hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA

被引：7

作者：

Aughton, Karen ^{[1
]}

Elander, Nils O. ^{[1
,2
]}

Evans, Anthony ^{[1
]}

Jackson, Richard ^{[1
]}

Campbell, Fiona ^{[1
]}

Costello, Eithne ^{[1
]}

Halloran, Christopher M. ^{[1
]}

Mackey, John R. ^{[3
]}

Scarfe, Andrew G. ^{[3
]}

Valle, Juan W. ^{[4
]}

Carter, Ross ^{[5
]}

Cunningham, David ^{[6
]}

Tebbutt, Niall C. ^{[7
]}

Goldstein, David ^{[8
]}

Shannon, Jennifer ^{[9
]}

Glimelius, Bengt ^{[10
]}

Hackert, Thilo ^{[11
]}

Charnley, Richard M. ^{[12
]}

Anthoney, Alan ^{[13
]}

Lerch, Markus M. ^{[14
]}

Mayerle, Julia ^{[14
,15
]}

Palmer, Daniel H. ^{[1
]}

Buechler, Markus W. ^{[11
]}

Ghaneh, Paula ^{[1
]}

Neoptolemos, John P. ^{[11
]}

Greenhalf, William ^{[1
]}

机构：

[1] Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England

[2] Linkoping Univ, Dept Oncol, SE-58183 Linkoping, Sweden

[3] Univ Alberta, Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada

[4] Univ Manchester, Christie NHS Fdn Trust, Manchester M20 4BX, Lancs, England

[5] Glasgow Royal Infirm, Glasgow G4 0SF, Lanark, Scotland

[6] Royal Marsden Natl Hlth Serv NHS Fdn Trust, London SW3 6JJ, England

[7] Austin Hlth, Melbourne, Vic 3084, Australia

[8] Univ New South Wales, Prince Wales Hosp & Clin Sch, Sydney, NSW 2052, Australia

[9] Univ Sydney, Nepean Canc Ctr, Sydney, NSW 2747, Australia

[10] Uppsala Univ, Dept Immunol Genet & Pathol, SE-75105 Uppsala, Sweden

[11] Heidelberg Univ, Dept Surg, D-69047 Heidelberg, Germany

[12] Freeman Rd Hosp, Newcastle Upon Tyne NE7 7DN, Tyne & Wear, England

[13] St James Univ Hosp, Leeds LS9 7TF, W Yorkshire, England

[14] Univ Med Greifswald, Dept Med A, D-17489 Greifswald, Germany

[15] Klinikum LMU Munchen Grosshadern, Med Klin & Poliklin 2, D-81377 Munich, Germany

来源：

CANCERS | 2021年 / 13卷 / 22期

关键词：

5-fluorouracil; gemcitabine; pyrimidine; biomarker; predictive marker; prognostic marker; chemotherapy; ADJUVANT CHEMOTHERAPY; DUCTAL ADENOCARCINOMA; CYTIDINE DEAMINASE; FOLINIC ACID; NUCLEOSIDE; RESECTION; TUMOR; CHEMORADIOTHERAPY; METABOLISM; RESISTANCE;

D O I：

10.3390/cancers13225758

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Simple Summary: Recent clinical trials suggest that combination therapies that include either gemcitabine or 5-fluorouracil (5-FU) both give significant survival benefits for pancreatic cancer patients. The tumor level of the nucleoside transporter hENT1 is prognostic in patients treated with adjuvant gemcitabine but not adjuvant 5-FU. This work shows for the first time that hENT1 is only predictive of benefit from gemcitabine over 5-FU in patients with low levels of CDA transcript. A choice between adjuvant 5-FU based combination therapies (such as FOLFIRINOX) and gemcitabine-based therapy (e.g., GemCap) could be made based on a combination of hENT1 protein and CDA mRNA measured in a resected tumor.Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.

引用

页数：15

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