Organoid Sensitivity Correlates with Therapeutic Response in Patients with Pancreatic Cancer

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a significant health issue. For most patients, there are no options for targeted therapy, and existing treatments are limited by toxicity. The HOPE trial (Harnessing Organoids for PErsonalized Therapy) was a pilot feasibility trial aiming to prospectively generate patient-derived organoids (PDO) from patients with PDAC and test their drug sensitivity and correlation with clinical outcomes.

Experimental design: PDOs were established from a heterogeneous population of patients with PDAC including both basal and classical PDAC subtypes.

Results: A method for classifying PDOs as sensitive or resistant to chemotherapy regimens was developed to predict the clinical outcome of patients. Drug sensitivity testing on PDOs correlated with clinical responses to treatment in individual patients.

Conclusions: These data support the investigation of PDOs to guide treatment in prospective interventional trials in PDAC.

Figure 1.

Design of the HOPE trial. A, Study schema. B, Consort diagram. This per-patient analysis includes all patients consented for the study regardless of confirmed diagnosis or adequate availability of tissue. Follow-up was performed on all patients when possible to assess clinical attributes that may contribute to successful PDO generation, and 43 patients were still living at last follow-up.

Figure 2.

Identification of clinically relevant DNA alterations and molecular subtypes of PDAC PDOs. A, A comparison of molecular subtyping using two algorithms on RNA-seq data from PDOs: Moffitt and DECODER, and IHC on patient tissue and PDOs. B–D, Nuclear staining of GATA6 (classical subtype marker in green) and KRT5/6 and p63 (basal subtype marker in red) expressed in biopsies and PDOs for patients 3, 6, and 19. E, Oncoplot of clinically relevant DNA alterations identified on biopsies using targeted sequencing annotated with relevant clinical parameters.

Figure 3.

Comparison of tumor histology and DNA alterations between tumor tissue and matched PDOs. A, H&E images of tumor tissue from patients 19, 34, and 38, with matched PDO H&E images. B, Comparison of DNA alterations identified in patient tissue using the FoundationOne CDx-targeted sequencing panel (bottom triangles) with DNA alterations identified in matched PDOs using whole-exome sequencing (top triangles).

Figure 4.

Correlation of PDO drug dose response to clinical response. A, Drug dose–response curves for drug testing on PDOs from patient 3. Drugs were selected based on treatments the patient received and was likely to receive, with a dose range of three orders of magnitude from 0.01 to 10 μmol/L. B, AUC calculated for drug responses in A. Dose–response curves were fitted using weighted n-parameter logistic regression, and AUC was estimated using Simpson rule. C, Correlation of AUC and disease control. Ranked AUC values are shown as black circles. Classification of AUC values using the Jenks natural breaks algorithm is shown by dotted lines. Clinical classification is superimposed on AUC circles, with blue representing disease control and red representing PD. D, For each patient with known clinical response to treatment: (a) drug combination received, (b) AUC estimated for the component drug responses in PDOs, and (c) clinical response classified as disease control (SD or PR) versus PD.