Emergence of human epidermal growth factor receptor 2 as a key biomarker and therapeutic target in advanced urothelial carcinoma

Abstract

Urothelial carcinoma (UC) represents a significant global health challenge, particularly in its advanced stages where treatment options remain limited and outcomes poor. While platinum-based chemotherapy has historically formed the backbone of first-line treatment for metastatic disease, the median overall survival rarely exceeds 15 months, highlighting the urgent need for more effective therapeutic strategies. The recent molecular characterization of UC has revealed human epidermal growth factor receptor 2 (HER2) as a frequently altered pathway, especially in upper tract UC, where it demonstrates a strong association with high-grade disease and aggressive behavior. The emergence of antibody-drug conjugates targeting HER2 has revolutionized the treatment landscape, offering new hope for patients with HER2-expressing tumors. This comprehensive review contextualizes the recent findings of Huang and He, who published a study in World Journal of Clinical Oncology on HER2 overexpression in upper tract UC within the evolving therapeutic paradigm, emphasizing the critical importance of integrating biomarker-driven strategies, particularly anti-HER2 antibody-drug conjugates in combination with immunotherapy, into the management algorithm of advanced UC. We synthesize evidence from multiple recent studies and clinical trials to provide a thorough overview of the current status and future directions of HER2-targeted therapy in UC.

Key Words: Human epidermal growth factor receptor 2; Urothelial carcinoma; Antibody-drug conjugate; Disitamab vedotin; Biomarker

Core Tip: This commentary highlights the critical findings published in the World Journal of Clinical Oncology by Huang and He, which establish a strong link between human epidermal growth factor receptor 2 (HER2) overexpression and high-grade upper tract urothelial carcinoma (UC), revealing a distinct biological profile compared to bladder cancer. These results gain immediate clinical relevance with the recent paradigm-shifting data from the phase 3 RC48-C016 trial. The combination of the anti-HER2 antibody-drug conjugate disitamab vedotin and the anti-programmed cell death protein-1 toripalimab has demonstrated superior efficacy over standard chemotherapy in first-line HER2-expressing metastatic UC, nearly doubling progression-free survival and significantly improving overall survival with a better safety profile. Given that nearly half of upper tract UC tumors are HER2-positive, these findings urgently position a substantial patient subset as potential candidates for this novel, biomarker-driven therapy, heralding a new era in UC treatment.

This editorial refers to “Human epidermal growth factor receptor 2 overexpression is associated with high-grade tumors in upper tract urothelial carcinoma” by Huang and He, 2026; https://doi.org/10.5306/wjco.v16.i10.110047.

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INTRODUCTION

Urothelial carcinoma (UC) ranks as the tenth most common cancer worldwide, with a striking male predominance (4:1 male to female ratio) and an estimated 570000 new cases annually resulting in over 210000 deaths[1,2]. The disease demonstrates considerable geographical variation in both incidence and etiology. In Western countries, tobacco smoking represents the primary risk factor, accounting for approximately 50% of cases, while in regions such as East Africa, chronic infection with Schistosoma haematobium constitutes the main etiology, typically associated with squamous cell carcinoma variants[3].

The management of advanced UC has historically relied on platinum-based chemotherapy regimens. Since the 1990s, the methotrexate, vinblastine, doxorubicin, and cisplatin regimen has served as the reference standard, with subsequent studies establishing gemcitabine plus cisplatin as an equally effective but better-tolerated alternative[4,5]. Despite these advances, the outcomes for metastatic UC (mUC) remain disappointing, with median overall survival (OS) ranging from 12 months to 15 months and fewer than 15% of patients surviving beyond five years[5]. The introduction of immune checkpoint inhibitors targeting programmed cell death protein 1/programmed death-ligand 1 axis initially promised to transform the therapeutic landscape. Drugs such as atezolizumab and pembrolizumab demonstrated encouraging response rates in phase II trials, leading to their accelerated approval in the second-line setting and for cisplatin-ineligible patients in the first-line setting[6,7]. However, subsequent phase III trials revealed more modest benefits, with response rates typically ranging from 15% to 23% in unselected populations[8]. This highlighted the crucial need for reliable predictive biomarkers and more effective treatment strategies. Recent practice-changing data from the enfortumab vedotin-302 trial established the combination of enfortumab vedotin [an anti-nectin-4 antibody-drug conjugate (ADCs)] and pembrolizumab as a new first-line standard of care across all patient populations, achieving a median overall survival of 31.5 months, thereby setting a new benchmark for efficacy in this disease[9].

