乳腺癌患者来源的异种移植模型 (PDX) 是发现新药和生物标志物的有效平台和工具。在 ARTEMIS 试验 (NCT02276443) 中，我们从 Triple Negative Breast Cancer (TNBC) 主要肿瘤中建立了正位 PDX 模型，包括患者在新辅助化疗 (NACT) 前和后。我们从治疗前 (NACT 前)、四个周期阿霉素和环磷酰胺治疗后反应较差的疾病 (NACT 中期) 和 AC 抗药情况下，通过实验性治疗和/或其他化疗药物 3 个月后获得肿瘤组织的连续活检。研究样本包括 269 个从 217 名妇女的细针穿刺活检中获得的样本，总共建立了 62 个 PDX 模型 (总体成功率为 23%)。在那些被证明对治疗反应不佳的癌症中，移植的成功率通常更高。根据中期 NACT 超声测量判定为对 AC 反应差 (p = 0.063)、NACT 后 RCB II / III 状态 (p = 0.046) 或手术后 2 年内转移性复发 (p = 0.008) 的癌症，移植成功的成功率相对较高。从治疗前 TNBC 分子亚型的基因表达微阵列中确定的 PDX 移植成功率没有明显的相关性 (p = 0.877)。最后，我们开发了一个统计模型，使用患者诊断性活检中 Ki67 阳性细胞的百分比、诊断时淋巴结阳性状态，以及阿霉素和环磷酰胺治疗后患者肿瘤体积的减少程度来预测 PDX 移植成功率。这 62 个 TNBC PDX 模型的新型库为发现生物标志物和改善 TNBC 患者的新辅助治疗反应率的临床前治疗试验提供了宝贵的资源。© 2022. 作者 (们)。

Patient-derived xenograft (PDX) models of breast cancer are an effective discovery platform and tool for preclinical pharmacologic testing and biomarker identification. We established orthotopic PDX models of triple negative breast cancer (TNBC) from the primary breast tumors of patients prior to and following neoadjuvant chemotherapy (NACT) while they were enrolled in the ARTEMIS trial (NCT02276443). Serial biopsies were obtained from patients prior to treatment (pre-NACT), from poorly responsive disease after four cycles of Adriamycin and cyclophosphamide (AC, mid-NACT), and in cases of AC-resistance, after a 3-month course of different experimental therapies and/or additional chemotherapy (post-NACT). Our study cohort includes a total of 269 fine needle aspirates (FNAs) from 217 women, generating a total of 62 PDX models (overall success-rate = 23%). Success of PDX engraftment was generally higher from those cancers that proved to be treatment-resistant, whether poorly responsive to AC as determined by ultrasound measurements mid-NACT (p = 0.063), RCB II/III status after NACT (p = 0.046), or metastatic relapse within 2 years of surgery (p = 0.008). TNBC molecular subtype determined from gene expression microarrays of pre-NACT tumors revealed no significant association with PDX engraftment rate (p = 0.877). Finally, we developed a statistical model predictive of PDX engraftment using percent Ki67 positive cells in the patient's diagnostic biopsy, positive lymph node status at diagnosis, and low volumetric reduction of the patient's tumor following AC treatment. This novel bank of 62 PDX models of TNBC provides a valuable resource for biomarker discovery and preclinical therapeutic trials aimed at improving neoadjuvant response rates for patients with TNBC.© 2022. The Author(s).