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Different Genomic Clusters Impact on Responses in Advanced Biliary Tract Cancer Treated with Cisplatin Plus Gemcitabine Plus Durvalumab

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Abstract

Background

The results reported in the TOPAZ-1 phase III trial led to the approval of the combination of cisplatin and gemcitabine with durvalumab as the new first-line standard of care for patients with locally advanced or metastatic cholangiocarcinoma.

Objective

We performed a clustering analysis to classify patients into different groups based on their mutation profile, correlating the results of the analysis with clinical outcomes.

Methods

We selected 51 patients with cholangiocarcinoma who were treated with the combination of chemotherapy and durvalumab and who were screened using the next-generation sequencing-based FoundationOne gene panel. We conducted mutation-based clustering of tumors and a survival analysis.

Results

Three main clusters were identified. Cluster 1 is mostly characterized by mutations in genes belonging to the chromatin modification pathway, altered in 100% of patients. Cluster 2 is characterized by the alteration of several pathways, among which DNA damage control, chromatin modification, RTK/RAS, cell-cycle apoptosis, TP53, and PI3K were the most affected. Finally, most altered pathways in cluster 3 were RTK/RAS and cell-cycle apoptosis. Overall response rate was 4/13 (31%), 12/24 (50%), and 0/10 (0%) in cluster 1, cluster 2, and cluster 3, respectively, and the difference between the three clusters was statistically significant (p = 0.0188).

Conclusions

By grouping patients into three clusters with distinct molecular and genomic alterations, our analysis showed that patients included in cluster 2 had higher overall response rates, whereas patients included in cluster 3 had no objective response. Further investigations on larger and external cohorts are needed in order to validate our results.

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Author information

Author notes

  1. Margherita Rimini, Eleonora Loi are Co-first authors.

  2. Patrizia Zavattari and Andrea Casadei-Gardini are Co-last authors.

Authors and Affiliations

  1. IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy

    Margherita Rimini, Stefano Cascinu & Andrea Casadei-Gardini

  2. Department of Oncology, IRCCS San Raffaele Hospital, Via Olgettina n. 60, Milan, Italy

    Margherita Rimini, Noemi Cornara, Federico Rossari, Francesco Vitiello, Elisabeth Amadeo, Stefano Cascinu & Andrea Casadei-Gardini

  3. Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy

    Eleonora Loi, Mara Persano, Mario Scartozzi & Patrizia Zavattari

  4. Department of Oncology, Veneto Institute of Oncology IOV, IRCCS, Padua, Italy

    Mario Domenico Rizzato, Vittoria Matilde Piva & Sara Lonardi

  5. Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy

    Mario Domenico Rizzato & Vittoria Matilde Piva

  6. Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

    Tiziana Pressiani, Rita Balsano & Lorenza Rimassa

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

    Caterina Vivaldi & Lorenzo Fornaro

  8. Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

    Caterina Vivaldi

  9. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

    Eleonora Gusmaroli, Chiara Pircher & Monica Niger

  10. Clinical Oncology Unit, Careggi University Hospital, Florence, Italy

    Lorenzo Antonuzzo

  11. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

    Lorenzo Antonuzzo

  12. Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy

    Erika Martinelli

  13. Medical Oncology Unit, University Hospital of Parma, Parma, Italy

    Ingrid Garajova

  14. Unit of Medical Oncology and Biomolecular Therapy, Policlinico Riuniti, Foggia, Italy

    Guido Giordano

  15. Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy

    Guido Giordano

  16. Division of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy

    Jessica Lucchetti

  17. Medical Oncology Unit, Department of Oncology and Hematology, Central Hospital of Belcolle, Strada Sammartinese Snc, Viterbo, Italy

    Marta Schirripa

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

    Francesca Salani

  19. Institute of Interdisciplinary Research “Health Science”, Scuola Superiore Sant’Anna, Pisa, Italy

    Francesca Salani

  20. Department of Biomedical Sciences, Humanitas University, Milan, Italy

    Lorenza Rimassa

Authors
  1. Margherita Rimini
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  2. Eleonora Loi
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  3. Mario Domenico Rizzato
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  4. Tiziana Pressiani
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  5. Caterina Vivaldi
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  6. Eleonora Gusmaroli
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  7. Lorenzo Antonuzzo
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  8. Erika Martinelli
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  9. Ingrid Garajova
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  14. Federico Rossari
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  19. Rita Balsano
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  20. Francesca Salani
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  22. Stefano Cascinu
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  23. Monica Niger
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  27. Mario Scartozzi
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  28. Patrizia Zavattari
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  29. Andrea Casadei-Gardini
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Corresponding author

Correspondence to Margherita Rimini.