MOLECULAR HETEROGENEITY AND EMERGING TARGETS

Comprehensive molecular characterization efforts, notably by The Cancer Genome Atlas research network, have revealed UC as a remarkably heterogeneous disease with several distinct molecular subtypes[10]. The initial classification identified basal and luminal subtypes, analogous to breast cancer, with recent refinements identifying five consensus classes: Luminal-papillary, luminal-infiltrated, luminal, basal-squamous, and neuronal[11]. This molecular diversity underpins the variable clinical behavior and treatment responses observed in UC patients.

Among the numerous molecular alterations identified, several have emerged as promising therapeutic targets. Fibroblast growth factor receptor (FGFR) alterations occur in approximately 20% of UC cases, leading to the development and approval of erdafitinib for patients with susceptible FGFR2/3 genetic alterations[12]. Similarly, the high prevalence of nectin-4 expression (approximately 89%) and trophoblast cell surface antigen-2 expression (approximately 92%) in UC has facilitated the development of targeted ADCs such as enfortumab vedotin and sacituzumab govitecan[13-15].

HER2 AS A THERAPEUTIC TARGET: HISTORICAL PERSPECTIVE AND RENEWED INTEREST

The human epidermal growth factor receptor 2 (HER2) has long been recognized as a critical oncogenic driver in multiple malignancies. HER2 is a transmembrane tyrosine kinase receptor that functions as a master regulator of cell proliferation and survival. In UC, HER2 overexpression or amplification, reported in 10%-50% of cases, leads to constitutive activation of these pathways, promoting tumor growth and metastasis[1,16]. A large-scale analysis of over 2000 UC samples using standardized immunohistochemistry (IHC) methods recently clarified that HER2 protein expression (IHC 1+, 2+, or 3+) is present in more than 50% of advanced UC cases, with HER2-positivity (IHC 3+ or IHC 2+ with erb-b2 receptor tyrosine kinase 2 amplification) accounting for approximately 15.6%[17].

Despite this strong biological rationale, early attempts to target HER2 in UC using monoclonal antibodies such as trastuzumab were disappointing. Used as monotherapy, response rates were below 10%. Furthermore, combining trastuzumab with conventional chemotherapy failed to demonstrate significant improvements. For instance, the phase II trial showed no significant benefit in objective response rate (ORR), progression-free survival (PFS), or OS with the addition of trastuzumab to chemotherapy[18,19]. This lack of efficacy is now understood to be partially due to the requirement for high-level, homogeneous HER2 expression for optimal activity of monoclonal antibodies, which contrasts with the more heterogeneous and lower-level expression patterns commonly observed in UC.

The advent of ADCs has since revitalized interest in HER2 as a therapeutic target. ADCs represent an innovative class of therapeutics that combine the specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule drugs. By delivering highly cytotoxic payloads directly to tumor cells expressing specific surface antigens, ADCs minimize systemic exposure while maximizing antitumor efficacy. This new approach has yielded transformative results. The phase II RC48-C005/RC48-C009 combined trials demonstrated the promising activity of the anti-HER2 ADC disitamab vedotin (DV) in pretreated HER2-positive UC patients, achieving an ORR of 50.5%, a median PFS of 5.6 months, and an OS of 14.2 months[20-22].

