Comparative molecular profiling of pancreatic ductal adenocarcinoma of the head versus body/tail reveals differences in the tumor immune microenvironment (TIME)

doi:10.21203/rs.3.rs-3317962/v1

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Comparative molecular profiling of pancreatic ductal adenocarcinoma of the head versus body/tail reveals differences in the tumor immune microenvironment (TIME)

https://doi.org/10.21203/rs.3.rs-3317962/v1

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published 06 Apr, 2024

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Background

Pancreatic ductal adenocarcinoma (PDAC) of the head (H) and body/tail (B/T) differ in embryonic origin, cell composition, blood supply, lymphatic and venous drainage, and innervation. We aimed to compare the molecular and tumor immune microenvironment (TIME) profiles of PDAC of the H vs. B/T.

Methods

A total of 3499 PDAC samples were analyzed via next-generation sequencing (NGS) of RNA (whole transcriptome, NovaSeq), DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing), and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Significance was determined as p values adjusted for multiple corrections (q) of < 0.05.

Results

Anatomic subsites of PDAC tumors were grouped by primary tumor sites into H (N = 2058) or B/T (N = 1384). There were significantly more metastatic tumors profiled from B/T vs. H (57% vs. 44%, p < 0.001). KRAS mutations (93.8% vs. 90.2%), genomic loss of heterozygosity (12.7% vs. 9.1%), and several copy number alterations (FGF3, FGF4, FGF19, CCND1, ZNF703, FLT4, MUTYH, TNFRS14) trended higher in B/T when compared to H (p < 0.05 but q > 0.05). Expression analysis of IO-related genes showed significantly higher expression of CTLA4 and PDCD1 in H (q < 0.05, fold change 1.2 and 1.3) and IDO1 and PDCD1LG2 expression trended higher in B/T (p < 0.05, fold change 0.95).

Conclusions

To our knowledge, this is one of the largest cohorts of PDAC tumors subjected to broad molecular profiling. Differences in IO-related gene expression and TIME cell distribution suggest that response to IO therapies may differ in PDAC arising from H vs B/T. Subtle differences in the genomic profiles of H vs. B/T tumors were observed.

Health sciences/Oncology/Cancer/Gastrointestinal cancer/Pancreatic cancer

Health sciences/Oncology/Surgical oncology

Pancreatic ductal adenocarcinoma (PDAC) is aggressive cancer whose occurrence has increased dramatically over the last decade, and it represents the seventh greatest cause of cancer mortality in males and females globally. In addition, the ratio of PDAC death to incidence is around 0.94, putting it at the top among all malignancies (1, 2). PDAC is a serious public health concern globally, with an increasing incidence and prevalence (3). The mortality rate of PDAC is the highest among all malignancies, and by 2030, it is expected to be the third greatest cause of cancer-related deaths worldwide and the second leading cause of cancer-related mortality in the US (4, 5). Despite all medical advancements, the 5-year survival rate of 10% has remained unchanged for the last 50 years (2). The lack of any noticeable early symptoms and the paucity of dependable and efficient screening and early detection tools renders the majority of patients diagnosed in unresectable stages with poor outcomes (6, 7).

PDAC relapse is observed in the majority of patients, and various studies have been conducted to assess PDAC prognosis, which may aid in its management. Well-known prognostic variables for PDAC include tumor size and histological features (8, 9). In addition to age, gender, pathological staging, serum cancer antigen 19 − 9 (CA19-9) level and associated genomic mutations have been suggested as important prognostic variables for PDAC in recent research (10, 11). The pancreas is also separated into various anatomic regions, the uncinate process, the head, the body, and the tail. Given these anatomical variations, a protracted discussion has been launched to determine if the site of PDAC may influence the development of the tumor (12, 13). Numerous studies have shown significant variations in the prognosis of pancreatic tumors localized in the head versus those found in the body and tail (B/T). Tumors of the head and uncinate process are often accompanied by jaundice and are thus believed to manifest sooner in the disease's progression. However, B/T pancreatic cancers often manifest with weight loss and discomfort, signs more consistent with advanced disease (14). Although variations in prognosis have mostly been attributable to the late presentation of the B/T compared to PDAC of the head tumors, earlier studies indicate that the tumor, lymph nodes, and metastasis TNM stage at presentation is not substantially different between the two tumor sites (15).

The postoperative survival of PDAC situated in the B/T appeared to be superior to that of PDAC positioned in the H [20]. However, these findings are not universal, as various research revealed that survival rates are comparable for B/T and H tumors (13, 16–18). Furthermore, The SEER data (Surveillance, Epidemiology, and End Results Program of the National Cancer Institute) revealed poorer outcomes and increased mortality and morbidity in patients with a tumor located in the B/T than in PDAC of the H (19).

