Faculty Bibliography

BACKGROUND:The existence of sociodemographic disparities in pancreatic cancer has been well-studied but how these disparities have changed over time is unclear. The purpose of this study was to longitudinally assess patient management in the context of sociodemographic factors to identify persisting disparities in pancreatic cancer care. METHODS:Using the National Cancer Database, patients diagnosed with pancreatic ductal adenocarcinoma from 2010 to 2017 were identified. The primary outcomes were surgical resection and/or receipt of chemotherapy. Outcome measures included changes in associations between sociodemographic factors (i.e., sex, age, race, comorbidity index, SES, and insurance type) and treatment-related factors (i.e., clinical stage at diagnosis, surgical resection, and receipt of chemotherapy). For each year, associations were assessed via univariate and multivariate analyses. RESULTS:Of 75,801 studied patients, the majority were female (51%), White (83%), and had government insurance (65%). Older age (range of OR 2010-2017 [range-OR]:0.19-0.29), Black race (range-OR: 0.61-0.78), lower SES (range-OR: 0.52-0.94), and uninsured status (range-OR: 0.46-0.71) were associated with lower odds of surgical resection (all p < 0.005), with minimal fluctuations over the study period. Older age (range-OR: 0.11-0.84), lower SES (range-OR: 0.41-0.63), and uninsured status (range-OR: 0.38-0.61) were associated with largely stable lower odds of receiving chemotherapy (all p < 0.005). CONCLUSIONS:Throughout the study period, age, SES, and insurance type were associated with stable lower odds for both surgery and chemotherapy. Black patients exhibited stable lower odds of resection underscoring the continued importance of mitigating racial disparities in surgery. Investigation of mechanisms driving sociodemographic disparities are needed to promote equitable care.

BACKGROUND/OBJECTIVES/OBJECTIVE:Overall survival for patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) remains limited, with a median survival of 12 to 15 months. Irreversible electroporation (IRE) is a local tumor ablation method that induces cancerous cell death by disrupting cell membrane homeostasis. The DIRECT Registry study was designed to assess the effectiveness and safety of IRE when combined with standard of care (SOC) treatment for Stage 3 PDAC versus SOC alone in a real-world setting after at least 3 months of induction chemotherapy; Methods: Patients with Stage 3 PDAC treated with IRE plus SOC or SOC alone were prospectively enrolled in a multicenter registry study. Enrollment required 3 months of active multi-agent chemotherapy with no progression before enrollment. Endpoints were 30- and 90-day mortality and adverse events (AEs). RESULTS:= 0.0066). All IRE procedures were performed using an open approach. The 90-day all-cause mortality was 5/83 (6.0%) and 2/27 (7.4%) for the IRE and SOC groups, respectively. Two subjects in the IRE group died from treatment-related complications, and one patient in the SOC group died due to chemotherapy-related complications. CONCLUSIONS:Initial results from the DIRECT registry study indicate the use of IRE for curative intent tumor ablation in combination with induction chemotherapy has equivalent morbidity and mortality rates when compared to standard-of-care chemotherapy alone.

OBJECTIVE:To analyze postrecurrence progression in the context of recurrence sites and assess implications for postrecurrence treatment. BACKGROUND:Most patients with resected pancreatic ductal adenocarcinoma (PDAC) recur within 2 years. Different survival outcomes for location-specific patterns of recurrence are reported, highlighting their prognostic value. However, a lack of understanding of postrecurrence progression and survival remains. METHODS:This retrospective analysis included surgically treated patients with PDAC at NYU Langone Health (2010-2021). Sites of recurrence were identified at the time of diagnosis and further follow-up. Kaplan-Meier curves, log-rank test, and Cox regression analyses were applied to assess survival outcomes. RESULTS:Recurrence occurred in 57.3% (196/342) patients with a median time to recurrence of 11.3 months (95% CI: 12.6-16.5). The first site of recurrence was local in 43.9% of patients, liver in 23.5%, peritoneal in 8.7%, lung in 3.6%, whereas 20.4% had multiple sites of recurrence. Progression to secondary sites was observed in 11.7%. Only lung involvement was associated with significantly longer survival after recurrence compared with other sites (16.9 vs 8.49 months, P = 0.003). In local recurrence, 21 (33.3%) patients were alive after 1 year without progression to secondary sites. This was associated with a CA19-9 of <100 U/mL at the time of primary diagnosis ( P = 0.039), nodal negative disease ( P = 0.023), and well-moderate differentiation ( P = 0.042) compared with patients with progression. CONCLUSION/CONCLUSIONS:Except for lung recurrence, postrecurrence survival after PDAC resection is associated with poor survival. A subset of patients with local-only recurrence do not quickly succumb to systemic spread. This is associated with markers for favorable tumor biology, making them candidates for potential curative re-resections when feasible.

