Skip to main content

Advertisement

SpringerLink
Log in

Correlation of CTNNB1 Mutation Status with Progression Arrest Rate in RECIST Progressive Desmoid-Type Fibromatosis Treated with Imatinib: Translational Research Results from a Phase 2 Study of the German Interdisciplinary Sarcoma Group (GISG-01)

  • Bone and Soft Tissue Sarcomas
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

CTNNB1 gene mutations are the molecular key events in the majority of sporadic desmoid-type fibromatosis (DF). The specific S45F mutation has been reported to be associated with a more aggressive clinical course in DF. For the current study, the CTNNB1 mutation status was analyzed in DF samples from the prospective German Interdisciplinary Sarcoma Group (GISG) phase 2 study evaluating imatinib to induce progression arrest in DF Response Evaluation Criteria In Solid Tumors (RECIST) progressive patients.

Methods

Thirty-seven patients were treated with a planned dose of imatinib 800 mg daily over 2 years (NCT01137916). The progression arrest rate (PAR) after 6 months of treatment was the primary endpoint of the study. CTNNB1 exon 3 mutation status was analyzed using Sanger sequencing.

Results

Thirty-three (97 %) of 34 patients reaching the primary endpoint were evaluable for CTNNB1 mutation exon 3 status. T41A mutations accounted for 30.3 % of the study samples and S45 mutations for 48.5 %, whereas CTNNB1 wild-type status was found in 21.2 %. The respective PAR at 6 months was 70, 81, and 43 %. Patients harboring CTNNB1 mutations demonstrated a higher PAR compared to wild-type DF. There was a statistically significant difference comparing patients with S45F mutations (85 % PAR) versus wild-type status (p = 0.05).

Conclusions

Mutations at position S45 were overrepresented in the GISG-01 trial recruiting RECIST progressive patients only. The positive correlation of CTNNB1 mutation status with the progression arrest rate after imatinib therapy supports the idea of a potential predictive impact of the mutation status on DF treatment decision making.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kasper B, Stroebel P, Hohenberger P. Desmoid tumors—clinical features and treatment options for advanced disease. Oncologist. 2011;16:682–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Goldblum JR, Fletcher JA. Desmoid-type fibromatosis. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. World Health Organisation classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC Press; 2013. p. 72–3.

    Google Scholar 

  3. Van Broekhoven DL, Grünhagen DJ, den Bakker MA, van Dalen T, Verhoef C. Time trends in the incidence and treatment of extra-abdominal and abdominal aggressive fibromatosis: a population-based study. Ann Surg Oncol. 2015;22:2817–23.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kasper B, Baumgarten C, Bonvalot S, et al; Desmoid Working Group. Management of sporadic desmoid-type fibromatosis: a European consensus approach based on patients’ and professionals’ expertise—a Sarcoma Patients EuroNet (SPAEN) and European Organisation for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG) initiative. Eur J Cancer. 2015;51:127–36.

    Article  CAS  PubMed  Google Scholar 

  5. Janinis J, Patriki M, Vini L, Aravantinos G, Whelan JS. The pharmacological treatment of aggressive fibromatosis: a systematic review. Ann Oncol. 2003;14:181–90.

    Article  CAS  PubMed  Google Scholar 

  6. Heinrich MC, McArthur GA, Demetri GD, et al. Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumour). J Clin Oncol. 2006;24:1195–203.

    Article  CAS  PubMed  Google Scholar 

  7. Penel N, Le Cesne A, Bui B et al. Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up. Ann Oncol. 2011;22:452–7.

    Article  CAS  PubMed  Google Scholar 

  8. Miyaki M, Yamaguchi T, Iijima T, et al. Difference in characteristics of APC mutations between colonic and extracolonic tumors of FAP patients: variations with phenotype. Int J Cancer. 2008;122:2491–7.

    Article  CAS  PubMed  Google Scholar 

  9. Huss S, Nehles J, Binot E, et al. Beta-catenin (CTNNB1) mutations and clinicopathological features of mesenteric desmoid-type fibromatosis. Histopathology. 2013;62:294–304.

