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Impact of Driver Mutations on the Evolution of Isolated Metachronous Lung Metastasis of Pancreatic Ductal adenocarcinoma

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Abstract

Background

The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing sharply. The survival of patients with metastases is usually about a year. However, the occurrence of isolated lung metastases after resection of the primary tumor, although rare, seems to indicate a better prognosis, with an average survival ranging from 40 to 80 months. KRAS, TP53, CDK2NA, and SMAD4 are the most common driver genes in pancreatic adenocarcinoma.

Objective

Our objectives were to determine whether a link exists between survival and mutations of driver genes in patients with isolated pulmonary metastases.

Methods

All patients who underwent curative surgery in our institution between 2010 and 2018 were included in the study. From these, we identified patients for whom recurrence was only pulmonary and those with metastases at other sites. KRAS, TP53, CDK2NA, and SMAD4 were analyzed on the primary tumor of patients with pulmonary metastases.

Results

Among 233 patients diagnosed with PDAC in our institution over 8 years, 41 (17.5%) underwent curative surgery. Of these, seven (3%) developed isolated pulmonary metastases, 32 developed other metastases, and two did not recur. Median survival was 59 months for patients with isolated lung metastases and 25.3 months for patients with metastases at other sites. An absence of mutations of two driver genes in primary tumors (CDK2NA and SMAD4) was observed in patients with isolated pulmonary metastases.

Conclusions

The absence of mutations in the CDK2NA and SMAD4 tumor-suppressor genes in patients with isolated pulmonary metastases contrasts with the commonly observed high rates of driver gene mutations and suggests a link with overall survival.

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References

  1. Bouvier AM, Uhry Z, Jooste V, Drouillard A, Remontet L, Launoy G, Leone N, French Network of Cancer Registries (FRANCIM). Focus on an unusual rise in pancreatic cancer incidence in France. Int J Epidemiol. 2017;46:1764–72.

    Article  Google Scholar 

  2. Hernandez JM, Morton CA, Al-Saadi S, Villadolid D, Cooper J, Bowers C, Rosemurgy AS. The natural history of resected pancreatic cancer without adjuvant chemotherapy. Ann Surg. 2010;76:480–5.

    Google Scholar 

  3. Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310:1473–81.

    Article  CAS  Google Scholar 

  4. Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, Choné L, Francois E, Artru P, Biagi JJ, Lecomte T, Assenat E, Faroux R, Ychou M, Volet J, Sauvanet A, Breysacher G, Di Fiore F, Cripps C, Kavan P, Texereau P, Bouhier-Leporrier K, Khemissa-Akouz F, Legoux JL, Juzyna B, Gourgou S, O’Callaghan CJ, Jouffroy-Zeller C, Rat P, Malka D, Castan F, Bachet JB, Canadian Cancer Trials Group and the Unicancer-GI-PRODIGE Group. FOLFIRINOX or Gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379:2395–406.

    Article  CAS  Google Scholar 

  5. Sahin IH, Elias H, Chou JF, Capanu M, O’Reilly EM. Pancreatic adenocarcinoma: insights into patterns of recurrence and disease behavior. BMC Cancer. 2018;18:769.

    Article  Google Scholar 

  6. Downs-Canner S, Zenati M, Boone BA, Varley PR, Steve J, Hogg ME, Zureikat A, Zeh HJ, Lee KK. The indolent nature of pulmonary metastases from ductal adenocarcinoma of the pancreas. J Surg Oncol. 2015;112:80–5.

    Article  Google Scholar 

  7. Lovecek M, Skalicky P, Chudacek J, Szkorupa M, Svebisova H, Lemstrova R, Ehrmann J, Melichar B, Yogeswara T, Klos D, Vrba R, Havlik R, Mohelnikova-Duchonova B. Different clinical presentations of metachronous pulmonary metastases after resection of pancreatic ductal adenocarcinoma: retrospective study and review of the literature. World J Gastroenterol. 2017;23:6420–8.

