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Clinical Studies

Dynamic nature of BRAF or KRAS p.G12C mutations in second-line therapy for advanced colorectal cancer patients: do early and late effects exist?

British Journal of Cancer volume 130, pages 777–787 (2024)Cite this article

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Abstract

Introduction

The mitogen-activated protein kinase (MAPK) signalling network aberrations in metastatic colorectal cancer (mCRC) generate intrinsic dynamic effects and temporal variations that are crucial but often overlooked in clinical trial populations. Here, we investigate the time-varying impact of MAPK pathway mutation genotype on each treatment line’s contribution to the overall clinical course.

Methods

The PROMETEO study focused on mCRC patients undergoing second-line treatment at 20 hospitals. We evaluated genotypes and employed flexible models to analyse the dynamic effect of each mutation.

Results

We examined data derived from 1160 patients. The effects of KRAS G12C or G12V, and BRAF V600E are clearly time-varying, with unexpected consequences such as the deleterious effect of BRAF V600E vs other genotypes dissipating over time when subjects receive antiangiogenics, or KRAS G12V and G12C showing increasing aggressiveness over time. Thus, contrary to expectations, the 12-month survival rate from the second line for those who survived >6 months was 49.9% (95% CI, 32.7–67.3) for KRAS G12C and 59% (95% CI, 38.5–80.6) for BRAF V600E.

Conclusions

The dynamic perspective is essential for understanding the behaviour of tumours with specific genotypes, especially from the second line onward. This may be relevant in patient monitoring and treatment decision-making, particularly in cases with distinct mutations.

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Fig. 1
Fig. 2: Kaplan–Meier plots for progression-free survival and overall survival from second-line treatment, stratified by genetic variant.
Fig. 3: Partitioned survival analysis.
Fig. 4: Time-varying hazard ratios for overall survival from second-line treatment (OS-2).

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank PROMETEO study researchers for their contribution to this study and Miguel Vaquero, Natalia Cateriano and the IRICOM S.L. team for the support of the website registry.

Funding

The study has been funded by Roche and Sanofi Spain.

Author information

Author notes

  1. These authors contributed equally: Débora Contreras-Toledo, Paula Jiménez-Fonseca.

Authors and Affiliations

  1. Department of Medical Oncology, Hospital Universitario Central de Asturias, ISPA, Universidad de Oviedo, Oviedo, Spain

    Débora Contreras-Toledo & Paula Jiménez-Fonseca

  2. Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Universidad de Cantabria (UNICAN), Santander, Spain

    Carlos López López

  3. Department of Medical Oncology, Complexo Hospitalario Universitario de Ourense, Ourense, Spain

    Ana Fernández Montes & Soledad Cameselle García

  4. Department of Medical Oncology, Hospital Universitario de Burgos, Burgos, Spain

    Ana María López Muñoz

  5. Department of Medical Oncology, Hospital Universitario de Santiago, Santiago de Compostela, Spain

    Francisca Vázquez Rivera

  6. Department of Medical Oncology, Hospital Universitario Miguel Servet, IISA, Zaragoza, Spain

    Vicente Alonso

  7. Department of Medical Oncology, Hospital Costa del Sol, Marbella, Medical Oncology Intercenter Unit, Hospital Universitario Regional y Virgen de la Victoria, IBIMA, Málaga, Spain

    Julia Alcaide

  8. Department of Medical Oncology, Hospital Universitario Vall D’Hebrón, Vall D´Hebrón Institute of Oncology (VHIO), Barcelona, Spain

    Francesc Salvà

  9. Department of Medical Oncology, Hospital Universitario Lucus Augusti, Lugo, Spain

    Marta Covela Rúa

  10. Department of Medical Oncology, Hospital Universitario Son Espases, Palma de Mallorca, Spain

    Mónica Guillot

  11. Department of Medical Oncology, Hospital San Pedro, Logroño, Spain

    Alfonso Martín Carnicero

  12. Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain

    Raquel Jimeno Mate

  13. Department of Medical Oncology, Hospital General Universitario de Elche, Elche, Spain

    Elena Asensio Martínez

  14. Department of Medical Oncology, Hospital Universitario Clínico San Cecilio, Granada, Spain

    Beatriz González Astorga

  15. Department of Medical Oncology, Hospital General de Valencia, Valencia, Spain

    Amaya B. Fernandez-Diaz

  16. Department of Medical Oncology, Hospital Universitario Álvaro Cunqueiro, Vigo, Spain

    Paula González Villaroel

  17. Department of Medical Oncology, Hospital Santa Creu i San Pau, Barcelona, Spain

    Anna C. Virgili Manrique

  18. Department of Medical Oncology, Instituto Valenciano de Oncología (IVO), Valencia, Spain

    Marcos Melián Sosa

  19. Department of Medical Oncology, Hospital Universitario de Canarias, Tenerife, Spain

    Beatriz Alonso

  20. Department of Medical Oncology, Complejo Hospitalario de Pontevedra, Pontevedra, Spain

    Antia Cousillas Castiñeiras

  21. Department of Medical Oncology, Hospital Universitario de León, León, Spain

    Carmen Castañón López

  22. Department of Medical Oncology, Hospital Universitario y Politécnico La Fe de Valencia, Valencia, Spain

    Jorge Aparicio

  23. Department of Medical Oncology, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB, Murcia, Spain

    Alberto Carmona-Bayonas

Authors
  1. Débora Contreras-Toledo
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  2. Paula Jiménez-Fonseca
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  3. Carlos López López
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  4. Ana Fernández Montes
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  5. Ana María López Muñoz
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  14. Soledad Cameselle García
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  25. Alberto Carmona-Bayonas
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Contributions

