PO.CL01.03 · 临床研究
分析抗体-药物偶联物靶点在纤维板层型肝细胞癌中的表达
Profiling the expression of antibody-drug conjugates in fibrolamellar hepatocellular carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：纤维板层癌（FLC）是一种罕见且侵袭性强的原发性肝癌，主要影响青少年和年轻成人。它在生物学上不同于其他形式的原发性肝癌，如肝细胞癌（HCC）和胆管癌（CCA）。目前尚无针对晚期 FLC 的标准或获批的系统性治疗，大多数患者就诊时已为不可切除疾病或在手术后出现复发。这些因素凸显了对新治疗方法的需求。抗体-药物偶联物（ADC）通过以更高的特异性将细胞毒性有效载荷递送至肿瘤相关表面抗原，已在多种实体瘤中显示出疗效，但其在 FLC 中的应用尚不明确。为评估基于 ADC 的治疗在 FLC 中的相关性，我们在一个扩大的 FLC 标本队列中评估了五个临床可操作 ADC 靶点（NECTIN4、TROP2、CLDN18.2、HER2 和 B7-H3）的表达。
方法：通过 Johns Hopkins 肝癌组织库和纤维板层癌基金会从知情同意的患者获取存档 FFPE 样本，包括 FLC 肿瘤（n=58；38 例原发和 20 例转移病灶）。对所有五个标志物进行免疫组织化学（IHC）检测。将 FLC 中感兴趣的表达模式与 HCC（n=10）和 CCA（n=10）对照队列进行比较。三名对临床数据设盲的病理学家使用 0 至 3 加的序数 IHC 分级和半定量 H 评分独立评分染色。
结果：在评估的五个 ADC 靶点中，仅 B7-H3 和 HER2 在 FLC 中显示出可检测的染色。NECTIN4、TROP2 和 CLDN18.2 一致为阴性，在所有肿瘤中评分为 0+，H 评分为 0。B7-H3 表现出最强的表达。在 58 例肿瘤中有 20 例（34.5%）观察到 3+ 染色。肿瘤细胞 H 评分范围为 10 至 240，平均为 132。B7-H3 也在肿瘤微环境中表达，在癌症相关基质和成纤维细胞中有显著染色。基质 H 评分范围为 40 至 300，平均为 199，通常超过肿瘤细胞表达。HER2 在 58 例肿瘤中有 12 例（21.7%）显示出可检测的 3+ 染色，H 评分范围为 2 至 270，平均为 70。该队列中一名 HER2 表达为 3+ 的患者接受了 fam-trastuzumab deruxtecan-nxki（德曲妥珠单抗）治疗，并经历了持续约一年的持久部分缓解。
结论：B7-H3 和 HER2 是 FLC 中有前景的 ADC 靶点。虽然一部分患者可能已经根据其泛肿瘤适应证符合接受 fam-trastuzumab deruxtecan-nxki 治疗的条件，但 B7-H3 在肿瘤和基质区室中均显示出尤为强烈且广泛的表达。这些发现支持进一步开展针对 B7-H3 和 HER2 的 ADC 作为晚期 FLC 靶向治疗策略的临床前和临床评估。
查看英文原文 English abstract
Background: Fibrolamellar carcinoma (FLC) is a rare and aggressive primary liver cancer that primarily affects adolescents and young adults. It is biologically distinct from other forms of primary liver cancer, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). There are no standard or approved systemic therapies for advanced FLC, and most patients present with unresectable disease or experience recurrence after surgery. These factors underscore the need for new therapeutic approaches. Antibody-drug conjugates (ADCs) have shown efficacy in several solid tumors by delivering cytotoxic payloads to tumor-associated surface antigens with improved specificity, but their utility in FLC is not known. To evaluate the relevance of ADC-based therapies in FLC, we assessed the expression of five clinically actionable ADC targets (NECTIN4, TROP2, CLDN18.2, HER2, and B7-H3) in an expanded cohort of FLC specimens.
Methods: Archival FFPE samples were obtained from consented patients through the Johns Hopkins Liver Cancer Tissue Bank and the Fibrolamellar Cancer Foundation, including FLC tumors (n=58; 38 primary and 20 metastatic lesions). Immunohistochemistry (IHC) was performed for all five markers. Expression patterns of interest in FLC were compared with control cohorts of HCC (n=10) and CCA (n=10). Three pathologists, blinded to clinical data, independently scored staining using both a 0 to 3 plus ordinal IHC scale and a semi-quantitative H-score.
Results: Among the five ADC targets evaluated, only B7-H3 and HER2 showed detectable staining in FLC. NECTIN4, TROP2, and CLDN18.2 were uniformly negative, scored as 0+ in all tumors, and had H-scores of 0. B7-H3 demonstrated the strongest expression. 3+ staining was observed in 20 of 58 tumors (34.5%). Tumor-cell H-scores ranged from 10 to 240, with a mean of 132. B7-H3 was also expressed in the tumor microenvironment, with prominent staining in cancer-associated stroma and fibroblasts. Stromal H-scores ranged from 40 to 300, with a mean of 199, often exceeding tumor-cell expression. HER2 showed detectable 3+ staining in 12 of 58 tumors (21.7%), with H-scores ranging from 2 to 270 and a mean of 70. One patient in this cohort with 3+ HER2 expression received fam-trastuzumab deruxtecan-nxki, and experienced a durable partial response lasting approximately one year.
Conclusions: B7-H3 and HER2 are promising ADC targets in FLC. While a subset of patients may already be eligible for fam-trastuzumab deruxtecan-nxki under its tumor-agnostic indication, B7-H3 shows particularly strong and widespread expression across both tumor and stromal compartments. These findings support further preclinical and clinical evaluation of B7-H3- and HER2-directed ADCs as targeted treatment strategies for advanced FLC.
利益披露 Disclosure
W. Arif, None..
E. Hallab, None..
P. Cogswell, None..
J. Birkness-Gartman, None.