The tumor immune microenvironment (TIME) profiles of PDAC are differently dysregulated depending on the tumor site. It appears that B/T tumors are highly proliferative compared to PDCA of the H (20). In addition, B/T tumors had been shown to be more aggressive with a higher invasion and desmoplasia and a relatively poorer response to tumor immunotherapy (21). Further analysis revealed a higher density of calcium-binding protein S100A2 mRNA transcripts in B/T tumors compared to a higher B cell signaling in PDAC of the H, which has been linked with favorable outcomes (20, 22). Our study aims to compare the molecular and tumor immune microenvironment (TIME) profiles of PDAC of the H vs. B/T.

Patient cohort

PDAC tumors were submitted to Caris Life Sciences (Phoenix, AZ). Tumors were then categorized according to primary tumor sites; H of the pancreas or B/T of the pancreas for analysis. This study was conducted in accordance with the guidelines of the Declaration of Helsinki, the Belmont report, and the U.S. Common rule. In keeping with 45 CFR 46.101(b)(4), this study was performed utilizing retrospective, de-identified clinical data. Therefore, this study is considered IRB exempt and no patient consent was necessary from the subject.

Next-Generation Sequencing (NGS)

Next-generation sequencing (NGS) (Illumina Next Seq, 592 genes) was performed on genomic DNA isolated from Formalin-Fixed Paraffin-Embedded FFPE samples. All variants were detected with > 99% confidence based on allele frequency and amplicon coverage, with an average sequencing depth of coverage of > 500 and an analytic sensitivity of 5%. Prior to molecular testing, tumor enrichment was achieved by harvesting targeted tissue using manual microdissection techniques. The genetic variants identified were interpreted by board-certified molecular geneticists and categorized as ‘pathogenic’, ‘presumed pathogenic’, ‘variant of unknown significance’, ‘presumed benign’, or ‘benign’, according to the American College of Medical Genetics and Genomics (ACMG) standards. When assessing mutation frequencies of individual genes, ‘pathogenic’ and ‘presumed pathogenic’ were counted as mutations while ‘benign’, ‘presumed benign’ variants, and ‘variants of unknown significance’ were excluded.

TMB

TMB was measured by counting all non-synonymous missense, nonsense, in frame insertion/deletion, and frameshift mutations found per tumor that had not been previously described as germline alterations in dbSNP151, Genome Aggregation Database (gnomAD) databases or benign variants identified by Caris’s geneticists. A cutoff point of ≥ 10 mutations per MB was used based on the KEYNOTE-158 pembrolizumab trial (Mirabelle et al., ESMO 2019), which showed that patients with a TMB of ≥ 10 mt/MB across several tumor types had higher response rates than patients with a TMB of < 10 mt/MB. Caris Life Sciences is a participant in the Friends of Cancer Research TMB Harmonization Project (Merino et al., 2020).

mRNA expression (WTS)

Tumors underwent RNA sequencing using full formalin-fixed paraffin-embedded (FFPE) specimens that were reviewed by a board-certified pathologist to measure percent tumor content and tumor size; a minimum of 20% of tumor content in the area for microdissection was required to enable enrichment and extraction of tumor-specific RNA. A Qiagen RNA FFPE tissue extraction kit was used for extraction, and the RNA quality and quantity were determined using the Agilent TapeStation. Biotinylated RNA baits were hybridized to the synthesized and purified cDNA targets and the bait-target complexes were amplified in a post-capture PCR reaction. The Illumina NovaSeq 6500 was used to sequence the whole transcriptome from patients to an average of 60M reads. Raw data was demultiplexed by Illumina Dragen BioIT accelerator, trimmed, counted, PCR-duplicates removed, and aligned to the human reference genome hg19 by STAR aligner. For transcription counting, transcripts per million molecules were generated using the Salmon expression pipeline. Human All Exon V7 bait panel (Agilent Technologies, Santa Clara, CA) was prepared. Immune cell fraction was calculated by QuantiSeq using this transcriptomic data (Finotello et al. Genom Med 2019). Additionally, this mRNA data was used as input for pathway gene enrichment analyses using Gene Set Enrichment Analysis (GSEA, Subramaniam 2015, PNAS).

Data and statistical analysis

The prevalence of molecular alterations among cohorts were analyzed using Chi-square or Fisher Exact tests. Expression distribution among cohorts were analyzed using non-parametric Kruskal-Wallis’s testing. Similarly, tumor microenvironment cell fractions were analyzed as described previously. A value of < 0.05 was considered a trending difference; p values were further corrected for multiple comparisons using the Benjamini-Hochberg method to avoid type I error and an adjusted p-value (i.e., q value) of < 0.05 was considered a significant difference.

Outcomes analysis

Real-world overall survival (rwOS) information was obtained from insurance claims data and calculated from the time of tissue collection to the last contact or treatment time to last treatment time (TOT). Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Significance was determined as p values < 0.05.

We included a total of 3499 PDAC in the analysis. These cases were grouped anatomically by primary tumor sites into H (N = 2058) or B/T (N = 1384). Neck (N = 57) tumors were reported as a separate pancreatic anatomical subtype and not included in the comparative analysis. The median age for H tumors was (67) years old compared to (68) in B/T. There were significantly more metastatic tumors profiled from B/T compared to H (57% vs. 44%, p < 0.001) (Fig. 1). Table 1 summarizes the demographics based on the anatomical subdivisions of PDAC.

In our analysis, molecular alterations varied among B/T tumors and H tumors. For instance, KRAS mutations trended more prevalent in B/T vs. H tumors (93.8% vs. 90.2%). Other trends included genomic loss of heterozygosity (by whole exome sequencing) (12.7% vs. 9.1%), and several copy number alterations (FGF3 (2.2% vs 1.1%), FGF4 (1.5% vs 0.6%), FGF19 (1.7% vs 0.9%), CCND1 (2.0% vs 0.8%), ZNF703 (2.8% vs 0.8%), FLT4 (1.1% vs 0.4%), MUTYH (2.4% vs 1.0%) and TNFRS14 (1.0% vs 0.4%)) (all p < 0.05 but q > 0.05). In contrast, GNAS mutations (2.2% vs. 0.7%) trended higher in H vs. B/T (Fig. 2).

Immuno-oncology (IO) markers, including TMB, PD-L1, and MSI-H showed no significant difference between B/T vs. H(Fig. 3), however, expression analysis of IO-related genes showed significantly higher expression of CTLA4 and PDCD1 in H (q < 0.05, fold change 1.2 and 1.3), compared to a higher expression of IDO1 and PDCD1LG2 in B/T (p < 0.05, fold change 0.95) shown in (Fig. 4).

In order to evaluate the TIME, median cell abundance values were compared using QuantiSeq. Our analysis revealed that H tumors had increased immune infiltration of B cells (0.045 vs. 0.043), M2 macrophages (0.035 vs. 0.032), neutrophils (0.056 vs. 0.052), NK cells (0.027 vs. 0.026), CD8 + T cells (%>0: 48.2% vs. 43.2%), while B/T had increased infiltration of M1 macrophages (0.035 vs. 0.032) (all q < 0.05) (Fig. 5). Pathway enrichment analysis using GESA showed that the CTLA4 pathway (Biocarta; normalized enrichment score (NES) 1.6, false discovery rate (FDR) 0.19) and primary immunodeficiency pathway (Kegg; NES 1.7, FDR 0.11) were significantly enriched in H compared to B/T (Fig. 6).

Comparison of survival between H and B/T tumors showed that pancreatic H tumors had a prognostic advantage when compared to B/T (HR of 1.20; 95% CI 1.03–1.39, p = 0.014) (Fig. 7).

Table 1. Demographics

This retrospective study was designed to compare H and B/T in terms of comparing the molecular and TIME profiles. Patients with B/T were more likely to present at later stages and were less likely to undergo resection (23, 24).

Several population-based studies (24–28) conveyed variations in survival for both B/T and H with a mildly better observed survival in the early stages of those reported with B/T. According to Winer et al. (26) H patients who underwent early tumor resection were more likely to have higher-grade tumors with worse overall survival (OS) and higher numbers of positive lymph nodes. The improved survival of B/T population observed in that study is supported by a single-center study (29) which examined survival in matched stage II B/T and H. Only one single-center study (30) reported worse outcomes for B/T patients with non-statistically significant improved survival in stage I disease. Despite similar survival outcomes for both location types, our study observed differences in gene expression and TIME cell distribution that may differ in H vs B/T outcomes.

