EMT-Related Genes Have No Prognostic Relevance in Metastatic Colorectal Cancer as Opposed to Stage II/III: Analysis of the Randomised, Phase III Trial FIRE-3 (AIO KRK 0306; FIRE-3)

Elise Pretzsch; Volker Heinemann; Sebastian Stintzing; Andreas Bender; Shuo Chen; Julian Walter Holch; Felix Oliver Hofmann; Haoyu Ren; Florian Bösch; Helmut Küchenhoff; Jens Werner; Martin Konrad Angele

doi:10.3390/cancers14225596

EMT-Related Genes Have No Prognostic Relevance in Metastatic Colorectal Cancer as Opposed to Stage II/III: Analysis of the Randomised, Phase III Trial FIRE-3 (AIO KRK 0306; FIRE-3)

Cancers (Basel). 2022 Nov 14;14(22):5596. doi: 10.3390/cancers14225596.

Authors

Elise Pretzsch^{1

2}, Volker Heinemann^{2

3

4}, Sebastian Stintzing⁵, Andreas Bender^{6

7}, Shuo Chen⁷, Julian Walter Holch³, Felix Oliver Hofmann^{1

2}, Haoyu Ren¹, Florian Bösch⁸, Helmut Küchenhoff⁶, Jens Werner¹, Martin Konrad Angele¹

Affiliations

¹ Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 80539 Munich, Germany.
² German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, partner site 80336 Munich, Germany.
³ Department of Hematology/Oncology and Comprehensive Cancer Center Munich, LMU University Hospital Munich, Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
⁴ Comprehensive Cancer Center (CCC Munich LMU), LMU University Hospital Munich, 81377 Munich, Germany.
⁵ Department of Hematology, Oncology, and Cancer Immunology (CCM), Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 10117 Berlin, Germany.
⁶ Statistical Consulting Unit, StaBLab, Department of Statistics, LMU Munich, 80539 Munich, Germany.
⁷ Munich Center for Machine Learning, LMU Munich, 81377 Munich, Germany.
⁸ Department of General, Visceral, and Pediatric Surgery, University Medical Center Goettingen, 37075 Göttingen, Germany.

Abstract

Introduction: There is no standard treatment after resection of colorectal liver metastases and the role of systemic therapy remains controversial. To avoid over- or undertreatment, proper risk stratification with regard to postoperative treatment strategy is highly needed. We recently demonstrated the prognostic relevance of EMT-related (epithelial-mesenchymal transition) genes in stage II/III CRC. As EMT is a major step in CRC progression, we now aimed to analyse the prognostic relevance of EMT-related genes in stage IV CRC using the study cohort of the FIRE-3 trial, an open-label multi-centre randomised controlled phase III trial of patients with metastatic CRC.

Methods: Overall and progression free survival were considered as endpoints (n = 350). To investigate the prognostic relevance of EMT-related genes on either endpoint, we compared predictive performance of different models using clinical data only to models using gene data in addition to clinical data, expecting better predictive performance if EMT-related genes have prognostic value. In addition to baseline models (Kaplan Meier (KM), (regularised) Cox), Random Survival Forest (RSF), and gradient boosted trees (GBT) were fit to the data. Repeated, nested five-fold cross-validation was used for hyperparameter optimisation and performance evaluation. Predictive performance was measured by the integrated Brier score (IBS).

Results: The baseline KM model showed the best performance (OS: 0.250, PFS: 0.251). None of the other models were able to outperform the KM when using clinical data only according to the IBS scores (OS: 0.253 (Cox), 0.256 (RSF), 0.284 (GBT); PFS: 0.254 (Cox), 0.256 (RSF), 0.276 (GBT)). When adding gene data, performance of GBT improved slightly (OS: 0.262 vs. 0.284; PFS: 0.268 vs. 0.276), however, none of the models performed better than the KM baseline.

Conclusion: Overall, the results suggest that the prognostic relevance of EMT-related genes may be stage-dependent and that EMT-related genes have no prognostic relevance in stage IV CRC.

Keywords: EMT; EMT-related genes; colorectal cancer; metastasis.

Grants and funding

The legal funder (sponsor) of the trial is University Hospital, LMU Munich. This work was supported by grants from Pfizer GmbH, Germany, and Merck KGaA, Darmstadt, Germany. The funding sources had a role in the design and conduct of the study, and in the collection, management, analysis and interpretation of the data. Prior to 2009, cetuximab was supplied by Merck Serono GmbH, an affiliate of Merck KGaA, Darmstadt, Germany. Merck KGaA reviewed the paper for medical accuracy only and had no role in the decision to submit the paper for publication. The authors are fully responsible for the content of this paper, and the views and opinions described in the publication solely reflect those of the authors. Open Access funding enabled and organised by Projekt DEAL.