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Tumor-Derived Organoids ID Colorectal Cancer Patients Who Don't Respond to Irinotecan-Based Chemo

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NEW YORK – Organoids grown from tumor biopsies may to be able to help guide treatment choices for colorectal cancer patients. 

While chemotherapy is a standard treatment approach for colorectal cancer patients, it comes with side effects, and not all patients actually respond to it. Being able to better guide that treatment choice would enable a precision oncology approach in which patients receive a treatment regime they are more likely to respond to.

"The key question is: how can we make the decision very quickly to give the patient that correct treatment?" said Shuibing Chen, an associate professor at Weill Cornell Medical College.

According to Chen, organoids are an attractive option for modeling patients' disease to examine how their tumors respond to different treatment scenarios, since it's possible to generate multiple organoids in a relatively short time.

A new study from researchers at the Netherlands Cancer Institute tested whether organoids can help identify which metastatic colorectal cancer patients responded to a standard, irinotecan-based chemotherapy regimen in the multicenter TUMOROID study.

As they reported last week in Science Translational Medicine, NKI's Emile Voest and his colleagues predicted which patients would not respond to a particular chemotherapy approach from their organoid models, suggesting that if the findings are validated, there could be a place for organoid testing clinically to save patients from exposure to a therapy that would not help them.

"We're very much interested in bringing precision to the [care of] individual patients, and until now we couldn't do that," Voest said. "With the organoid technology, there at least was a chance that we could use that as a tool to predict treatment."

However, their approach was not able to predict response to a different chemotherapy approach, 5-fluorouracil plus oxaliplatin, suggesting the clinical application of this technology may be complex

Organoid testing

The researchers enrolled 61 patients with metastatic colorectal cancer into their TUMOROID study and collected 67 biopsies for culturing. They successfully generated tumor organoids for 40 of the 63 biopsies they were able to culture, a success rate of about 63 percent.

At the same time, the patients in the prospective study underwent standard-of-care treatment with 5-fluorouracil or capecitabine — an oral pro-drug of 5-FU — in combination with either oxaliplatin or irinotecan, or with irinotecan alone. In most cases, these patient-derived organoids were established before the patients began treatment. In this way, the researchers were able to model how the organoids responded to these standard-of-care chemotherapy regimens and compared that to how the patients responded.

But, rather than try to predict patients who would respond to chemotherapy, Voest noted that he and his colleagues instead focused on identifying patients that were unlikely to respond to chemotherapy. That way, those patients could potentially be spared treatment that wouldn't work for them and its associated side effects.

In their study, the researchers tested 10 patient-derived organoids from 10 patients who were treated with irinotecan. Five organoids were from tumors determined to be stable and five were from progressive tumors. They exposed the organoids from these patients to irinotecan treatment and screened their growth rate in response to drug exposure. The researchers similarly tested organoids derived from 12 patients who underwent combined 5-fluorouracil–irinotecan therapy with that drug regimen.

Using a growth rate score classifier, they were able to distinguish non-responders to irinotecan treatment. Overall, this classifier could correctly predict non-responders in more than 80 percent of patients.

"That's actually the first test for chemotherapy that can do that, because there are no [predictive] biomarkers for any chemo," Voest said.

This patient-derived organoid approach, however, was unable to predict patient response to combination 5-fluorouracil-oxaliplatin therapy, the researchers reported.

This is helpful to know, Chen said. "They report both positive and negative results, which is actually quite important," she said. "Although we are all very interested in organoid use to predict drug response, of course we want to know which drug can be predicted well, but [also] which type of drug might not be able to be predicted very well."

Both Voest and Chen said that the ability to predict 5-fluorouracil–irinotecan treatment response and the inability to predict response to combination 5-fluorouracil-oxaliplatin therapy could be due to differences in the drugs' mechanisms. If a drug has an indirect effect on the tumor cell or DNA, by acting on the tumor microenvironment or through the immune system, that might not be captured by organoids, as those components might be missing from the organoids' culture system.

This finding also indicates that not all chemotherapies may be suitable for testing using organoids — that researchers or clinicians won't be able to just grow a bunch of organoids up and interrogate a suite of drugs to find which one works best.

"There are no shortcuts that you can take when it comes to using organoids as a predictive tool," Voest said.

While organoids might be able to predict colorectal cancer patients' response to some chemotherapies, there are still hurdles to their clinical implementation. Voest noted that while their test is promising, it still needs to be validated in a larger set of patients, something that he and his colleagues are working on.

Chen added that the efficiency of developing organoids would also have to improve for them to be used as a clinical service. She noted that the success rate for developing organoids the researchers in this study reported is similar to what her institution and others have achieved, but for the clinic it would be ideal to be able to develop organoids for every patient.  

Additionally, Chen said that the organoids would have to be generated on a timescale that is clinically useful. According to Voest, this test would take about four to six weeks.

In the paper, Voest and colleagues noted, as other researchers have, that multiple core biopsies, in tandem with pathologists who can identify samples with low cellularity, could improve the culture success rate for organoids. However, they acknowledged the need to improve the efficacy of patient-derived tumor organoids, writing that unlike sequencing gene panels, "a technical limitation of functional tests is that they cannot be 'rushed.'"

"Overall, it is very promising," Chen said of the work on organoids. "There's definitely a lot of clinical applications, and there's still a lot of things that need to be done before it can be used clinically."