Abstract P5-01-09: Establishment and characterization of two simultaneously developed T-DM1-resistant, ER+/HER2+ XPDX models from the same patient with differential in vivo sensitivity to trastuzumab deruxtecan (DS-8201a)

Abstract

Abstract Background: Trastuzumab deruxtecan (DS-8201a) is an antibody-drug conjugate (ADC) consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody linked to a topoisomerase I inhibitor payload using a cleavable tetrapeptide-based linker and was recently approved for unresectable or T-DM1-refractory HER2+ breast cancer. While some mechanisms for clinical T-DM1 resistance have been identified, less is known about acquired or innate resistance to DS-8201a. We established two XPDX models of ER+/HER2+ breast cancer from tissue and fluid samples collected simultaneously from the same patient. These models designated ST4480B and ST4480C were developed and characterized for receptor expression, genomic alterations, and in vivo drug sensitivities toward multiple chemotherapies and targeted agents including DS-8201a and T-DM1. Methods: ST4480B and ST4480C were established from a 70-year-old Caucasian female with ER+/HER2+ metastatic breast cancer pretreated with chemotherapy and targeted agents including T-DM1 for nine months followed by capecitabine/trastuzumab/tucatinib combination for one year prior to sample collections. ST4480B was established from a lymph node biopsy and ST4480C from a fluid sample collected the same day; both were grown subcutaneously in female athymic nude mice supplemented with estradiol. The resulting models were passaged and receptor expression confirmed immunohistochemically; genomic analysis, including WES and RNAseq, was performed to further characterize models. For in vivo studies, both models were evaluated with several chemotherapy and targeted agents alone and in combination including: trastuzumab, pertuzumab, T-DM1, DS-8201a, neratinib, tucatinib, alpelisib, everolimus, and irinotecan. In vivo study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20 versus control was considered sensitive. Tumor regression (%T/C=—<0) versus Day 0 tumor volume was also reported. Results: ST4480B and ST4480C retained comparable receptor expression (ER=2+/HER2=2+) over tested passages with similar histology compared with archival clinical samples. DNA/RNA sequencing identified several conserved variants including PIK3CAE545K and TP53Q192* mutations and an ESR1-CCDC170 fusion. However, two variants identified only in ST4480C sequences included PIK3CAG1007R and PTENS287L. In vivo, ST4480B and ST4480C were found resistant to T-DM1 up to 10 mg/kg weekly with an average %T/C of 46 and 100, respectively. However, DS-8201a treatment at 3 mg/kg weekly resulted in partial tumor regressions in ST4480B (%T/C=-68) while ST4480C was found resistant to the therapy up to 10 mg/kg weekly (%T/C=84%). Both models were found resistant to trastuzumab, pertuzumab, neratinib, tucatinib, and irinotecan but sensitive to both alpelisib and everolimus. Conclusion: We established two XPDX models representing T-DM1-resistant, ER+/HER2+ breast cancer from both tissue and fluid samples collected simultaneously from the same patient which were found differentially responsive to DS-8201a. These models can be utilized as a valuable tool in better understanding innate resistance to DS-8201a. Citation Format: Johnnie R Flores, Anna Stackpole, Abimael Garza, Alexandra Ulmer, Alyssa Simonson, Kyriakos Papadopoulos, April Cabang, Jun Ma, Amita Patnaik, Drew Rasco, Amy Lang, Gladys Rodriguez, Murali Beeram, Michael J Wick. Establishment and characterization of two simultaneously developed T-DM1-resistant, ER+/HER2+ XPDX models from the same patient with differential in vivo sensitivity to trastuzumab deruxtecan (DS-8201a) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-09.