Clinical significance of stromal ER and PR expression in periampullary adenocarcinoma
Tóm tắt
Tamoxifen treatment has previously been reported to confer life-prolonging effects in patients with advanced pancreatic cancer, and most evidently so in women. None of these trials did however include biomarkers, and the relevance of female hormone signaling in pancreatic or other periampullary adenocarcinoma remains largely unexplored. The aim of this study was to examine the extent and potential clinical significance of estrogen receptor-α (ER) and progesterone receptor (PR) expression in pancreatic and other periampullary cancers. ER and PR expression was examined using immunohistochemistry on tissue microarrays with primary tumors from a retrospective consecutive cohort of 175 patients with resected periampullary adenocarcinoma, with long-term clinical follow-up. Non-parametric and Chi square tests were applied to examine the associations of stromal ER and PR expression with patient and tumor characteristics. Kaplan-Meier analysis and log rank test were applied to illustrate survival differences in relation to ER and PR expression. Cox regression proportional hazards models were applied to examine the associations between investigative factors and risk of death and recurrence, and to test for interactions between KRAS mutation status and hormone receptor expression in relation to survival. Expression of both ER and PR was more frequent in the tumor-associated stroma than in the epithelium. A significant prognostic interaction, independent of tumor morphology, was found between stromal PR expression and KRAS mutation status in relation to both overall and recurrence-free survival (pinteraction = 0.026 and pinteraction = 0.005), in particular in women (pinteraction = 0.002 and pinteraction = 0.005). Specifically, stromal PR expression was associated with a prolonged survival in patients with KRAS-mutated tumors, whereas the opposite was seen for KRAS wild-type tumors. The prognostic value of ER positivity was limited to the subgroup of women with tumors of pancreatic origin. These results demonstrate that stromal PR rather than ER expression, together with KRAS mutation status, provides long-term prognostic information in patients with periampullary adenocarcinoma. Further study into the mechanistic basis for these observations may unveil important clues to the pathogenesis of these cancers and open up for the discovery of novel treatment options.
Tài liệu tham khảo
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.
Kimura W, Futakawa N, Zhao B. Neoplastic diseases of the papilla of Vater. J Hepato-Biliary-Pancreat Surg. 2004;11(4):223–31.
Carter JT, Grenert JP, Rubenstein L, Stewart L, Way LW. Tumors of the ampulla of vater: histopathologic classification and predictors of survival. J Am Coll Surg. 2008;207(2):210–8.
Westgaard A, Tafjord S, Farstad IN, Cvancarova M, Eide TJ, Mathisen O, et al. Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma. BMC Cancer. 2008;8:170.
Bronsert P, Kohler I, Werner M, Makowiec F, Kuesters S, Hoeppner J, et al. Intestinal-type of differentiation predicts favourable overall survival: confirmatory clinicopathological analysis of 198 periampullary adenocarcinomas of pancreatic, biliary, ampullary and duodenal origin. BMC Cancer. 2013;13:428.
McGuigan A, Kelly P, Turkington RC, Jones C, Coleman HG, McCain RS. Pancreatic cancer: a review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol. 2018;24(43):4846–61.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.
Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7(4):e1000267.
Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.
Grant TJ, Hua K, Singh A. Molecular pathogenesis of pancreatic cancer. Prog Mol Biol Transl Sci. 2016;144:241–75.
Chau I. Clinical development of PD-1/PD-L1 immunotherapy for gastrointestinal cancers: facts and hopes. Clin Cancer Res. 2017;23(20):6002–11.
Theve NO, Pousette A, Carlstrom K. Adenocarcinoma of the pancreas--a hormone sensitive tumor? A preliminary report on Nolvadex treatment. Clin Oncol. 1983;9(3):193–7.
Tonnesen K, Kamp-Jensen M. Antiestrogen therapy in pancreatic carcinoma: a preliminary report. Eur J Surg Oncol. 1986;12(1):69–70.
Horimi T, Takasaki M, Toki A, Nishimura W, Morita S. The beneficial effect of tamoxifen therapy in patients with resected adenocarcinoma of the pancreas. Hepatogastroenterology. 1996;43(11):1225–9.
Bakkevold KE, Pettersen A, Arnesjo B, Espehaug B. Tamoxifen therapy in unresectable adenocarcinoma of the pancreas and the papilla of Vater. Br J Surg. 1990;77(7):725–30.
Wong A, Chan A. Survival benefit of tamoxifen therapy in adenocarcinoma of pancreas. A case-control study. Cancer. 1993;71(7):2200–3.
