The prognostic significance of histologic variant on survival outcomes in patients with metastatic urothelial carcinoma receiving immune checkpoint inhibitor therapy

The impact of histologic variant on treatment response and survival outcomes in patients receiving ICI therapy remains a topic of ongoing debate. To address this, we conducted a retrospective study aiming to assess the effectiveness of ICI monotherapy in patients with pUC and vUC. Our findings revealed that the ORR was numerically higher in patients with pUC compared to those with vUC (34.5% vs. 23.1%). Notably, patients with pUC exhibited a more favorable depth of response, as evidenced by a higher complete response rate of 12.9%, while no complete responses were observed in vUC patients. Although our results showed similar PFS and OS between the two groups overall, subgroup analysis demonstrated that patients with pUC experienced improved OS in the context of first-line ICI treatment.

The findings of our study are consistent with several previous investigations. Miller et al. conducted a study that revealed similar ORR (28% vs. 29%, p = 0.9) and median OS (11 months vs. 10.1 months, p = 0.6) between patients with pUC and vUC who underwent ICI monotherapy [15]. In another study by Kobayashi et al., they found a comparable ORR between vUC and pUC patients (24.5% vs. 17.3%, p = 0.098), and no significant differences were observed in terms of PFS or OS between the two groups [16]. However, Minato et al. demonstrated higher ORR and complete response (CR) rates in vUC patients (59.1%, CR rate: 9.1%) compared to pUC patients (24.7%, CR rate: 4.9%) when treated with pembrolizumab monotherapy after platinum treatment failure, although there were no significant differences in PFS or OS [17]. A detailed comparison can be found on Table 6.

Given the conflicting findings, our data contributes novel evidence to the appropriateness of employing ICI for the treatment of vUC. Of note, our research findings are the first to demonstrate that ICI yield significantly superior OS benefits in pUC compared to vUC in the first-line treatment of mUC. These results can provide guidance in the selection of appropriate patients for ICI treatment.

Different histologic variants can potentially influence the response to ICI in a clinical setting. The 2016 WHO classification identifies vUC as a histologic variant encompassing a diverse range of subtypes, such as squamous, glandular, micropapillary, sarcomatoid, plasmacytoid, small cell carcinoma, and others [18]. The squamous and micropapillary variants, among others, have been associated with more aggressive characteristics, resistance to chemotherapy, and poorer overall survival outcomes [19‐22]. To gain insights into the response of specific variants to ICI, the most effective approach is to examine the ORR and pathologic response through neoadjuvant trials. The PURE-01 study observed that neoadjuvant pembrolizumab treatment in patients with muscle-invasive bladder cancer (MIBC) led to a substantial pathologic complete response (PCR) rate, with impressive outcomes of up to 42% [23]. Among all the enrolled variants, the squamous variant demonstrated tumor downstaging to pT1 or pTa in 86% of cases, with one case (14%) even achieving pCR [24]. The NABUCCO trial reported a 100% pCR rate in two out of two patients with the squamous variant who received neoadjuvant treatment with nivolumab and ipilimumab, suggesting that the squamous variant is not the determining factor for the effectiveness of ICI treatment [25]. Notably, the squamous variant exhibited a substantial presence of CD-274 gene amplification (5%), PD-L1 expression, and a high tumor mutational burden (TMB), all of which suggest its potential responsiveness to ICI treatment [26].

The lymphoepithelioma-like carcinoma (LELC) variant is a histologic subtype that closely resembles nasopharyngeal carcinoma and shares a connection with Epstein-Barr virus (EBV) activity [27]. A case series involving pulmonary LELC demonstrated a notable high response rate (80%) and a longer median PFS compared to standard chemotherapy when treated with ICI [28]. In the PURE-01 study, two out of three cases with LEL variants exhibited a pT0 response by neoadjuvant pembrolizumab treatment [24]. Urothelial carcinoma with sarcomatoid differentiation is a rare subtype characterized by advanced stage and associated with a worse survival [29]. Several case reports demonstrated that sarcomatoid variant had an exceptional response to ICI [30, 31]. In a study by Kobayashi et al., it was demonstrated that the sarcomatoid variant, when treated with ICI, exhibited a significantly higher ORR and improved OS compared to pUC [16]. The presence of sarcomatoid transformation in conventional bladder cancer is thought to entail a distinct mutational landscape and elevated PD-L1 expression. These findings provide supportive evidence for the potential effectiveness of ICI treatment [32].

When considering the depth of response to treatment, it should be noted that none of the vUC patients in our study achieved a clinical complete response (CR). However, other studies have reported clinical CR rates ranging from 6.1 to 9.1% [16, 17]. It is important to consider that the heterogeneity in patient backgrounds, various ICI agents used, and the small number of cases in these studies may be confounding factors. Nonetheless, our study found comparable disease control rates (DCR) between pUC and vUC patients (46.6% vs. 46.2%, p = 0.97).

In our research, we found that the Bajorin score, along with the baseline WBC and hemoglobin levels, hold substantial significance as prognostic factors. These outcomes align with the observations made by Bajorin et al. during the pre-immunotherapy era, when cisplatin-based therapy was primarily the established treatment protocol [33]. Leukocytosis, as indicated in previous reports, may be linked to tumors that produce granulocyte colony-stimulating factor (G-CSF), and this association is correlated with a less favorable prognosis [34]. Similarly, anemia has been identified as an independent factor associated with reduced OS and CSS among urothelial carcinoma patients [35]. Although cancer-related anemia typically has multiple contributing factors, the interaction between leukocytosis and anemia can, in part, be elucidated by G-CSF’s impact on inhibiting bone marrow erythropoiesis and promoting splenic erythropoiesis, ultimately exacerbating anemia [36].

There are a few limitations that are inherent to the nature of the retrospective design of this study including lack of randomized comparisons, lack of external validation, heterogeneity of clinical practice and missing PD-L1 status for further investigation. Notably, a greater proportion of pUC patients received anti-PD1 therapy as compared to vUC with statistical significance, which may affect further survival outcome. Second, the assignment of patients to different treatment groups relied on the physician’s discretion and patient preferences, leading to inherent selection bias. However, the analysis revealed no discernible differences in demographic variables, including sex, age and Bajorin prognostic factors, suggesting that that the imbalance treatment bias was partially mitigated. Third, in clinical practice, a significant number of diagnoses of mUC rely on small core biopsy specimens. Nonetheless, the limited number of tumor cells present in these small biopsies, coupled with the intrinsic heterogeneity of tumors, can result in an underestimation of the true proportion of vUC cases. Fourth, up to 40% cases lack the PD-L1 values in this study. This was primarily due to the earlier commencement of our study (Apr 2016) before the Food and Drug Administration (FDA) announced restrictions on the front-line use of ICI for cisplatin-ineligible patients in June 2018. The balanced distribution of missing PD-L1 values helped mitigate the bias to some extent.

In vUC patients, ICI monotherapy is an effective treatment option either as first line or chemotherapy resistant second-line treatment in advanced/metastatic UC. Future randomized prospective trial and response analysis of different histologic subtype to ICI is needed.