Consistent with previous reports (23, 31), the most common mutations in our study were KRAS mutations that were more prevalent in B/T vs. H tumors (93.8% vs. 90.2%). Though, a more recent study found that only TP53 mutations were significantly higher in B/T as well as the different clinical presentations. Moreover, the molecular profiles emphasized that the H and B/T are different tumors in addition to having differentiating OS, molecular profiles, and response to treatments (32). However, our study showed genomic loss of heterozygosity and numerous alterations (FGF3, FGF4, FGF19, CCND1, ZNF703, FLT4, MUTYH, TNFRS14) that were higher in B/T when compared to H (p < 0.05 but q > 0.05). In contrast, GNAS mutations (2.2% vs. 0.7%) were higher in H vs. B/T. Though there was a past study by Wu et al (33) that demonstrated pathways in papillary mucinous neoplasm (IPMN) and GNAS mutation in identifying adenocarcinoma in pancreatic cysts there is literature differentiating predicating tumor mutations of the H vs the B/T. Additionally, regarding the study of Sun et al., the total number of SMAD mutations was 12.12% rendering elevated SMAD mutations in H (15.5%) compared to B/T(5%) statistically insignificant because biopsy specimens or peripheral blood (66.7%) made up the majority of tissue samples and this may have lowered the detection of certain mutations.

In this study, expression analysis of IO-related genes showed significantly higher expression of CTLA-4 and PDCD1 in H (q < 0.05, fold change 1.2 and 1.3), compared to a higher expression of IDO1 and PDCD1LG2 in B/T (p < 0.05, fold change 0.95). These findings indicate that the response to IO treatments might be varied in PDAC originating from H vs B/T. The results of our study are also consistent with the previous study by Sun et al. that reported a different treatment response that was explained by greater TP53 mutations in B/T, indicating that gemcitabine-based adjuvant therapy should be considered in treating B/T pancreatic cancer. TP53 mutation is commonly seen in pancreatic squamous cell cancer (22). TP53 positively predicted sensitivity to gemcitabine-based adjuvant therapy in survival and mutational analysis from the CONKOO-001 study (31).

Given the potential impact of tumor location on pancreatic cancer prognosis, more studies to determine the broader molecular profiling aimed to directly compare the TIME profiles of pancreatic cancer H versus B/T microenvironments are essential for establishing improved treatment regimens. Our study demonstrated differences in immune-oncology related gene expression and TIME cell distribution suggesting that response to immunotherapies may differ in pancreatic cancer arising from the pancreatic H versus the pancreatic B/T (34). Moreover, subtle differences in the genomic profiles of pancreatic H versus B/T tumors were also observed in this study, might play a crucial role in supporting overall response regarding the interventions of coupling chemo/immunotherapy, specifically PD-1 and CTLA-4 inhibitors as well as improve the OS of PDAC. The biological criteria that established pancreatic H adenocarcinoma as a specific patient population might lead to improvements in the overall response to study immunotherapies interventions as well as giving us more accurate data on the pancreatic H adenocarcinoma responses to immunotherapies.

To our knowledge, our study is the largest cohort of PDAC tumors subjected to broad molecular profiling. Both H and B/T had differences in IO-related gene expression and TIME cell distribution suggesting that response to IO therapies may differ in PDAC arising from H vs B/T. Subtle differences in the genomic profiles of H vs. B/T tumors were also observed.

Based to our knowledge, this is one of the largest cohorts of PDAC tumors that has undergone extensive molecular profiling. Differences in IO-related gene expression and TIME cell distribution imply that PDAC resulting from the H vs. B/T may respond differently to IO therapies. The genomic profiles of H vs. B/T pancreatic tumors showed slight variations as well.

Data Availability Statement: The data of this study that supports our results are available on request from the corresponding author, Benjamin A. Weinberg, MD.

Conflicts of Interest: Yasmine Baca, MS, MB, and Joanne Xiu, Ph.D. are workers at Caris Life Sciences, Phoenix, AZ. All other authors have declared that there are no financial conflicts of interest concerning this work.

Author Contributions

Conceptualization Maen A, Abdullah E, Benjamin A. W. and Anup K; Resources Maen A, Abdullah E, Benjamin A. W. Anup K and Nestor F. E ; Data curation Maen A, Abdullah E, Benjamin A. W. Anup K, Nestor F. E,Joanne X, Yasmine B ; Software Joanne X, and Yasmine B ; Formal analysis Supervision Maen A, Abdullah E, Benjamin A. W. and Anup K, Validation Maen A, Abdullah E, Benjamin A. W. Anup K, Nestor F. E,Joanne X, Yasmine B; Investigation and Visualization Maen A, Abdullah E, Benjamin A. W. Anup K, Nestor F. E,Joanne X and Yasmine B; Writing-original draft Abdullah E and Maen A; Project administration Joanne X, and Yasmine B; Writing-review and editing Maen A, Abdullah E, Benjamin A. W. Anup K, Nestor F. E, Joanne X, and Yasmine B.

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Comparative molecular profiling of pancreatic ductal adenocarcinoma of the head versus body/tail reveals differences in the tumor immune microenvironment (TIME)

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Next-Generation Sequencing (NGS)

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mRNA expression (WTS)

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