    Article  CAS  Google Scholar 

  8. Groot VP, Gemenetzis G, Blair AB, Ding D, Javed AA, Burkhart RA, Yu J, Borel Rinkes IH, Molenaar IQ, Cameron JL, Fishman EK, Hruban RH, Weiss MJ, Wolfgang CL, He J. Implications of the pattern of disease recurrence on survival following pancreatectomy for pancreatic ductal adenocarcinoma. Ann Surg Oncol. 2018;25:2475–83.

    Article  Google Scholar 

  9. 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, Grützmann 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, 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, Australian Pancreatic Cancer Genome Initiative. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52.

    Article  CAS  Google Scholar 

  10. Grant TJ, Hua K, Singh A. Molecular pathogenesis of pancreatic cancer. Prog Mol Biol Transl Sci. 2016;144:241–75.

    Article  CAS  Google Scholar 

  11. Arnaoutakis GJ, Rangachari D, Laheru DA, Iacobuzio-Donahue CA, Hruban RH, Herman JM, Edil BH, Pawlik TM, Schulick RD, Cameron JL, Meneshian A, Yang SC, Wolfgang CL. Pulmonary resection for isolated pancreatic adenocarcinoma metastasis: an analysis of outcomes and survival. J Gastrointest Surg. 2011;15:1611–7.

    Article  Google Scholar 

  12. Mao C, Domenico DR, Kim K, Hanson DJ, Howard JM. Observations on the developmental patterns and the consequences of pancreatic exocrine adenocarcinoma. Findings of 154 autopsies. Arch Surg. 1995;130:125–34.

    Article  CAS  Google Scholar 

  13. Kamisawa T, Isawa T, Koike M, Tsuruta K, Okamoto A. Hematogenous metastases of pancreatic ductal adenocarcinoma. Pancreas. 1995;11:345–9.

    Article  CAS  Google Scholar 

  14. Barhli A, Cros J, Bartholin L, Neuzillet C. Prognostic stratification of resected pancreatic ductal adenocarcinoma: past, present, and future. Dig Liver Dis. 2018;50:979–90.

    Article  Google Scholar 

  15. Qian ZR, Rubinson DA, Nowak JA, Morales-Oyarvide V, Dunne RF, Kozak MM, Welch MW, Brais LK, Da Silva A, Li T, Li W, Masuda A, Yang J, Shi Y, Gu M, Masugi Y, Bui J, Zellers CL, Yuan C, Babic A, Khalaf N, Aguirre A, Ng K, Miksad RA, Bullock AJ, Chang DT, Tseng JF, Clancy TE, Linehan DC, Findeis-Hosey JJ, Doyle LA, Thorner AR, Ducar M, Wollison B, Laing A, Hahn WC, Meyerson M, Fuchs CS, Ogino S, Hornick JL, Hezel AF, Koong AC, Wolpin BM. Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma. JAMA Oncol. 2018;4:e173420.

    Article  Google Scholar 

  16. Bournet B, Muscari F, Buscail C, Assenat E, Barthet M, Hammel P, Selves J, Guimbaud R, Cordelier P, Buscail L. RAS G12D mutation subtype is a prognostic factor for advanced pancreatic adenocarcinoma. Clin Transl Gastroenterol. 2016;7:e157.

    Article  CAS  Google Scholar 

  17. 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. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27:1806–13.

    Article  CAS  Google Scholar 

  18. Tascilar M, Skinner HG, Rosty C, Sohn T, Wilentz RE, Offerhaus GJ, Adsay V, Abrams RA, Cameron JL, Kern SE, Yeo CJ, Hruban RH, Goggins M. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2001;7:4115–21.

