Abstract 487P
Background
Treatment strategies for chemo-refractory metastatic colorectal cancer (mCRC) remain limited. Three-dimensional in vitro patient-derived organoids (PDOs) represent an unmatched model to elucidate mechanisms of drug resistance, due to their capacity to resemble tumour characteristics.
Methods
We have set up a solid methodology for generating PDOs from mCRC metastases (mets). Selected patients (pts) with refractory mCRC were biopsied at progression. After tissue digestion, PDOs were expanded. In parallel, generated PDOs were dissociated and put in 96-well plates (500 cells/ well) and to underwent 6 days drug-screening assay (DSA) with a comprehensive pipeline of chemotherapies/targeted drugs against almost all the actionable mCRC molecular drivers (e.g. cetuximab (cet), BRAF inhibitor (inh) + cet, MEK inh + cet, PI3K inh, lapatinib+ trastuzumab, porcupine inh, WNT inh). Drug activity was measured based on IC50 calculations. Parallel PDO genotyping, using 300 genes next generation sequencing (NGS), nanostring® and copy number variation panels, has been matched to the DSA for more insight on underlying drug sensitivity mechanisms. Test turnover time: 2 weeks.
Results
A total of 9 biopsies were obtained from mCRC liver and node mets. DSAs were performed for all the 9 pts. For 5/9 pts an additional biopsy core was used for NGS. 4/9 DSAs/NGS data resulted in applicable treatment combinations. In particular, 2 pts with RAS mutant refractory mCRC were treated with FOLFOX-bevacizumab “rechallenge” and with mitomycin capecitabine in 3rd line, respectively, based on DSAs results, with stable disease (SD) as best response. One pt was treated with nivolumab/SMAC mimetic (phase I trial) due to the presence of high tumour mutational burden, experiencing SD. NGS showed the presence of a BRCA2 mutation in 1 pt that correlated with DSA sensitivity to olaparib.
Conclusions
We have designed an affordable fit-for-purpose functional screening assay with a very short turnover time of 2 weeks, that allows exploration of suitable treatment strategies for pts with mCRC. Our work sets a basis for further functional-driven approaches in the difficult decision making process for chemo-refractory mCRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Vall d'Hebron Institute of Oncology.
Funding
Asociación Española Contra el Cáncer (AECC).
Disclosure
R. Dienstmann: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Symphogen, Ipsen, Amgen, Sanofi, MSD, Servier; Honoraria (self): Merck. A. Vivancos: Advisory/Consultancy: sysmex, Novartis, Merck, Guardant Health, Roche, Bristol-Meyers Squibb. E. Elez: Honoraria (self): MSD, Servier; Honoraria (self), Research grant/Funding (self): Sanofi Aventis, ; Honoraria (self), Non-remunerated activity/ies: Hoffmann La Roche, Merck, Amgen. J. Tabernero: Advisory/Consultancy: Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Par. G. Argiles Martinez: Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Hoffmann La-Roche, Bristol Myers Squibb, Bayer, Servier, Amgen, Merck Serono, Menarini; Honoraria (institution): Bayer, Servier, Novartis, Boehringer Ingelheim, Boston Pharmaceuticals, HoffmanLa Roche, Genentech. All other authors have declared no conflicts of interest.