Tipifarnib is the only targeted therapy breakthrough forHRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles ofHRASmt cancers are difficult to explore given the low frequency ofHRASmt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524HRASmt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC.HRASmt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%).HRASmt was absent in Her2+ BC regardless of hormone receptor status.HRASmt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% inHRASwt,p= 0.002). The tumor microenvironment (TME) ofHRASmt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (allp< 0.05). Finally,HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16–2.11,p= 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles ofHRASmt tumors that may help to identify new targets and guide future clinical trial design.
替吡法尼是目前针对HRAS突变型复发或转移性头颈部鳞状细胞癌唯一取得突破的靶向疗法。由于HRAS突变发生率较低，其相关癌症的分子特征难以探究。本研究旨在分析524例HRAS突变型实体瘤（包括尿路上皮癌、乳腺癌、非小细胞肺癌、黑色素瘤及头颈部鳞状细胞癌）的分子共变异特征、免疫谱及临床结局。HRAS突变在尿路上皮癌中最为常见（3.0%），其次为头颈部鳞状细胞癌（2.82%）、黑色素瘤（1.05%）、乳腺癌（0.45%）和非小细胞肺癌（0.44%）。无论激素受体状态如何，Her2阳性乳腺癌中均未发现HRAS突变。与非鳞状非小细胞肺癌相比，HRAS突变更常见于鳞状非小细胞肺癌（HRAS野生型中鳞状与非鳞状比例为60%对40%，p=0.002）。HRAS突变型肿瘤微环境在三阴性乳腺癌、头颈部鳞状细胞癌、鳞状非小细胞肺癌及尿路上皮癌中显示M1型巨噬细胞增多；在三阴性乳腺癌中M2型巨噬细胞增多；在头颈部鳞状细胞癌中CD8+ T细胞增多（所有p值均<0.05）。最后，HRAS突变与头颈部鳞状细胞癌较短的总生存期相关（风险比：1.564，置信区间：1.16–2.11，p=0.003），但在其他癌症类型中未观察到这种关联。综上所述，本研究为HRAS突变型肿瘤独特的分子特征提供了新见解，可能有助于发现新靶点并指导未来临床试验设计。
The Genomic, Transcriptomic, and Immunologic Landscape ofHRASMutations in Solid Tumors
肿瘤(癌症)患者之家