At BTOG 2025 on Monday 3 March 2025 from 10:00 – 11:00 we will host a BTOG Trainees Networking/Introduction.
Please do use the BTOG trainee group-chat on Slack to continue your thoracic cancer conversations in the meantime. Feel free to contact the BTOG trainee representatives, Anand and Gerard, at anand.sundaralingam@ndm.ox.ac.uk or g.walls@qub.ac.uk
Respiratory
Clinical Utility of Tumour-Naïve Presurgical Circulating Tumour DNA Detection in Early-Stage NSCLC
Image from Wikimedia Commons used under The Creative Commons Attribution-Share Alike 4.0 International license..
In November’s edition of the Journal of Thoracic Oncology Hong et al describe the findings from their prospective study of ctDNA testing in patients with early stage NSCLC. Patients with stage I or II NSCLC (as per TNM 8), of wild-type EGFR and ALK were recruited prospectively from a single centre in South Korea from 2014-2020. Samples were collected prior to surgery and ctDNA was measured using a methylation-based multicancer early detection assay.
908 patients met the inclusion criteria of whom 895 had satisfactory ctDNA assessment. 188/602 (31%) of clinical stage I and 209/293 (71%) of stage II patients had detectable ctDNA prior to surgery. 121/554 (22%) of lung adenocarcinoma (LUAD) patients had detectable ctDNA compared to 228/282 (81%) of lung squamous cell carcinoma patients, consistent with the established literature. ctDNA positive NSCLC exhibited greater tumour volumes than ctDNA negative NSCLC (median tumour volume 19.46 cm3 vs 6.64 cm3 in LUAD and 16.33 cm3 vs 4.58 cm3 in non-LUAD, p < 0.001). SUVmax was also increased in ctDNA positive NSCLC (median SUVmax 10.32 vs 2.91 in LUAD and 12.77 vs 6.95 in non-LUAD, p < 0.001). There was a clear difference in pathological upstaging in clinical stage I NSCLC if ctDNA was detected, in both LUAD and non-LUAD subgroups (37% vs 12%, p < 0.001), but this was not observed in stage II NSCLC. Within their cohort they identified poor recurrence free survival (RFS) in clinical stage I LUAD patients with ctDNA detection (2-year RFS 69% vs 91%, p < 0.001), that more closely approached RFS rates of stage II LUAD patients. No differences in RFS were noted in clinical stage II LUAD patients, nor in clinical stage I or II non-LUAD patients, whether ctDNA was detected or not. Finally, ctDNA detection correlated strongly with greater programmed death-ligand 1 (PD-L1) expression.
The authors conclude that ctDNA testing in Stage 1 NSCLC is clinically useful, particularly in identifying high-risk patients who may benefit from additional peri-operative treatments.
Circulating tumour DNA is being integrated into routine clinical practice for patients with advanced disease and can provide molecular results in a fraction of the time. However, it currently performs poorly in early-stage NSCLC, for reasons that are explored within this study. In this prospective study, Hong et. al look to determine the use of ctDNA as a risk stratification tool in pre-surgical early-stage NSCLC.
The majority of the findings are consistent with published literature. Hong et al. demonstrate that ctDNA detection is influenced by tumour volume, size and histological subtype (more frequent in squamous cell carcinoma); and also correlates with FDG uptake on PET-CT. However, this group are the first to report the use of ctDNA detection in prognostication within stage I but not stage II LUAD. Data from TRACERx has demonstrated that tumour biology has a role to play in ctDNA detection, independent of tumour size and volume, which may explain some of the heterogeneity in these findings.
There are some important points to consider with this study.
The authors specifically chose to focus on patients with wild-type EGFR and ALK to reflect patients who might stand to benefit from neoadjuvant immune checkpoint inhibitors, which could limit generalisability and applicability.
The group also chose to utilise a tumour-agnostic approach. There is considerable variability in the published literature on tumour-informed vs tumour-agnostic approaches and so it is difficult to draw definite conclusions as to the optimal method. However, the tumour-agnostic approach is suited to early-stage NSCLC in that it is not negatively affected by tissue availability and provides results in significantly faster turnaround times.
Lastly, the group utilised a previously developed, ultra-sensitive multi-cancer early detection test that uses a cfDNA-based targeted methylation assay. Its ability to detect variant allele frequencies is as low as 0.07% (much lower than assays used in routine clinical practice at present). However, prognostic value only being demonstrable in stage I rather than stage II LUAD indicates that further testing is needed to determine the optimal threshold for detection in stage II patients.
Overall, this is a step forward in the world of ctDNA testing in early-stage NSCLC, which is in need of more prospective trials. Such trials should ideally demonstrate as little heterogeneity and as much transparency as possible in their detection strategies (i.e. assay coverage, timing of sampling, sensitivities/specificities, tumour-informed vs tumour-agnostic), to be able to confidently attribute clinical value to the inclusion of ctDNA testing in this cohort of patients.
