Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor survival. The dense desmoplastic stroma in PDAC contributes to treatment resistance. Among the components comprising the tumor stroma, hyaluronan (HA) has been demonstrated to play a critical role in tumor progression and survival. Previous preliminary studies have suggested differences in HA expression in primary and metastatic foci of PDAC. However, the effects of treatment and location of HA expression as a biomarker signature remain unknown; this study sought to compare HA expression in primary and metastatic sites of PDAC.

Methods

Tissue from primary and metastatic PDACs were obtained from Cedars-Sinai Medical Center along with associated clinical data. Tissue slides were stained for H&E, HA, and CD44. Associations between HA levels and the evaluated variables were examined including progression free survival and overall survival.

Results

HA score was significantly higher in primary PDACs compared to sites of metastases (p = 0.0148). Within the metastases, HA score was significantly higher in liver metastases compared to metastases at other sites (p = 0.0478). In the treatment-naive liver metastasis cohort, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status (p = 0.0032 and p = 0.0478, respectively).

Conclusions

HA score is variable between primary PDAC, PDAC metastatic to the liver, and PDAC metastatic to other sites. Within liver metastases, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status. HA levels can serve as a potential biomarker to guide pancreatic cancer treatments and trial design for agents targeting the stroma.

Nearly 80% of patients with pancreatic ductal adenocarcinoma (PDAC) develop cachexia along their disease course. Cachexia is characterized by progressive weight loss, muscle wasting, and systemic inflammation and has been linked to poorer outcomes and impairments in quality of life. Management of PDAC cachexia has historically involved a multidisciplinary effort comprised of nutritional support, pancreatic enzyme replacement therapy, and/or pharmacologic interventions. Despite current interventions to mitigate PDAC cachexia, a significant proportion of patients continue to die from complications associated with cachexia underscoring the need for novel insights and treatments for this syndrome. We highlight the feasibility and effectiveness of a recent enteral feeding prospective trial at our institution to improve cachexia outcomes in patients with advanced PDAC. Additionally, we were among the first to characterize the stool microbiome composition in patients with advanced PDAC receiving enteral feeding for the treatment of cachexia. Novel insights into the relationship between enteral nutritional support, cachexia, and the gut microbiome are presented. These promising results are discussed in the context of a potential ability to modulate the stool microbiome as a new interventional strategy to mitigate PDAC cachexia.

Pancreatic cancer (PC) is one of the deadliest cancers. Developing biomarkers for chemotherapeutic response prediction is crucial for improving the dismal prognosis of advanced-PC patients (pts). To evaluate the potential of plasma metabolites as predictors of the response to chemotherapy for PC patients, we analyzed plasma metabolites using high-performance liquid chromatography-mass spectrometry from 31 cachectic, advanced-PC subjects enrolled into the PANCAX-1 (NCT02400398) prospective trial to receive a jejunal tube peptide-based diet for 12 weeks and who were planned for palliative chemotherapy. Overall, there were statistically significant differences in the levels of intermediates of multiple metabolic pathways in pts with a partial response (PR)/stable disease (SD) vs. progressive disease (PD) to chemotherapy. When stratified by the chemotherapy regimen, PD after 5-fluorouracil-based chemotherapy (e.g., FOLFIRINOX) was associated with decreased levels of amino acids (AAs). For gemcitabine-based chemotherapy (e.g., gemcitabine/nab-paclitaxel), PD was associated with increased levels of intermediates of glycolysis, the TCA cycle, nucleoside synthesis, and bile acid metabolism. These results demonstrate the feasibility of plasma metabolomics in a prospective cohort of advanced-PC patients for assessing the effect of enteral feeding as their primary source of nutrition. Metabolic signatures unique to FOLFIRINOX or gemcitabine/nab-paclitaxel may be predictive of a patient's response and warrant further study.

Introduction

Hyaluronan (HA) accumulation is associated with tumorigenesis and aggressive tumor behavior.

Aims

We investigated the biomarker potential of HA in non-small cell lung cancer (NSCLC).

Methods

HA levels were scored using affinity histochemistry in 137 NSCLC samples stratified by HA score ≤10, 11-20, 21-30, and >30 with HA-high defined as ≥25% expression in the extracellular matrix (ECM) of the tumor surface area. Overall survival (OS) and time to progression from initiation of taxane therapy (TTP) were compared using log-rank tests based on HA score.

Results

Of 122 patients with recurrent/metastatic NSCLC, 93 had mean HA scores that were not significantly different across clinicopathologic variables. Frequency of HA-high tumors did not differ by histology (34/68 adenocarcinomas vs. 12/25 squamous tumors, Fisher's p = 1.0000). Median OS for recurrent/metastatic adenocarcinoma was 35.5 months (95%, 23.6-50.3) vs. 17.9 months for squamous (95%, 12.7-37.0, log-rank test, p = 0.0165). OS was not significantly different by HA quartiles, high or low (<25) HA score and tumor histology, and HA biopsy site (all p > 0.05). Median TTP (n = 98) significantly differed by HA quartile (2.8 months for HA score ≤10; 5.0 months for 11-20; 7.9 months for 21-30; 3.9 months for >30, p = 0.0265). Improved TTP trended in HA-high over HA-low tumors (n = 98, p = 0.0911).

Conclusion

In this NSCLC cohort, tumor HA level represents a potential biomarker for TTP, which remains a cornerstone of NSCLC therapy. Further validation is warranted to identify the HA accumulation threshold associated with clinical benefit.

In this phase I dose-escalation trial, we assess the maximum tolerated dose (MTD) of Bermekimab in combination with Nanoliposomal Irinotecan (Nal-Iri) and 5-Fluorouracil/Folinic Acid (5-FU/FA). Secondarily, we investigate effects on weight, lean body mass, quality-of-life, the gut microbiome composition, inflammatory biomarkers, progression-free survival, and overall survival. This was a single-arm, open-label adaptive Bayesian dose-escalation study of Bermekimab combined with Nal-Iri and 5FU/FA in patients with advanced or locally advanced PDAC who failed gemcitabine-based chemotherapy. 22 patients enrolled between 2017 and 2019. 3 of 21 patients experienced dose-limiting toxicities attributable to the chemotherapy backbone. 58% (10/17) of patients exhibited weight stability. Physical performance status was preserved among all subjects. Patients reported improvements in quality-of-life metrics via QLQ-PAN26 questioner (-3.6, p = 0.18) and functional well-being (1.78, p = 0.02). Subjects exhibited a decrease in inflammatory cytokines, notably, vascular endothelial growth factor (-0.86, p = 0.017) with Bermekimab. Bermekimab treatment was associated with an increased abundance of gut health-promoting bacterial genera Akkermansia, with 3.82 Log2-fold change from baseline. In sum, Bermekimab is safe to be used in conjunction with Nal-Iri and 5-FU/FA chemotherapy. This benign toxicological profile warrants further Phase I/II investigation of Bermekimab in combinatorial strategies, and the impact of anti-IL-1α antibodies on the gut microbiome.Clinical trials registration: NCT03207724 05/07/2017.