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In vitro drug screening of patient-derived 3D tumoroids replicates resistance to FOLFOX, FOLFIRI, and FOLFOXIRI in clinically resistant patients with metastatic colorectal cancer
Background
International guidelines present three different chemotherapy regimens for first- and subsequent-line treatment of unresectable metastatic colorectal cancer (mCRC). The main doublet therapies used in first-line treatment is FOLFIRI (5-FU + irinotecan) and FOLFOX (5-FU + oxaliplatin). The two combination treatments offer a similar response rate of 34-55%. The treatments are therefore used indistinctly in the clinic. Evidence is however starting to appear showing that there are differences between the individual patients as to which of the combination treatments that are superior. One approach to increase effectiveness of chemotherapy treatment is to use a patient-derived 3D tumoroid test (such as IndiTreat ® ) to identify the most efficacious treatment and also the ones to which the patient is resistant. The tumoroids closely recapitulate a patient’s tumor. The objective of the present study was to evaluate if IndiTreat ® could distinguish between patients that are clinically drug resistant (CDR) from patients that are chemonaive to the regimens FOLFOX and FOLFIRI plus the triple combination FOLFOXIRI (5-FU + oxaliplatin + irinotecan).
Methods
We included 8 chemonaive patients and 19 patients from the ongoing clinical trial, (ClinicalTrials.gov, NCT03251612). The latter were tested and treated in accordance with IndiTreat ® test results. To be enrolled in the trial, patients had to have progressive unresectable mCRC and be exposed to available standard therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and anti-EGFR agents if RAS/RAF wild-type. This group was defined as CDR patients. For CDR patients, ultrasound - or CT-guided biopsies were sampled from liver metastases. A 16-gauge needle was used (SuperCore TM , Argon Medical Devices, Athens, TX, USA). The biopsies were mechanically dissociated into tissue fragments and embedded in Matrigel (Corning Life Sciences, Merck, Germany). Screening of samples from CDR patients and chemonaive patients were done according to a modified version of a procedure previously described. The tumoroids were exposed to the drug treatments for seven days. Tumoroids growth was measured by taking brightfield images with a Cytation 1 (Biotek) imaging system and quantified using 2cureX’s artificial intelligence algorithm IndiNet TM.
Results
For all three treatment regimens, the IndiTreat ® test showed that the growth inhibition of tumoroids from CDR patients was significantly less compared to chemonaive patients. The clustering for the CDR patients showed that the IndiTreat ® test identified 81%-94% of the patients as having a low growth inhibition (FOLFIRI 94%, FOLFOX 81% and FOLFOXIRI 82%). Conversely, for chemonaive patients, the IndiTreat ® test identified 88%-100% of the patients presented high growth inhibition (FOLFIRI 88%, FOLFOX 100% and FOLFOXIRI 100%).
Conclusions
- The IndiTreat ® test is with a high degree of precision able to identify patients that are clinically resistant to the regimens of FOLFOX, FOLFIRI and FOLFOXIRI. - The present study was performed retrospectively in first- and third-line patients. To investigate the general applicability of the IndiTreat ® test, we plan to perform a prospective study in first-line treatment of mCRC with resistance as the primary endpoint. - Ultimately, the IndiTreat ® technology will assist in the identification of the most efficacious chemotherapy treatment in first-line unresectable mCRC patients.
Clinical trial identification
ClinicalTrials.gov, NCT03251612.
Legal entity responsible for the study
The authors.
Funding
European Union’s Horizon 2020 SME-Instrument Program under grant agreement ID 777718.
Disclosures
G. Hagel: Shareholder / Stockholder / Stock options: 2curex; Full / Part-time employment: 2curex. O. Thastrup: Officer / Board of Directors: 2cureX. J. Thastrup: Shareholder / Stockholder / Stock options: 2cureX; Full / Part-time employment: 2cureX. All other authors have declared no conflicts of interest.
