Charles Swanton Profile picture
Apr 13, 2023 22 tweets 13 min read Read on X
Excited to share our TRACERx nature publication on circulating tumor DNA (#ctDNA, #MRD) detection in resectable lung cancer led by @AbboshChris, @AFrankell, @juditkisistok, Thomas Harrison, Aaron Garnett, @nbirkbak and @NickyMcGranahan 👇👇👇 Tweetorial🧵…
🔬Circulating tumor DNA is a powerful biomarker that can guide and monitor treatment response in early-stage lung cancer patients. Technologies enabling ctDNA detection and characterization are advancing rapidly but we need to understand how to use them in the clinic…
👥 Through collaboration with scientists at @TheCrick and @uclcancer, @AstraZeneca and @Invitae, we developed and validated an anchored-multiplex PCR approach ctDNA detection in 197 patients who donated over 1000 plasma samples to TRACERx.
💉Detection of ctDNA before surgery predicted a higher risk of postoperative relapse and subsequent aggressive disease - but only in lung adenocarcinoma. 💭 Are adenocarcinomas releasing detectable ctDNA biologically different to their ctDNA negative counterparts?💭 Image
📈Multiomic analyses of adenocarcinomas releasing detectable ctDNA revealed chromosomal instability, upreg of proliferation-assoc transcriptomic pathways and copy-number gains. These tumors had high ORACLE scores, a clonal risk biomarker (@dhruva_biswas 10.1038/s41591-019-0595-z) Image
This builds upon findings such as from @JakeChabon, @max_diehn and @AshAlizadeh. We also observed that preoperative ctDNA was associated with clinically occult mediastinal disease in adenocarcinoma. Could this biomarker guide neoadjuvant therapy 💊?…
We next explored postoperative ctDNA detection alongside clinical metadata including imaging results, treatment and site of disease relapse. We really hope this of detail might help the design of future 🩺clinical trials🩺 using ctDNA as an MRD biomarker.
Patients with early-postoperative ctDNA detection (#MRD) were more likely to be at a higher stage at diagnosis, suffer early disease relapse and poor survival. Lead-times were longest here. 🛑This this is an at-need patient subgroup where therapeutic innovation is needed🛑 Image
Our findings support an expanding set of literature supporting #MRD as an important biomarker in NSCLC, including the recent manuscript from Davina Gale and Nitzan Rosenfeld (➡️ and a retrospective #ctDNA analysis of IMpower010, a phase 3 adjuvant study.
Outside of lung cancer steps are being made to incorporate #MRD into clinical decision making to guide adjuvant tx administration. See @tompowles1’s manuscript on the IMvigor010 study in bladder cancer and @JeanneTie’s manuscript in colorectal cancer.…
3 to 6 monthly ctDNA surveillance was able to identify impending disease relapse in 20% of landmark MRD negative patients, however lead-times in this group were shorter. Might next generation ctDNA technologies 🔍 like @ForesightDx help identify these patients earlier?
Finally, agreeing with findings from @AadelChaudhuri in unresectable NSCLC, post-intervention ctDNA detection helped interpret imaging not definitive for relapse. Reflex ctDNA testing might help tumor boards make treatment decisions earlier.
Next section 🧵! We found we could detect postoperative ctDNA, but we also wanted to know what we could learn about the process of NSCLC relapse from this signal. Research tissue biopsies can be difficult to obtain, could liquid biopsy help us here 🧬?
There are challenges to using liquid biopsy to profile which parts of the primary tumor are driving the metastatic process, mainly due to the very low levels of ctDNA encountered in this setting, @AFrankell came up with a solution 🤔💭.
To understand tumour subclonal architecture in ctDNA we built ECLIPSE (, a method which allows sensitive detection of subclones and estimation of subclone size (cancer cell fraction - CCF) from plasma containing ultra-low levels of ctDNA (down to 0.1%). Image
#cfDNA can capture clones across metastases to overcome sampling bias, but what about within the primary tumour? and how accurately? We found pre-surgery cfDNA could distinguish the tumour trunk from subclonal mutations masquerading as clonal in a single tissue biopsy (AUC 0.8) Image
Interestingly, metastatic subclones which were expanded in pre-surgery #cfDNA compared to non-metastatic subclones: an observation also made in tumor tissue, in our companion paper (…). 💥In the future could we predict the metastatic subclone from cfDNA??💥 Image
We applied ECLIPSE to postoperative plasma samples to track subclone dynamics over time. In CRUK0484, adjuvant chemo and nivolumab treatment were both associated with changes in growth dynamics of subclones, suggestive of subclone specific treatment sensitivities. Image
More metastasising primary tumour subclones were detectable in cfDNA compared to in available relapse tissue. Despite this, 73% of patients had only a single relapse dissemination event detectable (monoclonal dissemination). E.g.s for monoclonal and polyclonal patterns below Image
Patients with >1 disseminating clone (polyclonal dissemination) had poor outcome, even after adjusting for clinical outcome predictors and disease burden, suggesting that the heterogeneity of the metastatic seeding population may drive adaptation and disease progression Image
ctDNA is poised to change the way patients with early-stage lung cancer are managed and help scientists understand how lung cancer spreads. We would like to thank @SU2C, @bcrf, @RosetreesT, @royalsociety, @CRUKLungCentre and all TRACERx patients for supporting this work.
We also extend thanks to the Nature team including editors @mvicaracal, our peer-reviewers for their invaluable input into the development of this manuscript and our collaborator @HugoAerts and colleagues for support with analyses of preoperative tumor volumes.

