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Translational Therapeutics

Trop-2 and Nectin-4 immunohistochemical expression in metastatic colorectal cancer: searching for the right population for drugs’ development

British Journal of Cancer volume 128, pages 1391–1399 (2023)Cite this article

Subjects

Abstract

Background

Trop-2 and Nectin-4 are transmembrane proteins overexpressed in many tumours and targets of antibody–drug conjugates (ADC). In metastatic colorectal cancer (mCRC), the role of Trop-2 and Nectin-4 has been poorly investigated.

Methods

Tumour samples of patients randomised in the phase III TRIBE2 were assessed for Trop-2 and Nectin-4 expression.

Results

Three hundred eighty-six tumours were assessed for Trop-2 expression. 90 (23%), 115 (30%) and 181 (47%) were Trop-2 high, medium and low, respectively. Patients with low Trop-2 tumours achieved longer PFS (12 versus 9.9 months, p = 0.047) and OS (27.3 versus 21.3 months, p = 0.015) than those with high/medium Trop-2 tumours. These findings were confirmed in multivariate analysis (p = 0.022 and p = 0.023, respectively). A greater OS benefit from treatment intensification with FOLFOXIRI/bevacizumab was observed in patients with high/medium Trop-2 tumours (p-for-interaction = 0.041).

Two hundred fifty-one tumours were assessed for Nectin-4 expression. Fourteen (5%), 67 (27%) and 170 (68%) were high, medium and low, respectively. No prognostic impact was observed based on Nectin-4 expression and no interaction effect was reported between Nectin-4 expression groups and treatment arm.

Conclusions

In mCRC, expression levels of Trop-2 and Nectin-4 are heterogeneous, suggesting a target-driven development of anti-Trop2 and anti-Nectin-4 ADCs. Medium/high Trop-2 expression is associated with worse prognosis and higher benefit from chemotherapy intensification.

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Fig. 1: Kaplan-Meier curves according Trop-2 expression levels.
Fig. 2: Kaplan-Meier curves according Trop-2 expression levels and treatment.
Fig. 3: Kaplan-Meier curves according Nectin-4 expression levels.

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Data availability

Datasets supporting the results of this work are available to editors, referees and readers promptly upon request.

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Acknowledgements

We are grateful to GONO and ARCO Foundations, to all participating patients and their families, and to the GONO investigators from the participating Italian centres.

Funding

The study was supported by GONO and ARCO Foundations (no grant number applicable). The sponsors had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

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Author notes

  1. These authors contributed equally: Clara Ugolini, Chiara Cremolini.

Authors and Affiliations

  1. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

    Roberto Moretto, Marco Maria Germani, Veronica Conca, Gianluca Masi & Chiara Cremolini

  2. Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy

    Marco Maria Germani, Mirella Giordano, Veronica Conca, Gianluca Masi & Chiara Cremolini

  3. Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy

    Agnese Proietti, Cristina Niccoli, Gabriella Fontanini & Clara Ugolini

  4. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Filippo Pietrantonio & Michele Prisciandaro

  5. Medical Oncology Unit 3, Veneto Institute of Oncology—IRCCS, Padua, Italy

    Sara Lonardi & Francesca Bergamo

  6. Oncology Unit, Ospedale degli Infermi, Rimini, Italy

    Emiliano Tamburini

  7. Department of Oncology and Palliative Care, Cardinale Panico Tricase City Hospital, Tricase, Italy

    Emiliano Tamburini

  8. Medical Oncology Unit, Poliambulanza Foundation, Brescia, Italy

    Alberto Zaniboni

  9. Department of Medical Oncology, IRCCS Istituto Romagnolo per Lo Studio Dei Tumori (IRST) “Dino Amadori”, Meldola, Italy

    Alessandro Passardi

  10. Oncology Unit, Foundation IRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

    Tiziana Pia Latiano

  11. Department of Oncology, ASUFC University Hospital of Udine, Udine, Italy

    Valentina Fanotto

  12. Department of Medical Oncology, Santo Stefano General Hospital, Prato, Italy

    Samantha Di Donato

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  1. Roberto Moretto
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Contributions

Study concepts: RM, CU, MMG, CC. Study design: RM, CU, MMG, MG, CC. Data acquisition: CU, MMG, MG. Quality control of the data and algorithms: CU, MMG, MG. Data analysis and interpretation: RM, CU, MMG, MG, CC. Statistical analysis: RM, MMG. Manuscript preparation: RM, MMG. Manuscript editing: CU, GF, CC. Manuscript review: all authors.

Corresponding author

Correspondence to Chiara Cremolini.

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Competing interests

FP: Honoraria—Amgen, Merck-Serono, Sanofi, Lilly, Bayer, Servier, Astrazeneca, MSD; Research Grants—Astrazeneca, BMS, Incyte. SL: Speakers’ Bureau—Amgen, Merck, Roche, Lilly, Bristol-Myers Squibb, Pierre-Fabre, GSK and Servier. Consulting or advisory role—Amgen, MSD, Merck Serono, Lilly, Astra Zeneca, Incyte, Daiichi-Sankyo, Bristol-Myers Squibb, Servier, Research Grants—Bayer, Merck, Amgen, Roche, Lilly, Astra Zeneca Bristol-Myers Squibb. FB: Honoraria—Lilly. Travel, accommodations and expenses—Bayer, Ipsen. GM: Honoraria—Amgen, Hoffmane-La Roche, Bayer, Merk Serono, Sirtex. CC: Honoraria—Amgen, Bayer, Merck, Roche and Servier. Consulting or advisory role—Amgen, Bayer, MSD, Roche. Speakers’ Bureau—Servier. Research funding—Bayer, Merck, Servier. Travel, accommodations and expenses—Roche and Servier. The remaining authors declared no competing interests.

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All patients provided written informed consent to study procedures before enrolment. Approvals for TRIBE protocol were obtained from local ethics committees of participating sites.

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Moretto, R., Germani, M.M., Giordano, M. et al. Trop-2 and Nectin-4 immunohistochemical expression in metastatic colorectal cancer: searching for the right population for drugs’ development. Br J Cancer 128, 1391–1399 (2023). https://doi.org/10.1038/s41416-023-02180-7

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