Similarly, the DESTINY-PanTumor02 phase II basket trial established the activity of the HER2-directed ADC trastuzumab deruxtecan in HER2-expressing (IHC 3+ or 2+) UC, with an ORR of 39.0% and a median OS of 16.1 months in the overall UC cohort, leading to its Food and Drug Administration accelerated approval for HER2-positive solid tumors[23-25]. A comprehensive overview of these and other pivotal trials in HER2-expressing advanced UC is provided in Table 1.

Table 1 Pivotal clinical trials in the management of human epidermal growth factor receptor 2+ locally advanced or metastatic urothelial carcinoma.

Ref.	Study design	Population	Treatment arms	Outcomes	Safety profile
Hussain et al[14], 2007	Phase II, multicenter	109 patients with la/mUC; 57 patients (52%) with confirmed HER2 amplification	Trastuzumab + paclitaxel + carboplatin + gemcitabine	ORR: 70%; PFS: 9.3 months; OS: 14.1 months	Significant hematologic toxicity (neutropenia); peripheral neuropathy; limited cardiac toxicity
Oudard et al[15], 2015	Phase II, randomized, multicenter	75 patients with 1 L la/mUC overexpressing HER2 (IHC 3+ or FISH+)	Experimental arm: Gemcitabine + platinum + trastuzumab; control arm: Gemcitabine + platinum (cisplatin or carboplatin)	ORR: 44% vs 44% (P = NS); PFS: 8.2 months vs 6.1 months (HR = 0.89, P = 0.47); OS: 15.7 months vs 12.2 months (HR = 0.79, P = 0.29); NS benefit from adding trastuzumab to chemotherapy	Similar toxicity profile between arms; no significant increase in cardiac toxicity with trastuzumab
RC48-C005/RC48-C009 (Sheng et al[18], 2025)	Phase II	107 patients with pretreated la/mUC, all with HER2+ expression (IHC 2+ or 3+)	DV monotherapy	ORR: 50.5%; median PFS: 5.6 months; median OS: 14.2 months	Peripheral neuropathy (68.2%); myelosuppression; AST increase (42.1%)
DESTINY-PanTumor02 (Investigation of T-DXd)[20], 2023	Phase II, tumor-agnostic	41 patients with la/mUC, HER2-expressing (IHC 2+ or 3+), progressed after ≥ 1 systemic therapy, median 2 prior lines of therapy	T-DXd	ORR (all patients): 39.0%; ORR (IHC 3+): 56.3%; ORR (IHC 2+): 35.0%; median DOR: 11.8 months (overall)	Grade ≥ 3; AEs: 58.4%; treatment discontinuation due to AEs: 11.6%; adjudicated ILD/pneumonitis: 6.7% (G1-2: 6.4%; G5: 0.4%)
RC48-C016 (Sheng et al[18], 2025)	Phase III	1 L la/mUC patients with HER2 expression (IHC 1+, 2+ or 3+), prior platinum therapy not allowed	Experimental arm: DV + toripalimab; control arm: Platinum-based chemotherapy	PFS: 13.1 months vs 6.5 months (HR = 0.36); OS: 31.5 months vs 16.9 months (HR = 0.54); benefit consistent across all HER2 expression levels	Grade ≥ 3; TRAEs: 55.1% vs 86.9%; DV + toripalimab combination was better tolerated than chemotherapy
MYRETHA trial (RC48 in combo)	Phase II/III	1 L and 2 L settings for la/mUC, exploring combinations with immunotherapy	Multiple arms: DV ± immune checkpoint inhibitors	Primary outcomes pending; aims to establish optimal combination strategy	Safety profile under investigation, expected to be manageable based on prior data

la/mUC: Locally advanced or metastatic urothelial carcinoma; HER2: Human epidermal growth factor receptor 2; IHC: Immunohistochemistry; FISH: Fluorescence in situ hybridization; ORR: Objective response rate; NS: Not significant; PFS: Progression-free survival; OS: Overall survival; ILD: Interstitial lung disease; HR: Hazard ratio; T-DXd: Trastuzumab deruxtecan; TRAEs: Treatment-related adverse events; DV: Disitamab vedotin.

HER2 IN UPPER TRACT UC

The recent study by Huang and He[26], entitled “Human epidermal growth factor receptor 2 overexpression is associated with high-grade tumors in upper tract urothelial carcinoma”, published in the World Journal of Clinical Oncology, provides crucial insights into the prevalence and clinical significance of HER2 expression specifically in upper tract urothelial carcinoma (UTUC)[26]. UTUC accounts for only 5%-10% of all UCs but demonstrates distinct biological behavior and clinical course compared to bladder cancer. Patients with UTUC typically present with more advanced disease, with approximately two-thirds having muscle-invasive disease at diagnosis compared to 15%-25% in bladder cancer[27,28].

In their retrospective analysis of 145 UTUC patients, Huang and He[26] demonstrated that HER2 overexpression [defined as IHC 2+ or 3+] was present in 46.2% of cases, with a striking differential distribution according to tumor grade. While only 15% of low-grade tumors exhibited HER2 positivity, this proportion increased dramatically to 51.2% in high-grade carcinomas. This strong association between HER2 overexpression and high tumor grade [odds ratio (OR) = 3.56, 95% confidence interval (CI): 1.30-9.75; P = 0.013 in univariate analysis, and hazard ratio (HR) = 3.42, 95%CI: 1.22-9.60; P = 0.019 in multivariate analysis] underscores the potential role of HER2 signaling in tumor dedifferentiation and aggressive behavior in UTUC. These findings are consistent with a growing body of literature suggesting that HER2 expression is a key feature of high-grade and luminal UTUC[12,29].

Interestingly, and in contrast to patterns observed in breast and gastric cancers, HER2 status in this UTUC cohort showed no significant association with other conventional markers of disease progression, including pathological T stage (P = 0.426), nodal metastasis (P = 0.646), or lymphovascular invasion (P = 0.135)[26]. This dissociation suggests that HER2 may play a distinct biological role in UTUC compared to other epithelial malignancies, possibly reflecting tissue-specific signaling network configurations or interactions with the unique microenvironment of the upper urinary tract[27-29].

THE EVOLVING THERAPEUTIC LANDSCAPE: ADCS AND COMBINATION STRATEGIES

The recent presentation of the phase 3 RC48-C016 trial at the ESMO Congress 2025 represents a watershed moment in the management of HER2-expressing UC. This randomized controlled trial compared the combination of DV, an anti-HER2 ADCs, with toripalimab, an anti-programmed cell death protein-1 antibody, against standard platinum-based chemotherapy in the first-line treatment of locally advanced or mUC (la/mUC). The results were nothing short of practice-changing. PFS was nearly doubled, with a median PFS of 13.1 months in the DV plus toripalimab arm compared to 6.5 months in the chemotherapy arm, corresponding to a HR of 0.36. OS demonstrated a remarkable improvement, with median OS reaching 31.5 months vs 16.9 months in favor of the experimental arm, yielding a HR of 0.54. The clinical benefits were consistent across all pre-specified subgroups, including all levels of HER2 expression, encompassing IHC 1+, 2+, and 3+. Furthermore, the combination therapy exhibited a more favorable safety profile, with fewer grade 3 or higher treatment-related adverse events, reported at 55.1% compared to 86.9% in the chemotherapy group[30]. These findings collectively establish the DV plus toripalimab combination as the new standard of care for first-line treatment of HER2-expressing la/mUC, representing the first successful biomarker-directed strategy to demonstrate clear superiority over platinum-based chemotherapy in this setting.

