Saka Manduwa, Teramoto Yuki, Haga Hironori
Department of Diagnostic Pathology, Kyoto University Hospital, 54 Shogoin Kawahara-Cho, Sakyo-Ku, Kyoto, 606-8507, Japan.
Virchows Arch. 2025 Jul 24. doi: 10.1007/s00428-025-04196-1.
Patients with muscle-invasive bladder cancer (MIBC) are often treated with platinum-based neoadjuvant chemotherapy (NAC). NAC-treated patients have higher odds of pathological downstaging than untreated patients on subsequent cystectomy and, consequently, improved survival. However, not all patients achieve pathological downstaging. Notably, luminal MIBC shows a superior pathological response to cisplatin-based NAC compared with non-luminal MIBC. This study aimed to examine the relationship between human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) status and the molecular subtypes of MIBC and to evaluate its role in the prediction of response to platinum-based neoadjuvant chemotherapy. We performed IHC for GATA binding protein 3 (GATA3), cytokeratin (CK) 5/6, p16, and synaptophysin to classify MIBC on transurethral resection of bladder tumor/biopsy specimens into molecular subtypes. We then examined the association between HER2 IHC status and the subtypes and its utility in predicting subsequent pathological responses. Out of 49 patients, HER2 IHC positivity (scores 2 + , 3 +) was predominantly observed in the genomically unstable (GU) immunohistochemical molecular subtype (GATA3 + , CK5/6-, p16 +), a surrogate of the luminal unstable transcriptomic subtype. Additionally, all but one patient with HER2-positive GU tumors (n = 8) had absent invasive tumor on subsequent cystectomy following cisplatin-based NAC. Conversely, all patients with HER2-negative (score 0, 1 +) GU tumors had residual invasive tumors. Finally, favourable outcome trends in recurrence-free and cancer-specific survival were observed with HER2 IHC positivity in this subtype. Overall, combining immunohistochemical molecular subtyping with HER2 IHC status may help predict responses to cisplatin-based NAC, guiding MIBC management decisions.
肌层浸润性膀胱癌（MIBC）患者通常接受铂类新辅助化疗（NAC）。接受NAC治疗的患者在后续膀胱切除术中病理降期的几率高于未接受治疗的患者，因此生存期得到改善。然而，并非所有患者都能实现病理降期。值得注意的是，与非腔面型MIBC相比，腔面型MIBC对基于顺铂的NAC表现出更好的病理反应。本研究旨在探讨人表皮生长因子受体2（HER2）免疫组化（IHC）状态与MIBC分子亚型之间的关系，并评估其在预测铂类新辅助化疗反应中的作用。我们对膀胱肿瘤经尿道切除术/活检标本进行了GATA结合蛋白3（GATA3）、细胞角蛋白（CK）5/6、p16和突触素的免疫组化，以将MIBC分类为分子亚型。然后，我们研究了HER2 IHC状态与亚型之间的关联及其在预测后续病理反应中的效用。在49例患者中，HER2 IHC阳性（评分2 +、3 +）主要见于基因组不稳定（GU）免疫组化分子亚型（GATA3 +、CK5/6 -、p16 +），这是腔面型不稳定转录组亚型的替代指标。此外，除1例HER2阳性GU肿瘤患者（n = 8）外，所有患者在接受基于顺铂的NAC治疗后的后续膀胱切除术中均无浸润性肿瘤。相反，所有HER2阴性（评分0、1 +）GU肿瘤患者均有残留浸润性肿瘤。最后，在该亚型中观察到HER2 IHC阳性患者在无复发生存期和癌症特异性生存期方面有良好的预后趋势。总体而言，将免疫组化分子亚型与HER2 IHC状态相结合可能有助于预测对基于顺铂的NAC的反应，指导MIBC治疗决策。
