The Role of organoids and Whole Genome Sequencing in precision oncology

Organoids can help determine which patients with metastatic colorectal cancer (mCRC) are likely to respond to chemotherapy and which targeted therapies show real clinical potential. These findings come from the prospective multicenter OPTIC study, on which Lidwien Smabers, currently working as a resident (ANIOS) in internal medicine at the Diakonessenhuis, will defend her PhD in March. Complementary research within the same study demonstrates that whole genome sequencing (WGS) doubles the number of patients with actionable biomarkers compared to standard diagnostics. Together, organoid testing and WGS are bringing precision oncology closer to everyday clinical practice.

Predicting treatment response with Organoids

The prospective multicenter OPTIC study (Organoids to Predict Treatment Response in mCRC) included 232 patients across five Dutch hospitals. Based on these results, Smabers concludes that patient-derived organoids can predict with high precision which patients will or will not benefit from chemotherapy.

“This means unnecessary treatments and side effects can be avoided,” she explains. “The results are promising. But an interventional study still needs to demonstrate that this also translates into better outcomes for the patient. In addition, the culture process needs to be accelerated. Research is ongoing to determine whether the same results can be achieved with a smaller number of organoids.”

‘The time required for organoids to grow varies significantly. Sometimes it only takes days before the organoids grow, sometimes weeks,” says Smabers. “The success of the culture depends on various factors and improved significantly during the study, from 22 to 75%,’ says Smabers.

She emphasizes the importance of minimizing the time between biopsy and culture initiation. “The type of medium with growth factors, nutrients, and substances that prevent cell death has an impact, as do the quantity and quality of the collected tissue. The experience of the person obtaining the tissue and the person culturing the organoids also plays a role. But it also depends on characteristics of the tumor itself. Additional analyses revealed that colorectal tumors with abundant mucin production or peritoneal metastases were less likely to grow successfully in culture.” 

Investigating the Role of Whole Genome Sequencing

In a second phase of the study, the added value of WGS was evaluated in 96 patients. “In recent years, more targeted therapies have become available as alternatives to chemotherapy,” Smabers explains. “Effective application of these therapies requires broader diagnostics. At present, only a limited number of predefined biomarkers are tested, such as mutations in KRAS, NRAS, BRAF, and microsatellite instability (MSI). But with WGS, the entire genome is mapped, ensuring that treatment options are no longer overlooked.”

The research question was clear: how many additional actionable biomarkers can be identified with WGS compared to standard diagnostics, and in how many patients does this result in targeted treatment?

“With WGS, new biomarkers were identified that are not yet routinely used to guide treatment decisions. We discussed these findings in multidisciplinary meetings to determine whether the patient qualified for treatment, either registered therapies or within a clinical trial, with a potential positive treatment effect,” Smabers says. “Subsequently, we tested organoids carrying some of these biomarkers with the corresponding therapies to investigate whether the tumor actually responded.”

Significant Improvement

The results were remarkable The proportion of patients in whom a new actionable biomarker was identified rose to 80%, compared to 40–50% with traditional diagnostics.

“More patients therefore become eligible for personalized targeted treatment,” says Smabers. “The percentage of patients receiving targeted therapy increased from 11 to 24%. This is an important step toward precision oncology.”

Organoid testing further clarified which DNA alterations could lead to meaningful therapeutic responses. “Organoids can therefore also be used in advance to test which treatments in development have the biggest potential, and which do not,” Smabers explains.

Looking Ahead

Broader molecular testing is gaining momentum. “At UMC Utrecht, the transition to an expanded 500-gene panel has already been made,” Smabers notes. “This will increasingly be applied, and as a result, it will also become more affordable.”

WGS is currently reimbursed for patients without adequate treatment options, such as individuals with certain rare or difficult-to-treat tumors.

“It is clear that we need to move from performing separate tests sequentially to one integrated test early in the treatment process,” she says. “In this way, costs can also be reduced, because repeated testing is no longer necessary. WGS provides answers to all relevant questions at once, enabling faster and more targeted treatment.” The most important next step is to demonstrate that this expanded diagnostic strategy truly improves patient outcomes. “

Although each individual biomarker concerns relatively small numbers and not every biomarker will lead to successful treatment, we expect that the cumulative effect of WGS will be substantial for patients with metastatic colorectal cancer,” Smabers concludes.

1. Smabers L, Wensink G, Verissimo C et.al. Patient-derived organoids predict treatment response in metastatic colorectal cancer. Clin Cancer Res. 2025;31(23):5015-26.
2. Smabers L, Nienhuis H, De leng W et.al. Clinical implications of whole genome sequencing in metastatic colorectal cancer.  Oncogene 025;44(48):4686-98.