Impact of preoperative treatment on the CINSARC prognostic signature: translational research results from a phase 1 trial of the German Interdisciplinary Sarcoma Group (GISG 03)

  • Jens JakobEmail author
  • Tom Lesluyes
  • Anna Simeonova-Chergou
  • Frederik Wenz
  • Peter Hohenberger
  • Frederic Chibon
  • Sophie Le Guellec
Short Communication



CINSARC (Complexity INdex in SARComas) is a prognostic signature for soft tissue sarcoma that determines the risk for recurrence and may serve to guide the decision for adjuvant chemotherapy. The aim of this study was to compare the CINSARC signature of pre- and posttreatment biopsies of sarcoma patients treated within a phase I trial evaluating preoperative sunitinib and irradiation.


We retrieved 14 pairs of formalin-fixed paraffin-embedded blocks from pretreatment biopsies and posttreatment resection specimens and performed expression profiling of the 67 CINSARC signature genes.


In 5/14 patients, both probes were unsuitable for expression analysis because there was no (vital) tissue left in biopsies or resection specimens. Comparing the CINSARC risk classification before and after treatment in the remaining patients, 2/9 shifted from a high- to a low-risk classification for metastatic disease after preoperative treatment with radiation therapy plus sunitinib and 7/9 pairs of pre- and posttreatment biopsies revealed identical results.


Concurrent radiation therapy and sunitinib leads to diverging results of prognostic gene array testing in a relevant proportion of sarcoma patients. These changes may reflect tumor heterogeneity, local treatment effects, or prognostic changes of the disease. Caution is advised in the selection of samples and interpretation of test results.


Soft tissue sarcoma Radiation therapy Sunitinib Adjuvant chemotherapy Biopsy 

Einfluss der präoperativen Therapie auf die prognostische Gensignatur CINSARC: Translationale Forschungsergebnisse einer Phase-1-Studie der deutschen interdisziplinären Sarkomstudiengruppe (GISG 03)



CINSARC (Complexity INdex in SARComas) ist eine prognostische Signatur für Weichgewebesarkome, die zur Abschätzung des Metastasierungsrisikos eingesetzt wird und deren Ergebnis die Entscheidung über eine adjuvante Chemotherapie unterstützen kann. Ziel dieser Studie war es, zu untersuchen, inwieweit eine präoperative Therapie mit Bestrahlung und Sunitinib Einfluss auf das CINSARC-Ergebnis hat.


In 14 korrespondierenden Paaren von formalinfixierten und paraffineingebetteten Tumorproben (prätherapeutische Biopsie und posttherapeutisches Resektat) erfolgte die Expressionsanalyse der 67 CINSARC-Signaturgene.


Bei 5/14 Probenpaaren war ein Vergleich der CINSARC-Signatur nicht möglich, da nach diagnostischer Aufarbeitung bzw. durch Therapieansprechen kein (vitales) Gewebe in den Biopsien oder Resektaten vorhanden war. In 2/9 Patienten verschob sich das Untersuchungsergebnis von einem hohen zu einem niedrigen Metastasierungsrisiko. In 7/9 Probenpaaren blieb die Risikoeinschätzung identisch.


Die präoperative Therapie mit Bestrahlung und Sunitinib kann zu abweichenden Ergebnissen prognostischer Gensignaturen führen. Diese Unterschiede können auf Therapieeffekte oder Tumorheterogenität zurückgeführt werden und sollte bei der Probenauswahl und Testinterpretation von prognostischen Signaturen berücksichtigt werden.


Weichgewebesarkom Strahlentherapie Sunitinib Adjuvante Chemotherapie Biopsie 



GISG03 was designed at the EORTC/AACR workshop at Flims, Switzerland.


This research was funded by the German Research Foundation (Grant JA 2030/1-1) and the Ruprecht Karl University of Heidelberg, Germany.

Compliance with ethical guidelines

Conflict of interest

J. Jakob and P. Hohenberger received research support and honoraria from Pfizer. P. Hohenberger acted as a consultant for Pfizer. T. Lesluyes, A. Simeonova-Chergou, F. Wenz, F. Chibon, and S. Le Guellec declare that they have no competing interests.