Prof Neal Navani
Consultant/Professor in Respiratory Medicine
University College London Hospital
Dr Lavanya Anandan
ST5 Respiratory Registrar in Northwest Thames
Medical Oncology
LUN 16-081: Analysis of circulating tumour DNA in unresectable stage III NSCLC
Image from Wikimedia Commons used under a CC BY-SA 3.0 License.
Plasma analysis for tumour-derived fragments of DNA, known as circulating tumour DNA (ctDNA), are widely used for non-invasive molecular profiling in patients with metastatic non-small cell lung cancer (NSCLC), and hold promise for other indications such as disease monitoring during systemic therapy, and minimum residual disease detection following surgery. Less is known about the role of ctDNA following chemoradiotherapy (CRT) for stage 3 disease, which is an important opportunity as there are currently no biomarkers to help guide which patients are selected for one year of adjuvant immunotherapy. This is important as this treatment has considerable risks of toxicity and financial costs to the health system.
The Diehn Lab recently reported an exploratory ctDNA analysis from the LUN 16-081 trial, a phase 2 study exploring clinical outcomes after two 6-month post-radiotherapy immunotherapy regimes. The median radiation dose was 60Gy and the median duration of immunotherapy was 4.4 months. The full publication is awaited but in an ASCO 2022 presentation the investigators reported that across 105 patients, 6 months of immunotherapy led to comparable cancer control outcomes to previous trials for 12 months.
In this translational analysis, a pre-cycle 1 immunotherapy sample (pre-C1) was available for 38 patients, and ~75% also had pre-cycle 2 (pre-C2) and end-of-treatment (EOT) samples (median 5.5 months). ctDNA analysis was tumour-informed (i.e. the blood assay specifically looked for genetic alterations found in the tumour biopsy) and mutations related to normal clonal haematopoiesis were filtered for by parallel white blood cell sequencing (i.e. physiological genetic alterations were excluded to reduce false-positive rates). A median of 13 genetic variants were identified during tumour sequencing, including in expected genes such as TP53, KEAP1, STK11, PTEN, PIK3CA, KRAS, and CDKN2A. ctDNA levels were calculated as the average of the relative abundance (variant allele fraction (VAF)) of all mutations detected, and the limit of detection was a VAF of 0.01%.
A minority of patients (21%, n=8/38) had detectable ctDNA immediately post-CRT, and there was no relationship with disease stage or histology. Most patients (75%, n=6/8) that had detectable ctDNA in the post-CRT sample developed relapse, whereas few patients (17%, n=5/30) that had undetectable ctDNA at that point subsequently progressed. This was reflected in the hazards for progression-free survival (PFS, HR 4.1 (95%CI 1.4–12.0), p=0.005) and overall survival (OS, HR 3.9, 95%CI 1.1–13.5) p=0.021) for patients who were ctDNA-positive. Similar trends were observed for the pre-C2 and EOT samples. In terms of ctDNA kinetics, increasing levels in the pre-C2 sample was negatively associated with the cumulative incidence of relapse (83% vs 11%, p<0.001) and PFS (HR 14.4 (95%CI 3.5–60.1), p<0.001) and OS (HR 40.4 (95%CI 4.7–350), p<0.001) compared with stable, decreasing levels or undetectable.
Notably, 3 patients without disease progression had detectable pre-C1 ctDNA, and for two of these, ctDNA decreased after immunotherapy (by pre-C2 for one patient, by EOT for the other). This could suggest that immunotherapy after CRT may be truly adjuvant, with potential to eradicate micrometastatic disease. However, more sensitive assays and larger sample sizes with more follow-up will be needed to evaluate in how many patients this is true.
This eloquent translational study validates the signals from a similar previous analysis by this group. There appears to be good potential for ctDNA to serve as a biomarker for guiding treatment escalation/de-escalation in this setting, and this may improve in the coming years as the sensitivity of such analyses continue to improve in time.
Rising ctDNA levels during post-CRT immunotherapy appears to be particularly worrisome in terms of disease control and survival outcomes and perhaps will be an opportunity for stopping immunotherapy early to focus on other treatments for patients. The lead time of ctDNA-based relapse detection of 5 months before radiological relapse aligns with previous studies and is likely to change how we assess disease burden on treatment in the future. Whether this can be a tool to escalate or de-escalate therapy will probably require future studies specifically designed to address this question.
