Abstract OT1-1-08: Master regulator (MR)-directed therapy in residual breast cancer patient derived xenografts (PDXs)
Authors: Kalinsky Kevin , Mundi Prabhjot , Hershman Dawn L , Connolly Eileen , Crew Katherine D , Hibshoosh Hanina , Calfiano Andrea , Maurer Matthew 
Published: May 2015

Background: Neoadjuvant chemotherapy (NACT) is standard of care in operable breast cancer (BC). There are no therapies that have demonstrated benefit in patients who failed to achieve a pathologic complete response (pCR). There remains an unmet need to identify appropriate targets in which to direct therapy in this high-risk population to decrease BC mortality.

Computational approaches to reverse engineering of cell signaling networks from patient tumor-specific RNA expression data can identify key molecular dependencies that result in the malignant phenotype, i.e. MRs. These approaches out-perform traditional methods, such as identifying mutated or over-expressed genes, in determining true tumor dependencies. Successful targeting of MRs may be a means for rational selection of targeted drugs in the operable BC setting.

Trial Design: A single center pilot study that will accrue 35 subjects with BC who will have received standard NACT and at least 1.5 cm of residual disease. At the time of definitive surgery, resected tissue will be assessed for residual disease and then allocated. After reserving required tissue for pathologic diagnosis, 0.5 cm3 will be procured for xenografting and 0.5 cm3 will be flash frozen for RNA extraction. Tissue for xenografting is immediately sent to a Champions Oncology site for implantation. We will use fresh frozen tissue to perform RNA-seq. Previously validated computational algorithms at our center, including MARINa and VIPER, will be used to interrogate the expression data and identify the top MRs in individual tumors.

Upon maturation of a Champions Oncology Tumor Graft model, the second generation expansion group will be divided into four cohorts. We plan to test two drugs that target tumor-specific MRs, one vehicle control, and one negative control (paclitaxel, as these tumors have demonstrated paclitaxel resistance) in each model.

Eligibility Criteria

1. Patients ≥18 years with newly diagnosed BC, deemed candidates for definitive surgery.

2. Subjects must have received standard NACT with taxane (paclitaxel or docetaxel; herceptin +/- pertuzumab if HER2+) and/or adriamycin/cytoxan.

3. Clinical or radiographic evidence of ≥1.5 cm of residual BC.

4. ECOG PS ≤2

Specific Aims:

1) To computationally infer MRs in individual patient tumors resistant to NACT

2) To determine if targeting MRs results in superior tumor growth inhibition in PDX models

Statistical Methods: In the PDX model, pre- and post-treatment tumor volume (TV) is calculated: TV= width2 x length x 0.52, and is standardized as a tumor growth inhibition (TGI) percentage compared to the vehicle control. Since we anticipate the MR-directed arms will demonstrate a TGI (80%) twice that of the paclitaxel arm (40%), we have 80% power to detect a difference in 18 patients (one-sided alpha, 0.05). We assume a xenograft take-rate of 50% in the post-NACT setting and thus aim for an N of 35. Final data analysis will be adjusted using ANOVA.

Present and Target Accrual: 35 patients, projected to accrue in 18-24 months. Estimate based on number of locally advanced BC patients seen, competing studies, and likelihood of participation. The study will open in Fall 2014.

Citation Format: Kevin Kalinsky, Prabhjot Mundi, Dawn L Hershman, Eileen Connolly, Katherine D Crew, Hanina Hibshoosh, Andrea Calfiano, Matthew Maurer. Master regulator (MR)-directed therapy in residual breast cancer patient derived xenografts (PDXs) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-08.