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Application of histology-agnostic treatments in metastatic colorectal cancer

  • Andrea Sartore-Bianchi
    Affiliations
    Department of Oncology and Hemato-Oncology, Milano, Università degli Studi di Milano Italy

    Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, 20162, Milan, Italy
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  • Alberto Giuseppe Agostara
    Affiliations
    Department of Oncology and Hemato-Oncology, Milano, Università degli Studi di Milano Italy

    Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, 20162, Milan, Italy
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  • Giorgio Patelli
    Affiliations
    Department of Oncology and Hemato-Oncology, Milano, Università degli Studi di Milano Italy

    Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, 20162, Milan, Italy
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  • Gianluca Mauri
    Affiliations
    Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, 20162, Milan, Italy

    IFOM-FIRC Institute of Molecular Oncology, Milan, Italy
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  • Elio Gregory Pizzutilo
    Affiliations
    Department of Oncology and Hemato-Oncology, Milano, Università degli Studi di Milano Italy

    Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, 20162, Milan, Italy
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  • Salvatore Siena
    Correspondence
    Corresponding author at: Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3,20162 Milano, Italy.
    Affiliations
    Department of Oncology and Hemato-Oncology, Milano, Università degli Studi di Milano Italy

    Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, 20162, Milan, Italy
    Search for articles by this author

      Abstract

      Cancer treatment is increasingly focused on targeting molecular alterations identified across different tumor histologies. While some oncogenic drivers such as microsatellite instability (MSI) and NTRK fusions are actionable with the very same approach regardless of tumor type (“histology-agnostic”), others require histology-specific therapeutic adjustment (“histology-tuned”) by means of adopting specific inhibitors and ad hoc combinations.
      Among histology-agnostic therapies, pembrolizumab or dostarlimab demonstrated comparable activity in MSI metastatic colorectal cancer (mCRC) as in other tumors with MSI status (ORR 38% vs 40% and 36% vs 39%, respectively), while entrectinib or larotrectinib proved effective in NTRK rearranged mCRC even though less dramatically than in the overall population (ORR 20% vs 57%, and 50% vs 78%, respectively). Histology-tuned approaches in mCRC are those targeting BRAFV600E mutations and ERBB2 amplification, highlighting the need of simultaneous anti-EGFR blockade or careful choice of companion inhibitors in this tumor type. Anti-RET and anti-ALK therapies emerged as a potential histology-agnostic indications, while anti-KRASG12C strategies could develop as future histology-tuned therapies. Targeting of ERBB2 mutations and NRG1 fusion provided discrepant results. In conclusion, agnostic targets such as MSI and NTRK fusions are already exploitable in mCRC, while the plethora of emerging histology-tuned targets represent a challenging opportunity requiring concurrent evolution of molecular diagnostic tools.

      Keywords

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