High levels of human epididymis protein 4 mRNA and protein expression are associated with chemoresistance and a poor prognosis in pancreatic cancer

Ohkuma,Ryotaro; Yada,Erica; Ishikawa,Shumpei; Komura,Daisuke; Kubota,Yutaro; Hamada,Kazuyuki; Horiike,Atsushi; Ishiguro,Tomoyuki; Hirasawa,Yuya; Ariizumi,Hirotsugu; Shida,Midori; Watanabe,Makoto; Onoue,Rie; Ando,Kiyohiro; Tsurutani,Junji; Yoshimura,Kiyoshi; Sasada,Tetsuro; Aoki,Takeshi; Murakami,Masahiko; Norose,Tomoko; Ohike,Nobuyuki; Takimoto,Masafumi; Kobayashi,Shinichi; Tsunoda,Takuya; Wada,Satoshi

doi:10.3892/ijo.2020.5147

High levels of human epididymis protein 4 mRNA and protein expression are associated with chemoresistance and a poor prognosis in pancreatic cancer

Authors:
- Ryotaro Ohkuma
- Erica Yada
- Shumpei Ishikawa
- Daisuke Komura
- Yutaro Kubota
- Kazuyuki Hamada
- Atsushi Horiike
- Tomoyuki Ishiguro
- Yuya Hirasawa
- Hirotsugu Ariizumi
- Midori Shida
- Makoto Watanabe
- Rie Onoue
- Kiyohiro Ando
- Junji Tsurutani
- Kiyoshi Yoshimura
- Tetsuro Sasada
- Takeshi Aoki
- Masahiko Murakami
- Tomoko Norose
- Nobuyuki Ohike
- Masafumi Takimoto
- Shinichi Kobayashi
- Takuya Tsunoda
- Satoshi Wada
View Affiliations

Affiliations: Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo 157‑8577, Japan, Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa 241‑0815, Japan, Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113‑0033, Japan, Department of Medicine, Division of Medical Oncology, School of Medicine, Showa University, Tokyo 157‑8577, Japan, Department of Surgery, Division of General and Gastroenterological Surgery, School of Medicine, Showa University, Tokyo 157‑8577, Japan, Department of Pathology and Laboratory Medicine, School of Medicine, Showa University, Tokyo 157‑8577, Japan, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo 157‑8577, Japan
Published online on: November 12, 2020 https://doi.org/10.3892/ijo.2020.5147
Pages: 57-69
Copyright: © Ohkuma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Pancreatic cancer is associated with an exceedingly poor prognosis, warranting the development of novel therapeutic strategies and discovery of prognostic predictors. Given that chemoresistance‑related molecules are reportedly associated with the poor prognosis of pancreatic cancer, the present study aimed to identify molecules that could be efficacious therapeutic targets for pancreatic cancer. First, 10 patient‑derived xenografts (PDXs) were established from patients with pancreatic cancer. Subsequently, after treating tumor tissue generated from the PDXs with standard drugs, next‑generation sequencing (NGS) was performed using these tissues. The results of NGS analysis and immunohistochemical analysis on 80 pancreatic cancer tissues revealed that human epididymis protein 4 (HE4) expression in the anticancer drug‑treated PDX group was higher than that in the untreated PDXs. In addition, chemoresistance ability was observed in tumor cell lines overexpressing HE4. Furthermore, Kaplan‑Meier analysis of tumor tissues from 80 patients with pancreatic cancer was performed and it was found that patients with a high HE4 expression level had a poor survival rate compared with those who had a low HE4 expression level. Multivariate analysis also indicated the high expression level of HE4 was an independent poor prognostic biomarker. Thus, it was concluded that high gene and protein expression levels of HE4 mediate chemoresistance and are independent prognostic factors for pancreatic cancer.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
2	Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM and Matrisian LM: Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74:2913–2921. 2014. View Article : Google Scholar : PubMed/NCBI
3	Kamisawa T, Wood LD, Itoi T and Takaori K: Pancreatic cancer. Lancet. 388:73–85. 2016. View Article : Google Scholar : PubMed/NCBI
4	Lefebvre AC, Maurel J, Boutreux S, Bouvier V, Reimund JM, Launoy G and Arsene D: Pancreatic cancer: Incidence treatment and survival trends-1175 cases in Calvados (France) from 1978 to 2002. Gastroenterol Clin Biol. 33:1045–1051. 2009. View Article : Google Scholar : PubMed/NCBI
5	Sant M, Allemani C, Santaquilani M, Knijn A, Marchesi F and Capocaccia R; EUROCARE Working Group: EUROCARE-4: Survival of cancer patients diagnosed in 1995-1999 Results and commentary. Eur J Cancer. 45:931–991. 2009. View Article : Google Scholar : PubMed/NCBI
6	Li HB, Zhou J and Zhao FQ: A prognostic nomogram for disease-specific survival in patients with pancreatic ductal adenocarcinoma of the head of the pancreas following pancreatic-coduodenectomy. Med Sci Monit. 24:6313–6321. 2018. View Article : Google Scholar : PubMed/NCBI
7	Ahrendt SA and Pitt HA: Surgical management of pancreatic cancer. Oncology (Williston Park). 16:725–734. 2002.
8	Cecconi D, Palmieri M and Donadelli M: Proteomics in pancreatic cancer research. Proteomics. 11:816–828. 2011. View Article : Google Scholar : PubMed/NCBI
9	Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, et al: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 364:1817–1825. 2011. View Article : Google Scholar : PubMed/NCBI
10	Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, et al: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 369:1691–1703. 2013. View Article : Google Scholar : PubMed/NCBI
11	Wang Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, et al: Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine based therapy (NAPOLI-1): A global, randomised, open-label, phase 3 trial. Lancet. 387:545–557. 2016. View Article : Google Scholar
12	Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol. 15:2403–2413. 1997. View Article : Google Scholar : PubMed/NCBI
13	Kirchhoff C, Habben I, Ivell R and Krull N: A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors. Biol Reprod. 45:350–357. 1991. View Article : Google Scholar : PubMed/NCBI
14	Kirchhoff C: Molecular characterization of epididymal proteins. Rev Reprod. 3:86–95. 1998. View Article : Google Scholar : PubMed/NCBI
15	Clauss A, Lilja H and Lundwall A: A locus on human chromosome 20 contains several genes expressing protease inhibitor domains with homology to whey acidic protein. Biochem J. 368:233–242. 2002. View Article : Google Scholar : PubMed/NCBI
16	Bingle CD: Towards defining the complement of mammalian WFDC-domain-containing proteins. Biochem Soc Trans. 39:1393–1397. 2011. View Article : Google Scholar : PubMed/NCBI
17	Drapkin R, von Horsten HH, Lin Y, Mok SC, Crum CP, Welch WR and Hecht JL: Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. Cancer Res. 65:2162–2169. 2005. View Article : Google Scholar : PubMed/NCBI
18	Hellström I, Raycraft J, Hayden-Ledbetter M, Ledbetter JA, Schummer M, McIntosh M, Drescher C, Urban N and Hellström KE: The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res. 63:3695–3700. 2003.PubMed/NCBI
19	Trudel D, Têtu B, Grégoire J, Plante M, Renaud MC, Bachvarov D, Douville P and Bairati I: Human epididymis protein 4 (HE4) and ovarian cancer prognosis. Gynecol Oncol. 127:511–515. 2012. View Article : Google Scholar : PubMed/NCBI
20	Bignotti E, Ragnoli M, Zanotti L, Calza S, Falchetti M, Lonardi S, Bergamelli S, Bandiera E, Tassi RA, Romani C, et al: Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients. Br J Cancer. 104:1418–1425. 2011. View Article : Google Scholar : PubMed/NCBI
21	Li X, Gao Y, Tan M, Zhuang H, Gao J, Hu Z, Wang H, Zhu L, Liu J and Lin B: Expression of HE4 in endometrial cancer and its clinical significance. Biomed Res Int. 2015:4374682015.PubMed/NCBI
22	Iwahori K, Suzuki H, Kishi Y, Fujii Y, Uehara R, Okamoto N, Kobayashi M, Hirashima T, Kawase I and Naka T: Serum HE4 as a diagnostic and prognostic marker for lung cancer. Tumour Biol. 33:1141–1149. 2012. View Article : Google Scholar : PubMed/NCBI
23	Yamashita S, Tokuishi K, Hashimoto T, Moroga T, Kamei M, Ono K, Miyawaki M, Takeno S, Chujo M, Yamamoto S and Kawahara K: Prognostic significance of HE4 expression in pulmonary adenocarcinoma. Tumour Biol. 32:265–271. 2011. View Article : Google Scholar
24	Zhong H, Qian Y, Fang S, Yang L, Li L and Gu W: HE4 expression in lung cancer, a meta-analysis. Clin Chim Acta. 470:109–114. 2017. View Article : Google Scholar : PubMed/NCBI
25	Kamei M, Yamashita S, Tokuishi K, Hashioto T, Moroga T, Suehiro S, Ono K, Miyawaki M, Takeno S, Yamamoto S and Kawahara K: HE4 expression can be associated with lymph node metastases and disease-free survival in breast cancer. Anticancer Res. 30:4779–4783. 2010.PubMed/NCBI
26	Guo YD, Wang JH, Lu H, Li XN, Song WW, Zhang XD and Zhang WM: The human epididymis protein 4 acts as a prognostic factor and promotes progression of gastric cancer. Tumour Biol. 36:2457–2464. 2015. View Article : Google Scholar :
27	Kemal YN, Demirag GN, Bedir AM, Tomak L, Derebey M, Erdem DL, Gör U and Yücel I: Serum human epididymis protein 4 levels in colorectal cancer patients. Mol Clin Oncol. 7:481–485. 2017. View Article : Google Scholar : PubMed/NCBI
28	Galgano MT, Hampton GM and Frierson HF Jr: Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol. 19:847–853. 2006. View Article : Google Scholar : PubMed/NCBI
29	Jiang SW, Chen H, Dowdy S, Fu A, Attewell J, Kalogera E, Drapkin R, Podratz K, Broaddus R and Li J: HE4 transcription- and splice variants-specific expression in endometrial cancer and correlation with patient survival. Int J Mol Sci. 14:22655–22677. 2013. View Article : Google Scholar : PubMed/NCBI
30	Ryu B, Jones J, Blades NJ, Parmigiani G, Hollingsworth MA, Hruban RH and Kern SE: Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression. Cancer Res. 62:819–826. 2002.PubMed/NCBI
31	O'Neal RL, Nam KT, LaFleur BJ, Barlow B, Nozaki K, Lee HJ, Kim WH, Yang HK, Shi C, Maitra A, et al: Human epididymis protein 4 is up-regulated in gastric and pancreatic adenocarcinomas. Hum Pathol. 44:734–742. 2013. View Article : Google Scholar
32	Huang T, Jiang SW, Qin L, Senkowski C, Lyle C, Terry K, Brower S, Chen H, Glasgow W, Wei Y and Li J: Expression and diagnostic value of HE4 in pancreatic adenocarcinoma. Int J Mol Sci. 16:2956–2970. 2015. View Article : Google Scholar : PubMed/NCBI
33	Lu Q, Chen H, Senkowski C, Wang J, Wang X, Brower S, Glasgow W, Byck D, Jiang SW and Li J: Recombinant HE4 protein promotes proliferation of pancreatic and endometrial cancer cell lines. Oncol Rep. 35:163–170. 2016. View Article : Google Scholar
34	Ohkuma R, Yada E, Ishikawa S, Komura D, Ishizaki H, Tamada K, Kubota Y, Hamada K, Ishida H, Hirasawa Y, et al: High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer. PLoS One. 15:e02267072020. View Article : Google Scholar : PubMed/NCBI
35	Morton CL and Houghton PJ: Establishment of human tumor xenografts in immunodeficient mice. Nat Protoc. 2:247–250. 2007. View Article : Google Scholar : PubMed/NCBI
36	Chijiwa T, Kawai K, Noguchi A, Sato H, Hayashi A, Cho H, Shiozawa M, Kishida T, Morinaga S, Yokose T, et al: Establishment of patient-derived cancer xenografts in immune-deficient NOG mice. Int J Oncol. 47:61–70. 2015. View Article : Google Scholar : PubMed/NCBI
37	Langmead B, Trapnell C, Pop M and Salzberg SL: Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10:R252009. View Article : Google Scholar : PubMed/NCBI
38	Komura D, Isagawa T, Kishi K, Suzuki R, Sato R, Tanaka M, Katoh H, Yamamoto S, Tatsuno K, Fukayama M, et al: CASTIN: A system for comprehensive analysis of cancer stromal interactome. BMC Genomics. 17:8992016. View Article : Google Scholar
39	Livak KJ and Schmittgen TD: Analysis of relative gene expres sion data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
40	Jin K, Li G, Cui B, Zhang J, Lan H, Han N, Xie B, Cao F, He K, Wang H, et al: Assessment of a novel VEGF targeted agent using patient-derived tumor tissue xenograft models of colon carcinoma with lymphatic and hepatic metastases. PLoS One. 6:e283842011. View Article : Google Scholar : PubMed/NCBI
41	Yada E, Wada S, Yoshida S and Sanada T: Use of patient-derived xenograft mouse models in cancer research and treatment. Future Sci OA. 4:FSO2712017. View Article : Google Scholar
42	Hidalgo M, Amant F, Biankin AV, Budinská E, Byrne AT, Caldas C, Clarke RB, de Jong S, Jonkers J, Mælandsmo GM, et al: Patient derived xenograft models: An emerging platform for translational cancer research. Cancer Discov. 4:998–1013. 2014. View Article : Google Scholar : PubMed/NCBI
43	Cho SY, Kang W, Han JY, Min S, Kang J, Lee A, Kwon JY, Lee C and Park H: An integrative approach to precision cancer medi cine using patient-derived xenografts. Mol Cells. 39:77–86. 2016. View Article : Google Scholar : PubMed/NCBI
44	Lefford H: US Cancer Institute to overhaul tumour cell lines. Nature. 530:3912016. View Article : Google Scholar
45	Fujii E, Suzuki M, Matsubara K, Watanabe M, Chen YJ, Adachi K, Ohnishi Y, Tanigawa M, Tsuchiya M and Tamaoki N: Establishment and characterization of in vivo human tumor models in the NOD/SCID/gamma(c)(null) mouse. Pathol Int. 58:559–567. 2008. View Article : Google Scholar : PubMed/NCBI
46	Galimi F, Torti D, Sassi F, Isella C, Corà D, Gastaldi S, Ribero D, Muratore A, Massucco P, Siatis D, et al: Genetic and expression analysis of MET, MACC1, and HGF in metastatic colorectal cancer: Response to met inhibition in patient xenografts and pathologic correlations. Clin Cancer Res. 17:3146–3156. 2011. View Article : Google Scholar : PubMed/NCBI
47	Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, Corà D, Di Nicolantonio F, Buscarino M, Petti C, et al: A molecularly annotated platform of patient-derived xenografts ('xenopatients') identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 1:508–523. 2011. View Article : Google Scholar
48	de Sousa Abreu R, Penalva LO, Marcotte EM and Vogel C: Global signatures of protein and mRNA expression levels. Mol Biosyst. 5:1512–1526. 2009.PubMed/NCBI
49	Schwanhäusser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J, Chen W and Selbach M: Global quantification of mammalian gene expression control. Nature. 473:337–342. 2011. View Article : Google Scholar : PubMed/NCBI
50	Wu L, Candille SI, Choi Y, Xie D, Jiang L, Li-Pook-Than J, Tang H and Snyder M: Variation and genetic control of protein abundance in humans. Nature. 499:79–82. 2013. View Article : Google Scholar : PubMed/NCBI
51	Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, Chambers MC, Zimmerman LJ, Shaddox KF, Kim S, et al: Proteogenomic characterization of human colon and rectal cancer. Nature. 513:382–387. 2014. View Article : Google Scholar : PubMed/NCBI
52	Zou SL, Chang XH, Ye X, Cheng HY, Cheng YX, Tang ZJ, Zhang ZJ, Gao L, Chen XH and Cui H: Effect of human epididymis protein 4 gene silencing on the malignant phenotype in ovarian cancer. Chin Med J (Engl). 124:3133–3140. 2011.