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More from @CharlesSwanton

Apr 12, 2023
Excited to share our recent @SwantonLab @NickyMcGranahan & @MariamJHanjani lab work on the genomic evolution of non-small cell lung cancer metastases in #TRACERx, out @Nature…

A quick thread [1/13]
We analysed paired primary-metastasis data from 126 patients (218 metastatic & 476 primary tumour samples) within the first 421 patients recruited to TRACERx. We explored the timing of metastatic divergence, modes of metastatic dissemination and selection in seeding clones [2/13]
We reconstructed primary tumour phylogenies & timed metastatic divergence relative to the trunk. Divergence is when the metastatic clone first existed & differs from time of spread. The majority of cases (94/126) diverged late following a clonal sweep in the primary tumour [3/13]
Read 13 tweets
Apr 5, 2023
Today our important study on air pollutants in the promotion of lung cancer has been published in @Nature led by @WillHilliam @LimEmilia @DrClareWeeden @SwantonLab ...Thread below🧵… Image
Air pollution is linked with 7 million premature deaths annually and is associated with heart disease, cancer and dementia. The vast majority of people live in places where air pollution levels exceed @WHO guidelines Image
We focused on a growing public health concern: lung cancer in people who never smoke, because 85% of people in the UK do not smoke. If considered as a separate entity, lung cancer in non-smokers is the 8th most prevalent cause of cancer death in the UK. Image
Read 16 tweets
Sep 2, 2020
1/24 - Can we decipher order from cancer genomes? Our new paper “Pervasive chromosomal instability and karyotype order in tumour evolution” comes out in Nature today:… @BCRFcure @TheCrick @CRUKresearch @RosetreesT @uclcancer @SwantonLab @royalsociety
2/24 - Chromosomal instability (CIN) is common in cancer and consists of dynamic changes in chromosome number and structure. This instability can result in somatic copy number alterations - SCNAs - which may provide a substrate for tumour evolution.
3/24 - In our study, we aim to better understand the SCNA landscape in cancer. How prevalent are SCNAs in different tumour types? How homogeneous (clonal) or heterogeneous (subclonal) are SCNAs in tumours? Is CIN an ongoing process? Does the SCNA landscape change with metastasis?
Read 24 tweets

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