Advertisement

Journal of Gastrointestinal Cancer

, Volume 47, Issue 4, pp 381–388 | Cite as

Neoadjuvant Imatinib in Locally Advanced Gastrointestinal stromal Tumours, Will Kit Mutation Analysis Be a Pathfinder?

  • Anant Ramaswamy
  • Vikas Ostwal
  • Omshree Shetty
  • Arvind Sahu
  • Davinder Paul
  • Trupti Pai
  • Mamta Gurav
  • Nitin Shetty
  • Shailesh Shrikhande
Original Research
  • 90 Downloads

Abstract

Introduction

Longer duration of neoadjuvant (NA) imatinib (IM) used for locally advanced (LA) gastrointestinal stromal tumours (GIST) is not based on biology of the tumour reflected by kit mutation analysis.

Material and Methods

LA or locally recurrent (LR) GIST treated with NA IM from May 2008 to March 2015 from a prospective database were included in the analysis. Archived formalin-fixed paraffin-embedded tissues (FFPE) were used for testing KIT exons 9, 11, 13 and 17 by PCR.

Results

One hundred twenty-five patients with LA or LR GIST were treated with NA IM. Forty-five patients (36 %) had undergone c-kit mutation testing. Exon 11 was seen in 25 patients (55.5 %), 3 with exon 9 (6.7 %) and 2 with exon 13 (4.4 %). Twelve were wild type (26.6 %) and  3 (6.7 %) were declared uninterpretable. Response rate (RR) for the exon 11 mutants was higher than the non-exon 11 mutant group (84 vs. 40 %, p = 0.01). Disease stabilization rate (DSR) rates were also higher in the exon 11 subgroup than non-exon 11 group (92 vs. 75 %). Eighty-four per cent exon 11 and 75 % non-exon 11 mutants were surgical candidates. Patients undergoing surgery had significantly improved event free survival (EFS) (p < 0.001) compared to patients not undergoing surgery, with the same trend seen in OS (p = 0.021). Patients with a SD on response to NA IM had a lower EFS (p = 0.076) and OS compared to patients achieving CR/PR. There were no differences between the various exon variants in terms of outcomes and responses

Conclusion

Upfront evaluation of kit mutation status may help us in delineating separate treatment strategies for potentially biologically different tumours and assessing the correct timing of surgery for this subset of GIST.

Keywords

Gist Locally advanced Neoadjuvant imatinib KIT mutation analysis 

Notes

Compliance with Ethical Standards

Institutional Ethics Committee (IEC) approval was obtained.

Conflict of Interest

The authors declare that they do not have conflict of interest.

Funding

No funding received.

Inform Consent

Consent waiver was granted by the IEC as it was a retrospective study.

