Patient-derived Organoid Pharmacotyping As A Predictive Tool for Therapeutic Selection in Pancreatic Ductal Adenocarcinoma.

Autor:	Nicolson NG; Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA., Tandurella JA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.; Cell and Molecular Biology Cancer Biology Program, University of Pennsylvania, Philadelphia, PA, USA., Wu LW; Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.; Division of Hematology and Medical Oncology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA., Patel J; Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital., Morris E; Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA., Seppälä TT; Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA.; Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital., Guinn S; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA., Zlomke H; Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA.; Department of Surgery, Medical University of South Carolina, Charleston, SC., Shubert CR; Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA., Lafaro KJ; Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA., Burns WR; Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA., Cameron JL; Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA., He J; Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA., Fertig EJ; Division of Quantitative Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.; Cancer Convergence Institute, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA., Jaffee EM; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.; Cancer Convergence Institute, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA., Zimmerman JW; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.; Cancer Convergence Institute, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA., Burkhart RA; Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA.; Cancer Convergence Institute, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Jazyk:	angličtina
Zdroj:	Annals of surgery [Ann Surg] 2024 Sep 04. Date of Electronic Publication: 2024 Sep 04.
DOI:	10.1097/SLA.0000000000006517
Abstrakt:	Objective: We integrate a new approach to chemosensitivity data for clinically-relevant regimen matching, and demonstrate the relationship with clinical outcomes in a large PDO biobank. Summary Background Data: Pancreatic ductal adenocarcinoma (PDAC) usually recurs following potentially curative resection. Prior studies related patient-derived organoid (PDO) chemosensitivity with clinical responses. Methods: PDOs were established from pre-treatment biopsies in a multi-institution clinical trial (n=21) and clinical specimens at a high-volume pancreatectomy center (n=74, of which 48 were pre-treated). PDO in vitro chemosensitivities to standard-of-care chemotherapeutics (pharmacotypes) were matched to potential clinically-relevant regimens by a weighted nearest-neighbors analysis. Clinical outcomes were then compared for patients who had well-matched versus poorly-matched treatment according to this metric. Results: Our function matched 91% of PDOs to a standard-of-care regimen (9% pan-resistant). PDOs poorly-matched to the neoadjuvant regimen received would have matched to an alternative in 34% of cases. Patients receiving neoadjuvant chemotherapy well-matched to their pharmacotype experienced improved CA 19-9 response (60% decreased to normal when well-matched, 29% when poorly-matched, P<0.05) and lymph node down-staging (33% N0 after poorly-matched, 69% after well-matched, P<0.05). Patients receiving both well-matched neoadjuvant and adjuvant chemotherapy experienced improved recurrence-free- and overall survival (median RFS 8.5 mo poorly-matched, 15.9 mo well-matched, P<0.05; median OS 19.5 vs. 30.3 mo, P<0.05). Conclusion: In vitro PDO pharmacotyping can inform PDAC therapy selection. We demonstrate improved outcomes including survival for patients treated with regimens well-matched to their PDO chemosensitivities. A subsequent prospective study using PDO pharmacotype matching could improve oncologic outcomes and improve quality of life by avoiding therapies not expected to be effective. Competing Interests: The below disclosures are outside the context of the submitted work: TTS is the CEO and co-owner of Healthfund Finland and reports an interview honorarium from Boeringer Ingelheim. E.M.J is a paid consultant for Adaptive Biotech, Achilles, DragonFly, Candel Therapeutics, Genocea, and Roche. She receives funding from Lustgarten Foundation and Bristol Myer Squibb. She is the Chief Medical Advisor for Lustgarten and SAB advisor to the Parker Institute for Cancer Immunotherapy (PICI) and for the C3 Cancer Institute. She is a founding member of Abmeta. E.J.F is on the SAB for Resistance Biology, Consultant for Mestag Therapeutics and Merck. J.W.Z. reports grant funding from Genentech outside the submitted work. All other authors declare no potential conflict of interest. (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu