hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Tissue Microarray Manufacture
2.3. RNAscope® In Situ Hybridization (ISH)
2.4. Quantification Using RNAscope SpotStudio® Software
2.5. Immunohistochemistry
2.6. Statistical Analysis
3. Results
3.1. Determining Expression Levels of hENT1 and CDA in PDAC
3.2. Univariate and Multivariable Analyses of Clinical and Pathological Characteristics
3.3. Overall Survival Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Summary Statistics | Hazard Ratio (95% Confidence Interval) | |||||
---|---|---|---|---|---|---|
Characteristic | Level | 5-Fluorouracil | Gemcitabine | 5-Fluorouracil | Gemcitabine | Total |
Resection Margin | n = 132 | n = 145 | n = 277 | |||
Negative | 70 (53%) | 86 (59%) | 1 | 1 | 1 | |
Positive | 62 (47%) | 59 (41%) | 1.80 (1.23–2.63) | 1.35 (0.94–1.94) | 1.56 (1.20–2.03) | |
Wald χ2 = 9.05, p = 0.003 * | Wald χ2 = 2.62 p = 0.106 | Wald χ2 = 11.22, p = 0.001 | ||||
WHO | n = 132 | n = 145 | n = 277 | |||
0 | 52 (39%) | 49 (34%) | 1 | 1 | 1 | |
1 | 67 (51%) | 80 (55%) | 1.26 (0.86–1.96) | 1.40 (0.94–2.07) | 1.33 (1.01–1.76) | |
2 | 13 (10%) | 16 (11%) | 0.68 (0.29–1.59) | 1.24 (0.68–2.25) | 0.92 (0.56–1.53) | |
Wald χ2 = 2.89, p = 0.236 | Wald χ2 = 2.75 p = 0.253 | Wald χ2 = 5.24, p = 0.073 | ||||
Lymph Node Status | n = 132 | n = 145 | n = 277 | |||
Negative | 29 (22%) | 29 (20%) | 1 | 1 | 1 | |
Positive | 103 (78%) | 116 (80%) | 2.40 (1.47–3.90) | 1.56 (0.99–2.46) | 1.94 (1.39–2.71) | |
Wald χ2 = 12.30, p = 0.001 | Wald χ2 = 3.63, p = 0.057 | Wald χ2 = 15.18 p < 0.001 | ||||
Tumor Stage | n = 131 | n = 144 | n = 275 | |||
01/02 | 38 (29%) | 46 (32%) | 1 | 1 | 1 | |
03/04 | 93 (70%) | 98 (68%) | 1.69 (1.10–2.59) | 1.39 (0.95–2.01) | 1.51 (1.15–2.00) | |
Wald χ2= 5.81, p = 0.016 | Wald χ2 = 2.95, p = 0.086 | Wald χ2 = 8.47, p = 0.004 | ||||
Tumor Grade | N = 129 | n = 142 | n = 271 | |||
Well | 7 (5%) | 10 (7%) | 1 | 1 | 1 | |
Moderately | 89 (67%) | 98 (68%) | 0.60 (0.37–0.96) | 0.83 (0.44–1.58) | 0.72 (0.47–1.01) | |
Poorly | 33 (25%) | 34 (23%) | 0.67 (0.35–1.28) | 1.19 (0.58–2.44) | 0.91 (0.55–1.51) | |
Wald χ2 = 4.54, p = 0.103 | Wald χ2 = 2.75, p = 0.753 | Wald χ2 = 3.60 p = 0.165 | ||||
Local Invasion | n = 132 | n = 142 | n = 274 | |||
No | 73 (55%) | 72 (50%) | 1 | 1 | 1 | |
Yes | 59 (45%) | 70 (48%) | 1.25 (0.85–1.84) | 1.10 (0.77–1.58) | 1.17 (0.90–1.52) | |
Wald χ2 = 1.31, p = 0.252 | Wald χ2 = 0.26, p = 0.607 | Wald χ2 = 1.37 p = 0.242 | ||||
Maximum Tumor diameter | n = 128 | n = 139 | n = 267 | |||
<30 mm | 69 (52%) | 58 (40%) | 1 | 1 | 1 | |
