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30th January 2025
An ultrasensitive blood test which detects even low levels of circulating tumour DNA (ctDNA) could help to improve disease stratification in early-stage lung adenocarcinoma (LUAD), a UK study suggests.
It was known that ctDNA detection could predict clinical risk in early-stage tumours, the UK research team wrote in the journal Nature Medicine. However, it was challenging to detect preoperative ctDNA in early-stage LUADs due to low levels of ctDNA in plasma – frequently below 100 ppm.
In the Cancer Research UK-funded study, scientists from University College London (UCL), the Francis Crick Institute, University College London Hospitals NHS Foundation Trust (UCLH), and the biotechnology firm Personalis, collaborated to test the company’s NeXT Personal platform.
Described as an ultrasensitive, tumour-informed liquid-biopsy platform, the researchers said NeXT Personal had been analytically validated for ultrasensitive ctDNA detection at 1-3 ppm of ctDNA with 99.9% specificity.
They used the platform to analyse preoperative ctDNA in 171 adults with early-stage lung cancer from Cancer Research UK’s TRACERx study.
It detected ctDNA preoperatively in 81% of the patients with LUAD, including 57% of those with pathological tumour-node-metastasis (pTNM) stage 1 disease.
Analysis showed people with a low level of ctDNA before surgery were less likely to relapse and also had improved overall survival rates compared with people with a high level of ctDNA.
The researchers were also able to show that patients with <80 ppm preoperative ctDNA levels had reduced overall survival compared with ctDNA-negative patients with LUAD.
‘Although prospective studies are needed to confirm the clinical utility of the assay, these data show that our approach has the potential to improve disease stratification in early-stage LUADs,’ the study authors concluded.
The data from TRACERx was analysed retrospectively, the researchers acknowledged, with future data from prospective cohorts needed to evaluate the clinical utility of the assay.
‘Although NeXT Personal is already in use as a clinical diagnostic test, it, like other tumour-informed ctDNA detection assays, is of higher complexity and requires a longer turnaround period to develop the panel and obtain a clinically actionable result, compared with non-tumour-informed approached,’ they wrote.
Study first author Dr James Black, a postdoctoral clinical fellow at the Francis Crick Institute and the Cancer Research UK Lung Cancer Centre of Excellence at UCL, said the study had shown the presence or absence of tumour DNA in the blood was strongly predictive of prognosis.
‘ctDNA testing, especially using ultrasensitive platforms, could help clinicians make more informed decisions about treatment and give patients a more accurate idea of how their disease might progress,’ he said, adding that ‘more research to validate these tests will help to get them on the agenda for regular clinical use.’
Study senior author Professor Charles Swanton, who holds positions at the UCL Cancer Institute, the Francis Crick Institute and UCLH and is chief investigator of the TRACERx study, noted that lung cancer is one of the most common types of cancer in the UK and has a high relapse rate.
‘It’s vital to understand who would benefit from more aggressive treatment, especially for patients with stage 1 disease who are often diagnosed during CT screening for those at a higher risk,’ he said.
‘Using sensitive ctDNA tests is one way to do this, which we hope will maximise clinical benefit and minimise unnecessary treatment for individual patients.’
Speaking at Hospital Healthcare Europe’s recent Clinical Excellence in Respiratory Care event, Dr Zaheer Mangera,the lung cancer lead at North Middlesex University Hospital NHS Trust in London, said ctDNA tests were among the innovations to watch in lung cancer care, with the Trust involved in a ctDNA pilot in recent months.
6th October 2023
Taking a pre-radiation biopsy of circulating tumour DNA (ctDNA) in patients with oligometastatic non-small cell lung cancer (NSCLC) may help identify those most likely to benefit from locally consolidative radiotherapy (RT), according the findings of recent study.
Published in the journal NPJ Precision Oncology, the researchers sought to risk-stratify and identify the patients with oligometastatic NSCLC most likely to benefit from locally consolidative RT, which could help to achieve prolonged remission.
They performed 1,880 liquid biopsies and approximately 20% of patients (n = 309) had their ctDNA measured prior to RT and after their diagnosis of oligometastatic disease.
Patients with undetectable ctDNA before RT had significantly improved progression-free survival (PFS) (p = 0.004) and overall survival (OS) (p = 0.030).
