ORACLE test enhances prediction of lung cancer outcomes

A new test, developed by researchers from UCL Cancer Institute and the Francis Crick Institute, can better predict lung cancer survival at the point of diagnosis, which could inform treatment decisions and potentially reduce the risk of the cancer returning or spreading.

In research published in Nature Cancer, the team assessed the diagnostic test, called ORACLE, in 158 people with lung cancer as part of the Cancer Research UK-funded TRACERx study. They found that ORACLE, which looks at the genes expressed in a tumor, could better predict patient survival than currently used clinical standards like tumor stage.

ORACLE was developed in 2019 to overcome the lack of biological markers in lung cancer, which can indicate to doctors who might be at a greater risk of their cancer coming back or spreading to another part of the body.

This is particularly important for people with stage 1 lung cancer, who are normally given surgery without chemotherapy. For a quarter of stage 1 patients, their cancer returns, suggesting they may have benefitted from more frequent monitoring or chemotherapy.

When doctors take a sample from a tumor, they typically only capture less than 1% of the tumor, and the genetics can vary massively from region to region within the same tumor. ORACLE overcomes this by looking at genes expressed at a high or low level in every part of the tumor.

The new findings show that ORACLE could predict which patients with stage 1 lung cancer had a lower chance of survival, and might benefit from chemotherapy as well as surgery. Currently used clinical standards weren't able to give this information for stage 1 patients.

The researchers also found that high ORACLE risk scores were linked to regions of the tumor that were more likely to spread to another part of the body.

Finally, by looking at 359 current and potential lung cancer drugs, they found that a high ORACLE risk score predicted better response to some types of chemotherapy, particularly platinum-based drugs like cisplatin.

This is because tumor regions with high ORACLE scores are associated with unstable DNA (called 'chromosomal instability'), which is particularly targeted by platinum drugs. The same lab has recently found that changes in a key gene called FAT1 drives chromosomal instability, and is also one of the genetic variations ORACLE looks for.

The next steps for the researchers are to compare people with high ORACLE scores receiving standard care and those receiving more surveillance or chemotherapy to determine if the test improves survival, even for people diagnosed at the earliest stage.

Dr Dhruva Biswas, co-first author of the study from UCL Cancer Institute, the Crick and Yale School of Medicine, said: "ORACLE can now predict survival rates in patients diagnosed at the earliest stage. If validated in larger cohorts of patients with lung cancer, doctors could one day use ORACLE to help make informed treatment decisions, bringing lessons from cancer evolution into the clinic."

We wanted to build on the previous work developing ORACLE and show that it can predict survival at the point of a lung cancer diagnosis. We've also shown that it can predict who would benefit from certain types of chemotherapy drugs or if someone's cancer is likely to spread, giving a holistic measure of how a patient's cancer might progress and respond."

Ms. Yun-Hsin Liu, co-first author of the study from UCL Cancer Institute

Professor Charles Swanton, Chief Investigator of the CRUK TRACERx study from UCL Cancer Institute, the Crick and UCLH, said: "Lung cancer is the leading cause of cancer-related death throughout the world, so it's clear we need better markers to accurately classify tumors and predict who is at high risk. We're now working with the Translation team at the Crick and industry partners to progress ORACLE into a test which could hopefully be used in the clinic as soon as possible."