Systemic inflammatory biomarkers as prognostic tools in patients with gastroesophageal adenocarcinoma

Gastroesophageal cancer represents a major global disease burden with high mortality rates (Sung et al. 2021). Although recent advances in treatment strategies have improved overall survival, prognosis remains poor, even in resectable settings (Lordick et al. 2022; Obermannová et al. 2022). Thus, novel prognostic markers are warranted to improve patient management(Dhakras et al. 2020).

The rise of checkpoint inhibition did not only lead to several practices—changing drug approvals, but also raised awareness of local as well as systemic inflammatory parameters as predictive and prognostic parameters in several oncological entities including gastroesophageal cancers (Moehler et al. 2021; Shitara et al. 2022; Li et al. 2021). Systemic inflammatory biomarkers, including leucocyte ratios, such as neutrophil–lymphocyte ratio (NLR), lymphocyte–leucocyte ratio (LLR), platelet–lymphocyte ratio (PLR) and the systemic inflammation response index (SIRI; neutrophils*monocytes/lymphocytes) as well as the C-reactive protein (CRP) and albumin-based modified Glasgow prognostic score (mGPS), propose potential association with treatment outcome (Laird et al. 2013; Proctor et al. 2011). Retrospective analyses in Asian cohorts showed that systemic inflammation might be an important prognostic factor independent of tumour stage and treatment regimen (Matsumoto et al. 2023; Liu et al. 2021; Huang et al. 2020). However, large real-world investigations of Western cohorts comprising all tumour stages are lacking as existing data focus largely on prediction of surgical as well as pathological outcomes and do not investigate inflammatory markers in association with other known prognostic factors in multivariate settings (Kim et al. 2020; Schietroma et al. 2022; Nechita et al. 2022; Pikuła et al. 2022; Jomrich et al. 2021; Petrillo et al. 2018). As tumour biology, biomarker expression, treatment response and survival differ between Asian and Western cohorts (Rha et al. 2022; Zhang et al. 2022b), the aim of this analysis was to investigate systemic inflammatory processes at the time of first cancer diagnosis as prognostic markers in a large European cohort of gastroesophageal cancer patients.

Inflammatory parameters play a key role in cancer development and progression. Yet, prognostic effects of systemic inflammatory parameters have rarely been studied in large Western cohorts with gastroesophageal adenocarcinoma and it is unclear which inflammatory parameter is the best predictor for overall survival. The results of our analyses shed some light on this issue, as they show that mGPS is a feasible prognostic tool to estimate overall survival in a large, representable European cohort of gastroesophageal adenocarcinoma patients.

Although the leucocyte ratios NLR, LLR and PLR also showed prognostic potential in univariate analyses, only high mGPS scores at first diagnosis could be identified as an independent tool in multivariate analysis of the locally advanced cohort. NLR and LLR are surmised to reflect an increased inflammatory response to tumour cells (Buonacera et al. 2022). Whether this mechanism is associated with immune cell infiltration in tumour tissue is widely discussed (Choi et al. 2016; Puhr et al. 2022), but no clear association has been proven yet. In addition, PLR may represent the important role of platelet-derived tumour angiogenesis maintained by vascular endothelial growth factor and platelet-derived growth factor leading to tumour progression and dissemination. Thus, several trials have shown distinctive associations of these ratios with tumour progression and outcome in gastroesophageal cancer patients as well as patients with other cancer entities (Namikawa et al. 2016; Starzer et al. 2021; Pikuła et al. 2022; Miyamoto et al. 2018; Lian et al. 2015; Kim et al. 2022; Petrillo et al. 2018). Yet, the definition of clear cut-off levels for risk stratification is still lacking (Schiefer et al. 2022). This might be due to the fact that although higher levels are associated with more severe tumour stages and survival, differences between ratios are small and effected by outliers (see Supplementary Figs. 1–3). Systemic inflammation parameters not only serve as prognostic tools but could also be used to predict response to immunotherapy. Initial emerging data from translational research programmes of clinical trials indicate potential usability of these markers, particularly NLR, in decision-making between chemotherapy and immunotherapy doublet (Chau et al. 2022). Although the implementation of these ratios outside of academic evaluations is still not feasible, further translational research of clinical trials will provide valuable data and an improved understanding of these markers for the clinical routine.

The mGPS, which is based on CRP and albumin levels, presents a more robust and feasible tool than systemic inflammatory ratios as it is easily calculated and only encompasses three levels (score 0 to 2). mGPS has been shown to be associated with postoperative outcome in gastroesophageal cancer patients in several Asian cohorts (Jiang et al. 2012; Chen et al. 2020; Hirashima et al. 2014; Zhang et al. 2022a, b). Yet, data on Western cohorts and comparisons between tumour stages are scarce.

In our cohort, mGPS was also associated with more severe tumour staging. Further analyses of stage subgroups showed that mGPS was an independent prognostic marker in multivariate analysis of the locally advanced cohort. These results suggest that although scores are the highest in advanced and metastatic settings, the prognostic value is the greatest in locally advanced settings. This finding is in line with perioperative studies of Asian cohorts (Jiang et al. 2012; Chen et al. 2020; Hirashima et al. 2014; Zhang et al. 2022a, b). Recently published data from a Romanian cohort, investigating leucocyte ratios, also suggests that the prognostic value of inflammatory biomarkers is the greatest in locally advanced settings (Nechita et al. 2022). This is further supported by two European studies investigating inflammatory biomarkers in resectable gastric cancer (Pikuła et al. 2022; Schietroma et al. 2022). However, multivariate analyses and recommendations for clear cut-off levels of leucocyte ratios are lacking in these trials. Furthermore, the role of tumour location in systemic inflammatory processes is unclear.

Thus, based on our findings, mGPS might pose a feasible prognostic tool in everyday practice and could improve patient management in perioperative settings by raising physicians’ awareness of early recurrences as well as perioperative morbidity in patients with higher scores. Yet, the exact mechanisms behind these consistent results of associations between elevated systemic inflammatory biomarkers and inferior outcome in locally advanced settings have not been identified and need to be further explored.

In a recently published analysis of advanced gastroesophageal cancer patients undergoing first-line treatment from the phase III EXPAND trial, mGPS could be associated with sarcopenia (Hacker et al. 2022). Our results show that elevated systemic inflammation parameters were associated with weight loss rather than with BMI. Although not directly assessed in the current cohort, sarcopenia, which is often characterised by weight loss independent of BMI, might also be a large contributor to higher mGPS scores in our cohort. However, concerning multivariate analyses in the overall cohort, mGPS stayed statistically significantly associated with the OS and so did weight loss. Thus, the prognostic value of mGPS might not only be associated with sarcopenia but other values. This theory is supported by the findings of Hacker et al. as mGPS carried full prognostic information for OS, but direct causal path from sarcopenia to survival was lacking (Hacker et al. 2022).

Moreover, elevated systemic inflammatory parameters and consequently higher mGPS levels might be caused by circulating tumour cells in more advanced stages, as these tumours are known to be associated with higher levels of circulating tumour components. Circulating tumour DNA (ctDNA) has gained scientific interest as a key prognostic value after tumour resection in various cancers (Moati et al. 2021). First attempts to guide adjuvant therapy by the analysis of ctDNA in colorectal cancer have shown promising results (Tie et al. 2022). Prognostic effects of ctDNA in gastroesophageal cancer patients have recently been published and feasibility as a widely used prognostic markers is under evaluation (van Velzen et al. 2022; Shoda et al. 2017; Iqbal et al. 2019). Moreover, trials investigating further systemic treatment in patients with high ctDNA levels in gastroesophageal cancer are underway and might shed some light on the association of ctDNA with systemic inflammatory parameters such as mGPS.

Furthermore, it was hypothesised that systemic inflammatory biomarkers might pose as predictive parameters for response to immunotherapy. A recently published retrospective analysis of hepatocellular carcinoma patients undergoing checkpoint inhibition suggests that NLR and PLR are independent negative prognostic factors (Muhammed et al. 2021). Similar associations could be drawn in other tumour entities and with various immunotherapeutic agents (Stares et al. 2022; Ye et al. 2023). Yet, so far, only tumour tissue-based markers, such as PD-L1, tumour mutational burden (TMB-H) and mismatch repair deficiency/microsatellite instability (dMMR/MSI-H), are approved biomarkers for administration of immunotherapy (Food and Drug Administration 2017a, b, 2020, 2021). First attempts to correlate these markers with soluble counterparts form liquid biopsies showed promising potential (Mair et al. 2020; Shin et al. 2023). In addition, a post hoc examination of clinical data from the CheckMate-648 trial suggested a potential association between baseline NLR and different response rates in esophageal squamous cell carcinoma patients receiving immunotherapy, chemotherapy or immuno-chemotherapy (Chau et al. 2022). However, data on gastroesophageal adenocarcinoma are still scarce as immunotherapy has only been approved within the last few years. This is underlined by the relatively small subgroup of patients who were tested for PD-L1 or dMMR/MSI-H expression in our cohort.

Furthermore, patients without PD-L1, TMB-H or dMMR/MSI-H tumours in some cases also show exceedingly promising responses leading to the hypothesis that other biomarkers might provide more sufficient predictive value (Zhang et al. 2021). Thus, further research is warranted to investigate the predictive potential of systemic inflammatory biomarkers in respect to immunotherapeutic strategies.

Due to the retrospective design of our analyses, further exploration of associations with immuno-histochemical staining, such as PD-L1 and dMMR/MSI-H, as well as underlying infectious or autoimmune diseases, therapeutic strategies and longitudinal evaluation of systemic inflammatory parameters could not be performed and therefore pose limitations to our work. In addition, the large timespan of patient recruitment poses a potential bias and is included in our analyses. However, year of first diagnosis was only significantly associated with the OS in the overall but not in the stage-based subgroups as throughout the last decades, more severe cases have been transferred and treated at our department. Despite these limitations of the analysis, our results pose an important cornerstone for further evaluation of mGPS in gastroesophageal adenocarcinoma patients.

In conclusion, higher systemic inflammatory biomarkers were statistically significantly associated with more severe tumour stages and weight loss at first diagnosis. Concerning subgroups based on tumour stages, mGPS showed robust prognostic value in patients with locally advanced disease, which is in line with results from Asian cohorts. Further analyses are warranted to explore the cause and potential clinical applications of elevated mGPS scores.