Organoids for Functional Precision Medicine in Advanced Pancreatic Cancer

Alice Boilève, Jérôme Cartry, Negaar Goudarzi, Sabrina Bedja, Jacques R.R. Mathieu, Mohamed Amine Bani, Rémy Nicolle, Ali Mouawia, Ryme Bouyakoub, Claudio Nicotra, Maud Ngo-Camus, Bastien Job, Karélia Lipson, Valérie Boige, Marine Valéry, Anthony Tarabay, Peggy Dartigues, Lambros Tselikas, Thierry de Baere, Antoine ItalianoSimona Cosconea, Maximiliano Gelli, Elena Fernandez-de-Sevilla, Maxime Annereau, David Malka, Cristina Smolenschi, Michel Ducreux, Antoine Hollebecque, Fanny Jaulin

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    2 Citations (Scopus)

    Résumé

    Background & Aims: Patient-derived organoids (PDOs) are promising tumor avatars that could enable ex vivo drug tests to personalize patients’ treatments in the frame of functional precision oncology. However, clinical evidence remains scarce. This study aims to evaluate whether PDOs can be implemented in clinical practice to benefit patients with advanced refractory pancreatic ductal adenocarcinoma (PDAC). Methods: During 2021 to 2022, 87 patients were prospectively enrolled in an institutional review board–approved protocol. Inclusion criteria were histologically confirmed PDAC with the tumor site accessible. A panel of 25 approved antitumor therapies (chemogram) was tested and compared to patient responses to assess PDO predictive values and map the drug sensitivity landscape in PDAC. Results: Fifty-four PDOs were generated from 87 pretreated patients (take-on rate, 62%). The main PDO mutations were KRAS (96%), TP53 (88%), and CDKN2A/B (22%), with a 91% concordance rate with their tumor of origin. The mean turnaround time to chemogram was 6.8 weeks. In 91% of cases, ≥1 hit was identified (gemcitabine (n = 20 of 54), docetaxel (n = 18 of 54), and vinorelbine (n = 17 of 54), with a median of 3 hits/patient (range, 0–12). Our cohort included 34 evaluable patients with full clinical follow-up. We report a chemogram sensitivity of 83.3% and specificity of 92.9%. The overall response rate and progression-free survival were higher when patients received a hit treatment as compared to patients who received a nonhit drug (as part of routine management). Finally, we leveraged our PDO collection as a platform for drug validation and combo identification. We tested anti-KRASG12D (MRTX1133), alone or combined, and identified a specific synergy with anti-EGFR therapies in KRASG12D variants. Conclusions: We report the largest prospective study aiming at implementing PDO-based functional precision oncology and identify very robust predictive values in this clinical setting. In a clinically relevant turnaround time, we identify putative hits for 91% of patients, providing unexpected potential survival benefits in this very aggressive indication. Although this remains to be confirmed in interventional precision oncology trials, PDO collection already provides powerful opportunities for drugs and combinatorial treatment development.

    langue originaleAnglais
    Pages (de - à)961-976.e13
    journalGastroenterology
    Volume167
    Numéro de publication5
    Les DOIs
    étatPublié - 1 oct. 2024

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