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Molecular characteristics and clinical outcomes of patients with Neurofibromin 1-altered metastatic colorectal cancer

Oncogene volume 41, pages 260–267 (2022)Cite this article

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Abstract

Loss-of-function alterations of Neurofibromin 1 (NF1) activate RAS, a driver of colorectal cancer. However, the clinical implications of NF1 alterations are largely unknown. We performed a comprehensive molecular profiling of NF1-mutant colorectal cancer using data from 8150 patients included in a dataset of commercial CLIA-certified laboratory (Caris Life Sciences). In addition, NF1 expression levels were tested for associations with clinical outcomes using data from 431 patients in the CALGB/SWOG 80405 trial. In the Caris dataset, 2.2% of patients had pathogenic or presumed pathogenic NF1 mutations. NF1-mutant tumors more frequently harbored PIK3CA (25.0% vs. 16.7%) and PTEN mutations (24.0% vs. 4.2%) than wild type tumors. Gene set enrichment analysis revealed that MAPK and PI3K pathway signatures were enriched in NF1-mutant tumors. In the CALGB/SWOG 80405 cohort, low NF1 expression was associated with poor prognosis, and high NF1 expression was associated with better efficacy of cetuximab than bevacizumab. Together, we revealed concurrent genetic alterations in the PI3K pathways in NF1-mutant tumors, suggesting the need to simultaneously block MAPK and PI3K pathways in treatment. The potential of NF1 alteration as a novel biomarker for targeted therapy was highlighted, warranting further investigations in clinical settings.

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Fig. 1: Alterations of MAPK and PI3K pathways.
Fig. 2: Gene set enrichment analysis of specific gene sets in RAS-related signaling pathways.
Fig. 3: Kaplan–Meier curves stratified by gene expression and treatment regimen in the CALGB/SWOG 80405 trial.
Fig. 4: Kaplan–Meier curves comparing the Bev and Cet arms in patient subsets according to NF1 expression levels in the CALGB/SWOG 80405 trial.
Fig. 5: Distinct activities of the MAPK and PI3K pathways and suggestive treatment approaches in NF1-mutant (NF1-MT) colorectal cancer.

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Acknowledgements

We thank all patients who contributed to this study. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), UG1CA233163, P30CA 014089 [to H-JL], Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Victoria and Philip Wilson Research Fund, San Pedro Peninsula Cancer Guild, and Daniel Butler Research Fund. Also supported in part by funds from Bristol-Myers Squibb, Genentech, and Pfizer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Hiroyuki Arai, Jingyuan Wang, Francesca Battaglin, Priya Jayachandran, Natsuko Kawanishi, Shivani Soni, Wu Zhang & Heinz-Josef Lenz

  2. Clinical & Translational Research, Medical Affairs, Caris Life Sciences, Phoenix, AZ, USA

    Andrew Elliott, Joanne Xiu, Jim P. Abraham, Daniel Magee, Phillip Stafford, Jian Zhang & W. Michael Korn

  3. Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Joshua Millstein

  4. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    Fang-Shu Ou

  5. UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Federico Innocenti

  6. Division of Hematology/Oncology, University of Cincinnati, Cincinnati, OH, USA

    Davendra Sohal

  7. West Virginia University Cancer Institute, Morgantown, WV, USA

    Richard M. Goldberg

  8. Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA

    Michael J. Hall

  9. Division of Hematology and Oncology, Department of Medicine, Banner-University of Arizona, Tucson, AZ, USA

    Aaron J. Scott

  10. Medical Oncology, Mitchell Cancer Institute, The University of South Alabama, Mobile, AL, USA

    Mohd Khushman

  11. Department of Solid Tumor Oncology, GI Medical Oncology, Levine Cancer Institute, Charlotte, NC, USA

    Jimmy J. Hwang

  12. Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA

    Emil Lou

  13. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    Benjamin A. Weinberg

  14. Department of Medicine, Division of Oncology, University of Miami, Miller School of Medicine, Miami, FL, USA

    Albert Craig Lockhart

  15. Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Anthony Frank Shields

  16. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA

    Alan P. Venook

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  1. Hiroyuki Arai
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Contributions

HA and HJL planned, designed, and administered this study. The original draft was written by HA, AE, and HJL. AE, JM, and JZ were responsible for the statistical analysis. JX, FSO and FI contributed to administrative, technical, or material support. JX, JW, FB, PJ, NK, SS, WZ, DS, RMG, MJH, AJS, MK, JJH, EL, BAW, ACL, AFS, JPA, DM, PS, made substantial contributions to data resource, investigations, and manuscript review and editing. APV, WMK, and HJL supervised this study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Heinz-Josef Lenz.

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Competing interests

DS reports consulting role for Ability Pharmaceuticals, honoraria from Foundation Medicine, Speakers bureau from Incyte, and research funding at institution from Amgen, Apexigen, Bristol-Myers Squibb, Celgene, FibroGen, Genentech, Medimmune, Merck, OncoMed, and Rafael. RMG reports consulting/advisory role for Merck, Taiho Pharmaceutical, Merck KGaA and Novartis, research funding from Bristol-Myers Squibb, and travel paid from Merck KGaA and Merck. WMK reports consulting role for Merck. HJL reports a role of advisory board for Merck KG, Merck, Bayer, Roche/Genentech, G1 Therapeutics, Oncocyte, Fulgent, Jazz Therapeutics, and Bicara. AE, JX, JPA, DM, PS, JZ, and WMK are Caris employee. All remaining authors declare no competing interests.

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Arai, H., Elliott, A., Millstein, J. et al. Molecular characteristics and clinical outcomes of patients with Neurofibromin 1-altered metastatic colorectal cancer. Oncogene 41, 260–267 (2022). https://doi.org/10.1038/s41388-021-02074-z

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