Introduction: Preoperative autophagy inhibition with hydroxychloroquine (HCQ) in combination with gemcitabine in pancreatic adenocarcinoma (PDAC) has been shown to be safe and effective in inducing a serum biomarker response and increase resection rates in a previous phase I/II clinical trial. We aimed to analyze the long-term outcomes of preoperative HCQ with gemcitabine for this cohort.
4126 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. Neutropenia is a common side effect of cytotoxic chemotherapy, managed with administration of recombinant granulocyte-colony stimulating factor (G-CSF, Filgrastim). The interleukin 17 – G-CSF – neutrophil extracellular trap (NET) axis promotes oncogenesis and progression of PDAC, inhibiting adaptive immunity. We evaluated the impact of G-CSF administration during neoadjuvant therapy (NAT) on oncologic outcomes in patients with operable pancreatic cancer. Methods: A retrospective review of all patients with localized PDAC treated with NAT prior to pancreatic resection between 2014 – 2020 was completed at a single institution. G-CSF administration, type, and dose were collected from inpatient and outpatient medical records. Results: Of 351 patients treated, 138 (39%) received G-CSF during NAT with a median follow-up of 45.8 months. Patients who received G-CSF were younger (64.0 vs 66.7, p = 0.008), had lower BMI (26.5 vs 27.9, p = 0.021), and were more likely to receive 5-FU based chemotherapy (42% vs 28.2%, p < 0.0001), NAT dose reduction (40.6% vs 25.4%, p = 0.003), or experience febrile neutropenia (8.7% vs 3.3%, p = 0.029). No differences were observed in baseline or pathologic tumor staging. In patients who received G-CSF, 130 (94%) received Pegfilgrastim with a median cumulative dose of 12 mg (IQR 6-12). Patients who received G-CSF were more likely to have an elevated post-NAT neutrophil to lymphocyte ratio (45% vs 29.6%, p = 0.004) and systemic immune-inflammation index (39.5% vs 29.6%, p = 0.061). Receiving G-CSF was an independent predictor of perineural invasion (HR 2.4, 95 CI [1.08, 5.5], p = 0.031) and margin positive resection (HR 1.69, 95 CI [1.01, 2.83], p = 0.043). Patients who received G-CSF had decreased overall survival compared to patients who did not receive G-CSF (median OS: 29.2 vs 38.7 months, p = 0.0001). Receiving G-CSF during NAT was an independent negative predictor of progression free (HR 1.38, 95 CI [1.04, 1.83], p = 0.022) and overall survival (HR 2.02, 95 CI [1.45, 2.79], p < 0.0001). In a subset of patients with available pre- and post-NAT serum specimens (n = 28), G-CSF administration resulted in an increased number of citrullinated histone H3 complexes following NAT (+1378±1502 vs -300.7±1147 pg/ml, p = 0.007), indicative of enhanced peripheral NET formation. Conclusions: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration is associated with worse oncologic outcomes and should be administered with caution. Prospective randomized as well as confirmatory clinical studies are in order.
4143 Background: The prognostic role of the gut microbiome, which modulates cancer development and therapeutic response, is unknown in patients with pancreatic ductal adenocarcinoma (PDAC). With increasing utilization of neoadjuvant therapy (NAT) prior to pancreatic cancer surgery, identification of patient-specific biologic signatures associated with NAT response a priori could help inform PDAC precision medicine. Thus, we assessed the influence of the baseline gut microbiome on clinical outcomes in patients with PDAC receiving NAT. Methods: Stool samples were collected at diagnosis from 42 consenting patients with localized PDAC intending to undergo NAT and surgical resection between 2018 and 2020. 16S rRNA sequencing was completed on pre-NAT stool and resected tumor samples. Microbiota alpha diversity and log transformed taxonomic classifications were utilized in multiple regression analyses to predict oncologic outcomes. Results: Five patients progressed during NAT and eight of the 37 operated patients were deemed NAT responders, demonstrating pathologic near complete or partial response (CAP 0-2), T1N0 AJCC 8th staging, and ≥ 80% CA 19-9 reduction. Compared to the gut, the tumor microbiota demonstrated remarkably reduced Shannon diversity (2.4±0.5 vs 1.5±0.4, p< 0.0001) and distinct taxa (75.2±19.7 vs 8.0±4.5, p< 0.0001) and, accordingly, was not associated with clinical outcomes. Overall, several taxa, including Bacteroides and Akkermansia, were enriched in the gut relative to the tumor ( p< 0.001). The gut microbiota of NAT non-responders had an increased proportion of the gemcitabine metabolizing Enterobacteriaceae (additive log ratio (ALR) -3.4±2.0 vs -8.7±0.8, p= 0.0004). NAT responders, by contrast, had an increased proportion of the adaptive immune cell activating Akkermansia (ALR -0.9±1.2 vs -6.2±3.3, p= 0.0004). The incidence of jaundice or biliary stent placement was associated with relative increases in Enterobacteriaceae (+3.3 ALR, p< 0.01 and +4.9 ALR, p< 0.0001) and decreases in Akkermansia (-3.2 ALR, p= 0.02 and -2.4 ALR, p= 0.057), without altering total gut microbiota diversity. Age, sex, BMI, comorbidities, receipt of pre-NAT antibiotics, diagnostic EUS tumor size, resectability, and pre-NAT CA 19-9 were not predictive of NAT response or survival in a univariate regression model. However, inclusion of gut microbiota data improved the ability of the model to predict NAT response ( p= 0.016, adjusted R2 0.76) and survival ( p= 0.001, adjusted R2 0.89), with Enterobacteriaceae (FDR p= 0.012) and Akkermansia (FDR p= 0.015) being significant negative and positive predictors of NAT response, respectively. Conclusions: The baseline gut microbiota could be leveraged as a biomarker of NAT response and prognosis in patients with pancreatic cancer and warrants further investigation.
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