References

  1. 1.
    Fletcher CDM, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33(5):459–65.CrossRefPubMedGoogle Scholar
  2. 2.
    Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130(10):1466–78.PubMedGoogle Scholar
  3. 3.
    Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, et al. One vs three years of adjuvant Imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307(12):1265–72.CrossRefPubMedGoogle Scholar
  4. 4.
    Shrikhande SV, Marda SS, Suradkar K, Arya S, Shetty GS, Bal M, et al. Gastrointestinal stromal tumors: case series of 29 patients defining the role of Imatinib prior to surgery. World J Surg. 2012;36(4):864–71.CrossRefPubMedGoogle Scholar
  5. 5.
    Koontz MZ, Visser BM, Kunz PL. Neoadjuvant Imatinib for borderline resectable GIST. J Natl Compr Cancer Netw JNCCN. 2012;10(12):1477–82. quiz 1482.PubMedGoogle Scholar
  6. 6.
    Tielen R, Verhoef C, van Coevorden F, Gelderblom H, Sleijfer S, Hartgrink HH, et al. Surgical treatment of locally advanced, non-metastatic, gastrointestinal stromal tumours after treatment with Imatinib. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol. 2013;39(2):150–5.Google Scholar
  7. 7.
    Wang D, Zhang Q, Blanke CD, Demetri GD, Heinrich MC, Watson JC, et al. Phase II trial of neoadjuvant/adjuvant Imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of radiation therapy oncology group 0132. Ann Surg Oncol. 2012;19(4):1074–80.CrossRefPubMedGoogle Scholar
  8. 8.
    Rutkowski P, Gronchi A, Hohenberger P, Bonvalot S, Schöffski P, Bauer S, et al. Neoadjuvant Imatinib in locally advanced gastrointestinal stromal tumors (GIST): the EORTC STBSG experience. Ann Surg Oncol. 2013;20(9):2937–43.CrossRefPubMedGoogle Scholar
  9. 9.
    Neoadjuvant treatment of locally advanced GIST: results of APOLLON, a prospective, open label phase II study in KIT- or PDGFRA-positive tumors. J Clin Oncol [Internet]. [cited 2016 Jan 4]; Available from: http://meetinglibrary.asco.org/content/93393-114.
  10. 10.
    Fiore M, Palassini E, Fumagalli E, Pilotti S, Tamborini E, Stacchiotti S, et al. Preoperative Imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumors (GIST). Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol. 2009;35(7):739–45.Google Scholar
  11. 11.
    Andtbacka RHI, Ng CS, Scaife CL, Cormier JN, Hunt KK, Pisters PWT, et al. Surgical resection of gastrointestinal stromal tumors after treatment with Imatinib. Ann Surg Oncol. 2007;14(1):14–24.CrossRefPubMedGoogle Scholar
  12. 12.
    Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and Imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21(23):4342–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Wozniak A, Rutkowski P, Piskorz A, Ciwoniuk M, Osuch C, Bylina E, et al. Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumours (GIST): Polish Clinical GIST Registry experience. Ann Oncol. 2011 Apr 28; mdr127.Google Scholar
  14. 14.
    Kang HJ, Ryu M-H, Kim K-M, Park YS, Choi J, Ryoo B-Y, et al. Imatinib efficacy by tumor genotype in Korean patients with advanced gastrointestinal stromal tumors (GIST): the Korean GIST study group (KGSG) study. Acta Oncol Stockh Swed. 2012;51(4):528–36.CrossRefGoogle Scholar
  15. 15.
    Bednarski BK, Araujo DM, Yi M, Torres KE, Lazar A, Trent JC, et al. Analysis of prognostic factors impacting oncologic outcomes after neoadjuvant tyrosine kinase inhibitor therapy for gastrointestinal stromal tumors. Ann Surg Oncol. 2014;21(8):2499–505.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT, et al. KIT mutations and dose selection for Imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer Oxf Engl. 1990;42(8):1093–103.CrossRefGoogle Scholar
  17. 17.
    Debiec-Rychter M, Dumez H, Judson I, Wasag B, Verweij J, Brown M, et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to Imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC soft tissue and bone sarcoma group. Eur J Cancer. 2004;40(5):689–95.CrossRefPubMedGoogle Scholar
  18. 18.
    Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014 25(suppl 3):iii21–6.Google Scholar
  19. 19.
    Blesius A, Cassier PA, Bertucci F, Fayette J, Ray-Coquard I, Bui B, et al. Neoadjuvant Imatinib in patients with locally advanced non metastatic GIST in the prospective BFR14 trial. BMC Cancer. 2011;11:72.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Three vs. 1 year of adjuvant imatinib (IM) for operable high-risk GIST: the second planned analysis of the randomized SSGXVIII/AIO trial. J Clin Oncol [Internet]. [cited 2016 Jan 10]; Available from: http://meetinglibrary.asco.org/content/147687-156.
  21. 21.
    Raut CP, Gronchi A. Cytoreductive surgery in advanced GIST: timing is everything. Ann Surg Oncol. 2013;20(13):4059–60.CrossRefPubMedGoogle Scholar
  22. 22.
    Jakob J, Mussi C, Ronellenfitsch U, Wardelmann E, Negri T, Gronchi A, et al. Gastrointestinal stromal tumor of the rectum: results of surgical and multimodality therapy in the era of Imatinib. Ann Surg Oncol. 2013;20(2):586–92.CrossRefPubMedGoogle Scholar
  23. 23.
    Du C-Y, Zhou Y, Song C, Wang Y-P, Jie Z-G, He Y-L, et al. Is there a role of surgery in patients with recurrent or metastatic gastrointestinal stromal tumours responding to Imatinib: a prospective randomised trial in China. Eur J Cancer. 2014;50(10):1772–8.CrossRefPubMedGoogle Scholar
  24. 24.
    DeMatteo RP, Maki RG, Singer S, Gonen M, Brennan MF, Antonescu CR. Results of tyrosine kinase inhibitor therapy followed by surgical resection for metastatic gastrointestinal stromal tumor. Ann Surg. 2007;245(3):347–52.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Rubió-Casadevall J, Martinez-Trufero J, Garcia-Albeniz X, Calabuig S, Lopez-Pousa A, del Muro JG, et al. Role of surgery in patients with recurrent, metastatic, or unresectable locally advanced gastrointestinal stromal tumors sensitive to Imatinib: a retrospective analysis of the Spanish group for research on sarcoma (GEIS). Ann Surg Oncol. 2015;22(9):2948–57.CrossRefPubMedGoogle Scholar
  26. 26.
    Gronchi A, Fiore M, Miselli F, Lagonigro MS, Coco P, Messina A, et al. Surgery of residual disease following molecular-targeted therapy with Imatinib mesylate in advanced/metastatic GIST. Ann Surg. 2007;245(3):341–6.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Anant Ramaswamy
    • 1
  • Vikas Ostwal
    • 1
  • Omshree Shetty
    • 2
  • Arvind Sahu
    • 1
  • Davinder Paul
    • 1
  • Trupti Pai
    • 2
  • Mamta Gurav
    • 2
  • Nitin Shetty
    • 3
  • Shailesh Shrikhande
    • 4
  1. 1.Department of Medical OncologyTMHMumbaiIndia
  2. 2.Department of PathologyTMHMumbaiIndia
  3. 3.Department of Interventional RadiologyTMHMumbaiIndia
  4. 4.Department of Surgical OncologyTMHMumbaiIndia

Personalised recommendations