Faculty Bibliography

OBJECTIVES:There is a need for validated predictive markers of gemcitabine response to guide precision medicine treatment in pancreatic cancer. We previously validated human equilibrative nucleoside transporter 1 as a predictive marker of gemcitabine treatment response using Radiation Therapy Oncology Group 9704. Controversy exists about the predictive value of gemcitabine metabolism pathway biomarkers: deoxycytidine kinase (DCK), ribonucleotide reductase 1 (RRM1), RRM2, and p53R2. METHODS:Radiation Therapy Oncology Group 9704 prospectively randomized 538 patients after pancreatic resection to receive either 5-fluorouracil or gemcitabine. Tumor DCK, RRM1, RRM2, and p53R protein expressions were analyzed using a tissue microarray and immunohistochemistry and correlated with treatment outcome (overall survival and disease-free survival) by unconditional logistic regression analysis. RESULTS:There were 229 patients eligible for analysis from both the 5-fluorouracil and gemcitabine arms. Only RRM2 protein expression, and not DCK, RRM1, or p53R2 protein expression, was associated with survival in the gemcitabine treatment arm. CONCLUSIONS:Despite limited data from other nonrandomized treatment data, our data do not support the predictive value of DCK, RRM1, or p53R2. Efforts should focus on human equilibrative nucleoside transporter 1 and possibly RRM2 as valid predictive markers of the treatment response of gemcitabine in pancreatic cancer.

OBJECTIVES/OBJECTIVE:Pancreatic cysts are a group of lesions with heterogeneous malignant potential. Currently, there are no reliable biomarkers to aid in cyst diagnosis and classification. The objective of this study was to identify potential microRNA (miR) biomarkers in endoscopically acquired pancreatic cyst fluid that could be used to distinguish between benign, premalignant, and malignant cysts. METHODS:A list of candidate miRs was developed using a whole-genome expression array analysis of pancreatic cancer (pancreatic ductal adenocarcinoma) and nonmalignant samples overlapped with existing literature and predicted gene targets. Endoscopically acquired pancreatic cyst fluid samples were obtained from a group of 38 patients who underwent cyst fluid aspiration and surgical resection. Selected miR expression levels in cyst fluid samples were assessed by quantitative real-time-PCR. Additionally, in situ hybridization (ISH) on corresponding cyst tissue samples was performed to identify the source and validate the expression level of fluid miRs. RESULTS:Of the six miRs that were profiled in the study, two showed differential expression in malignant cysts. miR-221 was expressed at significantly higher levels in malignant cysts compared with benign or premalignant cysts (P=0.05). miR-21 was also expressed at significantly higher levels in malignant cysts (P<0.01). Additionally, the expression of miR-21 was significantly higher in premalignant cysts than benign cysts (P=0.03). The differential expression of miR-21 among cyst categories was confirmed by ISH. CONCLUSIONS:In this small single-center study, miRs are potential pancreatic cyst fluid diagnostic biomarkers. In particular, miR-21 is identified as a candidate biomarker to distinguish between benign, premalignant, and malignant cysts. Additionally miR-221 may be of use in the identification of more advanced malignant disease.

The aim of this study is to validate the prognostic and predictive value of the non-synonymous cytidine deaminase (CDA) Lys²⁷Gln polymorphism for hematological toxicity and survival using a randomized phase III adjuvant trial (Radiation Therapy Oncology Group (RTOG) 9704) in pancreatic cancer in which one treatment arm received gemcitabine. CDA is involved in gemcitabine inactivation, and there is conflicting data on the role of the non-synonymous CDA Lys²⁷Gln polymorphism in predicting toxicity and survival in cancer patients treated with gemcitabine. RTOG 9704 randomized 538 patients after pancreatic resection to receive radiotherapy with either 5-fluorouracil (5-FU) or gemcitabine. CDA Lys²⁷Gln polymorphism genotype was analyzed. We tested an association between CDA single-nucleotide polymorphism genotype and the survival outcome by the Cox proportional hazard model adjusting for other covariates, as well as toxicity by the logistic regression model. There is statistically significant more severe hematological toxicity in patients treated with gemcitabine with either the homozygote wild-type genotype (Lys/Lys) alone (odds ratio (OR)=0.06, P=0.01), or in combination with the heterozygote (Lys/Gln; OR=0.14, P=0.03) when compared with homozygote variant genotype (Gln/Gln) when adjusted for other covariates. This was not seen in the non-gemcitabine treated arm. There are no genotype differences with respect to survival outcome. In conclusion, in this prospective randomized adjuvant study of patients with pancreatic cancer, the CDA Lys²⁷Gln polymorphism is validated as a predictive marker of gemcitabine hematological toxicity, but not with treatment response or survival.