BACKGROUND:Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced cohorts of CheckMate 040 are presented here. PATIENTS AND METHODS/METHODS:Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator per RECIST version 1.1 (dose expansion). RESULTS:Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR per BICR was 20% (95% CI 12-30) and 14% (95% CI 9-21) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6) and 15.1 months (95% CI 13.0-18.2) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced group; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% in the sorafenib-naive and sorafenib-experienced patients, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year. CONCLUSION/CONCLUSIONS:With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that harbors mutations in homologous recombination-repair (HR-repair) proteins in 20%-25% of cases. Defects in HR impart a specific vulnerability to poly ADP ribose polymerase inhibitors and platinum-containing chemotherapy in tumor cells. However, not all patients who receive these therapies respond, and many who initially respond ultimately develop resistance. Inactivation of the HR pathway is associated with the overexpression of polymerase theta (Polθ, or POLQ). This key enzyme regulates the microhomology-mediated end-joining (MMEJ) pathway of double-strand break (DSB) repair. Using human and murine HR-deficient PDAC models, we found that POLQ knockdown is synthetically lethal in combination with mutations in HR genes such as BRCA1 and BRCA2 and the DNA damage repair gene ATM. Further, POLQ knockdown enhances cytosolic micronuclei formation and activates signaling of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), leading to enhanced infiltration of activated CD8+ T cells in BRCA2-deficient PDAC tumors in vivo. Overall, POLQ, a key mediator in the MMEJ pathway, is critical for DSB repair in BRCA2-deficient PDAC. Its inhibition represents a synthetic lethal approach to blocking tumor growth while concurrently activating the cGAS-STING signaling pathway to enhance tumor immune infiltration, highlighting what we believe to be a new role for POLQ in the tumor immune environment.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.

Background: Metastatic colorectal (CRC), pancreatic (PANC), and gastroesophageal cancers are the leading causes of GI cancer-related mortality (5-y survival: 15%, 3%, and 5%-6%, respectively) (ACS 2022). HLA LOH is a recurrent mechanism of immune escape observed in 15%-20% of GI cancers (Hecht R., ASCO GI 2022). The Tmod platform is a logic-gated chimeric antigen receptor (CAR) T-cell modular system, comprising a carcinoembryonic antigen (CEA)- or mesothelin (MSLN)-targeting CAR activator and a separate HLA-A*02-targeting blocker receptor. Both in vitro/in vivo, Tmod CAR T therapy kills cells with HLA-A*02 LOH (tumor) without harming cells with retained HLA-A*02 expression (normal). However, HLA-A*02 LOH can only be therapeutically exploited if patients are identifiable through a feasible and timely clinical workflow.
Method(s): We established a biobanking protocol (BASECAMP-1, NCT04981119) to determine whether HLA-A*02 LOH patients can be prospectively identified. Patients with CRC, PANC, or non-small cell lung cancer (NSCLC), and a high risk for incurable relapse, were screened first using a standard HLA assay. Heterozygous HLAA* 02 positive tumor samples were then assessed for LOH using a bioinformatic algorithm applied via the Tempus xT platform.
Result(s): As of Sep 1, 2022, 83 patients were consented at 4 institutions. HLA status was obtained from 70 patients and 28 were identified as HLA-A*02:01 heterozygous (40%; expected frequency based on USA NMDP data, 27.6%). LOH results were available for 16 patients; 4 LOH-positive patients were identified (25%, 2 PANC, 2 NSCLC). The LOH assay sensitivity declines below a tumor purity of 40% (Hecht R., ASCO GI 2022). Six patients had a tumor purity of 20% (all with PANC, a tumor known for high stromal content), limiting possible LOH detection. The impact of tumor purity on LOH sensitivity was highlighted in a patient with a low initial sample tumor purity (30%) that resulted in a 41% probability of HLA-A*02:01 LOH (below positive threshold). A second sample with a higher tumor purity (70%), obtained from formalin-fixed, paraffin-embedded sections, resulted in a 92% probability of HLA-A*02:01 LOH (positive).
Conclusion(s): BASECAMP-1 prospective identification of HLA-A*02 LOH is feasible in the real-world setting. The frequencies of the HLA-A*02 allele and of HLA-A*02 LOH in this cohort mirrored expected population frequencies. LOH results can be obtained within a clinically feasible workflow and timeframe, although samples with a,40% tumor purity have a reduced sensitivity for LOH detection, an issue recurrently observed in patients with PANC. The BASECAMP-1 strategy enables prospective identification of appropriate patients for future therapeutic clinical trials using Tmod CEA and MSLN logic-gated CAR T cells

Hepato-pancreatico-biliary (HPB) malignancies are difficult-to-treat and continue to to have a high mortality and significant therapeutic resistance to standard therapies. Immune oncology (IO) therapies have demonstrated efficacy in several solid malignancies when combined with chemotherapy, whereas response rates in pancreatic ductal adenocarcinoma (PDA) are poor. While promising in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), there remains an unmet need to fully leverage IO therapies to treat HPB tumors. We therefore defined T cell subsets in the tumor microenvironment of HPB patients utilizing a novel, multiparameter flow cytometry and bioinformatics analysis. Our findings quantify the T cell phenotypic states in relation to checkpoint receptor expression. We demonstrate the presence of CD103⁺ tissue resident memory T cells (T_RM), CCR7⁺ central memory T cells, and CD57⁺ terminally differentiated effector cells across all HPB cancers, while the anti-tumor function was dampened by expression of multiple co-inhibitory checkpoint receptors. Terminally exhausted T cells lacking co-stimulatory receptors were more prevalent in PDA, whereas partially exhausted T cells expressing both co-inhibitory and co-stimulatory receptors were most prevalent in HCC, especially in early stage. HCC patients had significantly higher T_RM with a phenotype that could confer restored activation in response to immune checkpoint therapies. Further, we found a lack of robust alteration in T cell activation state or checkpoint expression in response to chemotherapy in PDA patients. These results support that HCC patients might benefit most from combined checkpoint therapies, whereas efforts other than cytotoxic chemotherapy will likely be necessary to increase overall T cell activation in CCA and PDA for future clinical development.

[This corrects the article DOI: 10.3389/fimmu.2023.1067352.].