In contrast, patients with detectable ctDNA pre-RT had a median PFS of 5.4 months versus 8.8 months for those with undetectable levels (Hazard ratio, HR = 1.57, 95% CI 1.15 – 2.13, p = 0.004). There were similar findings for OS, with a median OS of 16.8 months versus 25 months (HR = 1.65, 95% CI 1.05 – 2.61, p = 0.030). Multivariate analysis, including additional parameters, revealed a similar trend.
Based on these findings, the authors wrote: ’Our analysis reveals that ctDNA testing performed pre-RT can risk-stratify those patients with truly oligometastatic NSCLC from those who likely harbour widespread micrometastatic disease (below current imaging limits of detection).’
Senior study author Aadel Chaudhuri, an assistant professor of radiation oncology at the Siteman Cancer Center, based at Barnes-Jewish Hospital and Washington University School of Medicine in St Louis, said: ‘Our findings suggest the level of ctDNA, rather than the number of tumours themselves, is a more precise measure of disease burden.’
The authors added: ‘This approach should be prospectively evaluated in a clinical trial that redefines oligometastatic NSCLC to include a discrete liquid biopsy metric encompassing a low or undetectable ctDNA level.‘
13th April 2022
The presence of residual ctDNA after treatment of patients with non-small cell lung cancer (NSCLC) is associated with a shorter recurrence-free survival and overall survival. This was the key finding of a study carried out in Cambridge, UK.
In 2020, there were over 2.2 million cases of lung cancer which resulted in nearly 1.8 million deaths. Lung cancer has two main forms; small cell and non-small cell, and in the UK, the latter accounts for around 85% of all cases.
Treatment options for NSCLC depend upon disease stage and range from surgical resection or radiotherapy (stage 1) through to surgery and adjuvant chemotherapy or chemo-radiotherapy for those with stage 3. However, an important consideration for any of the different forms of treatment, is the ability to detect the presence of post-therapy residual disease.
One emerging potential biomarker is circulating tumour DNA (ctDNA), which is a component of cell-free DNA shed by malignant tumours into the bloodstream and other bodily fluids. It has the potential for prognostication, molecular profiling and monitoring of patients with cancer and has, for example, been shown to be an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer.
In fact, highly precise ctDNA detection and quantification methods have the potential to transform clinical practice via non-invasive monitoring of solid tumour malignancies, residual disease detection at earlier timepoints than standard clinical and/or imaging surveillance.
For the present study, the researchers set out to assess ctDNA levels in patients with stage 1 to 3 NSCLC to determine whether detection of this DNA tumour fragment post-therapy could predict patient outcomes.
Using samples from the Lung cancer circulating tumour DNA study (Lucid), the team first determined the levels of ctDNA prior to lung cancer treatment and then sought to detect the DNA two weeks to four months after therapy.
Predictive value of ctDNA
A total of 363 plasma samples from 88 patients with early-stage NSCLC (stages 1, 2 and 3) treated with curative intent surgery (61), surgery and adjuvant chemotherapy/radiotherapy (8) and chemo-radiotherapy (19) were included in the study.
Prior to therapy, ctDNA was detected in 24%, 77% and 87% of patients with stage I, II and III disease respectively. Post-treatment, ctDNA was found in 64.3% of patients (28) who had a clinical recurrence of their cancer.
Detection of ctDNA within the time period of two weeks to 4 months post-treatment occurred in 17% of patients and was associated with shorter recurrence-free survival (hazard ratio, HR = 14.8, 95% CI 5.82 – 37.48, p < 0.00001) and a reduced overall survival (HR = 5.48, 95% CI 2.18 – 13.76, p < 0.0003).
Interestingly, ctDNA was also detected 1 – 3 days after surgery in 25% of patients but not associated with disease recurrence.
Among those where ctDNA was found before treatment, there was also a reduced overall survival (HR = 2.97, p = 0.01) and recurrence free survival (HR = 3.14, p = 0.003) compared to samples where ctDNA was not detected prior to treatment.
The authors concluded that their data supported the clinical utility of ctDNA testing to identify residual disease and recurrence and that this was a potentially sensitive tool to determine which patients were at high risk of relapse and who could benefit from additional adjuvant therapy.
Citation
Gale D et al. Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer Ann Oncol 2022
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