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Funding

No external funding was used in the preparation of this article.

Conflict of Interest/Competing Interests

Monica Niger received travel expenses from AstraZeneca, speaker honoraria from Accademia della Medicina and Incyte; honoraria from Sandoz, Medpoint SRL, Incyte, and Servier for editorial collaboration; and consultant honoraria from EMD Serono, Basilea Pharmaceutica, Incyte, MSD Italia, Servier, Astrazeneca, and Taiho. TP: Swedish Orpahn Biovitrum AB, Ability Pharmaceuticals SL, Aptitude Health, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Ellipses, Genzyme, Got It Consulting SL, Hirslanden/GITZ, Imedex, Incyte, Ipsen Bioscience , Inc, Janssen, Lilly. Marketing Farmacéutico & Investigación Clínica, S.L, MDS, Medscape, Novocure, Paraxel, PPD Development, Polaris, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, Scilink Comunicación Científica SC, Surface Oncology, and Zymeworks. Tiziana Pressiani received/reports consulting fees from Bayer, Ipsen, and Astra Zeneca; institutional research funding from Roche, Bayer, and Astra Zeneca; and travel accommodations from Roche. Lorenza Rimassa declares consulting/advisory roles for AstraZeneca, Basilea, Bayer, BMS, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; honoraria for lectures from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, Merck Serono, Roche, and Servier; travel expenses from AstraZeneca; and research funding (to institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks. Sara Lonardi reports research funding (to institution) from Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, and Servier; personal honoraria as an invited speaker from Amgen, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre-Fabre, Roche, and Servier; and participation in advisory boards for Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, GSK, Incyte, Lilly, Merck Serono, MSD, Servier, and Takeda. Lorenzo Fornaro reports personal honoraria as an invited speaker from Incyte, Bristol Myers Squibb and Lilly; research funding (to institution) from MSD, Bristol Myers Squibb, AstraZeneca, Incyte, BeiGene, Astellas, Daiichi Sankyo, and Roche; and participation in advisory boards for MSD, AstraZeneca, Incyte, Taiho, Servier, Daiichi Sankyo, and Lilly. Margherita Rimini, Eleonora Loi, Mario Domenico Rizzato, Caterina Vivaldi, Eleonora Gusmaroli, Lorenzo Antonuzzo, Erika Martinelli, Ingrid Garajova, Guido Giordano, Jessica Lucchetti, Marta Schirripa, Noemi Cornara, Federico Rossari, Francesco Vitiello, Elisabeth Amadeo, Mara Persano, Vittoria Matilde Piva, Rita Balsano, Francesca Salani, Chiara Pircher, Stefano Cascinu, Mario Scartozzi, Patrizia Zavattari, Andrea Casadei-Gardini have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval

The ethics review board of each institutional hospital approved the present study. This study was performed in line with the principles of the Declaration of Helsinki.

Consent to Participate

Written informed consent for treatment was obtained for all patients.

Consent for Publication

Not applicable.

Availability of Data and Material

Data are available on request from the authors.

Code Availability

Not applicable.

Authors’ Contributions

Conception and design: EL, MR, PZ, AC-G; acquisition of data (acquired and managed patients): all authors. analysis and interpretation of data: EL, MR, PZi, AC-G; writing, review, and/or revision of the manuscript: EL, MR, PZ, AC-G; final approval of manuscript: all authors.

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Rimini, M., Loi, E., Rizzato, M.D. et al. Different Genomic Clusters Impact on Responses in Advanced Biliary Tract Cancer Treated with Cisplatin Plus Gemcitabine Plus Durvalumab. Targ Oncol 19, 223–235 (2024). https://doi.org/10.1007/s11523-024-01032-5

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