Ethical standards

The GISG 03 study was approved by the independent ethics committee II of the University of Heidelberg, Germany, and the German Federal Institute for Drugs and Medical Devices (BfArm). All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1975 Helsinki declaration and its later amendments. Informed consent was obtained from all indiviual participants included in the study.

Supplementary material

66_2019_1543_MOESM1_ESM.pdf (22 kb)
Supplementary file 1: Correlation of the expression of CINSARC signature genes in the biopsies (blue) and the resection specimens (red).


  1. 1.
    Casali PG, Abecassis N, Bauer S, Biagini R, Bielack S, Bonvalot S, Boukovinas I, Bovee J, Brodowicz T, Broto JM, Buonadonna A, De Alava E, Dei Tos AP, Del Muro XG, Dileo P, Eriksson M, Fedenko A, Ferraresi V, Ferrari A, Ferrari S, Frezza AM, Gasperoni S, Gelderblom H, Gil T, Grignani G, Gronchi A, Haas RL, Hannu A, Hassan B, Hohenberger P, Issels R, Joensuu H, Jones RL, Judson I, Jutte P, Kaal S, Kasper B, Kopeckova K, Krakorova DA, Le Cesne A, Lugowska I, Merimsky O, Montemurro M, Pantaleo MA, Piana R, Picci P, Piperno-Neumann S, Pousa AL, Reichardt P, Robinson MH, Rutkowski P, Safwat AA, Schoffski P, Sleijfer S, Stacchiotti S, Sundby Hall K, Unk M, Van Coevorden F, Van der Graaf W, Whelan J, Wardelmann E, Zaikova O, Blay JY (2018) Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 29(Suppl 4):iv67–iv51. CrossRefGoogle Scholar
  2. 2.
    von Mehren M, Randall RL, Benjamin RS, Boles S, Bui MM, Ganjoo KN, George S, Gonzalez RJ, Heslin MJ, Kane JM 3rd, Keedy V, Kim E, Koon H, Mayerson J, McCarter M, McGarry SV, Meyer C, Morris ZS, O’Donnell RJ, Pappo AS, Paz IB, Petersen IA, Pfeifer JD, Riedel RF, Ruo B, Schuetze S, Tap WD, Wayne JD, Bergman MA, Scavone JL (2018) Soft tissue sarcoma, version 2.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 16(5):536–563. CrossRefGoogle Scholar
  3. 3.
    Kirste S, Landenberger N, Scholber J, Henne K, Wittel UA, Grosu AL (2019) Retroperitoneal soft tissue sarcoma: low-dose neoadjuvant radiation therapy followed by surgery with or without intraoperative radiotherapy and adjuvant radiation therapy. Strahlenther Onkol 195(6):558–565. CrossRefPubMedGoogle Scholar
  4. 4.
    Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ, Leahy M, Van Coevorden F, Verweij J, Hogendoorn PC, Ouali M, Marreaud S, Bramwell VH, Hohenberger P, EORTC Soft Tissue and Bone Sarcoma Group, NCIC Clinical Trials Group Sarcoma Disease Site Committee (2012) Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol 13(10):1045–1054. CrossRefPubMedGoogle Scholar
  5. 5.
    Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M (2008) A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 113(3):573–581. CrossRefPubMedGoogle Scholar
  6. 6.
    Chibon F, Lagarde P, Salas S, Perot G, Brouste V, Tirode F, Lucchesi C, de Reynies A, Kauffmann A, Bui B, Terrier P, Bonvalot S, Le Cesne A, Vince-Ranchere D, Blay JY, Collin F, Guillou L, Leroux A, Coindre JM, Aurias A (2010) Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity. Nat Med 16(7):781–787. CrossRefPubMedGoogle Scholar
  7. 7.
    Italiano A, Lagarde P, Brulard C, Terrier P, Lae M, Marques B, Ranchere-Vince D, Michels JJ, Trassard M, Cioffi A, Piperno-Neumann S, Chevreau C, Blay JY, Delcambre C, Isambert N, Penel N, Bay JO, Bonvalot S, Le Cesne A, Coindre JM, Chibon F (2013) Genetic profiling identifies two classes of soft-tissue leiomyosarcomas with distinct clinical characteristics. Clin Cancer Res 19(5):1190–1196. CrossRefPubMedGoogle Scholar
  8. 8.
