Delta 样蛋白 3 在 Merkel 细胞癌中的表达和靶向治疗。
Delta-Like Protein 3 Expression and Targeting in Merkel Cell Carcinoma.
机构信息
Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Division of Hematology-Oncology, Department of Medicine, University of Florida, Gainesville, Florida, USA.
出版信息
Oncologist. 2020 Sep;25(9):810-817. doi: 10.1634/theoncologist.2019-0877. Epub 2020 May 14.
PURPOSE
Delta-like protein 3 (DLL3) is being developed as a predictive biomarker for DLL3-targeting antibody-drug conjugate and other therapies. Given the neuroendocrine features of Merkel cell carcinoma (MCC), we sought to evaluate DLL3 expression and its role in MCC.
EXPERIMENTAL DESIGN
Formalin-fixed and paraffin-embedded MCC cases were consecutively selected. Immunohistochemistry was performed for DLL3 (SC16.65 antibody) and polyomavirus large T-antigen (sc-136172 antibody). Slides were read out for percentage of positive tumor cells. Cox proportional hazards model was applied to assess the association between DLL3 expression and overall survival (OS). A patient with a DLL3-expressing MCC was treated with rovalpituzumab tesirine (Rova-T) in the "other tumor" cohort of NCT02709889 and assessed for response.
RESULTS
The median H-score of DLL3 expression of 65 patients included was 60 (interquartile range, 30-100). Fifty-eight cases (89%) had ≥1% tumor cells positive for DLL3 expression with any intensity, of which the median DLL3 expression was 50% (interquartile range, 25%-70%). Thirty-four cases (52%) had ≥50% tumor cells positive for DLL3 expression with any intensity. Higher H-score of DLL3 expression was associated with higher polyomavirus nuclear expression (p = .003) when it was dichotomized to negative versus positive. H-score of DLL3 expression did not predict OS of patients with MCC (p = .4) after being adjusted for common clinicopathological factors. A patient treated with Rova-T for refractory metastatic MCC achieved partial response.
CONCLUSIONS
DLL3 overexpression is very common in MCC by immunohistochemistry. The response to treatment suggests that DLL3 expression may have predictive relevance for DLL3-targeting therapies in MCC.
IMPLICATIONS FOR PRACTICE
Delta-like protein 3 (DLL3) is being developed as a predictive biomarker to identify patients for treatment with DLL3-targeting agents. Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. It was found that DLL3 overexpression is very common in MCC by immunohistochemistry and significantly associated with Merkel cell polyomavirus expression. Despite the lack of prognostic significance in this cohort, DLL3 expression may have predictive relevance for DLL3-targeting therapies in MCC. The high levels of DLL3 expression in a subset of MCC may potentially be used to select patients to receive DLL3-targeting therapies.
目的
Delta-like 蛋白 3（DLL3）被开发为用于 DLL3 靶向抗体药物偶联物和其他疗法的预测性生物标志物。鉴于 Merkel 细胞癌（MCC）的神经内分泌特征，我们试图评估 DLL3 的表达及其在 MCC 中的作用。
实验设计
连续选择福尔马林固定石蜡包埋的 MCC 病例。对 DLL3（SC16.65 抗体）和多瘤病毒大 T 抗原（sc-136172 抗体）进行免疫组织化学染色。根据阳性肿瘤细胞的百分比读取幻灯片。Cox 比例风险模型用于评估 DLL3 表达与总生存（OS）之间的关联。在 NCT02709889 的“其他肿瘤”队列中，对一名表达 DLL3 的 MCC 患者进行了 rovalpituzumab tesirine（Rova-T）治疗，并对其反应进行了评估。
结果
纳入的 65 例患者的 DLL3 表达中位数 H 评分为 60（四分位距，30-100）。58 例（89%）有≥1%的肿瘤细胞表达 DLL3，其表达中位数为 50%（四分位距，25%-70%）。34 例（52%）有≥50%的肿瘤细胞表达 DLL3，其表达强度任意。当 DLL3 表达被分为阴性与阳性时，更高的 DLL3 表达 H 评分与更高的多瘤病毒核表达相关（p =.003）。经调整常见临床病理因素后，DLL3 表达 H 评分与 MCC 患者的 OS 无关（p =.4）。一名接受 Rova-T 治疗难治性转移性 MCC 的患者获得部分缓解。
结论
通过免疫组织化学，DLL3 在 MCC 中过度表达非常常见。治疗反应表明，DLL3 表达可能对 MCC 中的 DLL3 靶向治疗具有预测相关性。
意义
Delta-like 蛋白 3（DLL3）正在被开发为一种预测生物标志物，以识别接受 DLL3 靶向药物治疗的患者。Merkel 细胞癌（MCC）是一种侵袭性的皮肤神经内分泌癌。研究发现，通过免疫组织化学，DLL3 在 MCC 中过度表达非常常见，并且与 Merkel 细胞多瘤病毒的表达显著相关。尽管在本队列中无预后意义，但 DLL3 表达可能对 MCC 中的 DLL3 靶向治疗具有预测相关性。MCC 中一部分患者的 DLL3 表达水平较高，可能有助于选择接受 DLL3 靶向治疗的患者。
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