Machiraju Devayani, Ziener Christian H, Clementi Elena, García-Asencio Francisco, Hüllein Jennifer, Richter Jasmin, Lenoir Bénédicte, Wiecken Melanie, Hübschmann Daniel, Jäger Dirk, Hassel Jessica C
Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany.
Heidelberg University, Faculty of Biosciences, Heidelberg, Germany.
J Exp Clin Cancer Res. 2025 Jul 19;44(1):213. doi: 10.1186/s13046-025-03451-2.
Metastatic uveal melanoma (mUM) is a rare malignancy and is different from metastatic cutaneous melanoma (mCM) in tumor characteristics and efficacy to immunotherapies. Tumor-specific biomarkers are required for mUM patients to monitor early disease progression on immunotherapies.
We investigated clinical characteristics such as liver tumor burden and routine blood tumor markers, including lactate dehydrogenase (LDH) and transaminases in patients with mUM and with liver metastasized cutaneous melanoma (LmCM), treated with immune checkpoint inhibitors (ICIs) between May 2013-February 2024. In addition, we analyzed soluble cMET (scMET) in serum samples from these patients along with a cohort of mCM patients without liver metastases (nLmCM) using ELISA. Circulating tumor DNA (ctDNA) in the plasma was analyzed using digital droplet PCR (ddPCR) in mUM patients receiving immunotherapies. scMET, ctDNA, and LDH combination was used to simultaneously monitor disease progression in ICI and tebentafusp-receiving mUM patients.
Sixty-nine patients with mUM and seventy-six patients with LmCM were treated with either anti-PD1 monotherapy (n = 69, 48%) or ipi + nivo combination therapy (n = 76, 52%). Irrespective of the type of melanoma and type of immunotherapy, patients with liver metastasis size greater than 8cm experienced rapid disease progression. ICI-treated mUM patients with increased LDH, aspartate aminotransferase (AST), alanine transaminase (ALT), scMET, ctDNA, and rapidly growing tumors were significantly associated with treatment resistance and shorter progression-free and overall survival (p < 0.05). scMET (AUC: 0.82) outperforms LDH (AUC: 0.77) and S100 (0.68) in predicting one-year overall survival in these patients. A validation set with LmCM and nLmCM patient samples showed that increased scMET is likely a mUM-specific feature and does not predict ICI outcomes in LmCM or nLmCM patients (p > 0.05). Moreover, monitoring ctDNA and scMET in mUM patients under ICIs or tebentafusp treatment revealed the potential for early detection of disease progression.
Soluble cMET might serve as a tumor-specific biomarker to predict clinical outcomes in mUM patients. A combinational assessment of scMET and ctDNA in mUM patients' blood offers a highly sensitive potential approach to monitor early disease progression under immunotherapies with ICI or tebentafusp.
转移性葡萄膜黑色素瘤（mUM）是一种罕见的恶性肿瘤，在肿瘤特征和免疫治疗疗效方面与转移性皮肤黑色素瘤（mCM）不同。mUM患者需要肿瘤特异性生物标志物来监测免疫治疗期间的早期疾病进展。
我们调查了2013年5月至2024年2月期间接受免疫检查点抑制剂（ICI）治疗的mUM患者和肝转移皮肤黑色素瘤（LmCM）患者的临床特征，如肝肿瘤负荷和常规血液肿瘤标志物，包括乳酸脱氢酶（LDH）和转氨酶。此外，我们使用酶联免疫吸附测定（ELISA）分析了这些患者以及一组无肝转移的mCM患者（nLmCM）血清样本中的可溶性cMET（scMET）。使用数字液滴聚合酶链反应（ddPCR）分析接受免疫治疗的mUM患者血浆中的循环肿瘤DNA（ctDNA）。scMET、ctDNA和LDH联合用于同时监测接受ICI和替贝福司治疗的mUM患者的疾病进展。
69例mUM患者和76例LmCM患者接受了抗PD1单药治疗（n = 69，48%）或伊匹单抗+纳武单抗联合治疗（n = 76，52%）。无论黑色素瘤类型和免疫治疗类型如何，肝转移灶大小大于8cm的患者疾病进展迅速。接受ICI治疗的mUM患者，若LDH、天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、scMET、ctDNA升高且肿瘤快速生长，则与治疗耐药以及无进展生存期和总生存期缩短显著相关（p < 0.05）。在预测这些患者的一年总生存期方面，scMET（曲线下面积：0.82）优于LDH（曲线下面积：0.77）和S100（0.68）。一组LmCM和nLmCM患者样本的验证集表明，scMET升高可能是mUM的特异性特征，不能预测LmCM或nLmCM患者的ICI治疗结果（p > 0.05）。此外，在接受ICI或替贝福司治疗的mUM患者中监测ctDNA和scMET显示了早期发现疾病进展的潜力。
可溶性cMET可能作为一种肿瘤特异性生物标志物来预测mUM患者的临床结局。对mUM患者血液中的scMET和ctDNA进行联合评估，为在ICI或替贝福司免疫治疗期间监测早期疾病进展提供了一种高度敏感的潜在方法。
