A novel patient-derived organoid model for triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy for screening personalized drugs.

Abstract

e12625 Background: Triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence. In this study, we developed a novel organoid culture method for growing TNBC patient samples after NAC, with the goal of generating models that more faithfully recapitulates the key features of the primary tumor for screening personalized drugs. Methods: We established organoid lines derived from TNBC patients who had residual tumors after anthracycline and taxane±platinum based NAC as well as normal human mammary tissues. The histopathology signatures of organoid lines were characterized by H&E staining and immunohistochemistry. The genetic and transcriptional features of organoids were analyzed by targeted sequencing and RNA sequencing. A set of clinical drugs were screened for their ability to suppress cancer organoids in vitro and the consistency was also analyzed between clinical response and drug efficacy of organoid models. Results: A total of 10 cancer organoid lines were successfully established, and cultured stably for more than 4 months. For comparison, 2 organoids derived from normal mammary tissues were generated as well. Our success rate for establishing cancer organoids from TNBC patient samples after NAC was 83% (10 out of 12 samples), and for organoids from normal mammary tissues, it was 100% (2 out of 2 samples). These organoid lines closely recapitulated the histopathology, genetic and transcriptional signature, and intratumor heterogeneity of the primary tissues. We found that active PI3K/AKT/mTOR pathways signaling is always required for cancer organoids from TNBC patient samples after NAC, while Wnt pathway activation is dispensable for generation of them in comparison to the organoid cultures from normal breast tissues. More importantly, we found that the anti-Trop-2 antibody-drug conjugate sacituzumab govitecan (IMMU-132) showed higher sensitivity to most cancer organoids from TNBC patient samples after NAC (8 out of 10 samples) with IC50 ranging from 0.3 nM to 86 nM in contrast to 5-FU (5 out of 10 samples) with IC50 ranging from 0.9 μM to 10.2 μM in vitro, whose prodrug capetabine is considered as a standard option in the postneoadjuvant setting. These results were also confirmed in patient-derived tumor xenograft models. The consistency of drug efficacy in the established cancer organoids and the patient responses in the clinic reached to 70% (7 out of 10 samples). Conclusions: We established a novel organoid culture system for TNBC patient samples after NAC, which was potentially a useful platform to explore molecular characteristics of TNBC patients after NAC and discover personalized drugs for intensive treatment.