It is important to contextualize these results within the current global treatment landscape. While the enfortumab vedotin-302 regimen (enfortumab vedotin plus pembrolizumab) has become the standard of care for all patients irrespective of biomarker status[9,31], the disitamab vedotin-toripalimab combination offers a potent alternative specifically for the substantial subset (approximately 50%) of patients with HER2-expressing tumors[30,32]. Its superior tolerability compared to platinum-based chemotherapy makes it a particularly attractive option for this population. However, it is crucial to note that while RC48-C016 establishes disitamab vedotin plus toripalimab as a new standard in HER2-expressing UC, this regimen is currently approved in China and has not yet been incorporated into international guidelines such as the National Comprehensive Cancer Network Guidelines[33]. The National Comprehensive Cancer Network Guidelines Version 1.2026 for bladder cancer currently recognize enfortumab vedotin plus pembrolizumab as the preferred first-line option for all patients regardless of HER2 status, and list fam-trastuzumab deruxtecan as a biomarker-directed therapy for HER2-positive (IHC 3+) tumors in the second-line setting. The absence of disitamab vedotin from current Western guidelines reflects the need for confirmatory trials in diverse populations to validate the generalizability of the RC48-C016 findings beyond Asian cohorts[32]. Ongoing and planned international studies will be critical to determine whether the remarkable efficacy observed in the Chinese population translates to Western patients, who may exhibit differences in tumor biology, HER2 expression patterns, and treatment history. Until such data are available, the integration of disitamab vedotin-based regimens into routine clinical practice outside of Asia should be considered in the context of clinical trials or after careful multidisciplinary discussion[33].

Beyond DV, several other HER2-targeted ADCs are under investigation in UC. Trastuzumab deruxtecan, which has demonstrated transformative activity in HER2-low breast cancer, is being evaluated in UC through several clinical trials[34,35]. In the DESTINY-PanTumor02 trial, trastuzumab deruxtecan demonstrated an ORR of 39.0% in all UC patients (n = 41), with particularly impressive activity in IHC 3+ tumors (ORR = 56.3%) and maintained efficacy in IHC 2+ tumors (ORR = 35.0%), along with a median duration of response of 11.8 months[23]. The drug’s unique mechanism of action, characterized by a high drug-to-antibody ratio and potent bystander effect, makes it particularly promising for tumors with heterogeneous HER2 expression[25].

MECHANISTIC INSIGHTS AND RATIONALE FOR COMBINATION WITH IMMUNOTHERAPY

The remarkable efficacy of the DV plus toripalimab combination in the RC48-C016 trial can be attributed to several interconnected mechanisms. First, HER2 signaling has been shown to modulate the tumor immune microenvironment through multiple pathways. Preclinical studies have demonstrated that HER2 inhibition can enhance antigen presentation, increase T-cell infiltration, and upregulate programmed death-ligand 1 expression, thereby potentially sensitizing tumors to immune checkpoint blockade[35]. Second, the specific mechanism of action of ADCs may inherently promote antitumor immunity. The targeted delivery of cytotoxic payloads induces immunogenic cell death, characterized by the release of damage-associated molecular patterns, tumor-associated antigens, and inflammatory cytokines. This process can stimulate dendritic cell maturation and enhance T-cell priming and activation, effectively turning the tumor into an in-situ vaccine[36]. Third, the payloads used in many ADCs, including the microtubule-disrupting agent monomethyl auristatin E in DV, have been shown to modulate various components of the tumor immune microenvironment. These effects include the depletion of regulatory T cells and suppression of myeloid-derived suppressor cells, further augmenting the activity of immune checkpoint inhibitors[36,37].

INTEGRATION INTO CLINICAL PRACTICE AND BIOMARKER CONSIDERATIONS

The compelling results from the RC48-C016 trial necessitate a fundamental re-evaluation of the diagnostic and treatment algorithm for advanced UC. HER2 testing should now be considered standard for all patients with la/mUC, similar to the established practice in breast and gastric cancers. However, several important considerations emerge regarding biomarker testing and patient selection. Based on the evolving data, we propose an updated clinical algorithm for the management of advanced UC, which is summarized in Figure 1[27,33,38,39].

