Radiofrequency ablation for locally advanced pancreatic cancer: SMAD4 analysis segregates a responsive subgroup of patients

  • Salvatore Paiella
  • Giuseppe Malleo
  • Ivana Cataldo
  • Clizia Gasparini
  • Matteo De Pastena
  • Giulia De Marchi
  • Giovanni Marchegiani
  • Borislav Rusev
  • Aldo Scarpa
  • Roberto Girelli
  • Alessandro Giardino
  • Isabella Frigerio
  • Mirko D’Onofrio
  • Erica Secchettin
  • Claudio Bassi
  • Roberto Salvia
ORIGINAL ARTICLE

Abstract

Purpose

SMAD4 mutational status correlates with pancreatic ductal adenocarcinoma (PDAC) failure pattern. We investigated in a subset of locally advanced patients submitted to radiofrequency ablation (RFA) whether the assessment of SMAD4 status is a useful way to select the patients.

Methods

Clinical, radiological, and follow-up details of patients submitted to RFA for locally advanced pancreatic cancer (LAPC), in whom cytohistological material was available at our institution, were retrospectively retrieved. SMAD4 expression was evaluated by immunohistochemistry (IHC) and considered “negative” or “positive.” The survival analysis was conducted using Kaplan-Meier and Cox proportional hazards models.

Results

The study population consisted of 30 patients. Thirteen patients (43.3%) received RFA upfront, whereas 17 (56.7%) after induction treatments. SMAD4 was mutant in 18 out of 30 patients (60%). The overall estimated post-RFA disease-specific survival (DSS) was 15 months (95% CI 11.64–18.35). The estimated post-RFA DSS of patients with wild-type and mutant SMAD4 was 22 and 12 months, respectively (log-rank p < 0.05). At the multivariate analysis, SMAD4 was the only independent predictor of survival (p = 0.05). The pattern of failure was not associated with SMAD4 status (p = 0.4).

Conclusions

Within patients undergoing RFA for LAPC, SMAD4 analysis could segregate a subgroup of subjects with improved survival, who likely benefited from tumor ablation.

Keywords

Pancreatic cancer Radiofrequency ablation SMAD4 Locally advanced pancreatic cancer 

Notes

Acknowledgements

The authors thank Ossian Elkington for his kind English language editing of the manuscript.

