Braden Jorja, Potter Alison, Rawson Robert V, Adegoke Nurudeen A, Lo Serigne N, Conway Jordan W, Menzies Alexander M, Carlino Matteo S, Au-Yeung George, Saw Robyn P M, Spillane Andrew J, Shannon Kerwin F, Pennington Thomas E, Ch'ng Sydney, Gyorki David E, Howle Julie R, Wilmott James S, Scolyer Richard A, Long Georgina V, Pires da Silva Ines
Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Charles Perkins Centre, The University of Sydney, Sydney, Australia.
Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; NSW Health Pathology, Sydney, Australia.
Mod Pathol. 2025 Apr 14;38(8):100776. doi: 10.1016/j.modpat.2025.100776.
Despite advances in systemic therapies, cutaneous melanoma remains a highly deadly disease. Patients with high-risk stage III melanoma have a significant likelihood of recurrence following surgery. Although adjuvant immunotherapy has been the standard of care, recent evidence demonstrates that neoadjuvant immunotherapy is more effective for higher-risk stage III patients, showing superior survival outcomes compared with adjuvant immunotherapy. This has led to an immediate paradigm shift in clinical practice toward neoadjuvant therapy for this cohort. The NeoTrio clinical trial assessed the efficacy of sequential or combination BRAF-targeted therapy with anti-programmed cell death-1 in the neoadjuvant setting. However, research on longitudinal histopathologic changes during this treatment period remains limited. Analysis of hematoxylin and eosin slides from 60 patients across 4 matched neoadjuvant timepoints revealed dynamic changes in a number of treatment response features. Females achieved significantly higher rates of major pathologic response (P = .002) and displayed higher levels of inflammatory fibrosis (P = .04) and hyalinized fibrosis (P = .01). The presence of tertiary lymphoid structures (P = .013) and plasma cells (P = .02) at resection was significantly associated with response. Combination scoring of histopathologic features (composite score and the immune-related pathologic response [irPR] score) was significantly associated with response early during the neoadjuvant period (composite score at week 2 on-treatment, P = .03; high irPR score at week 2 on-treatment, P = .01). A high irPR score at week 2 on-treatment was also found to be significantly associated with a lower chance of recurrence at this early neoadjuvant timepoint (P = .02). Other features associated with a lower likelihood of recurrence included increased hyalinized fibrosis (P = .015) and the presence of extensive lymphocyte density score (P = .01), tertiary lymphoid structures (P = .03), and plasma cells (P = .01). This study deepens our understanding of treatment response markers and their dynamic changes during neoadjuvant therapy. It underscores the significance of these features, particularly given their early emergence and strong associations with response and recurrence.
尽管全身治疗取得了进展，但皮肤黑色素瘤仍然是一种高度致命的疾病。高危III期黑色素瘤患者术后复发的可能性很大。虽然辅助免疫疗法一直是标准治疗方法，但最近的证据表明，新辅助免疫疗法对高危III期患者更有效，与辅助免疫疗法相比，显示出更好的生存结果。这导致了临床实践立即向针对该队列的新辅助治疗范式转变。NeoTrio临床试验评估了在新辅助治疗中序贯或联合BRAF靶向治疗与抗程序性细胞死亡-1的疗效。然而，在此治疗期间对纵向组织病理学变化的研究仍然有限。对来自4个匹配的新辅助时间点的60名患者的苏木精和伊红切片进行分析，发现许多治疗反应特征存在动态变化。女性的主要病理反应率显著更高（P = 0.002），并且表现出更高水平的炎性纤维化（P = 0.04）和玻璃样纤维化（P = 0.01）。切除时三级淋巴结构（P = 0.013）和浆细胞（P = 0.02）的存在与反应显著相关。组织病理学特征的联合评分（综合评分和免疫相关病理反应[irPR]评分）在新辅助治疗早期与反应显著相关（治疗第2周时的综合评分，P = 0.03；治疗第2周时的高irPR评分，P = 0.01）。还发现治疗第2周时的高irPR评分与在这个新辅助治疗早期复发的可能性较低显著相关（P = 0.02）。与复发可能性较低相关的其他特征包括玻璃样纤维化增加（P = 0.015）以及广泛淋巴细胞密度评分（P = 0.01）、三级淋巴结构（P = 0.03）和浆细胞（P = 0.01）的存在。这项研究加深了我们对新辅助治疗期间治疗反应标志物及其动态变化的理解。它强调了这些特征的重要性，特别是考虑到它们的早期出现以及与反应和复发的强烈关联。
