In the current study, we constructed AAPR, an easily available index comprised of serum ALB and ALP level. We further investigated its prognostic significance in unresectable PDAC patients. Analysis of the patient characteristics showed that low AAPR was closely associated with more advanced stage and higher CA19-9 level. PSM analysis was performed to generate well-balanced patients in low and high AAPR groups for survival comparison. Univariate and multivariate Cox analysis indicated that APPR served as an independent prognostic predictor for OS in both entire cohort and PSM cohort. In addition, we found that AAPR could be used in most subgroups except for the group of age ≤ 60. More importantly, inclusion of AAPR improved the prediction performance of conventional prognostic model.
To our best knowledge, Chan et al. [26] were the first to report that AAPR can act as a novel prognostic index for patients with hepatocellular carcinoma patients underwent curative surgery. Since then, numerous studies have looked into the prognostic performance of AAPR for various malignancies, such as metastatic nasopharyngeal cancer [15], non-small-cell lung cancer[14], cholangiocarcinoma[16], upper tract urothelial carcinoma[17], renal cell carcinoma [18], and cervical cancer[19]. Particularly, Pu et al. [20] examined the AAPR in patients receiving surgery for PDAC and concluded that preoperative AAPR could independently predict postoperative OS in PDAC patients. Consistently, our data reveled that low AAPR correlated with poor OS. Also, we revealed that AAPR might function as an independent prognostic predictor in unresectable PDAC patients. In the subgroup analyses, the outcome of survival consistently favored the high AAPR group across most subgroups except in the group of age ≤ 60. Despite the findings not being significant, the trend in the group of age ≤ 60 was consistent with other groups.
Cancer is marked by rapid tumor cell proliferation and invasion[27], which may lead to various metabolic changes, such as enhanced production of some serum proteins, cytokines, and hormones. Thus, serum ALB and ALP might reflect tumor progression, and can, therefore, be used to predict clinical outcomes. The following mechanisms may explain the biological relationship between AAPR and prognosis of unresectable PDAC.
As the most abundant protein in serum, ALB is the primary determinant of plasma oncotic pressure. Besides, ALB offers storages and conveyors for many exogenous and endogenous substances[28]. Serum ALB levels reflect the nutritional status and liver function in humans. It is widely recognized that inflammation, tumor microenvironment, and their interaction play critical roles in tumor progression[29]. Studies have shown that ALB can modulate the inflammatory reaction by binding prostaglandins, lipopolysaccharide, and reactive oxygen species [30]. Moreover, ALB has been found to suppress the cell cycle and progression of hepatocellular carcinoma[31][32]. Recent lines of evidence have identified ALB as an independent prognostic indicator in various malignant tumors, including lung[33], breast[34], and gastric cancers[35].
As a phosphate monoester hydrolase, ALP promotes the hydrolysis and transfer of phosphate groups in alkaline conditions[36]; therefore, it is regularly examined to evaluate liver function in clinical practice. Increasing evidence has shown that ALP can serve as a tumor-associated antigen and biomarker of cancer cell proliferation [11][37]. On the contrary, a reduction of ALP activity induces cell death, mesenchymal-to-epithelial transition, and suppresses cell migration[38]. Besides, ALP activity level is commonly used to predict bone metastasis in various types of cancer[39][40]. In the present study, patients with lower AAPR displayed poor prognosis, an observation that was consistent with the previous findings.
As a result of inflammation, oxidative stress produces reactive oxygen species that can damage protein, lipids, DNA, and facilitate the production of highly mutagenic metabolites[41]. Accordingly, oxidative stress plays a vital role in the tumorigenesis of PDAC[42]. Elevated ALP levels may serve as a potential predictor of oxidative stress[43], thereby contributing to cancer progression and poor disease outcomes[44][45]. Because of this, patients with low AAPR might have a poor prognosis.
Herein, we demonstrated the prognostic value of AAPR for unresectable PDAC by multivariate and univariate models as well as PSM analyses. Besides, patients’ characteristics were well matched to minimize potential confounding bias. The prognostic value of AAPR was investigated in the entire cohort and further validated in the PSM cohort. Moreover, AAPR was confirmed to be associated with OS in most subgroups, which suggested that AAPR could be applied in patients with different clinicopathological features.
However, this study had a few limitations. First, our cohort was a retrospective cohort in a single center and composed of Chinese patients only; therefore, these results do not apply to other populations. Further multicenter prospective studies are thus recommended. Second, FOLFIRINOX is a standard regimen option for patients with metastasized PDAC. However, FOLFIRINOX is not widely used by Chinese patients because of its severe side effects. Whether AAPR could be used in patients receiving FOLFIRINOX remains unclear. Third, the underlying mechanism between the AAPR and cancer biology was not investigated and therefore needs further research.