Introduction

Irinotecan is a useful anticancer drug for colorectal cancer treatment. UGT1A1*28 and *6 gene polymorphisms are known risk factors for irinotecan-associated toxicity. However, severe adverse effects due to irinotecan have been observed even in patients who do not harbor UGT1A1*28 or *6. Moreover, 5-fluorouracil with leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) therapy has been shown to be effective as a triplet chemotherapy for poor prognostic pancreatic cancer, however, a high frequency of severe neutropenia is known.

Aims & Methods

We investigated gene polymorphisms in the whole exome to identify useful biomarkers correlated with the toxicity of a triplet chemotherapy other than UGT1A. A total of 50 patients with pancreatic cancer and 33 patients with metastatic colorectal cancer (mCRC) were treated with modified FOLFIRINOX (mFOLFIRINOX), and FOLFOXIRI, respectively. Genome-wide screening was performed using whole-exome sequencing (WES), and validation analysis was performed using qPCR with a hydrolysis probe. Screening analysis using genotype data from WES was performed using the Cochran–Armitage trend test (P <0.01) and standardized difference (>1.6). The Cochran–Armitage trend test was used to examine the linearity of the relationship between each genotype and irinotecan toxicity. Logistic regression analysis was used to analyze gene polymorphisms and toxicity in univariate and multivariate analyses.

Results

Among 50 patients treated with mFOLFIRINOX therapy, 26 patients (52%) showed neutropenia; 14 patients were grade 3 and 12 patients were grade 4. Using WES after a triplet chemotherapy regimen (6 control vs 6 test), five single nucleotide polymorphisms (SNPs) were identified as candidate biomarkers for neutropenia (>grade 3) as the toxicity or mFOLFIRINOX. Among the five SNPs, SNPs in NFATC1, SLC14A1, and HAUS8 showed significant association or associated tendency with neutropenia (>grade 3) after triplet chemotherapy (P = 0.004, 0.007, and 0.074, respectively). In multivariate analysis using age, sex, and three genotypes of above-mentioned genes, NFATC1 (OR = 3.03, 95% CI; 1.19–7.7, P = 0.020) and SLC14A1 (OR = 2.59, 95% CI; 1.08–6.22, P = 0.034) were identified as independent risk factors for susceptibility to the toxicity. Combination of the genotypes of NFATC1 and SLC14A1 showed discriminating performance in the occurrence of neutropenia (> grade 3) after the triplet chemotherapy (OR = 2.79, 95% CI; 1.48–5.25, P = 0.002; AUC of 0.778, sensitivity of 73.1%, and specificity of 70.8%). In 90.9% (10 of 11) of patients harboring either or both the NFATC1 or SLC14A1 homologous variant allele suffered from grade 3 or higher neutropenia. Interestingly, an SNP in SLC14A1 also showed a linear trend between polymorphism and efficacy of mFOLFIRINOX treatment (P = 0.0198), and odds ratio of 3.23 (P = 0.0294). Patients receiving a triplet chemotherapy, FOLFOXIRI, for mCRC showed significant linear trends between HAUS8 polymorphism and grade 4 neutropenia (P = 0.0496), although other SNPs were not showed the significant association.

Conclusion

The combination of biomarker SNPs in the NFTC1 and SLC14A1 genes may be a useful predictor for the toxicity of triplet chemotherapy for pancreatic cancer.

Introduction

First-line FOLFIRINOX or gemcitabine plus nab-paclitaxel (GNP) have improved the survival outcomes of patients with advanced pancreatic cancer (APC) and nano-liposomal irinotecan (nal-IRI) plus 5-FU/leucovorin is proven as the second-line agents.

Aims & Methods

The current study aims to assess the efficacy of third-line palliative chemotherapy in APC.
Medical records were retrospectively reviewed in a single tertiary hospital between 2012 and 2021. We enrolled patients with APC who experienced progression after the second-line chemotherapy following the first-line FOLFIRINOX or GNP. To define the efficacy of the third-line chemotherapy, Cox-regression analysis was performed. To identify the clinical factors affecting the survival, multivariable logistic regression analysis was also performed.

Results

Total 141 patients were enrolled. The median age at diagnosis was 61.8 years (range 36.0 – 86.0), and males were 54.9% (n=78). The first-line chemotherapy regimen was FOLFIRINOX (95, 67.4%) and GNP (46, 32.6%). The second-line chemotherapy regimen was FOLFIRINOX (38, 27.0%), GNP (74, 52.5%), and others (29, 20.4%). Regarding the third-line regimen, TS-1 and nal-IRI plus 5-FU/leucovorin were 69 (27.0%) and 53 (37.6%). The median overall survival (OS) from diagnosis was 18.0 months (95% confidence interval (CI), 15.3 – 20.7). The median OS and median progression-free survival after the third-line treatment were 14.6 (95% CI, 12.1 – 17.0) and 7.3 weeks (95% CI, 6.3– 8.3). About the best tumor response during the third-line chemotherapy, there was no complete response, 2 (1.4%) with a partial response, 41 (29.1%) with stable disease, and 80 (56.7%) with progressive disease. Consequently, the disease control rate in the third-line treatment was 30.5%. Of the patients with the third-line chemotherapy, the following clinical factors affected OS; ECOG of 2 at third-line chemotherapy (HR: 2.64, 95% CI: 1.58-4.42; p <0.001), serum CA19-9 level ≥ 1,000 U/ml before the third-line chemotherapy (HR: 1.67, 95% CI: 1.11-2.52; p=0.014), duration of the second-line chemotherapy < 19 weeks (HR: 1.51, 95% CI: 1.03-2.21; p=0.034), and peritoneal seeding before the third-line chemotherapy (HR: 1.53, 95% CI: 1.03-2.25; p=0.033).