Figure 1 Proposed clinical algorithm for the management of advanced urothelial carcinoma in the era of human epidermal growth factor receptor 2-directed therapy. This algorithm integrates mandatory human epidermal growth factor receptor 2 (HER2) biomarker testing into the contemporary treatment paradigm for locally advanced or metastatic urothelial carcinoma (la/mUC). First-line treatment selection is primarily guided by HER2 expression status, with disitamab vedotin plus toripalimab representing a new standard for HER2-expressing tumors (immunohistochemistry 1+, 2+, 3+). In contrast, enfortumab vedotin plus pembrolizumab remains the global standard for all patients, particularly those with HER2-negative disease. Alternative options are available depending on cisplatin eligibility, resource availability, and access to clinical trials. Maintenance avelumab following initial platinum-based chemotherapy and subsequent-line therapies is also incorporated. HER2: Human epidermal growth factor receptor 2; IHC: Immunohistochemistry; PD-L1: Programmed death-ligand 1; ADC: Antibody-drug conjugate; DV: Disitamab vedotin; PFS: Progression-free survival; OS: Overall survival; CR: Complete response; QoL: Quality of life; HR: Hazard ratio; FGFR: Fibroblast growth factor receptor.

The optimal method for HER2 assessment in UC remains an area of active investigation. While IHC has been the traditional approach, emerging data suggest that HER2-low tumors (IHC 1+ or 2+ with negative in situ hybridization) may also derive significant benefit from newer ADCs. This contrasts with the historical experience with trastuzumab, which was largely restricted to HER2-positive (IHC 3+ or 2+ with amplification) tumors. The study by Huang and He[26] utilized the Chinese expert consensus on HER2 testing in UC (2021 edition), which defines HER2 positivity as IHC 2+ or 3+. However, the RC48-C016 trial demonstrated benefit across all HER2 expression levels (IHC 1+, 2+, and 3+), suggesting that the current binary classification of HER2 status may need refinement in the context of ADC therapy. This parallels the evolving understanding of HER2-low as a therapeutically relevant category in breast cancer following the results of the DESTINY-Breast04 trial[34]. Recent large-scale analyses have confirmed that erb-b2 receptor tyrosine kinase 2 gene amplification is present in only about 12% of advanced UC cases, and is highly enriched in IHC 3+ tumors, indicating that IHC alone may be a sufficient screening tool for identifying candidates for HER2-directed ADCs[20].

The issue of biomarker heterogeneity presents another challenge in optimizing HER2-targeted therapy. Huang and He[26] reported that 25% (2/8) of recurrent bladder tumors transitioned from HER2-positive status in the primary UTUC to HER2-negative upon recurrence, highlighting the dynamic nature of HER2 expression. This phenomenon of clonal evolution under therapeutic pressure underscores the importance of repeated biomarker assessment whenever feasible, particularly at the time of disease progression. Spatial heterogeneity also represents a significant consideration. Differences in HER2 expression between primary tumors and metastatic lesions, as well as intratumoral heterogeneity, have been well-documented in various malignancies. The development of novel diagnostic approaches, including circulating tumor DNA analysis and molecular imaging with HER2-targeted PET tracers, may help address these challenges by providing a more comprehensive assessment of HER2 status across all disease sites[40].