53	Zhu YF, Gao GL, Tang SB, Zhang ZD and Huang QS: Effect of WFDC 2 silencing on the proliferation, motility and invasion of human serous ovarian cancer cells in vitro. Asian Pac J Trop Med. 6:265–272. 2013. View Article : Google Scholar : PubMed/NCBI
54	Zhuang H, Hu Z, Tan M, Zhu L, Liu J, Liu D, Yan L and Lin B: Overexpression of Lewis yantigen promotes human epididymis protein 4-mediated invasion and metastasis of ovarian cancer cells. Biochimie. 105:91–98. 2014. View Article : Google Scholar : PubMed/NCBI
55	Lu R, Sun X, Xiao R, Zhou L, Gao X and Guo L: Human epididymis protein 4 (HE4) plays a key role in ovarian cancer cell adhesion and motility. Biochem Biophys Res Commun. 419:274–280. 2012. View Article : Google Scholar : PubMed/NCBI
56	Li J, Chen H, Mariani A, Chen D, Klatt E, Podratz K, Drapkin R, Broaddus R, Dowdy S and Jiang SW: HE4 (WFDC2) promotes tumor growth in endometrial cancer cell lines. Int J Mol Sci. 14:6026–6043. 2013. View Article : Google Scholar : PubMed/NCBI
57	Lee S, Choi S, Lee Y, Chung D, Hong S and Park N: Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer. J Obstet Gynaecol Res. 43:220–227. 2017. View Article : Google Scholar
58	Moore RG, Hill EK, Horan T, Yano N, Kim K, MacLaughlan S, Lambert-Messerlian G, Tseng YD, Padbury JF, Miller MC, et al: HE4 (WFDC2) gene overexpression promotes ovarian tumor growth. Sci Rep. 4:35742014. View Article : Google Scholar : PubMed/NCBI
59	Maihle NJ, Baron AT, Barrette BA, Boardman CH, Christensen TA, Cora EM, Faupel-Badger JM, Greenwood T, Juneja SC, Lafky JM, et al: EGF/ErbB receptor family in ovarian cancer. Cancer Treat Res. 107:247–258. 2002.PubMed/NCBI
60	Gotlieb WH, Bruchim I, Gu J, Shi Y, Camirand A, Blouin MJ, Zhao Y and Pollak MN: Insulin-like growth factor receptor I targeting in epithelial ovarian cancer. Gynecol Oncol. 100:389–396. 2006. View Article : Google Scholar
61	Spannuth WA, Nick AM, Jennings NB, Armaiz-Pena GN, Mangala LS, Danes CG, Lin YG, Merritt WM, Thaker PH, Kamat AA, et al: Functional significance of VEGFR-2 on ovarian cancer cells. Int J Cancer. 124:1045–1053. 2009. View Article : Google Scholar :
62	Braicu EI, Fotopoulou C, Van Gorp T, Richter R, Chekerov R, Hall C, Butz H, Castillo-Tong DC, Mahner S, Zeillinger R, et al: Preoperative HE4 expression in plasma predicts surgical outcome in primary ovarian cancer patients: Results from the OVCAD study. Gynecol Oncol. 128:245–251. 2013. View Article : Google Scholar
63	Ribeiro JR, Schorl C, Yano N, Romano N, Kim KK, Singh RK and Moore RG: HE4 promotes collateral resistance to cisplatin and paclitaxel in ovarian cancer cells. J Ovarian Res. 9:282016. View Article : Google Scholar : PubMed/NCBI
64	Wang H, Zhu L, Gao J, Hu Z and Lin B: Promotive role of recombinant HE4 protein in proliferation and carboplatin resistance in ovarian cancer cells. Oncol Rep. 33:403–412. 2015. View Article : Google Scholar
