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

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.

Informations de copyright

Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.

Déclaration de conflit d'intérêts

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.