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Organoids as tools for functional precision oncology in advanced pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) has a steadily increasing incidence and a poor prognosis, notably due to frequent and early resistance to standard-of-care treatments (SOC). Patient tumors’ derived organoids (PDO) are promising models for functional precision oncology (FPO). To be implemented in clinical practice and to provide benefit to most patients, FPO must meet 3 conditions: i) be feasible with a limited amount of material, ii) have a wide panel of drugs, and iii) obtain the test results as quickly as possible. This study aims to evaluate whether PDO can be implemented in clinical practice for the management of PDAC patients.
During 2021-2022, patients were prospectively enrolled in an IRB-approved protocol (NCT04932525). Main inclusion criteria were: histologically confirmed PDAC, at least one tumor accessible site (biopsy, surgery or ascites), and ECOG performance status 0-1. Molecular profile from tumors was obtained through liquid biopsy (FoundationOne®Liquid). PDO were established from aspiration/biopsy, peritoneal effusions or surgical specimens. The efficacy of 25 antitumor therapies (chemotherapies and targeted therapies) was tested to obtain a chemogram. To predict sensitivity/resistance of a patient's tumor to a given treatment, the viability of PDO was studied after drug exposure (ATP luminescence test). A scoring system was developed to rank drugs and a hit was defined if the score was >1.5. We also performed Whole-Exome-Sequencing (WES) and pathological assessment on PDO to match with initial tumor.
Overall, 76 samples (73 patients; median age 63years; median number of previous treatment lines, 2 [range:0-5]) were collected. 91% of patients had previously received FOLFIRINOX, 53% gemcitabine and 44% (nab)-paclitaxel. The PDO take-on rate was 62% (n=47/76), respectively 55% for metastasis biopsy (liver, 25/41 (61%); other, 1/7 (14%)), 40% (2/5) for pancreas aspiration, 93% (14/15) for ascites, 25% (1/4) for pleural effusion and 100% (3/3) for primary tumor resection. Mean turnaround-time to obtain chemogram was 7.7 weeks (6.2 weeks for ascites/surgery, 7.9 weeks for biopsy). Overall survival (OS) from metastasis diagnosis was 17.2 months (IC95% 10.8-22.8). Median OS was higher in patients for whom PDO were not established (5.2 months [4.4-NR]) than in patients for whom PDO were established (3.3 months [1.9-5.0], p < 0.01). Median number of hits was 3 (range, 0-10). In 90% of cases, at least 1 hit was identified, and in 87% of cases, at least one of the hits was not a SOC (i.e. fluorouracil, irinotecan, oxaliplatin, gemcitabine, or paclitaxel). Main identified hits were olaparib (n=15/47), gemcitabine (n=14/47), and everolimus (n=11/47), Main identified molecular alterations on PDO were KRAS (98%), TP53 (72%), CDKN2A/B (17%) and SMAD4 (17%). Genomic (WES data) correlated with initial tumor with good concordance rate (88%).
We report a large prospective monocentric study that aims to implement PDO-based functional precision oncology for PDAC. We could identify in a clinically relevant turnaround time at least one putative hit on the chemogram in 90% of cases, and in 87% of cases hits were not SOC. These results warrant to be confirmed in a prospective randomized trial to address the efficacy of PDO-based functional precision oncology for the management of PDAC.
NCT04932525.
The authors.
Agence Nationale de la Recherche (ANR) grant ANR-20-CE13-0031-01 Institut National du Cancer (INCa) grant 2020-1-PLBIO-04-IGR-1 Fundraising against CRC and Mars Bleu from the Gustave Roussy foundation Inserm Cancer 3R program (20CR046-00) Agence Nationale de la Recherche (ANR) grant ANR-21-RHUS-0003 Gustave Roussy Philantropia foundation.
A. Italiano: Advisory / Consultancy: Bayer, Daiichi Sankyo, Epizyme, Ipsen, Roche, and Springworks; Research grant / Funding (institution): AstraZeneca, Bayer, Merck, MSD, Pharmamar, and Roche. A. Hollebecque: Honoraria (Institution): Astra-Zeneca, Roche; Advisory / Consultancy: Abbvie, Amgen, Basilea, BMS, Incyte, Servier, QED therapeutics, Relay Therapeutics, Seagen, Taiho; Research grant / Funding (self): Incyte; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: AstraZeneca. F. Jaulin: Leadership role: orakl. All other authors have declared no conflicts of interest.