    Article  PubMed  Google Scholar 

  10. Lazar AJ, Tuvin D, Hajibashi S, et al. Specific mutations in the beta-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors. Am J Pathol. 2008;173:1518–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Colombo C, Miceli R, Lazar AJ, et al. CTNNB1 45F mutation is a molecular prognosticator of increased postoperative primary desmoid tumor recurrence: an independent, multicenter validation study. Cancer. 2013;119:3696–702.

    Article  CAS  PubMed  Google Scholar 

  12. Van Broekhoven DL, Verhoef C, Grünhagen DJ, et al. Prognostic value of CTNNB1 gene mutation in primary sporadic aggressive fibromatosis. Ann Surg Oncol. 2015;22:1464–70.

    Article  PubMed  Google Scholar 

  13. Domont J, Salas S, Lacroix L, et al. High frequency of beta-catenin heterozygous mutations in extra-abdominal fibromatosis: a potential molecular tool for disease management. Br J Cancer. 2010;102:1032–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mullen JT, Delaney TF, Rosenberg AE, et al. Beta-catenin mutation status and outcomes in sporadic desmoid tumors. Oncologist. 2013;18:1043–9.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Therasse P, Arbruck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92:205–21.

    Article  CAS  PubMed  Google Scholar 

  16. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.

    Article  Google Scholar 

  17. Kasper B, Grünwald V, Reichardt P, et al. Phase II study evaluating imatinib to induce progression arrest in RECIST progressive desmoid tumors not amenable to surgical resection with R0 intent or accompanied by unacceptable function loss—a study of the German Interdisciplinary Sarcoma Group (GISG). Ann Oncol. 2014;25(suppl 4):iv494.

    Google Scholar 

  18. Chugh R, Wathen JK, Patel SR, et al; Sarcoma Alliance for Research through Collaboration (SARC). Efficacy of imatinib in aggressive fibromatosis: results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial. Clin Cancer Res. 2010;16:4884–91.

    Article  CAS  PubMed  Google Scholar 

  19. Crago AM, Chmielecki J, Rosenberg M, et al. Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid-type fibromatosis by whole-exome sequencing and genomic analysis. Genes Chromosomes Cancer. 2015;54:606–15.

    Article  CAS  PubMed  Google Scholar 

  20. Hamada S, Futamura N, Ikuta K, et al. CTNNB1 S45F mutation predicts poor efficacy of meloxicam treatment for desmoid tumors: a pilot study. PLoS One. 2014;9:e96391.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Colombo C, Bolshakov S, Hajibashi S, et al. “Difficult to diagnose” desmoid tumours: a potential role for CTNNB1 mutational analysis. Histopathology. 2011;59:336–40.

    Article  PubMed  Google Scholar 

  22. Le Guellec S, Soubeyran I, Rochaix P, et al. CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics. Mol Pathol. 2012;25:1551–8.

    Article  Google Scholar 

  23. Gounder MM, Lefkowitz RA, Keohan ML, et al. Activity of sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res. 2011;17:4082–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Disclosure

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Sarcoma Unit, Interdisciplinary Tumor Center, Mannheim University Medical Center, University of Heidelberg, Mannheim, Germany

    Bernd Kasper MD, PhD & Peter Hohenberger MD, PhD

  2. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    Viktor Gruenwald MD, PhD

  3. Sarcoma Center Berlin-Brandenburg, HELIOS Klinikum Berlin-Buch, Berlin, Germany

    Peter Reichardt MD

  4. Sarcoma Center, West German Cancer Center, Essen, Germany

    Sebastian Bauer MD, PhD

  5. Institute of Pathology, Friedrich Alexander University, Erlangen-Nürnberg, Erlangen, Germany

    Florian Haller MD, PhD

Authors
  1. Bernd Kasper MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Viktor Gruenwald MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Reichardt MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sebastian Bauer MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Hohenberger MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Florian Haller MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernd Kasper MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kasper, B., Gruenwald, V., Reichardt, P. et al. Correlation of CTNNB1 Mutation Status with Progression Arrest Rate in RECIST Progressive Desmoid-Type Fibromatosis Treated with Imatinib: Translational Research Results from a Phase 2 Study of the German Interdisciplinary Sarcoma Group (GISG-01). Ann Surg Oncol 23, 1924–1927 (2016). https://doi.org/10.1245/s10434-016-5132-4

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-016-5132-4

Keywords

Search

Navigation