65	Angioli R, Capriglione S, Aloisi A, Guzzo F, Luvero D, Miranda A, Damiani P, Montera R, Terranova C and Plotti F: Can HE4 predict platinum response during first-line chemotherapy in ovarian cancer? Tumour Biol. 35:7009–7015. 2014. View Article : Google Scholar : PubMed/NCBI
66	Oweira H, Petrausch U, Helbling D, Schmidt J, Mannhart M, Mehrabi A, Schöb O, Giryes A, Decker M and Abdel-Rahman O: Prognostic value of site-specific metastases in pancreatic adenocarcinoma: A Surveillance epidemiology and end results database analysis. World J Gastroenterol. 23:1872–1880. 2017. View Article : Google Scholar : PubMed/NCBI
67	Nipp R, Tramontano AC, Kong CY, Pandharipande P, Dowling EC, Schrag D and Hur C: Disparities in cancer outcomes across age, sex, and race/ethnicity among patients with pancreatic cancer. Cancer Med. 7:525–535. 2018. View Article : Google Scholar : PubMed/NCBI
68	Maisey NR, Norman AR, Hill A, Massey A, Oates J and Cunningham D: CA19-9 as a prognostic factor in inoperable pancreatic cancer: The implication for clinical trials. Br J Cancer. 93:740–743. 2005. View Article : Google Scholar : PubMed/NCBI
69	Piciucchi M, Stigliano S, Archibugi L, Zerboni G, Signoretti M, Barucca V, Valente R, Fave GD and Capurso G: The neutrophil/lymphocyte ratio at diagnosis is significantly associated with survival in metastatic pancreatic cancer patients. Int J Mol Sci. 18:7302017. View Article : Google Scholar :
70	Luo J, Xiao L, Wu C, Zheng Y and Zhao N: The incidence and survival rate of population-based pancreatic cancer patients: Shanghai Cancer Registry 2004-2009. PLoS One. 8:e760522013. View Article : Google Scholar : PubMed/NCBI
71	Baine M, Sahak F, Lin C, Chakraborty S, Lyden E and Batra SK: Marital status and survival in pancreatic cancer patients: A SEER based analysis. PLoS One. 6:e210522011. View Article : Google Scholar : PubMed/NCBI
72	David M, Lepage C, Jouve JL, Jooste V, Chauvenet M, Faivre J and Bouvier AM: Management and prognosis of pancreatic cancer over a 30-year period. Br J Cancer. 101:215–218. 2009. View Article : Google Scholar : PubMed/NCBI
73	Liu X, Fu Y, Chen Q, Wu J, Gao W, Jiang K, Miao Y and Wei J: Predictors of distant metastasis on exploration in patients with potentially resectable pancreatic cancer. BMC Gastroenterol. 18:1682018. View Article : Google Scholar : PubMed/NCBI
74	Hohla F, Hopfinger G, Romeder F, Rinnerthaler G, Bezan A, Stättner S, Hauser-Kronberger C, Ulmer H and Greil R: Female gender may predict response to FOLFIRINOX in patients with unresectable pancreatic cancer: A single institution retrospective review. Int J Oncol. 44:319–326. 2014. View Article : Google Scholar
75	Lambert A, Jarlier M, Gourgou Bourgade S and Conroy T: Response to FOLFIRINOX by gender in patients with metastatic pancreatic cancer: Results from the PRODIGE 4/ACCORD 11 randomized trial. PLoS One. 12:e01832882017. View Article : Google Scholar