DC-T, PJ-F, AFM, CLL, and ACB conceived the project, monitored variables, analysed data, and wrote the initial draft of the manuscript. The remaining authors were involved in patient recruitment, supplying clinical information, and offering comments and suggestions for manuscript improvement. All authors contributed to data interpretation, discussion, and critical review of the manuscript.

Corresponding authors

Correspondence to Débora Contreras-Toledo or Alberto Carmona-Bayonas.

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Competing interests

PJ-F discloses honoraria as speaker from Astellas, Astra Zeneca, BMS, Lilly, MSD, Novartis, Roche. CLL discloses consulting/advisory role for Amgen, Roche, Sanofi, MSD, Merck, Servier, Bayer; research grants from Amgen, Roche, MSD, Merck, Servier and travel grants and/or congress support from Servier, Sanofi, Amgen, Roche, MSD, Merck. AFM discloses honoraria as speaker from Amgen, Astra Zeneca, Astra Zeneca, Eisai, Lilly, MSD, Pierre Fabre, Servier. AMLM discloses consulting/advisory role for Amgen, Bayer, Roche, Eisai; honoraria as speaker from Eisai, Lilly, Amgen, Bayer, Sanofi, Merck Serono, Roche, Bristol, Servier, Pierre Fabre; travel grants and/or congress support from Amgen, Roche, Servier. FVR discloses consulting/advisory role for MSD; honoraria from Roche, Servier, Lilly, Merck, Astra-Zeneca; travel grants and/or congress support from Merck, Roche, Servier. VA discloses advisory role for Amgen, Roche, Merck, Servier, Ipsen pharma, Novartis; travel grants and/or congress support from Merck. JA discloses consulting/advisory role for Merck; honoraria as speaker from Amgen, Merck and Servier; travel grants and/or congress support from Roche, Amgen, Merck, Servier and Sanofi. FS discloses consulting/advisory role for Merck Serono, Amgen; honoraria and travel grants and/or congress support from Hoffman La-Roche, Sanofi Aventis, Amgen, Merck Serono, Servier, Bristol-Myers Squibb and Terumo corporation. MG discloses travel grants and/or congress support from Roche, Amgen and Servier. AMC discloses consulting/advisory role for BMS, Sanofi and Novartis; honoraria as speaker from Roche, BMS, MSD, Novartis, Merck and Servier; travel grants and/or congress support from BMS, Novartis, Merck and Servier. RJM discloses honoraria as speaker from Servier, Sanofi, Pfizer and Pierre Fabre; travel grants and/or congress support from Merck. SCG discloses travel grants and/or congress support from Bristol Myers Squibb, MSD, Rovi, Amgem. BGA discloses consulting/advisory role for Sanofi; honoraria as speaker from Roche, BMS, Amgen MSD, Merck and Servier; travel grants and/or congress support from Amgen, Merck and Servier. PGV discloses consulting/advisory role for Servier, Amgen; travel grants and/or congress support from Merck, Sanofi, Amgen. ACVM discloses travel grants and/or congress support from Amgen, Merck, MSD, Roche, Sanofi, Servier. MMS discloses consulting/advisory role: Merck, Servier; honoraria as speaker from Amgen, Merck, Servier and Bayer; travel grants and/or congress support from Roche, Amgen, Merck, Servier. CCL discloses consulting/advisory role for Merck, honoraria as speaker from Amgen, Bayer, Sanofi, Merck Serono, Roche, Servier; travel grants and/or congress support from: Amgen, Bayer, Sanofi, Merck Serono, Roche, Servier. JAp discloses consulting/advisory role for Amgen, Bayer, Merck, Merck Sharp & Dohme, Pierre Fabre and Servier. AC-B discloses honoraria as speaker from Amgen, Astellas, Bayer, BMS, Eisai, Lilly, MSD, Merck, Novartis, Roche, Servier. DC-T, MCR, EAM, ABF-D, BA, and ACC have no conflict of interest, financial or otherwise, in relation to the scope of this work.

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Contreras-Toledo, D., Jiménez-Fonseca, P., López, C.L. et al. Dynamic nature of BRAF or KRAS p.G12C mutations in second-line therapy for advanced colorectal cancer patients: do early and late effects exist?. Br J Cancer 130, 777–787 (2024). https://doi.org/10.1038/s41416-023-02563-w

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