Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial.
- Stintzing S Department of Medicine, Division of Hematology, Oncology, and Tumor Immunology (CCM), Charité Universitaetsmedizin Berlin, Berlin, Germany. Electronic address: sebastian.stintzing@charite.de.
- Wirapati P SIB Swiss Institute of Bioinformatics, Bioinformatic Core Facility, Lausanne, Switzerland.
- Lenz HJ USC Norris Comprehensive Cancer Center, Los Angeles, USA.
- Neureiter D Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria.
- Fischer von Weikersthal L Gesundheitszentrum St. Marien, Amberg.
- Decker T Oncological Practice, Ravensburg.
- Kiani A Medizinische Klinik IV, Klinikum Bayreuth, Bayreuth.
- Kaiser F VK&K Studien GbR, Landshut.
- Al-Batran S Department of Hematology and Oncology, Krankenhaus Nordwest, Frankfurt/Main.
- Heintges T Department of Medicine II, Städtisches Klinikum Neuss, Neuss.
- Lerchenmüller C Oncological Practice, Münster.
- Kahl C Haematology and Oncology, Staedtisches Klinikum Magdeburg, Magdeburg.
- Seipelt G Oncological Practice, Bad Soden.
- Kullmann F Department of Medicine I, Klinikum Weiden, Weiden.
- Moehler M University Hospital Mainz, Mainz, Germany.
- Scheithauer W Department of Internal Medicine I & Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
- Held S ClinAssess GmbH, Leverkusen.
- Modest DP Department of Medicine III, University Hospital, LMU Munich, Munich.
- Jung A Institute of Pathology University of Munich, Munich, Germany.
- Kirchner T Institute of Pathology University of Munich, Munich, Germany.
- Aderka D Department of Gastrointestinal Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel.
- Tejpar S Molecular Digestive Oncology, UZ Leuven, Belgium.
- Heinemann V Department of Medicine III, University Hospital, LMU Munich, Munich.
- 2019-12-24
Published in:
- Annals of oncology : official journal of the European Society for Medical Oncology. - 2019
CMS
bevacizumab
cetuximab
colorectal cancer
Aged
Antineoplastic Combined Chemotherapy Protocols
Bevacizumab
Biomarkers, Tumor
Camptothecin
Cetuximab
Clinical Decision-Making
Colon
Colorectal Neoplasms
DNA Mutational Analysis
Female
Fluorouracil
Gene Expression Profiling
Humans
Kaplan-Meier Estimate
Leucovorin
Male
Middle Aged
Mutation
Prognosis
Progression-Free Survival
Rectum
English
BACKGROUND
FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined.
PATIENTS AND METHODS
In this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan-Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method.
RESULTS
CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n = 592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P = 0.051), PFS (P < 0.001), and OS (P < 0.001). Within the RAS wild-type population, OS observed in CMS4 significantly favored FOLFIRI cetuximab over FOLFIRI bevacizumab. In CMS3, OS showed a trend in favor of the cetuximab arm, while OS was comparable in CMS1 and CMS2, independent of targeted therapy.
CONCLUSIONS
CMS classification is prognostic for mCRC. Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS3 and CMS4. CMS classification provides deeper insights into the biology to CRC, but at present time has no direct impact on clinical decision-making.The FIRE-3 (AIO KRK-0306) study had been registered at ClinicalTrials.gov: NCT00433927.
FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined.
PATIENTS AND METHODS
In this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan-Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method.
RESULTS
CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n = 592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P = 0.051), PFS (P < 0.001), and OS (P < 0.001). Within the RAS wild-type population, OS observed in CMS4 significantly favored FOLFIRI cetuximab over FOLFIRI bevacizumab. In CMS3, OS showed a trend in favor of the cetuximab arm, while OS was comparable in CMS1 and CMS2, independent of targeted therapy.
CONCLUSIONS
CMS classification is prognostic for mCRC. Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS3 and CMS4. CMS classification provides deeper insights into the biology to CRC, but at present time has no direct impact on clinical decision-making.The FIRE-3 (AIO KRK-0306) study had been registered at ClinicalTrials.gov: NCT00433927.
- Language
-
- English
- Open access status
- hybrid
- Identifiers
-
- DOI 10.1093/annonc/mdz387
- PMID 31868905
- Persistent URL
- https://sonar.ch/global/documents/112468
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