PO.TB04.08 · 肿瘤生物学
序贯3D功能分析显示一例卵巢癌患者在新辅助治疗后药物耐药和敏感性特征得以保留
Sequential 3D functional profiling shows preserved drug resistance and sensitivity profiles after neoadjuvant treatment in an ovarian cancer patient
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景
尽管采用标准的铂类双药治疗，大多数晚期卵巢癌患者最终仍会复发[1]，且后续治疗的获益各不相同。功能性精准检测可指导治疗选择并减少对无效疗法的暴露。在此，我们对新辅助治疗前后采集的标本使用了多重3D功能分析平台，捕捉不断演变的细胞毒性和抗增殖反应，并识别有效的治疗选择。
方法
从一位高级别浆液性卵巢癌患者获取新鲜标本：III期疾病的基线腹水样本，以及IV期疾病在接受卡铂-紫杉醇新辅助治疗后采集的手术活检样本。标本经处理以获得离体微肿瘤[2]，并暴露于NCCN推荐的疗法。药物暴露4天后，进行多重活力和增殖分析[3]。拟合四参数逻辑剂量-反应曲线，并计算基线和治疗后样本之间在标准化药物浓度下细胞毒性和抗增殖疗效的差异（Δ）。
结果
卡铂-紫杉醇联合在新辅助治疗前后均显示出中等的细胞毒性（0.37，估计95% CI [0.34-0.41]）和抗增殖作用（0.37 [0.36-0.39]），治疗后分别为（0.30 [0.25-0.36]和0.33 [0.31-0.36]），与有限的客观肿瘤反应一致。VAC（长春新碱、放线菌素和环磷酰胺）在治疗前（0.85，[0.75-0.90]，和0.97 [0.92-0.99]）和治疗后（0.73 [0.64-0.78]，和0.99 [0.94-1.00]）均表现出高细胞毒性和抗增殖疗效。有趣的是，PARP抑制剂奥拉帕利和鲁卡帕利显示出有限的细胞毒性（0.10 [0.08-0.12]和0 [0-0.08]），但具有显著的抗增殖作用（0.60 [0.53-0.70]和0.58 [0.49-0.74]），治疗前后无实质性变化。
结论
对这例晚期卵巢癌进行的序贯离体多重分析显示，新辅助卡铂-紫杉醇对VAC和PARP抑制剂的细胞毒性和抗增殖药物反应敏感性及耐药模式改变极小。因此，在肿瘤组织易于获得时，治疗前功能分析可能提供有用的后续治疗选择，以避免未来对无效方案的暴露。
[1] Pignata S等，复发性卵巢癌的治疗。Ann Oncol. 2017 [2] Apfel C. 细胞、细胞聚集体和组织片段的制备。发表于2014年10月 [3] Apfel C等，高通量多重敏感性和耐药性检测。美国专利US 12,312,631 B1
查看英文原文 English abstract
Background
Despite standard platinum-based doublet therapy, most patients with advanced ovarian cancer do eventually relapse[1], and subsequent therapies exhibit variable benefit. Functional precision assays can guide treatment selection and reduce exposure to ineffective therapies. Here we used a multiplexed 3D functional profiling platform on specimens collected before and after neoadjuvant treatment, capturing evolving cytotoxic and antiproliferative responses and identifying effective treatment options.
Methods
Fresh specimens were obtained from a patient with high-grade serous ovarian carcinoma: a baseline ascites sample from stage III disease, and a surgical biopsy sample collected at stage IV disease after neoadjuvant carboplatin-paclitaxel treatment. Specimens were processed to obtain ex-vivo microtumors[2] and exposed to NCCN-recommended therapies. After 4 days of drug exposure, multiplexed viability and proliferation profiling was performed[3]. Four-parameter logistic dose-response curves were fitted, and differences (Δ) in cytotoxic and antiproliferative efficacies at standardized drug concentrations between the baseline and post-treatment samples were calculated.
Results
The carboplatin paclitaxel combination showed moderate cytotoxic (0.37, estimated 95% CI [0.34-0.41]) and antiproliferative effects (0.37 [0.36-0.39]) before and after neo-adjuvant treatment (0.30 [0.25-0.36] and 0.33 [0.31-0.36]), aligning with the limited objective tumor response. VAC (vincristine, actinomycin, and cyclophosphamide) demonstrated high cytotoxic and antiproliferative efficacy before (0.85, [0.75-0.90], and 0.97 [0.92-0.99]) and after therapy (0.73 [0.64-0.78], and 0.99 [0.94-1.00]). Interestingly, the PARP-inhibitors olaparib and rucaparib showed limited cytotoxicity (0.10 [0.08-0.12] and 0 [0-0.08]) but pronounced antiproliferation (0.60 [0.53-0.70] and 0.58 [0.49-0.74]) before the treatment with no material change after it.
Conclusions
Sequential ex-vivo multiplexed profiling of this advanced ovarian cancer revealed that neoadjuvant carboplatin paclitaxel minimally altered cytotoxic and antiproliferative drug response sensitivity and resistance patterns to VAC and PARP inhibitors. Thus, pre-treatment functional profiling, when tumor tissue is readily available, might provide useful follow-on treatment options to avoid exposure to ineffective regimens in the future.
[1] Pignata S et al., Treatment of recurrent ovarian cancer. Ann Oncol. 2017 [2] Apfel C. Preparation of cells, cell aggregates and tissue fragments. Published October 2014 [3] Apfel C et al., High-throughput multiplexed sensitivity and resistance assay. US Patent US 12,312,631 B1
利益披露 Disclosure
C. Maestri,
SageMedic Corp Employment, Stock Option.