Conclusion

The current study suggested that proceeding with the third-line chemotherapy could be recommended in some patients. There is no difference in survival rate according to the type of the third-line chemotherapy regimen. ECOG 0 or 1, CA 19-9 <1,000U/ml, duration of second-line chemotherapy ≥ 19 weeks, and no peritoneal seeding showed significantly more benefit from the third-line therapy.

References

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2. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369(18): 1691-1703
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Introduction

Patients with new onset diabetes (NODM) have a higher risk of pancreatic cancer (PAC) development. We aimed to (1) compare the incidence of PAC among NODM and non-DM patients and (2) develop a risk prediction model for incident PAC within 1 year after diagnosis of DM.

Aims & Methods

We included adult patients who were newly diagnosed with type 2 DM (i.e. NODM group) or had any clinical consultation without a diagnosis of DM (i.e. non-DM group) between 2008 and 2015 from a territory-wide electronic healthcare database in Asia. Patients with type 1 DM or prior history of PAC were excluded. Each patient was followed from the diagnosis date of DM (or first consultation in non-DM group) till PAC development, death or 1 year. The incidence rate of PAC was calculated under Poisson distribution and compared between NODM and non-DM groups. The NODM cohort with complete data was further randomly split in a ratio of 7:3 into a training set (to develop the prediction model) and a validation set, respectively. Logistic regression with forward stepwise selection was conducted to identify the potential predictors of PAC. Model performance against the validation set was assessed by the area under receiver operating characteristic curve (AUC).

Results

Among 4,002,826 patients identified, 261,046 (6.5%) of whom had NODM. The incidence of PAC at 1 year was 11.68 per 10,000 persons (95% CI: 10.41-13.07) for NODM group and 1.82 per 10,000 persons (95% CI: 1.68-1.96) for non-DM group, with an incidence rate ratio of 6.43 (95% CI: 5.60-7.37). To develop a prediction model for PAC at 1 year, 19,210 NODM patients (28 PAC cases) were included, of whom 13,447 (18 PAC cases) were in the training set and 5,763 (10 PAC cases) in the validation set. After forward stepwise selection, the final prediction model included age, baseline body mass index (BMI), BMI change in 1 year, baseline blood glucose, prescription of anti-diabetic medications (oral drugs or insulin) and high-density lipoprotein cholesterol (HDL-C) change in previous 1 year. NODM patients who were older (OR: 1.06, 95% CI: 1.01, 1.11), had higher baseline blood glucose (OR: 1.01, 95% CI: 1.00, 1.01), were prescribed anti-diabetic medications at baseline (OR: 3.40, 95% CI: 1.92, 9.70), had larger drop in BMI (OR: 1.24, 95% CI: 1.05, 1.45) and HDL-C (OR: 3.28, 95% CI: 1.33, 8.09) in previous year were more likely to be diagnosed with PAC (Table 1). Using the validation set, the model showed an AUC of 0.89 (95% CI:0.81-0.96) with a sensitivity of 90.0% and specificity of 72.3%. The number-needed-to-screen (NNS) to identify one PAC case among all NODM and high-risk NODM patients was 763 and 234, respectively.
Table 1: The final model for 1-year risk prediction of pancreatic cancer using logistic regression with forward stepwise.

Conclusion

Patients with NODM had 6.4-times higher risk of developing PAC within 1 year than patients without DM, and our new prediction model may help to identify high risk patients.

Introduction

Although TNM staging is a well-established system, improvements to guide individualized patient care, especially in regards to immunotherapy, are sought. Recent studies pointed out tertiary lymphoid structures (TLS) to be a predictive biomarker for response to immunotherapy in many solid tumors; however, its role in pancreatic cancer (PCa) is still unknown. Our aim was to develop and validate a standardized scoring system for the quantification of TLS in PCa.

Aims & Methods

For validation purposes we analyzed the presence of TLS in a total of 114 patients with PCa from our institution (M-Cohort) and 151 patients from the publicly available TCGA database. Multiplex immunofluorescence was used to quantify the expression of the classical TLS-morphology markers (CD3, CD20, PanCK, Ki67, PGP9.5 and PNAd) in 52 PCa patients in which TLS were analyzed using our newly developed HE-based TLS-classification. Differential gene expression in patients with high numbers of late-stage TLS was analyzed using bulk RNA sequencing in fresh frozen PCa samples (n=24).

Results

TLS maturation stages are characterized based on morphological criteria: (i) round dense lymphocytic aggregation and (ii) sharp delineation edges for early TLS (E-TLS); primary follicular TLS (PF-TLS) present in addition high endothelial venules and/or a nerve in the immediate vicinity. Secondary follicular TLS (SF-TLS) contain B-cell follicles with actively replicating B-cell germinal centers (GCs) surrounded by a T-cell region. SF-TLS were present in 41% of primary resected patients and correlated with improved survival (M-Cohort: 22 vs. 10 months, p=0,001; TCGA Cohort: 19 vs 10 months, p=0,043). In the tumor microenvironment, the presence of late-stage TLS correlated with increased numbers of B cells and massively reduced amounts of M2 macrophages. Lastly, bulk RNA-seq analysis of PCa samples demonstrated an upregulation of antigen presentation and pathways related to immune responses in patients with high numbers of SF-TLS in the tumor microenvironment.

Conclusion

Late-stage TLS are associated with prolonged survival in PCa patients and might serve as a potential predictor for immune activity within the pancreatic tumor microenvironment. TLS scoring is an emerging prognostic marker to be considered for prospective inclusion in the TNM classification, especially after immunotherapy.