Authors’ contributions

Study conception and design: SP, GDM, RS, MDM, CB, AS; acquisition of data: CG, ES, GDM, IC, AG, IF, BR; analysis and interpretation of data: SP GM, GM, RG, RS, MDO; drafting of the manuscript: SP, GM, MDP, GM, AG, RS, IC; critical revision of the manuscript: SP, GM, IC, GDM, MDP, GM, RS, AG, IF, RG, AS, RS, CB, MDO.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was available for all the patients.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29.  https://doi.org/10.3322/caac.21254 CrossRefPubMedGoogle Scholar
  2. 2.
    Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Eshleman JR, Goggins M, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Cameron JL, Olino K, Schulick R, Winter J, Herman JM, Laheru D, Klein AP, Vogelstein B, Kinzler KW, Velculescu VE, Hruban RH (2009) SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res 15(14):4674–4679.  https://doi.org/10.1158/1078-0432.CCR-09-0227 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Seufferlein T, Van Laethem JL, Van Cutsem E, Berlin JD, Buchler M, Cervantes A, Haustermans K, Hidalgo M, O’Reilly EM, Verslype C, Schmiegel W, Rougier P (2014) The management of locally advanced pancreatic cancer: European Society of Digestive Oncology (ESDO) expert discussion and recommendations from the 14th ESMO/ World Congress on Gastrointestinal Cancer, Barcelona. Ann Oncol 25(Supplement 2):ii1–ii4.  https://doi.org/10.1093/annonc/mdu163 CrossRefGoogle Scholar
  4. 4.
    Mollberg N, Rahbari NN, Koch M, Hartwig W, Hoeger Y, Buchler MW, Weitz J (2011) Arterial resection during pancreatectomy for pancreatic cancer: a systematic review and meta-analysis. Ann Surg 254(6):882–893.  https://doi.org/10.1097/SLA.0b013e31823ac299 CrossRefPubMedGoogle Scholar
  5. 5.
    Giovinazzo F, Turri G, Katz MH, Heaton N, Ahmed I (2016) Meta-analysis of benefits of portal-superior mesenteric vein resection in pancreatic resection for ductal adenocarcinoma. Br J Surg 103(3):179–191.  https://doi.org/10.1002/bjs.9969 CrossRefPubMedGoogle Scholar
  6. 6.
    Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouche O, Shannon J, Andre T, Mineur L, Chibaudel B, Bonnetain F, Louvet C, Group LAPT (2016) Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 Randomized Clinical Trial. JAMA 315(17):1844–1853.  https://doi.org/10.1001/jama.2016.4324 CrossRefPubMedGoogle Scholar
  7. 7.
    Cantore M, Girelli R, Mambrini A, Frigerio I, Boz G, Salvia R, Giardino A, Orlandi M, Auriemma A, Bassi C (2012) Combined modality treatment for patients with locally advanced pancreatic adenocarcinoma. Br J Surg 99(8):1083–1088.  https://doi.org/10.1002/bjs.8789 CrossRefPubMedGoogle Scholar
  8. 8.
    Takaori K, Bassi C, Biankin A, Brunner TB, Cataldo I, Campbell F, Cunningham D, Falconi M, Frampton AE, Furuse J, Giovannini M, Jackson R, Nakamura A, Nealon W, Neoptolemos JP, Real FX, Scarpa A, Sclafani F, Windsor JA, Yamaguchi K, Wolfgang C, Johnson CD, cancer IEsgotcmop (2015) International Association of Pancreatology (IAP)/European Pancreatic Club (EPC) consensus review of guidelines for the treatment of pancreatic cancer. Pancreatology.  https://doi.org/10.1016/j.pan.2015.10.013
  9. 9.
    Paiella S, Salvia R, Ramera M, Girelli R, Frigerio I, Giardino A, Allegrini V, Bassi C (2016) Local ablative strategies for ductal pancreatic cancer (radiofrequency ablation, irreversible electroporation): a review. Gastroenterol Res Pract 2016:4508376.  https://doi.org/10.1155/2016/4508376 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Iacobuzio-Donahue CA, Fu B, Yachida S, Luo M, Abe H, Henderson CM, Vilardell F, Wang Z, Keller JW, Banerjee P, Herman JM, Cameron JL, Yeo CJ, Halushka MK, Eshleman JR, Raben M, Klein AP, Hruban RH, Hidalgo M, Laheru D (2009) DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 27(11):1806–1813.  https://doi.org/10.1200/JCO.2008.17.7188 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Iacobuzio-Donahue CA (2012) Genetic evolution of pancreatic cancer: lessons learnt from the pancreatic cancer genome sequencing project. Gut 61(7):1085–1094.  https://doi.org/10.1136/gut.2010.236026 CrossRefPubMedGoogle Scholar
  12. 12.
    Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA, Velculescu VE, Kinzler KW, Vogelstein B, Iacobuzio-Donahue CA (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467(7319):1114–1117.  https://doi.org/10.1038/nature09515 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    D’Onofrio M, Barbi E, Girelli R, Tinazzi Martini P, De Robertis R, Ciaravino V, Salvia R, Butturini G, Frigerio I, Milazzo T, Crosara S, Paiella S, Pederzoli P, Bassi C (2016) Variation of tumoral marker after radiofrequency ablation of pancreatic adenocarcinoma. J Gastrointest Oncol 7(2):213–220.  https://doi.org/10.3978/j.issn.2078-6891.2015.085 PubMedPubMedCentralGoogle Scholar
  14. 14.
    Girelli R, Frigerio I, Giardino A, Regi P, Gobbo S, Malleo G, Salvia R, Bassi C (2013) Results of 100 pancreatic radiofrequency ablations in the context of a multimodal strategy for stage III ductal adenocarcinoma. Langenbeck’s Arch Surg 398(1):63–69.  https://doi.org/10.1007/s00423-012-1011-z CrossRefGoogle Scholar
  15. 15.
    Boone BA, Sabbaghian S, Zenati M, Marsh JW, Moser AJ, Zureikat AH, Singhi AD, Zeh HJ 3rd, Krasinskas AM (2014) Loss of SMAD4 staining in pre-operative cell blocks is associated with distant metastases following pancreaticoduodenectomy with venous resection for pancreatic cancer. J Surg Oncol 110(2):171–175.  https://doi.org/10.1002/jso.23606 CrossRefPubMedGoogle Scholar
  16. 16.
    Rombouts SJ, Vogel JA, van Santvoort HC, van Lienden KP, van Hillegersberg R, Busch OR, Besselink MG, Molenaar IQ (2015) Systematic review of innovative ablative therapies for the treatment of locally advanced pancreatic cancer. Br J Surg 102(3):182–193.  https://doi.org/10.1002/bjs.9716 CrossRefPubMedGoogle Scholar
  17. 17.
    D’Onofrio M, Crosara S, De Robertis R, Butturini G, Salvia R, Paiella S, Bassi C, Pozzi Mucelli R (2016) Percutaneous radiofrequency ablation of unresectable locally advanced pancreatic cancer: preliminary results. Technol Cancer Res Treat.  https://doi.org/10.1177/1533034616649292
  18. 18.
    Chu KF, Dupuy DE (2014) Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat Rev Cancer 14(3):199–208.  https://doi.org/10.1038/nrc3672 CrossRefPubMedGoogle Scholar
  19. 19.
    Yachida S, White CM, Naito Y, Zhong Y, Brosnan JA, Macgregor-Das AM, Morgan RA, Saunders T, Laheru DA, Herman JM, Hruban RH, Klein AP, Jones S, Velculescu V, Wolfgang CL, Iacobuzio-Donahue CA (2012) Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clin Cancer Res 18(22):6339–6347.  https://doi.org/10.1158/1078-0432.CCR-12-1215 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wilentz RE, Su GH, Dai JL, Sparks AB, Argani P, Sohn TA, Yeo CJ, Kern SE, Hruban RH (2000) Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas : a new marker of DPC4 inactivation. Am J Pathol 156(1):37–43.  https://doi.org/10.1016/S0002-9440(10)64703-7 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    David CJ, Huang YH, Chen M, Su J, Zou Y, Bardeesy N, Iacobuzio-Donahue CA, Massague J (2016) TGF-beta tumor suppression through a lethal EMT. Cell 164(5):1015–1030.  https://doi.org/10.1016/j.cell.2016.01.009 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH (2000) Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 60(7):2002–2006PubMedGoogle Scholar
  23. 23.
    Iacobuzio-Donahue CA, Wilentz RE, Argani P, Yeo CJ, Cameron JL, Kern SE, Hruban RH (2000) Dpc4 protein in mucinous cystic neoplasms of the pancreas: frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am J Surg Pathol 24(11):1544–1548CrossRefPubMedGoogle Scholar
  24. 24.
    Du Y, Zhou X, Huang Z, Qiu T, Wang J, Zhu W, Wang T, Liu P (2014) Meta-analysis of the prognostic value of smad4 immunohistochemistry in various cancers. PLoS One 9(10):e110182.  https://doi.org/10.1371/journal.pone.0110182 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Shugang X, Hongfa Y, Jianpeng L, Xu Z, Jingqi F, Xiangxiang L, Wei L (2016) Prognostic value of SMAD4 in pancreatic cancer: a meta-analysis. Transl Oncol 9(1):1–7.  https://doi.org/10.1016/j.tranon.2015.11.007 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Shin SH, Kim HJ, Hwang DW, Lee JH, Song KB, Jun E, Shim IK, Hong SM, Kim HJ, Park KM, Lee YJ, Kim SC (2017) The DPC4/SMAD4 genetic status determines recurrence patterns and treatment outcomes in resected pancreatic ductal adenocarcinoma: a prospective cohort study. Oncotarget 8(11):17945–17959.  10.18632/oncotarget.14901 PubMedPubMedCentralGoogle Scholar
  27. 27.
    Infante JR, Matsubayashi H, Sato N, Tonascia J, Klein AP, Riall TA, Yeo C, Iacobuzio-Donahue C, Goggins M (2007) Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol 25(3):319–325.  https://doi.org/10.1200/JCO.2006.07.8824 CrossRefPubMedGoogle Scholar
  28. 28.
    Winter JM, Tang LH, Klimstra DS, Liu W, Linkov I, Brennan MF, D’Angelica MI, DeMatteo RP, Fong Y, Jarnagin WR, O’Reilly EM, Allen PJ (2013) Failure patterns in resected pancreas adenocarcinoma: lack of predicted benefit to SMAD4 expression. Ann Surg 258(2):331–335.  https://doi.org/10.1097/SLA.0b013e31827fe9ce CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Biankin AV, Morey AL, Lee CS, Kench JG, Biankin SA, Hook HC, Head DR, Hugh TB, Sutherland RL, Henshall SM (2002) DPC4/Smad4 expression and outcome in pancreatic ductal adenocarcinoma. J Clin Oncol 20(23):4531–4542CrossRefPubMedGoogle Scholar
  30. 30.
    Bachet JB, Marechal R, Demetter P, Bonnetain F, Couvelard A, Svrcek M, Bardier-Dupas A, Hammel P, Sauvanet A, Louvet C, Paye F, Rougier P, Penna C, Vaillant JC, Andre T, Closset J, Salmon I, Emile JF, Van Laethem JL (2012) Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma. Ann Oncol 23(9):2327–2335.  https://doi.org/10.1093/annonc/mdr617 CrossRefPubMedGoogle Scholar
  31. 31.
    Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grutzmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM, Australian Pancreatic Cancer Genome I, Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM (2016) Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531(7592):47–52.  https://doi.org/10.1038/nature16965 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Salvatore Paiella
    • 1
  • Giuseppe Malleo
    • 1
  • Ivana Cataldo
    • 2
  • Clizia Gasparini
    • 1
  • Matteo De Pastena
    • 1
  • Giulia De Marchi
    • 3
  • Giovanni Marchegiani
    • 1
  • Borislav Rusev
    • 2
    • 3
    • 4
  • Aldo Scarpa
    • 2
    • 3
    • 4
  • Roberto Girelli
    • 5
  • Alessandro Giardino
    • 5
  • Isabella Frigerio
    • 5
  • Mirko D’Onofrio
    • 6
  • Erica Secchettin
    • 1
  • Claudio Bassi
    • 1
  • Roberto Salvia
    • 1
  1. 1.General and Pancreatic Surgery Department, Pancreas InstituteUniversity of Verona Hospital TrustVeronaItaly
  2. 2.Department of Pathology and DiagnosticsUniversity of Verona Hospital TrustVeronaItaly
  3. 3.Gastroenterology B Department, Pancreas InstituteUniversity of Verona Hospital TrustVeronaItaly
  4. 4.ARC-Net Research CentreUniversity of Verona Hospital TrustVeronaItaly
  5. 5.HPB Unit, Casa di Cura PederzoliVeronaItaly
  6. 6.Department of Radiology, Pancreas InstituteUniversity of Verona Hospital TrustVeronaItaly

Personalised recommendations