    CAS  PubMed  Google Scholar 

  19. Waddell N, Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, Quinn MC, Robertson AJ, Fadlullah MZ, Bruxner TJ, Christ AN, Harliwong I, Idrisoglu S, Manning S, Nourse C, Nourbakhsh E, Wani S, Wilson PJ, Markham E, Cloonan N, Anderson MJ, Fink JL, Holmes O, Kazakoff SH, Leonard C, Newell F, Poudel B, Song S, Taylor D, Waddell N, Wood S, Xu Q, Wu J, Pinese M, Cowley MJ, Lee HC, Jones MD, Nagrial AM, Humphris J, Chantrill LA, Chin V, Steinmann AM, Mawson A, Humphrey ES, Colvin EK, Chou A, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Pettitt JA, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Jamieson NB, Graham JS, Niclou SP, Bjerkvig R, Grützmann R, Aust D, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Falconi M, Zamboni G, Tortora G, Tempero MA, Australian Pancreatic Cancer Genome Initiative, Gill AJ, Eshleman JR, Pilarsky C, Scarpa A, Musgrove EA, Pearson JV, Biankin AV, Grimmond SM. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495–501.

    Article  CAS  Google Scholar 

  20. Felsenstein M, Hruban RH, Wood LD. New developments in the molecular mechanisms of pancreatic tumorigenesis. Adv Anat Pathol. 2018;25:131–42.

    Article  CAS  Google Scholar 

  21. Oshima M, Okano K, Muraki S, Haba R, Maeba T, Suzuki Y, Yachida S. Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Ann Surg. 2013;258:336–46.

    Article  Google Scholar 

  22. Cui Y, Brosnan JA, Blackford AL, Sur S, Hruban RH, Kinzler KW, Vogelstein B, Maitra A, Diaz LA Jr, Iacobuzio-Donahue CA, Eshleman JR. Genetically defined subsets of human pancreatic cancer show unique in vitro chemosensitivity. Clin Cancer Res. 2012;18:6519–30.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank Nathanaelle Cornet for her contribution to this work.

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Authors and Affiliations

  1. Department of Gastroenterology and Digestive Oncology, CHU Angers, 4 rue Larrey, 49933, Angers Cedex 9, France

    Carole Vitellius, Océane Griveaux, Olivier Ingster, Eloise Dincuff & François-Xavier Caroli-Bosc

  2. Department of Pathology, CHU Angers, Angers Cedex 9, France

    Benjamin Morvant & Marie-Christine Rousselet

  3. Department of Genomic Oncology, CHU Angers, Angers Cedex 9, France

    Estelle Pedrono & Philippe Guardiola

  4. Department of Visceral Surgery, CHU Angers, Angers Cedex 9, France

    Aurélien Venara

  5. Transverse Unit of Innovative Therapeutics in Medical Oncology, CHU Angers, Angers Cedex 9, France

    Nathalie Baize

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  1. Carole Vitellius
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Correspondence to François-Xavier Caroli-Bosc.

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Funding

No sources of funding were used to conduct this study or prepare this manuscript.

Conflict of interest

Carole Vitellius, Océane Griveaux, Benjamin Morvant, Estelle Pedrono, Aurélien Venara, Olivier Ingster, Nathalie Baize, MD, Eloise Dincuff, Marie-Christine Rousselet, Philippe Guardiola, and François-Xavier Caroli-Bosc have no conflicts of interest that are directly relevant to the content of this article.

Ethical approval

This study was approved by the Committee for the Protection of Persons of the University Hospital of Angers for deceased patients on 9 July 2019.

Informed consent

Informed consent was obtained from each living patient.

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Vitellius, C., Griveaux, O., Morvant, B. et al. Impact of Driver Mutations on the Evolution of Isolated Metachronous Lung Metastasis of Pancreatic Ductal adenocarcinoma. Mol Diagn Ther 24, 443–449 (2020). https://doi.org/10.1007/s40291-020-00472-9

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  • DOI: https://doi.org/10.1007/s40291-020-00472-9

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