To our knowledge, this study is the first study to assess the prognostic significance of the AGR in patients with advanced UC. Here we analyzed a multi-institutional cohort of 150 patients with advanced UC patients treated with pembrolizumab. We found that pretreatment AGR < 0.95 and ECOG PS ≥ 2 were independent predictors of PFS, CSS, and OS. Furthermore, we developed a prognostic risk model incorporating these two variables, which classified patients into three risk groups with significantly different PFS, CSS, and OS values. The model achieved a relatively high Harrell’s concordance index for all study endpoints.
Although the concept of AGR was introduced long ago, it was not applied to oncology until the 2010s [14, 15]. Several studies assessed the prognostic significance of the AGR of patients with UC [16–24] in settings of bladder cancer treated with radical cystectomy [16, 17], non-muscle-invasive bladder cancer [18], and upper tract UC treated with radical nephroureterectomy [19–24]. Most of these studies [16–23] demonstrate the utility of the AGR as a readily available predictive biomarker for patients with UC. To our knowledge, the present study is the first to demonstrate the potential utility of the AGR in the setting of advanced UC, and thus adds further evidence in this field.
The link between a low AGR and poor outcomes of patients with cancer is not fully established but may be explained in general terms as follows [23, 29]: First, previous studies show that poor nutritional status or hypoalbuminemia is a predictor of poor prognosis for patients with cancer [29]. Second, chronic inflammation involving serum globulins is required for tumor proliferation, immune evasion, and metastasis. Evidence indicates that serum globulins secreted by tumor-related cells promote tumor development, immunosuppression, and metastasis [29]. Third, a low AGR may thus more sensitively reflect the degree of poor nutritional status (hypoalbuminemia) and tumor progression (hyperglobulinemia) than either measure alone, and may therefore serve as a highly significant prognostic biomarker [23].
Similar to the concept of the AGR (i.e. use of a ratio), the NLR was developed in 2001 by Roman Zahorec [7] and has subsequently been investigated in oncology. Numerous studies show an association with an increased NLR with worse outcomes of certain malignancies including UC [8–13]. The NLR sensitively reflects the degree of tumor progression; this is because both an increased neutrophil-dependent inflammatory reaction and a decreased lymphocyte-mediated anti-tumor immune response contribute to the elevation of the NLR [8, 30].
We previously reported the prognostic significance of the NLR using a multi-institutional cohort of 185 patients with advanced UC undergoing first-line chemotherapy [8]. Pretreatment NLR ≥ 3 was identified as an independent predictor of CSS and OS together with ECOG PS ≥ 2 and liver metastasis, whereas the AGR was not evaluated [8]. In the present study, pretreatment NLR ≥ 3 was significantly associated with all endpoints of PFS, CSS, and OS on univariate analyses (Table 2–4), and showed a non-significant trend for shorter CSS on a multivariate analysis (P = 0.08) (Table 3). These data indicate that the NLR may still serve as a valid biomarker in the setting of later-line pembrolizumab.
We further reported the critical impact of liver metastasis on worse outcomes in the said study [8]. In the present study, liver metastasis was significantly associated with all endpoints of PFS, CSS, and OS on univariate analyses (Table 2–4), and was identified as an independent predictor of shorter PFS (Table 2) with showing a non-significant trend for shorter OS (P = 0.08) (Table 4) on multivariate analyses. Although liver metastasis was not incorporated into the final risk model applied here, it undoubtedly serves as an essential prognostic marker for advanced UC, even in the era of immune checkpoint inhibitors.
The limitations of this study include its retrospective design and the limited number of patients. Further studies with larger populations are required to validate our results.
In conclusion, pretreatment AGR < 0.95 may serve as a prognostic marker for patients with advanced UC treated with pembrolizumab. Our newly developed prognostic risk model, including pretreatment AGR and ECOG PS, may serve as an excellent discriminator of survival.