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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)

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

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

Zusammenfassung

Hintergrund

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.

Methoden

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

Ergebnisse

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.

Schlussfolgerung

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.

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Acknowledgements

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

Funding

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

Author information

Authors and Affiliations

  1. Department of General‑, Visceral- and Paediatric Surgery, University Medical Center Göttingen, 37099, Göttingen, Germany

    Jens Jakob

  2. Department of Pathology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France

    Tom Lesluyes

  3. Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany

    Anna Simeonova-Chergou

  4. University Medical Center, University of Freiburg, Freiburg, Germany

    Frederik Wenz

  5. Department of Surgery, University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany

    Peter Hohenberger

  6. INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31037, Toulouse, France

    Frederic Chibon

  7. Department of Pathology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France

    Sophie Le Guellec

Authors
  1. Jens Jakob
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  2. Tom Lesluyes
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  3. Anna Simeonova-Chergou
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  4. Frederik Wenz
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  5. Peter Hohenberger
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  6. Frederic Chibon
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  7. Sophie Le Guellec
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Corresponding author

Correspondence to Jens Jakob.

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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.

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The data that support the findings of this study are presented here and in the supplementary file or are available from the corresponding author upon reasonable request.

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66_2019_1543_MOESM1_ESM.pdf

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

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Jakob, J., Lesluyes, T., Simeonova-Chergou, A. et al. 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). Strahlenther Onkol 196, 280–285 (2020). https://doi.org/10.1007/s00066-019-01543-5

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