Paper published in Science Translational Medicine, 9 October 2019:
Salo N. Ooft et al., 'Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients'.
The problem: over-treatment
Patients with metastatic cancer are almost always treated with chemotherapy. Chemotherapy can prolong the life of cancer patients by months to years, but the problem is that the treatment is not effective for all patients. A significant proportion of the patients do not benefit from the treatment, but do have to suffer all the side effects. At a stage where the quality of life should be paramount, quite a number of the patients are very ill due to treatment that has no effect and does not prolong life. This is called over-treatment.
Need for chemo test
This is why there is currently a great need for a test that can predict exactly which patients will benefit from treatment and, above all, which patients will not. Although genetic tests of this kind exist for the more recent targeted types of treatment, it has not been possible to develop a test for chemotherapy, a treatment that has existed since the 1950s.
Testing chemotherapy on organoids
It has been possible for a few years now to grow patient-derived organoids in the lab from a small piece of the patient's tumour tissue. These mini tumours retain the morphological and genetic characteristics of the original tumour. In theory, it is possible to first test the chemotherapy in the lab on these 'mini tumours' grown from the patient's tissue. The next question is: does a patient-derived organoid respond to the treatment in exactly the same way as the actual tumour does?
In a clinical trial, led by Emile Voest of the Netherlands Cancer Institute, researchers have now investigated whether the treatment response of these 'mini tumours' could indeed be correlated with the response of the patients, which would mean that these patient-derived organoids could be used as a predictive test to determine the effect of chemotherapy on individual patients.
Metastatic colorectal cancer
The researchers focussed on metastatic colorectal cancer, a type of cancer for which the standard treatment for every patient is chemotherapy. A widely used chemotherapeutic second-line drug to treat this cancer is irinotecan, which makes the tumour shrink in approximately 20% of the patients. The large majority of the patients do not benefit from it but do suffer such side effects as baldness, diarrhoea and fatigue. The aim of the study was to specifically identify these so-called non-responders.
Addressing over-treatment
The researchers tested the drug irinotecan on the organoids. "The researchers tested the drug irinotecan on the organoids. "What we saw was that in 80% of the cases we were able to predict which patients would benefit from the treatment using the test", says researcher Salo Ooft, lead author of the article. 'This means that organoids can help improve decision-making on the best treatment options."
In turn, the test correctly predicted which patients had benefited from the treatment. Salo Ooft says: "The latter is very important as you don't want to deny patients treatment that could have prolonged their life."
These two important points were also shown when irinotecan was combined with 5-FU, another chemotherapeutic drug, a widely-used combination therapy from which also only a small proportion of the patients benefit.
Next step: testing in a larger group of patients
The two tests for irinotecan and 5-FU + irinotecan are still under development. The most important thing to do now is to try out the tests in a larger group of patients to confirm the predictive value. Another obstacle that needs to be addressed is that it was not possible to culture the tumour cells of all the patients. This could be done in 63% of the cases. So an important question for the future is how to improve this process in order to make the test broadly applicable.
Response to other treatment not predicted
The technique has its limitations. The mini tumours could not predict the response to another combination therapy, namely 5-FU and oxaliplatin, a chemotherapy treatment that, as a first-line treatment, benefits 40-45% of the patients. Salo Ooft: 'It is possible that more factors than just the tumour cells in the petri dish play a role in this type of treatment.'
This research has financially supported by the Dutch Cancer Society and Oncode Institute
Hospitals and organisations involved in the TUMOROID study:
- Netherlands Cancer Institute
- Elisabeth-Tweesteden Ziekenhuis
- TilburgMeander Medisch Centrum
- Oncode Institute
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