The ORACLE test may be capable of predicting lung cancer survival at the point of diagnosis more effectively than currently used clinical risk factors, according to a recent study published by Biswas et al in Nature Cancer. The findings could help physicians make more informed treatment decisions for patients with stage I lung cancer and reduce the risk of cancer recurrence and metastasis.
Background
The ORACLE test was developed in 2019 to overcome the lack of biological markers in lung cancer, which can indicate to physicians who might be at a greater risk of cancer recurrence or metastasis.
About 25% of patients with stage I lung cancer—who normally undergo surgery without chemotherapy—experience cancer recurrence, suggesting they may have benefitted from more frequent monitoring or chemotherapy.
When physicians take a sample from a tumor, they typically only capture less than 1% of the tumor, and the genetics can vary from region to region within the same tumor. The ORACLE test was designed to overcome these shortcomings by assessing genes expressed at a high or low level in every part in the tumor.
“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 [Francis] Crick [Institute] and industry partners to progress ORACLE into a test which could hopefully be used in the clinic as soon as possible,” underscored co–senior study author Charles Swanton, FRCP, BSc, PhD, Deputy Clinical Director and Head of the Cancer Evolution and Genome Instability Laboratory at the Francis Crick Institute, Chair in Personalised Cancer Medicine at the UCL Cancer Institute, a medical oncologist at University College London Hospitals, and chief investigator for TRACERx.
Study Methods and Results
In the study, researchers examined the efficacy of the ORACLE test in 158 patients with lung cancer as part of the Cancer Research UK–funded TRACERx study.
Compared with currently used clinical standards such as tumor stage, the researchers found that the ORACLE test could better predict patient survival. The researchers demonstrated that the ORACLE test could predict which patients with stage I lung cancer had a lower chance of survival and may benefit from chemotherapy as well as surgery. Currently used clinical standards weren’t able to provide this information for this patient population.
“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,” explained co–lead study author Yun-Hsin Liu, a research assistant at the UCL Cancer Institute.
The researchers revealed that high ORACLE test risk scores were linked to regions of the tumor that were more likely to spread to another part of the body. By evaluating 359 current and potential lung cancer drugs, the researchers found that a high ORACLE test risk score predicted greater response to some types of chemotherapy, particularly platinum drugs like cisplatin. They noted that tumor regions with high ORACLE test scores were associated with unstable DNA, known as chromosomal instability, which is particularly targeted by platinum drugs. Separate research has indicated that changes in the FAT1 gene may drive chromosomal instability, which is one of the genetic variations the ORACLE test searchers for.
Conclusions
“ORACLE can now predict survival rates in patients diagnosed at the earliest stage. If validated in larger cohorts of patients with lung cancer, [physicians] could one day use ORACLE to help make informed treatment decisions, bringing lessons from cancer evolution into the clinic,” highlighted co–lead study author Dhruva Biswas, MD, PhD, a translation fellow at the Francis Crick Institute, a postdoctoral fellow at the UCL Cancer Institute, and an associate research scientist at the Yale School of Medicine.
The researchers plan to compare patients with high ORACLE test scores receiving standard care with those receiving more surveillance or chemotherapy to determine if the test improves survival, even among those diagnosed at the earliest stage.
“This is an important step forward, translating our understanding of the infinite complexities of lung cancer mutation into a diagnostic tool, prioritizing patients for the most effective therapies. We look forward to working with partners to take this work forward and maximize patient benefit from ORACLE,” added Paul Mercer, BSc, PhD, Head of Industry Partnerships in the Crick Translation team.
“Although survival for lung cancer has improved since the 1970s, it’s still one of the most challenging cancers to treat,” underlined Dani Edmunds, PhD, Science Engagement Manager at Cancer Research UK. “New tests to predict lung cancer’s behavior could help [physicians] tailor treatment strategies to each [patient’s] condition, giving the best chance of a successful outcome. This research reflects Cancer Research UK’s commitment to tackle this hard-to-treat cancer. While ORACLE still needs testing in larger-scale trials, these initial results show it could take us a step closer to more personalized approaches to treating lung cancer, so more [patients] live longer, better lives,” she concluded.
Disclosure: The research in this study was supported by the National Institute for Health and Care Research UCLH Biomedical Research Centre. For full disclosures of the study authors, visit nature.com.
