Abstract P6-04-02: Evaluation of breast cancer intratumor heterogeneity and its implications to the therapeutic agents with organoids subclones

Abstract

Abstract Background: Breast cancer is the second most common cancer in women, accounting for 15.3% new cancer cases and 6.7% cancer death in 2018. Chemotherapy, target therapy and endocrine therapy are main strategies for breast cancer treatment after surgery to prevent cancer recurrence and metastasis. The choice of these strategies is mainly based on the molecular and pathological markers as well as experience from clinicians. However, due to the heterogeneity of intra-tumor and also between different patients, it is hard for clinicians to make the best therapeutic regimen to target all the cancer sub-population at current stage. Developing more precise and personalized chemotherapy strategy for individual patient would be of great importance. Cancer organoids, established based on in vitro 3-D culture techniques, were demonstrated to largely retain the biological characteristics of tumors from patients, and made it possible to assess the responses to various strategies for individual patient. Comparing with other cancer type such as colon cancer, breast cancer organoids study was relatively immature. This study was designed to efficiently establish breast cancer organoids from clinical patients and further test the sensitivity of these organoids to therapeutic agents. Methods: Fresh breast cancer tissues from patients were dissected into small pieces and subjected to enzyme digestion to prepare a single cell suspension. Organoids were established from the single cell suspension in Matrigel and modified PDTO culture medium. Organoid clones derived from various cancer cells were heterogeneous, which were isolated with pipette tips to establish breast cancer organoids subclones. First line chemotherapy drugs such as Docetaxel, Adriamycin, and Fluorouracil, target therapy agents and endocrine therapy drug such as PD-991, Neratinib and Afimoxifene were used to treat each organoid clones. Cell survival rate was measured by CellTiter-Glo Kit and drug sensitivity was assessed by IC50 value. Results: 23 organoid subclones from 5 patients were successfully established. Drug response (effect) varied to individual organoid subclones from the same patient. Some subclones showed totally resistance while others were sensitive or parcial sensitive to indicated therapeutic agents, indicating the heterogeneity of breast cancer and different intra-tumor subpopulation have distinct drug response. The heterogeneity, especially the resistant subclones put forward to explain the acquired drug resistance and relapse in clinical practice. Conclusion:Breast cancer organoids are good in vitro models for drug sensitivity screening, which would assist clinicians make better chemotherapy strategy to achieve precise and personalized medication for patients. Moreover, organoid models would also be an ideal platform to help dissect the underlying mechanism of cancer heterogeneity induced drug resistance. Citation Format: Zhang B, Xu X, Cai H, Sun Z. Evaluation of breast cancer intratumor heterogeneity and its implications to the therapeutic agents with organoids subclones [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-04-02.