Abstract 1603: Patient derived tumor organoids identify actionable targets in heavily pretreated metastatic breast cancer patients
Authors: Churchill Michael J. , Schaub Franz X. , Swan Hallie A. , Rosati Rachele , Yan Fengting , Shaw Reid C. , Gurley Kay E. , Diaz Robert L. , Pereira Shalini C. , Grandori Carla , Kemp Christopher J. , Gadi Vijayakrishna K. 
Published: August 2018

Abstract
Recurrent metastatic breast cancer is difficult to treat and patients often exhaust standard-of-care regimens. P.A.R.I.S. is a CLIA certified high throughput chemosensitivity test developed by SEngine Precision Medicine. (Seattle, WA USA) Tumor cells derived from patient breast tissue are expanded as mammospheres, and challenged with a library of 123 clinically actionable, targeted drugs. These results are integrated with patient genomic data and reported to the oncologist to prioritize treatment options. To date, we have performed over 100 such drug screens using low passage patient-derived tumor cells in 70 independent replicate pairs. Of 18 viable primary breast tumor samples received to date, we have successfully derived organotypic cultures in 13 cases. (72%) Of these, 7 were challenged to the full 123 agent library. Three of the seven cases were HER2 positive and demonstrated clear sensitivity to HER2 kinase inhibitors. Overall, patients can be separated into two groups, characterized by families of drug sensitivities. Patients in group one respond preferentially to inhibitors of signaling pathways such as IGF1R, ALK, FGFR and EGFR. Patients in the second group responded to therapies targeting epigenetic modifiers, cell cycle control and apoptosis.
Presented here is a premenopausal female, diagnosed in 2010 as pT2N0M0 (stage IIA), ER+ PR+ HER2+. This patient underwent surgery and received adjuvant chemotherapy, followed by tamoxifen. Upon progression to metastatic disease, biopsy of her recurrent lesion showed loss of ER and PR expression, but remained positive for HER-2 amplification. Sequencing of this biopsy exposed a PIK3CA G106R mutation and amplification of unknown significance. Tumor cells were isolated from ascites, cultured and the P.A.R.I.S. test was performed. Patient derived tumor cells were sensitive to HER2 targeting agents, concordant with the patient's HER2 amplification. Of these, the non-reversible inhibitor neratinib exhibited a significantly enhanced effect and achieved maximum growth inhibition of 80% over the duration of the assay. Two different AKT inhibitors, afuresertib and AZD5363, demonstrated activity in the patient cells consistent with the activating PIK3CA mutation. Also consistent with the loss of ER/PR expression, the patient derived tumor cells no longer responded to anti-estrogen therapies nor to chemotherapies the patient had been refractory to prior: cyclophosphamide, docetaxel, doxorubicin, gemcitabine, and paclitaxel.The PARIS assay is a robust ex vivo screening platform to objectively quantify patient specific sensitivities to a panel of 123 clinically actionable oncology drugs. We show here concordance with both genomic data and prior treatments the patient received in the course of disease however the same approach may be used to successfully identify unique sensitivities in the absence of established biomarkers.
Citation Format: Michael J. Churchill, Franz X. Schaub, Hallie A. Swan, Rachele Rosati, Fengting Yan, Reid C. Shaw, Kay E. Gurley, Robert L. Diaz, Shalini C. Pereira, Carla Grandori, Christopher J. Kemp, Vijayakrishna K. Gadi. Patient derived tumor organoids identify actionable targets in heavily pretreated metastatic breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1603.