    Le Guellec S, Lesluyes T, Sarot E, Valle C, Filleron T, Rochaix P, Valentin T, Perot G, Coindre JM, Chibon F (2018) Validation of the Complexity INdex in SARComas prognostic signature on formalin-fixed, paraffin-embedded, soft-tissue sarcomas. Ann Oncol 29(8):1828–1835. CrossRefPubMedGoogle Scholar
  9. 9.
    Chibon F, Lesluyes T, Valentin T, Le Guellec S (2019) CINSARC signature as a prognostic marker for clinical outcome in sarcomas and beyond. Genes 58(2):124–129. CrossRefGoogle Scholar
  10. 10.
    Kroeze SGC, Fritz C, Basler L, Gkika E, Brunner TB, Grosu AL, Guckenberger M (2019) Combination of stereotactic radiotherapy and targeted therapy: patterns-of-care survey in German-speaking countries. Strahlenther Onkol 195(3):199–206. CrossRefPubMedGoogle Scholar
  11. 11.
    Jakob J, Rauch G, Wenz F, Hohenberger P (2013) Phase I trial of concurrent sunitinib and radiation therapy as preoperative treatment for soft tissue sarcoma. BMJ Open 3(9):e3626. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Jakob J, Simeonova A, Kasper B, Ronellenfitsch U, Wenz F, Hohenberger P (2015) Combined radiation therapy and sunitinib for preoperative treatment of soft tissue sarcoma. Ann Surg Oncol 22(9):2839–2845. CrossRefPubMedGoogle Scholar
  13. 13.
    Jakob J, Simeonova A, Kasper B, Ronellenfitsch U, Rauch G, Wenz F, Hohenberger P (2016) Combined sunitinib and radiation therapy for preoperative treatment of soft tissue sarcoma: results of a phase I trial of the German interdisciplinary sarcoma group (GISG-03). Radiat Oncol 11:77. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Datta K, Hyduke DR, Suman S, Moon BH, Johnson MD, Fornace AJ Jr. (2012) Exposure to ionizing radiation induced persistent gene expression changes in mouse mammary gland. Radiat Oncol 7:205. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Smyth EC, Nyamundanda G, Cunningham D, Fontana E, Ragulan C, Tan IB, Lin SJ, Wotherspoon A, Nankivell M, Fassan M, Lampis A, Hahne JC, Davies AR, Lagergren J, Gossage JA, Maisey N, Green M, Zylstra JL, Allum WH, Langley RE, Tan P, Valeri N, Sadanandam A (2018) A seven-gene signature assay improves prognostic risk stratification of perioperative chemotherapy treated gastroesophageal cancer patients from the MAGIC trial. Ann Oncol 29(12):2356–2362. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Pasquali S, Pizzamiglio S, Touati N, Litiere S, Marreaud S, Kasper B, Gelderblom H, Stacchiotti S, Judson I, Dei Tos AP, Verderio P, Casali PG, Woll PJ, Gronchi A (2019) The impact of chemotherapy on survival of patients with extremity and trunk wall soft tissue sarcoma: revisiting the results of the EORTC-STBSG 62931 randomised trial. Eur J Cancer 109:51–60. .2018.12.009CrossRefGoogle Scholar
  17. 17.
    Peeken JC, Goldberg T, Knie C, Komboz B, Bernhofer M, Pasa F, Kessel KA, Tafti PD, Rost B, Nusslin F, Braun AE, Combs SE (2018) Treatment-related features improve machine learning prediction of prognosis in soft tissue sarcoma patients. Strahlenther Onkol 194(9):824–834. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of General‑, Visceral- and Paediatric SurgeryUniversity Medical Center GöttingenGöttingenGermany
  2. 2.Department of Pathology, Institut Claudius RegaudIUCT-OncopoleToulouseFrance
  3. 3.Department of Radiation Oncology, University Medical Center MannheimUniversity of HeidelbergHeidelbergGermany
  4. 4.University Medical CenterUniversity of FreiburgFreiburgGermany
  5. 5.Department of Surgery, University Medical Center MannheimUniversity of HeidelbergHeidelbergGermany
  6. 6.INSERM U1037Cancer Research Center in Toulouse (CRCT)ToulouseFrance
  7. 7.Department of Pathology, Institut Claudius RegaudIUCT-OncopoleToulouseFrance

Personalised recommendations