≥30 mm | 59 (45%) | 81 (56%) | 1.31 (0.89–1.95) | 1.64 (1.13–2.39) | 1.47 (1.12–1.92) | |
Wald χ2 = 1.82, p = 0.177 | Wald χ2 = 6.73, p = 0.010 | Wald χ2 = 7.84 p = 0.005 | ||||
Diabetes mellitus | n = 129 | n = 141 | n = 270 | |||
No | 102 (77%) | 106 (73%) | 1 | 1 | 1 | |
Yes | 27 (20%) | 35 (24%) | 1.06 (0.65–1.75) | 0.99 (0.64–1.53) | 1.02 (0.74–1.41) | |
Wald χ2 = 0.07, p = 0.797 | Wald χ2 = 0.00, p = 0.951 | Wald χ2 = 0.01, p = 0.905 | ||||
Gender | n = 132 | n = 145 | n = 277 | |||
Male | 75 (57%) | 88 (61%) | 1 | 1 | 1 | |
Female | 57 (43%) | 57 (39%) | 0.88 (0.59–1.32) | 1.25 (0.86–1.81) | 1.06 (0.81–1.39) | |
Wald χ2= 0.38, p = 0.537 | Wald χ2 = 1.42, p = 0.234 | Wald χ2 = 0.16, p = 0.686 | ||||
Age, years | n = 132 | n = 145 | n = 277 | |||
≥64 | 65 (49%) | 80 (55%) | 1 | 1 | 1 | |
<64 | 67 (51%) | 65 (45%) | 1.37 (0.93–2.02) | 0.84 (0.58–1.21) | 1.07 (0.83–1.40) | |
Wald χ2= 2.55, p = 0.110 | Wald χ2 = 0.90, p = 0.342 | Wald χ2 = 0.28, p = 0.598 | ||||
Smoking | n = 125 | n = 128 | n = 253 | |||
Never | 52 (39%) | 58 (40%) | 1 | 1 | 1 | |
Ex | 51 (39%) | 52 (36%) | 0.93 (0.60–1.43) | 1.08 (0.70–1.66) | 1.00 (0.74–1.35) | |
Current | 22 (17%) | 18 (12%) | 0.91 (0.53–1.57) | 1.76 (1.02–3.05) | 1.20 (0.81–1.78) | |
Wald χ2 = 0.17, p = 0.917 | Wald χ2 = 4.16, p = 0.125 | Wald χ2 = 0.95, p = 0.623 |
5FU | Gemcitabine | ||||||
---|---|---|---|---|---|---|---|
Characteristic | est (se) | HR (95% CI) | Pval | est (se) | HR (95% CI) | p-Value | |
Single biomarker: CDA or hENT1 combined with stage, resection margin and lymph node involvement | |||||||
CDA mRNA Expression | Per unit increase in MSPC | 1.47 (0.685) | 4.35 (1.14, 16.62) | 0.032 | 1.15 (0.623) | 3.15 (0.93, 10.68) | 0.066 |
CDA mRNA Expression (Low vs. High) | Low | 1 (Reference) | 1 (Reference) | ||||
High | 0.34 (0.221) | 1.41 (0.91, 2.17) | 0.120 | 0.49 (0.192) | 1.62 (1.12, 2.39) | 0.011 * | |
hENT1 protein expression | Per unit increase in (log) H-score | −0.03 (0.159) | 0.97 (0.71, 1.33) | 0.861 | −0.26 (0.129) | 0.77 (0.60, 0.99) | 0.047 |
hENT1 protein expression (Low vs. High) | Low | 1 (Reference) | 1 (Reference) | ||||
High | 0.18 (0.207) | 1.21 (0.80, 1.81) | 0.374 | −0.43 (0.192) | 0.65 (0.45, 0.95) | 0.025 | |
Multiple biomarker: CDA and hENT1 combined with stage, resection margin and lymph node involvement | |||||||
CDA mRNA Expression (Low vs. High) | Low | 1 (Reference) | 1 (Reference) | ||||
High | 0.39 (0.226) | 1.48 (0.95, 2.31) | 0.082 | 0.50 (0.193) | 1.65 (1.13, 2.41) | 0.009 | |
hENT1 protein expression (Low vs. High) | Low | 1 (Reference) | 1 (Reference) | ||||
