NEW YORK – Researchers used patient-derived organoids to test the activity of different drugs, and based on the results, changed treatments for two metastatic colorectal cancer patients, according to a recently published study.
An Australian-led team of researchers used SEngine Precision Medicine's PARIS test, which combines genomic and drug screening analyses, to evaluate how patients with colorectal cancer that has metastasized to the peritoneum would respond to standard and targeted therapeutics. According to the results of this study, published in Clinical Cancer Research this week, two out of 19 patients for whom organoids were generated were able to receive treatments based on insights from PARIS, and one of them had a partial response on the recommended treatment despite being previously refractory to multiple drugs. Â
SEngine believes the study supports the clinical utility of its test, and its organoid-based precision oncology approach warrants further evaluation. "Each patient's cancer is a unique mosaic created by combinations of genetic and epigenetic alterations, and its complexity makes it difficult to translate this information into therapies," co-author Carla Grandori, the co-founder and CEO of SEngine, said in a statement.
Grandori presented initial data supporting the test's concordance with patient responses at the second virtual session of the American Association for Cancer Research's annual meeting.Â
In the study published this week, the researchers ranked drug sensitivities for a cohort of colorectal cancer patients with peritoneal metastases using SEngine's test.
Researchers from the Peter MacCallum Cancer Center and elsewhere collected samples from 28 metastatic colorectal cancer patients. The researchers were able to generate peritonoids for 68 percent of the patients, a success rate they noted was similar to previous reports, and it took between three and six weeks to generate the organoids.
To identify genomic and copy-number alterations that might predict sensitivity or resistance to targeted therapies, the team sequenced the exomes of both peritonoids and germline blood samples obtained from patients. At the same time, peritonoids from 15 patients underwent drug-dose response screening using SEngine's PARIS platform.
The drug sensitivities predicted through drug-dose response screening were in line with the genomic analyses. For instance, one patient with EGFR, ERBB2, and ERBB4 copy gains was sensitive via organoid screening to seven EGFR inhibitors.
But other sensitivities uncovered through drug screening could not be explained by genomic alterations.
According to the researchers, the combined genomics and drug sensitivity reports were ready within about two months and were provided to treating physicians when patients progressed on standard-of-care treatment. They noted that they collected tissue samples from patients while they were still undergoing standard-of-care treatment so the results would be available in a clinically actionable time frame. However, there was a time lag between tissue sampling and when oncologists could act on the results, the researchers acknowledged.
"Our platform delivers functional testing and genomic data in a form and time-frame that is clinically relevant for our current care pathways," the authors wrote in the paper. "We were limited in our impact by the anticipated difficulties in drug funding and access for off-label indications. Because of this limitation we were not able to change patient treatment to the most efficacious drugs identified from ex vivo peritonoid screening."
Ultimately, two patients had treatment changes based on their reports, though their therapy choice was complicated by obtaining access to the off-label drugs.
One patient with a KRAS mutation was predicted to be sensitive to MEK inhibitors and multi-tyrosine kinase inhibitors. The researchers, though, were unable to receive compassionate access to a MEK inhibitor. They were, however, able to secure off-label access to the multi-tyrosine kinase inhibitor vandetanib (Sanofi/Genzyme's Caprelsa), currently approved for medullary thyroid cancer, but noted no disease response after four weeks of therapy.
Another patient was predicted to be sensitive to a number of therapies, including a striking response to the experimental WEE1 inhibitor adavosertib. As access to adavosertib was unavailable, the patient was treated with a gemcitabine-capecitabine combination, which was also suggested by peritonoid testing. The patient exhibited a partial response upon treatment but experienced disease progression after five months.
According to the researchers, these findings provide a basis for a Phase II trial to further examine the utility of an organoid-based approach to guide personalized treatments.
"In this study, we showed that the tools and techniques exist to grow, propagate, transport and analyze living tumor samples and define each patient's individual drug sensitivities," first author Vignesh Narasimhan from Peter MacCallum said in a statement. "These advances will lead to a better understanding of cancer, inform practice, and most importantly, help our patients."