McHenry Austin, Liang Brooke, Libert Diane, Hammer Phoebe M, Tokuyama Minami, Tenney Troy, Zhang Xiaoming, Folkins Ann, Longacre Teri A, Howitt Brooke E
Department of Pathology, School of Medicine, Stanford University, Stanford, California, USA.
Department of Pathology and Laboratory Medicine, College of Medicine, The University of Arizona, Tucson, Arizona, USA.
Histopathology. 2025 Aug 6. doi: 10.1111/his.15533.
Mirvetuximab soravtansine is an anti-FOLR1 (folate receptor 1/alpha) antibody-drug conjugate with a companion diagnostic immunohistochemical (IHC) biomarker for platinum-resistant ovarian, fallopian tube and primary peritoneal carcinoma. Its effectiveness has sparked interest in FOLR1 expression in endometrial carcinoma. We evaluate the relationship of FOLR1 and HER2-IHC expression in high-grade p53-aberrantly expressed endometrial carcinomas, as overexpression of both is associated with high-grade histologic features and aggressiveness.
Carcinomas were scored for HER2-IHC by both gastric and endometrial serous criteria and FOLR1-IHC by Ventana package insert on tissue microarray cores. Intratumoral heterogeneity was quantified for HER2 and FOLR1 expression across multiple cores from the same tumour. A total of 291 cores (226 endometrial serous, 47 high-grade endometrioid and 18 high-grade Müllerian carcinoma, nos) were collected from 66 cases (discrete accession dates) from 62 patients. When stratified by two-category HER2-IHC status (0/1+ vs. 2+/3+, either criteria), significantly more HER2 2+/3+ cores (16/133, 12%) were FOLR1-positive by a ≥75% cut-off than HER2 0/1+ specimens (8/158, 5%, P = 0.031). Results were similar by a ≥25% cut-off (49/133, 37% vs. 38/158, 24%; P = 0.018). More cases with high HER2-IHC heterogeneity (2-3-pt difference) also demonstrated FOLR1-IHC heterogeneity (≥50% score difference between cores from the same case) than cases with no or low (1-pt) HER2-IHC heterogeneity, though most cases did not show high HER2 or FOLR1 intratumoral heterogeneity (16.7%-18.2% 2-3-pt difference and 12.1% ≥50% score difference).
A positive correlation between HER2 and FOLR1 overexpression may be seen in high-grade endometrial carcinomas with aberrant p53 expression, which may extend to intratumoral heterogeneity of biomarker expression.
Mirvetuximab soravtansine是一种抗FOLR1（叶酸受体1/α）抗体药物偶联物，具有用于铂耐药卵巢癌、输卵管癌和原发性腹膜癌的伴随诊断免疫组化（IHC）生物标志物。其有效性引发了人们对子宫内膜癌中FOLR1表达的兴趣。我们评估了高级别p53异常表达的子宫内膜癌中FOLR1与HER2-IHC表达的关系，因为两者的过表达均与高级别组织学特征和侵袭性相关。
根据胃癌和子宫内膜浆液性标准对癌组织进行HER2-IHC评分，并根据Ventana试剂盒说明书对组织微阵列芯片上的FOLR1-IHC进行评分。对同一肿瘤多个芯片上HER2和FOLR1表达的瘤内异质性进行量化。共从62例患者的66例病例（不同的入组日期）中收集了291个芯片（226个子宫内膜浆液性癌、47个高级别子宫内膜样癌和18个高级别苗勒管癌）。当按两类HER2-IHC状态（0/1+与2+/3+，任何一种标准）分层时，HER2 2+/3+芯片中FOLR1阳性（≥75%截断值）的比例（16/133，12%）显著高于HER2 0/1+标本（8/158，5%，P = 0.031）。按≥25%截断值时结果相似（49/133，37%对38/158，24%；P = 0.018）。与HER2-IHC无或低（1分）异质性的病例相比，更多HER2-IHC异质性高（2 - 3分差异）的病例也表现出FOLR1-IHC异质性（同一病例的芯片之间≥50%评分差异），尽管大多数病例未显示出高HER2或FOLR1瘤内异质性（16.7% - 18.2% 2 - 3分差异和12.1%≥50%评分差异）。
在p53表达异常的高级别子宫内膜癌中，HER2与FOLR1过表达之间可能存在正相关，这可能延伸至生物标志物表达的瘤内异质性。