Kreiger N, Lacroix J, Sloan M. Hormonal factors and pancreatic cancer in women. Ann Epidemiol. 2001;11(8):563–7.
Skinner HG, Michaud DS, Colditz GA, Giovannucci EL, Stampfer MJ, Willett WC, et al. Parity, reproductive factors, and the risk of pancreatic cancer in women. Cancer Epidemiol Biomark Prev. 2003;12(5):433–8.
Teras LR, Patel AV, Rodriguez C, Thun MJ, Calle EE. Parity, other reproductive factors, and risk of pancreatic cancer mortality in a large cohort of U.S. women (United States). Cancer Causes Control. 2005;16(9):1035–40.
Lin Y, Kikuchi S, Tamakoshi A, Kawamura T, Inaba Y, Kurosawa M, et al. Association of menstrual and reproductive factors with pancreatic cancer risk in women: findings of the Japan collaborative cohort study for evaluation of cancer risk. J Gastroenterol. 2006;41(9):878–83.
Prizment AE, Anderson KE, Hong CP, Folsom AR. Pancreatic cancer incidence in relation to female reproductive factors: Iowa women’s health study. JOP. 2007;8(1):16–27.
Zhang Y, Coogan PF, Palmer JR, Strom BL, Rosenberg L. A case-control study of reproductive factors, female hormone use, and risk of pancreatic cancer. Cancer Causes Control. 2010;21(3):473–8.
Lucenteforte E, Zucchetto A, Bosetti C, Talamini R, Negri E, Serraino D, et al. Reproductive and hormonal factors and pancreatic cancer risk in women. Pancreas. 2011;40(3):460–3.
Lee E, Horn-Ross PL, Rull RP, Neuhausen SL, Anton-Culver H, Ursin G, et al. Reproductive factors, exogenous hormones, and pancreatic cancer risk in the CTS. Am J Epidemiol. 2013;178(9):1403–13.
Andersson G, Borgquist S, Jirstrom K. Hormonal factors and pancreatic cancer risk in women: the Malmo diet and cancer study. Int J Cancer. 2018;143(1):52–62.
Bueno de Mesquita HB, Maisonneuve P, Moerman CJ, Walker AM. Anthropometric and reproductive variables and exocrine carcinoma of the pancreas: a population-based case-control study in The Netherlands. Int J Cancer. 1992;52(1):24–9.
Fernandez E, La Vecchia C, D'Avanzo B, Negri E. Menstrual and reproductive factors and pancreatic cancer risk in women. Int J Cancer. 1995;62(1):11–4.
Ji BT, Hatch MC, Chow WH, McLaughlin JK, Dai Q, Howe GR, et al. Anthropometric and reproductive factors and the risk of pancreatic cancer: a case-control study in Shanghai, China. Int J Cancer. 1996;66(4):432–7.
Karlson BM, Wuu J, Hsieh CC, Lambe M, Ekbom A. Parity and the risk of pancreatic cancer: a nested case-control study. Int J Cancer. 1998;77(2):224–7.
Duell EJ, Holly EA. Reproductive and menstrual risk factors for pancreatic cancer: a population-based study of San Francisco Bay Area women. Am J Epidemiol. 2005;161(8):741–7.
Greenway B, Iqbal MJ, Johnson PJ, Williams R. Oestrogen receptor proteins in malignant and fetal pancreas. Br Med J (Clin Res Ed). 1981;283(6294):751–3.
Georgiadou D, Sergentanis TN, Sakellariou S, Vlachodimitropoulos D, Psaltopoulou T, Lazaris AC, et al. Prognostic role of sex steroid receptors in pancreatic adenocarcinoma. Pathol Res Pract. 2016;212(1):38–43.
Elebro J, Jirstrom K. Use of a standardized diagnostic approach improves the prognostic information of histopathologic factors in pancreatic and periampullary adenocarcinoma. Diagn Pathol. 2014;9:80.
Elebro J, Heby M, Gaber A, Nodin B, Jonsson L, Fristedt R, et al. Prognostic and treatment predictive significance of SATB1 and SATB2 expression in pancreatic and periampullary adenocarcinoma. J Transl Med. 2014;12:289.
Fristedt R, Elebro J, Gaber A, Jonsson L, Heby M, Yudina Y, et al. Reduced expression of the polymeric immunoglobulin receptor in pancreatic and periampullary adenocarcinoma signifies tumour progression and poor prognosis. PLoS One. 2014;9(11):e112728.
Heby M, Elebro J, Nodin B, Jirstrom K, Eberhard J. Prognostic and predictive significance of podocalyxin-like protein expression in pancreatic and periampullary adenocarcinoma. BMC Clin Pathol. 2015;15:10.