High | 0.28 (0.212) | 1.32 (0.87, 1.99) | 0.193 | −0.41 (0.191) | 0.66 (0.46, 0.96) | 0.030 |
Arm | Biomarker Expression (High or Low) | Number | Median OS | 95% Confidence Interval | Log Rank | p-Value |
---|---|---|---|---|---|---|
5-FU/FA | CDA High | 36 | 14.6 | 8.4–24.1 | 5.17 | 0.0229 |
CDA Low | 96 | 26.4 | 21.4–29.7 | |||
GEM | CDA High | 56 | 21.2 | 15.7–26.2 | 5.14 | 0.0234 |
CDA Low | 89 | 24.8 | 18.3–33.0 | |||
5-FU/FA | hENT1 High | 59 | 22.6 | 17.3–28.6 | 0.53 | 0.4658 |
hENT1 Low | 69 | 24.1 | 15.9–30.4 | |||
GEM | hENT1 High | 82 | 26.0 | 21.2–32.8 | 7.58 | 0.0059 |
hENT1 Low | 58 | 16.8 | 14.1–24.8 | |||
5-FU | CDA Low, hENT1 Low | 44 | 29.3 | 21.9–41.9 | 6.14 | 0.1050 |
CDA High, hENT1 Low | 25 | 14.2 | 7.9–24.1 | |||
CDA Low, hENT1 High | 49 | 22.6 | 16.9–29.6 | |||
CDA High, hENT1 High | 10 | 20.1 | 5.0–37.5 | |||
GEM | CDA Low, hENT1 Low | 34 | 18.3 | 13.9–28.3 | 12.0 | 0.0073 |
CDA High, hENT1 Low | 24 | 14.6 | 11.1–25.1 | |||
CDA Low, hENT1 High | 52 | 28.0 | 21.1–45.5 | |||
CDA High, hENT1 High | 30 | 23.8 | 16.6–28.7 |
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Aughton, K.; Elander, N.O.; Evans, A.; Jackson, R.; Campbell, F.; Costello, E.; Halloran, C.M.; Mackey, J.R.; Scarfe, A.G.; Valle, J.W.; Carter, R.; Cunningham, D.; Tebbutt, N.C.; Goldstein, D.; Shannon, J.; Glimelius, B.; Hackert, T.; Charnley, R.M.; Anthoney, A.; Lerch, M.M.; Mayerle, J.; Palmer, D.H.; Büchler, M.W.; Ghaneh, P.; Neoptolemos, J.P.; Greenhalf, W. hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA. Cancers 2021, 13, 5758. https://doi.org/10.3390/cancers13225758
Aughton K, Elander NO, Evans A, Jackson R, Campbell F, Costello E, Halloran CM, Mackey JR, Scarfe AG, Valle JW, Carter R, Cunningham D, Tebbutt NC, Goldstein D, Shannon J, Glimelius B, Hackert T, Charnley RM, Anthoney A, Lerch MM, Mayerle J, Palmer DH, Büchler MW, Ghaneh P, Neoptolemos JP, Greenhalf W. hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA. Cancers. 2021; 13(22):5758. https://doi.org/10.3390/cancers13225758
Chicago/Turabian StyleAughton, Karen, Nils O. Elander, Anthony Evans, Richard Jackson, Fiona Campbell, Eithne Costello, Christopher M. Halloran, John R. Mackey, Andrew G. Scarfe, Juan W. Valle, Ross Carter, David Cunningham, Niall C. Tebbutt, David Goldstein, Jennifer Shannon, Bengt Glimelius, Thilo Hackert, Richard M. Charnley, Alan Anthoney, Markus M. Lerch, Julia Mayerle, Daniel H. Palmer, Markus W. Büchler, Paula Ghaneh, John P. Neoptolemos, and William Greenhalf. 2021. "hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA" Cancers 13, no. 22: 5758. https://doi.org/10.3390/cancers13225758