By Lina carolina 
Researchers at the Francis Crick Institute, the UCL Cancer Institute, and University College London Hospitals (UCLH) have developed a groundbreaking test, named ORACLE, that demonstrates a superior ability to predict lung cancer survival at the point of diagnosis compared to current clinical risk factors. This advancement holds significant potential for refining treatment decisions, particularly for individuals diagnosed with stage 1 lung cancer, with the aim of reducing the likelihood of cancer recurrence or metastasis.
A New Era in Lung Cancer Prognosis
The findings, published in the prestigious journal Nature Cancer, stem from an extensive evaluation of the ORACLE test conducted on 158 lung cancer patients as part of the Cancer Research UK-funded TRACERx study. The research unequivocally indicates that ORACLE possesses a greater predictive power for patient survival than established clinical benchmarks, such as tumour stage. This breakthrough is particularly timely given the persistent challenges in effectively managing lung cancer, which remains the leading cause of cancer-related death globally.
The impetus behind ORACLE’s development in 2019 was to address a critical unmet need: the scarcity of reliable biological markers in lung cancer that could accurately identify patients at higher risk of their disease returning or spreading. This gap in diagnostic capability has direct implications for treatment strategies, especially for early-stage lung cancer patients.
Addressing the Dilemma of Stage 1 Lung Cancer
A significant focus of the research is on patients diagnosed with stage 1 lung cancer. Typically, these individuals undergo surgery as their primary treatment, often without adjuvant chemotherapy. However, a sobering reality is that approximately a quarter of these patients experience a recurrence of their cancer. This statistic suggests that a subset of stage 1 patients might have benefited from more intensive monitoring or the inclusion of chemotherapy in their treatment regimen from the outset. The challenge lies in accurately identifying this at-risk group at the time of diagnosis.
Current diagnostic methods, while valuable, have limitations. When a tumour sample is analysed, it often represents less than 1% of the entire tumour. Furthermore, the genetic makeup of a tumour can be highly heterogeneous, varying significantly from one region to another within the same cancerous growth. ORACLE circumvents this limitation by examining gene expression levels across all regions of the tumour, providing a more comprehensive genomic snapshot.
The recent findings highlight ORACLE’s capacity to differentiate stage 1 lung cancer patients who have a poorer prognosis and might therefore benefit from a combination of surgery and chemotherapy. This granular level of prediction was not achievable with the clinical standards currently in use for this patient population.
Linking ORACLE Scores to Tumour Behaviour
Beyond survival prediction, the researchers discovered a compelling correlation between high ORACLE risk scores and specific regions within the tumour that exhibit a greater propensity for metastasis – the spread of cancer to other parts of the body. This linkage provides crucial insights into the biological drivers of aggressive disease and offers a potential avenue for targeted interventions.
Further investigation delved into the response of lung cancer cells with high ORACLE scores to various therapeutic agents. By examining 359 current and experimental lung cancer drugs, the team found that a high ORACLE risk score was associated with a more favourable response to certain types of chemotherapy, notably platinum-based drugs such as cisplatin.
The underlying mechanism for this enhanced response is attributed to the fact that tumour regions with high ORACLE scores are characterised by unstable DNA, a phenomenon known as chromosomal instability. Platinum drugs are particularly effective at targeting and damaging such unstable DNA. This discovery aligns with recent findings from the same research group, which identified alterations in a key gene, FAT1, as a driver of chromosomal instability – a genetic variation that ORACLE is designed to detect.
The Path Forward: Clinical Validation and Translation
The immediate next steps for the research team involve rigorous clinical validation. They plan to compare outcomes for patients with high ORACLE scores who receive standard care against those who undergo more intensive surveillance or receive chemotherapy. This comparative analysis will be crucial in determining whether the ORACLE test can demonstrably improve survival rates, even for individuals diagnosed at the earliest stages of lung cancer.
Dr. Dhruva Biswas, a Translation Fellow at the Crick and co-first author of the study, emphasized the transformative potential of ORACLE. "ORACLE can now predict survival rates in patients diagnosed at the earliest stage," Dr. Biswas stated. "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."
Yun-Hsin Liu, a Research Assistant at the UCL Cancer Institute and co-first author, elaborated on the comprehensive nature of the test. "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," Liu explained. "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."
Professor Charles Swanton, Deputy Clinical Director and Head of the Cancer Evolution and Genome Instability Laboratory at the Crick, and co-senior author of the study, underscored the global significance of this research. "Lung cancer is the leading cause of cancer-related death throughout the world, so it’s clear we need better markers to accurately classify tumours and predict who is at high risk," Professor Swanton remarked. "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."
Paul Mercer, Head of Industry Partnerships in the Crick Translation team, highlighted the practical implications. "This is an important step forward, translating our understanding of the infinite complexities of lung cancer mutation into a diagnostic tool, prioritising patients for the most effective therapies," Mercer said. "We look forward to working with partners to take this work forward and maximise patient benefit from ORACLE."
A Collaborative Effort for Better Outcomes
The research was made possible through substantial support from Cancer Research UK. Dani Edmunds, Science Engagement Manager at Cancer Research UK, expressed optimism about the findings. "In the last 50 years, cancer survival has doubled in the UK. However, progress has not been equal across all types of cancer," Edmunds noted. "Although survival for lung cancer has improved since the 1970s, it’s still one of the most challenging cancers to treat."
Edmunds continued, "New tests to predict lung cancer’s behaviour could help doctors tailor treatment strategies to each person’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 personalised approaches to treating lung cancer, so more people live longer, better lives."
The study also received support from the National Institute for Health and Care Research UCLH Biomedical Research Centre, underscoring the collaborative nature of this vital scientific endeavor.
Broader Implications and Future Directions
The implications of the ORACLE test are far-reaching. For clinicians, it offers the potential to move beyond a one-size-fits-all approach to early-stage lung cancer treatment. By providing a more precise prognostic assessment, doctors can better stratify patients and tailor interventions, potentially sparing those at lower risk from unnecessary chemotherapy side effects while ensuring those who would benefit receive it.
For patients, this translates to more personalized care, improved chances of successful treatment, and a greater understanding of their individual risk profile. The ability to predict response to specific chemotherapy agents, like platinum drugs, could also lead to more effective and less toxic treatment regimens.
The research into chromosomal instability and its link to FAT1 gene mutations further illuminates the complex biological landscape of lung cancer. This deeper understanding not only informs the development of diagnostic tools like ORACLE but also opens avenues for novel therapeutic strategies targeting these specific vulnerabilities.
The journey from laboratory discovery to widespread clinical application is often long and complex. However, the robust validation of ORACLE within the TRACERx study, coupled with strong collaborative partnerships and funding, positions it as a promising candidate for translation into a routine clinical diagnostic tool. The ongoing validation studies are critical to confirming its efficacy and safety in larger, more diverse patient populations, paving the way for its adoption in clinical practice and ultimately improving outcomes for lung cancer patients worldwide.