Professor Alastair Greystoke
Newcastle upon Tyne Hospitals NHS Foundation Trust
Northern Institute for Cancer Research, Newcastle University
Clinical Oncology
NRG-LU002
Image in the Public Domain
The routine use of radiotherapy (RT) for the primary tumour after first-line systemic therapy in cases of metastatic disease is limited to a small number of cancers. eg. extensive-stage small cell lung cancer (CREST trial) and low-volume metastatic prostate cancer (STAMPEDE trial, Arm H). While there has not been a phase 3 study in oligometastatic non-small cell lung cancer (NSCLC), the phase 2 “Oligomez” trial and a meta-analysis of retrospective studies suggest that this approach may be clinically beneficial. Whether this principle holds true for the biologically distinct oncogene-driven subsets of NSCLC is less clear.
NROG-002 was an open-label, academic trial that evaluated this question in EGFR-mutant disease, with a multicentre phase 3 design. Patients with metastases in three or fewer organs received icotinib (1st generation EGFR tyrosine kinase inhibitor (TKI)) and were randomised (1:1) to receive 60Gy/30# to the primary tumour and involved nodes within 14 days, or not. TKI was continued during thoracic RT. To be eligible, patients must have had an ECOG of 0–1, confirmed 19del or L858R mutation, and a maximum of two cycles of induction chemotherapy. Symptomatic brain metastases must have been treated with stereotactic +/– whole-brain radiotherapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS) and treatment-related adverse events (TRAEs).
A total of 118 patients were enrolled 2016–2022, and the two groups were broadly similar at baseline. Greater proportions in the TKI only arm had >10 metastases (41% vs 32%) and ≥2 affected organs (44% vs 32%), and fewer patients received palliative RT in the TKI only arm (46% vs 58%), but none of these differences were statistically significant. In the intention-to-treat analysis, PFS was markedly improved with the addition of RT (HR 0.57, p=0.004), as evidenced by prolonged median PFS (17.1 months vs 10.6 months). This was driven by better local control, as distant metastases and brain metastases occurred at similar rates between the two arms. OS was also improved (HR 0.62; p=0.029), as evidenced by prolonged median OS (34.4 months vs 26.2 months). The results were even more positive in the per-protocol analysis (ie. excluding n=13 that didn’t receive the allocated treatment or follow-up). The rates of oesophagitis, pneumonitis and lymphopenia were higher in the RT arm, as expected, but other TRAEs were similar.
In summary, NROG-002 is the first phase 3 evidence for treating the primary tumour in oligometastatic NSCLC, albeit with a non-classic definition of “oligo”, and in the setting of a first-generation TKI. Whether these encouraging data can be applied to other oncogenes or non-oncogene driven tumours remains to be evaluated, and data in Western populations will be useful, but this data strongly supports the delivery of a radical radiation dose in EGFR-mutated disease.
The authors cite the limitations of their data based on small study population and the use of a first-generation TKI. While the FLAURA trial of third-generation osimertinib vs first-generation erlotinib or gefinitib demonstrated mOS and mPFS of 38.6 months and 18.9 months for osimertinib alone (compared with 26.2m and 10.6m for the TKI only arm of NROG-002), only patients with stable or asymptomatic brain metastases were eligible for randomisation. In the NROG-002 study, 42% of patients in TKI only arm and 40% in the TKI + thoracic RT arm had brain metastases, and these included symptomatic disease requiring local therapy. The study design and these data therefore represent ‘real-world’ clinical presentations more realistically.
Dr Petra Jankowska
Consultant Clinical Oncologist
Beacon Centre at Musgrove Park Hospital
Medical Director for Professional Practice
The Royal College of Radiologists (Clinical Oncology)
BTOG Events
Noticeboard
Other event dates for your diary
Thoracic Oncology Conferences, Study Days and Other Events - please note that this list includes events from other organisations not related to BTOG - inclusion on this list does not suggest endorsement by BTOG.
European Respiratory Society (ERS) Congress
5th-9th September 2026
Barcelona, Spain
2026 World Conference on Lung Cancer (WCLC26)
12th-15th September 2026
Seoul, Korea
ESMO Congress 2026
23rd-27th October 2026
Madrid, Spain
Cancer Research UK Lung Cancer Centre of Excellence Conference
4th-6th November 2026
Manchester, UK
BIR Annual Congress 2026
12th-13th November 2026
Birmingham, UK
BTS Winter Meeting 2026
25th-27th November 2026
London, UK
ETOP Annual Meeting 2026
27th-28th November 2026
Zurich, Switzerland
ETOP Residential Workshop 2026
27th-28th November 2026
Zurich, Switzerland
2027
ASCO Annual Meeting 2027
4th- 8th June 2027
Chicago, IL
Also included are Useful Core Resources: educational resources, guidelines, and other materials relevant to UK thoracic oncology professionals from organisations worldwide.
You can choose a speciality and then filter by tumour type, theme, and sub-category if you wish.
You can also search text in titles and descriptions of all our resources. You can search by keyword(s) e.g. ‘lung cancer screening’, or presenter surname, e.g. Popat.