TY - JOUR
T1 - Organoids for Functional Precision Medicine in Advanced Pancreatic Cancer
AU - Boilève, Alice
AU - Cartry, Jérôme
AU - Goudarzi, Negaar
AU - Bedja, Sabrina
AU - Mathieu, Jacques R.R.
AU - Bani, Mohamed Amine
AU - Nicolle, Rémy
AU - Mouawia, Ali
AU - Bouyakoub, Ryme
AU - Nicotra, Claudio
AU - Ngo-Camus, Maud
AU - Job, Bastien
AU - Lipson, Karélia
AU - Boige, Valérie
AU - Valéry, Marine
AU - Tarabay, Anthony
AU - Dartigues, Peggy
AU - Tselikas, Lambros
AU - de Baere, Thierry
AU - Italiano, Antoine
AU - Cosconea, Simona
AU - Gelli, Maximiliano
AU - Fernandez-de-Sevilla, Elena
AU - Annereau, Maxime
AU - Malka, David
AU - Smolenschi, Cristina
AU - Ducreux, Michel
AU - Hollebecque, Antoine
AU - Jaulin, Fanny
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/10/1
Y1 - 2024/10/1
N2 - 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.
AB - 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.
KW - KRAS
KW - Organoids
KW - Pancreatic Adenocarcinoma
KW - Precision Medicine
UR - http://www.scopus.com/inward/record.url?scp=85201603014&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2024.05.032
DO - 10.1053/j.gastro.2024.05.032
M3 - Article
C2 - 38866343
AN - SCOPUS:85201603014
SN - 0016-5085
VL - 167
SP - 961-976.e13
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -