo-insensitive disease (CID) resulting in extensive residual disease at the time of surgery. 40-80% of these pts will recur PRIMARY OBJECTIVE: Evaluate the rate of pathologic complete response (pCR)/RCB-0 + residual cancer burden (RCB)-I responses in TNBC pts, determined to have CID after anthracycline-based chemotherapy, then treat with atezolizumab + nab-paclitaxel preoperatively. TRIAL DESIGN AND STATISITCAL METHODS: Pts deemed to have CID on the ARTEMIS trial can enter this non-randomized phase II study. Pts without response to their initial chemotherapy cycles have a low likelihood (5%) of achieving pCR with additional cycles of chemotherapy. It would be clinically meaningful for pCR to improve to 20%. Counting pCR (RCB-0) or RCB-I as response given similar survival outcomes, a two-stage Gehan-type design will be employed with 14 pts in the first stage. If at least one pt responds, 23 more will be added. This design has a 49% chance of terminating after the first stage if the true response rate is 0.05, 23% chance if the true rate is 0.10, 10% if the true rate is 0.15 and 4% if the true rate is 0.20. If accrual continues to the second stage, the 95% confidence interval for a 0.20 response rate will extend from 0.10 to 0.35. BRIEF ELIGIBILITY CRITERIA:Inclusion: localized TNBC enrolled onto ARTEMIS and determined to have CID at the time of response assessment after anthracycline chemotherapy, adequate organ, bone marrow and cardiac parameters. Exclusion: prior immunotherapy, IBC, history of autoimmune disease, HIV, Hep-B, Hep-C, active tuberculosis, pregnant. CORRELATIVE SCIENCE: Evaluate the presence and phenotype of TIL and other immune cell populations in tumor tissue pre/post treatment; determine changes in expression of co-stimulatory and co-inhibitory molecules on tumor cells and immune cells in the microenvironment; evaluate the immune repertoire and cytokine responses in serially collected peripheral blood mononuclear cells and serum respectively. Citation Format: Litton JK, Moulder S, Helgason T, Clayborn AR, Rauch GM, Gilcrease M, Adrada BE, Huo L, Hess KR, Symmans WF, Thompson A, Tripathy D, Mittendorf EA. Triple-negative first-line study: Neoadjuvant trial of nab-paclitaxel and atezolizumab, a PD-L1 inhibitor, in patients with triple negative breast cancer (TNBC) (NCT02530489) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-14.

Abstract OT3-02-05: NCI-2016-00367: A phase IIB study of neoadjuvant ZT regimen (enzalutamide therapy in combination with weekly paclitaxel) for androgen receptor (AR)-positive triple-negative breast cancer (TNBC)

BACKGROUND: Approximately 50% of TNBC expresses AR by immunohistochemical (IHC) staining. Luminal androgen receptor (LAR) subtype is heavily enriched in hormonally regulated genes, yet negative for ER by IHC. LAR is associated with low pCR rates and long survival. Preclinical data have shown that taxanes inhibit translocation of AR from the cytoplasm to the nucleus where AR is activated. Combining paclitaxel with enzalutamide may inhibit the AR pathway synergistically thereby increasing pCR rates. We hypothesized that patients with AR-positive TNBC who have chemo-insensitive disease (CID) after initial anthracycline-based chemotherapy treated with ZT would have higher RCB-0 and RCB-I rates than those who receive conventional taxane-based chemotherapy. Our team developed a clinical trial to identify patients with CID (ARTEMIS: A R andomized, T NBC E nrolling trial to confirm M olecular profiling I mproves S urvival). In the ARTEMIS trial, treatment-naive patients with localized TNBC undergo a pretreatment biopsy and then begin anthracycline-based chemotherapy. Molecular testing results and radiographic response assessment are used to identify CID and will guide the second phase of neoadjuvant chemotherapy (NACT) to overcome CID. PRIMARY OBJECTIVE: To determine RCB-0 and RCB-I rates of patients with TNBC who have CID to initial anthracycline-based chemotherapy and who received ZT. TRIAL DESIGN AND STATISTICAL METHODS: Patients with CID from the ARTEMIS trial can enroll in the 12-week ZT (paclitaxel, 80 mg/m 2 intravenously per week; enzalutamide, 160 mg orally per day). We will define pCR (RCB-0) or RCB-I as a response, using a Simon optimal 2-stage design with alpha=beta=10% and then setting the threshold for an acceptable pCR or RCB-I rate at 20%. We will enroll 12 patients into the first stage. If no patients experience pCR or RCB-I, we will stop the study after the first stage. If at least 1 patient experiences pCR or RCB-I, we will enroll 25 more patients for a total of 37 patients. We would declare the treatment worthy of further study if at least 4 of the 37 patients experience pCR or RCB-I. This design has a 54% probability of early termination after the first stage if the true pCR or RCB-I probability is 5%. Because patients with CID have a very low chance (5%) of achieving pCR with additional chemotherapy, improving pCR rates to 20% in this patient population would be clinically meaningful. BRIEF ELIGIBILITY CRITERIA: Inclusion criteria: Primary invasive TNBC patients who have CID under the ARTEMIS trial; AR+ ≥1% nuclear staining by IHC; and adequate physical, organ, bone marrow, and cardiac functions. Exclusion criteria: Pregnant or lactating patients, history of colitis or absorption abnormality, known or suspected brain metastasis or leptomeningeal disease, or history of seizure. CORRELATIVE SCIENCE: Enumeration of circulating tumor cells (CTCs) and expression of CTC-related gene transcripts will be measured to correlate CTC characteristics and/or gene profiles related to the AR pathway and treatment response to ZT. Citation Format: Fujii T, Lim B, Helgason T, Hess KR, Gilcrease MZ, Willey JS, Tripathy D, Litton JK, Moulder S, Krishnamurthy S, Yang W, Reuben JM, Symmans WF, Ueno NT. NCI-2016-00367: A phase IIB study of neoadjuvant ZT regimen (enzalutamide therapy in combination with weekly paclitaxel) for androgen receptor (AR)-positive triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-02-05.

Abstract 2273: Targeting the PI3K/AKT/mTOR pathway for the treatment of metaplastic breast cancer: Does location of PIK3CA mutation or histology affect response

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.