FUTURE DIRECTIONS AND RESEARCH PRIORITIES

While the results of the RC48-C016 trial are practice-changing, several important questions remain unanswered and represent priorities for future research. First, the efficacy of HER2-targeted ADCs in specific UC subgroups, particularly UTUC, requires a dedicated prospective randomized investigation. The findings of Huang and He[26] suggest that HER2 overexpression may have distinct biological implications in UTUC compared to bladder cancer, potentially influencing treatment response. Preliminary real-world data suggest that disitamab vedotin-based regimens are active in advanced UTUC, with an ORR of 40.9% and a median PFS of 12.6 months, supporting the extrapolation of these benefits to this specific subtype[41]. In this context, the phase II DISTINCT-I trial evaluated a novel nephron-sparing strategy combining endoscopic thulium laser ablation or ureteral segmental resection with preoperative HER2-targeted therapy in high-risk UTUC. In this ongoing study, 20 patients with high-risk UTUC and indications for renal preservation received 2 cycles to 4 cycles of disitamab vedotin plus tislelizumab every 3 weeks as induction therapy before kidney-sparing surgery[42]. At a median follow-up of 13.0 months, the ORR was 65%, the disease control rate was 85%, and the 1-year kidney-intact event-free survival was 68.4%. Notably, treatment efficacy was strongly linked to higher levels of HER2 overexpression (IHC 2+/3+), and no grade ≥ 3 systemic toxicities were observed. These promising results, although preliminary, suggest that the combination of HER2-directed ADCs with immunotherapy may enable effective organ preservation in selected patients with high-risk UTUC, challenging the historical dominance of radical nephroureterectomy in this setting. Further validation in larger cohorts and randomized studies will be essential to establish this paradigm-shifting approach.

Second, the optimal sequencing of HER2-targeted therapy relative to other active agents in UC, including enfortumab vedotin (targeting nectin-4) and erdafitinib (targeting FGFR), remains to be determined. As the arsenal of effective targeted therapies expands, understanding mechanisms of resistance and developing rational combination strategies will be crucial. Third, the potential role of HER2-targeted therapy in neoadjuvant and adjuvant applications represents promising avenues to improve cure rates and prevent metastatic recurrence.

Building on the success of ADC plus immune checkpoint inhibitor combinations, several other rational combinations deserve investigation. The combination of HER2-targeted ADCs with other immunomodulatory agents, such as T-cell engagers or cancer vaccines, may further enhance antitumor immunity. Similarly, combinations with targeted therapies against complementary pathways, such as FGFR or epidermal growth factor receptor inhibitors, may help overcome or prevent resistance.

The development of more sophisticated predictive biomarkers represents another critical research priority. Beyond simple HER2 expression levels, integration of additional molecular features, such as HER2 mutation status, co-amplification of other ERBB family members, or specific immune gene signatures, may enable more precise patient selection. Additionally, the identification of early response biomarkers could facilitate adaptive treatment strategies and help avoid unnecessary toxicity in non-responding patients.

CONCLUSION

The comprehensive characterization of HER2 expression patterns in UTUC by Huang and He[26], published in the World Journal of Clinical Oncology, combined with the groundbreaking results of the RC48-C016 trial, heralds a new era in the management of advanced UC. HER2 has emerged not only as a robust prognostic biomarker, particularly in high-grade UTUC, but also as a predictive biomarker for response to novel ADC-based therapies. The demonstrated efficacy of DV in combination with toripalimab across all HER2 expression levels establishes a new standard of care and validates the concept of biomarker-directed therapy in UC. As we incorporate these advances into clinical practice, several challenges remain, including the optimization of HER2 testing methodologies, management of spatial and temporal heterogeneity, and development of rational combination strategies. The proposed clinical algorithm (Figure 1) provides a framework for integrating these novel therapies into practice[33,38,39]. Future research should focus on validating these approaches in UTUC-specific cohorts, exploring their application in earlier disease stages, and identifying novel biomarkers to further refine patient selection. The work of Huang and He[26], published in the World Journal of Clinical Oncology, provides a crucial foundation for these efforts, emphasizing the distinct biological features of UTUC and reinforcing the importance of tissue-specific molecular characterization. As the field continues to evolve, the integration of comprehensive biomarker assessment and targeted therapeutic approaches promises to significantly improve outcomes for patients with this challenging disease.