Elebro J, Ben Dror L, Heby M, Nodin B, Jirstrom K, Eberhard J. Prognostic effect of hENT1, dCK and HuR expression by morphological type in periampullary adenocarcinoma, including pancreatic cancer. Acta Oncol. 2016;55(3):286–96.
Heby M, Lundgren S, Nodin B, Elebro J, Eberhard J, Jirstrom K. Relationship between mismatch repair immunophenotype and long-term survival in patients with resected periampullary adenocarcinoma. J Transl Med. 2018;16(1):66.
Lundgren S, Olsson Hau S, Elebro J, Heby M, Karnevi E, Nodin B, et al. Mutational landscape in resected periampullary adenocarcinoma: relationship with morphology and clinical outcome. JCO Precision Oncol. 2019;3:1–8.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1.
Bender R, Lange S. Adjusting for multiple testing--when and how? J Clin Epidemiol. 2001;54(4):343–9.
Crippa S, Salvia R, Warshaw AL, Dominguez I, Bassi C, Falconi M, et al. Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients. Ann Surg. 2008;247(4):571–9.
Ishida K, Sasano H, Moriya T, Takahashi Y, Sugimoto R, Mue Y, et al. Immunohistochemical analysis of steroidogenic enzymes in ovarian-type stroma of pancreatic mucinous cystic neoplasms: comparative study of subepithelial stromal cells in intraductal papillary mucinous neoplasms of the pancreas. Pathol Int. 2016;66(5):281–7.
Izumo A, Yamaguchi K, Eguchi T, Nishiyama K, Yamamoto H, Yonemasu H, et al. Mucinous cystic tumor of the pancreas: immunohistochemical assessment of “ovarian-type stroma”. Oncol Rep. 2003;10(3):515–25.
Reid MD, Saka B, Balci S, Goldblum AS, Adsay NV. Molecular genetics of pancreatic neoplasms and their morphologic correlates: an update on recent advances and potential diagnostic applications. Am J Clin Pathol. 2014;141(2):168–80.
Jang KT, Park SM, Basturk O, Bagci P, Bandyopadhyay S, Stelow EB, et al. Clinicopathologic characteristics of 29 invasive carcinomas arising in 178 pancreatic mucinous cystic neoplasms with ovarian-type stroma: implications for management and prognosis. Am J Surg Pathol. 2015;39(2):179–87.
Jimenez RE, Warshaw AL, Z'Graggen K, Hartwig W, Taylor DZ, Compton CC, et al. Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy. Ann Surg. 1999;230(4):501–9 discussion 9-11.
Janzen DM, Rosales MA, Paik DY, Lee DS, Smith DA, Witte ON, et al. Progesterone receptor signaling in the microenvironment of endometrial cancer influences its response to hormonal therapy. Cancer Res. 2013;73(15):4697–710.
Seeliger H, Pozios I, Assmann G, Zhao Y, Muller MH, Knosel T, et al. Expression of estrogen receptor beta correlates with adverse prognosis in resected pancreatic adenocarcinoma. BMC Cancer. 2018;18(1):1049.
Pozios I, Knosel T, Zhao Y, Assmann G, Pozios I, Muller MH, et al. Expression of phosphorylated estrogen receptor beta is an independent negative prognostic factor for pancreatic ductal adenocarcinoma. J Cancer Res Clin Oncol. 2018;144(10):1887–97.
Andersson S, Sundberg M, Pristovsek N, Ibrahim A, Jonsson P, Katona B, et al. Insufficient antibody validation challenges oestrogen receptor beta research. Nat Commun. 2017;8:15840.
Gagliardi A, Collins DC. Inhibition of angiogenesis by antiestrogens. Cancer Res. 1993;53(3):533–5.
O'Brian CA, Liskamp RM, Solomon DH, Weinstein IB. Inhibition of protein kinase C by tamoxifen. Cancer Res. 1985;45(6):2462–5.
Su HD, Mazzei GJ, Vogler WR, Kuo JF. Effect of tamoxifen, a nonsteroidal antiestrogen, on phospholipid/calcium-dependent protein kinase and phosphorylation of its endogenous substrate proteins from the rat brain and ovary. Biochem Pharmacol. 1985;34(20):3649–53.
Johnson KE, Forward JA, Tippy MD, Ceglowski JR, El-Husayni S, Kulenthirarajan R, et al. Tamoxifen directly inhibits platelet angiogenic potential and platelet-mediated metastasis. Arterioscler Thromb Vasc Biol. 2017;37(4):664–74.