Abstract 344P
Background
Patients with colorectal cancer (CRC) have limited systemic treatment options compared to other major cancer types. Tumor heterogeneity is a major cause of treatment failure.
Methods
We have generated a living biobank of 208 patient-derived organoids (PDOs) from liver metastases of 100 patients treated by hepatic resection for advanced CRC at Oslo University Hospital. The biobank includes multiple synchronous lesions (n=2-6) from 66 of the patients, and recurrent lesions sampled at hepatic re-resections of four patients. All PDOs have been screened for sensitivity to custom-made and clinically relevant drug libraries for CRC (n=40-47 drugs). Subsets of PDOs and corresponding tumor tissue samples have been analyzed by multi-omics approaches.
Results
Metastatic lesions from individual patients showed only modest heterogeneity in drug sensitivities with distribution of mean Euclidean distances skewed towards lower intra-patient heterogeneity. Also, there was no correlation between the number of PDOs analyzed per patient and their mean Euclidean distances. TP53 mutated PDOs were generally multidrug resistant, and TP53 wild type PDOs were sensitive to several chemotherapies, including 5-FU, SN-38, TAS-102, and gemcitabine. Furthermore, sensitivity to the PARP inhibitor talazoparib was significantly higher in TP53 wild type PDOs that supports our previous study suggesting wild-type TP53 activity as a mechanism of response to PARP inhibition in CRC cell lines (EBioMedicine. 2020;59:10292). A TP53 mutated PDO harboring an ATM mutation was hypersensitive to PARP inhibition, suggesting that other mechanisms of PARP inhibitor sensitivity are also involved. Among patients with lack of sensitivity to standard of care drugs for CRC, seven and four percent presented strong sensitivities towards conventional chemotherapies methotrexate and gemcitabine, respectively. Ex vivo drug vulnerabilities from the living biobank are currently being used as a reference basis for an interventional phase II umbrella clinical study for patients with advanced CRC.
Conclusions
In conclusion, PDOs from multifocal liver metastases model pharmacogenomic heterogeneity of advanced colorectal cancers and have strong potential for personalized oncology.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Norwegian Cancer Society, Regional Health Authority South-Eastern Norway and Research Council of Norway.
Disclosure
R.A. Lothe: Other, Institutional, Member of the Board of Directors: Inven2, TTO, LLC. All other authors have declared no conflicts of interest.