Race-based differences in serum biomarkers for cancer-associated cachexia in a diverse cohort of patients with pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related deaths by 2040, with the highest disease burden expected amongst Non-Hispanic Blacks. One of the most significant predictors of poor outcomes is the presence of cancer-associated cachexia (CCa). Yet, race- and ethnicity-specific biomarkers for early CCa diagnosis are lacking. Thus, evaluated a panel of candidate biomarkers of CCa in a diverse cohort of pre-treatment serum. Our study shows that GDF-15 was associated with cachexia severity, was superior to standard CCa-associated biomarkers at classifying cachexia, and differentiated between non-cachexia and pre-cachexia status, but only among Hispanic/Latinx and non-Hispanic Whites. Furthermore, high GDF-15 levels at diagnosis were associated with a ~ 2-fold increase in weight loss over the 6 months post-diagnosis. Thus, GDF-15 may be a potential biomarker for pre-cachexia (prior to weight loss) in the White and the Hispanic population, but not Black individuals. These findings underscore the fact that enrollment of minority individuals in clinical trials to evaluate treatments for CCa is of utmost importance.

Figure 1. Cachexia status and stage are linked to overall survival in a PDAC cohort with baseline blood available.

Survival was analyzed based on cachexia status using either weight loss alone (A), cachexia status based on weight loss and other blood biomarkers (B) stage (stage 1/2 vs 3/4, C) or R/E (D). Time to event (x-axis) is measured in months.

Figure 2. Cachectic and pre-cachectic PDAC patients demonstrate significant differences in stress-related markers at baseline and GDF-15 can be used to classify patients into cachexia categories:

Boxplots showing a log-scale value of all significantly different serum biomarkers between cachectic and non-cachectic PDAC patients (A) and when stratified into 4 stages as in Vigano et al. (B). NCa=non cachectic, PCa=pre cachectic, Ca=cachectic, RCa=refractory cachectic. All plots in A and B are significant based on a Wilcoxon rank sum or Kruskal-Wallis test and BH-adjusted p-value. Significant differences in serum biomarkers between groups (pairwise Dunn’s test) are denoted with a red line in B. Outliers are denoted by a red dot. C) ROC curves for percent self-reported weight loss (Pct Weightloss), GDF-15, TNF-alpha, white blood cell count (WBC), Hemoglobin and Albumin and a combined TNF-alpha * GDF-15 model (Combined Model) using cachexia status at baseline as the “ground truth”. Youden’s optimal thresholds are denoted with a black dot. D: Boxplot of percent weight loss (negative values indicate weight gain) from baseline to 6-month follow-up time point. Patients were dichotomized based on levels of GDF-15, TNF-alpha or combined GDF-15 * TNF-alpha levels (Low vs High based on the Youden’s threshold values calculated by the ROC in Figure 2C).

Figure 3. Both NHW and H/L participants demonstrate significant differences between non cachexia and cachexia status in stress-related markers at baseline:

Boxplots showing a log-scale value of serum biomarkers which are significantly different between cachectic and non-cachectic PDAC patients for at least two R/Es stratified into Non-Hispanic Black, Hispanic/Latinx and Non-Hispanic White patients. NHB=Non-Hispanic Black, H/L=Hispanic/Latinx, NHW=Non-Hispanic White, NCa=non cachectic, Ca=cachectic. Significant differences in serum biomarkers between groups are denoted with a red line. Outliers are denoted by a red dot.

Figure 4. PDAC and other patients demonstrate wide racial variation in select serum biomarkers at baseline:

A) Boxplots showing a log-scale value of select significant biomarkers when PDAC R&E groups are compared (ENA-78/CXCL5, and GRO-α/CXCL1, IL-10 and TNF-α; GDF-15 was added as a control) and B) when stratified into cachexia groups (NHB=Non-Hispanic Black, HL=Hispanic/Latino, NHW=Non-Hispanic White, NCa=non cachexia, Ca=Cachexia). C) Boxplots showing ENA-78 and GRO-alpha levels after filtering the full FPC cohort to non-PDAC diagnoses. D) Boxplot of neutrophil to lymphocyte ratio (NLR) for PDAC patients in the study. Significant differences between relevant groups are denoted with a red line. Significance between NHBCa/NHBNCa and all other groups is denoted with a *. N/S = not significant. Outliers are denoted by a red dot.

Figure 5. GDF-15 and IL-6 are linked to overall survival both CoxPH models and by Kaplan estimation:

A-B) Forest plots of dichotomized analytes found to be associates with survival as continuous variables in a univariate analysis when controlled for demographic and patho-clinical variables (A). B represents the final model. NHB=Non-Hispanic Black, HL=Hispanic/Latinx, NHW=Non-Hispanic White, NCa=non cachectic, Ca=Cachectic. C-D) Median levels of GDF-15 (C) or IL-6 (D) were calculated and participants were classed into either low (Low) or high (High) groups based on a median split. C) and D) represent Kaplan-Meier survival curves (time in months) for GDF-15 and IL-6, respectively. Time = time to event in months.

Figure 6

Overview of IL-6 and GDF-15 levels throughout the cancer-associated cachexia continuum.