Highlights in this article:

Dr. Swanton’s group found that Circulating tumor DNA (ctDNA) is a promising method to detect leftover cancer cells after treatment in early-stage non-small-cell lung cancer (NSCLC). The groundbreaking TRACERx study used advanced ctDNA techniques to track 200 mutations in over 1,000 plasma samples from 197 patients. Results showed that when ctDNA was not detected before surgery, patients had a slower-growing cancer with better outcomes. Additionally, ctDNA detection within 120 days after surgery found 25% of patients with ctDNA, including 49% of those who had a relapse. The innovative tool, ECLIPSE, allowed for tracking cancer cell changes at low ctDNA levels, identifying patients with poor outcomes due to widespread cancer spread. These findings can help improve cancer treatment trials and offer valuable insights into cancer spread using low-ctDNA-level liquid biopsy.

Background:

What is Circulating tumor DNA?

Circulating tumor DNA (ctDNA) refers to small fragments of DNA that are shed into the bloodstream by cancerous tumors. As cancer cells die or multiply, they release these DNA fragments into the circulation, making ctDNA a valuable, non-invasive biomarker for detecting and monitoring cancer. By analyzing ctDNA in blood samples, also known as liquid biopsies, clinicians and researchers can gain insights into tumor genetics, monitor tumor progression, and assess treatment response. This method is less invasive than traditional tissue biopsies, allowing for more frequent monitoring and a better understanding of cancer dynamics. ctDNA can be used for various purposes in cancer diagnosis, monitoring, and treatment. Some common uses of ctDNA include:

• Early detection and diagnosis: ctDNA can be used as a non-invasive biomarker for detecting cancer at an early stage, even before symptoms appear or imaging tests detect the tumor. Analyzing ctDNA can help identify cancer-specific mutations that may aid in diagnosis.

• Tumor profiling: ctDNA analysis allows for the identification of specific genetic mutations and alterations within the tumor. This information can help guide personalized treatment strategies, as certain therapies may be more effective against tumors with specific mutations.

• Monitoring treatment response: ctDNA levels can be monitored during treatment to assess the effectiveness of therapies. A decrease in ctDNA levels may indicate a positive response to treatment, while an increase could suggest tumor progression or resistance to therapy.

• Detecting minimal residual disease and relapse: After initial treatment, ctDNA can be used to monitor for the presence of minimal residual disease, which is a small number of cancer cells that remain in the body but are undetectable through conventional methods. Detecting ctDNA after treatment may indicate a higher risk of relapse and the need for closer monitoring or additional therapy.

• Tracking tumor evolution and resistance: By analyzing ctDNA at multiple time points during treatment, researchers can study how tumors evolve and acquire resistance to therapies. This information can guide the development of new treatment strategies and combination therapies to overcome resistance.

Overall, ctDNA has the potential to revolutionize cancer care by providing a non-invasive, real-time snapshot of tumor genetics and dynamics, enabling personalized treatment strategies and better patient outcomes.

What is TRACERx study?

TRACERx (Tracking Cancer Evolution through Therapy (Rx)) is a large-scale research study focused on understanding the evolution of cancer and the development of resistance to treatment in non-small cell lung cancer (NSCLC) patients. Launched by Cancer Research UK and led by a team of scientists at the Francis Crick Institute and University College London Cancer Institute, the study aims to track the genomic changes within tumors as they develop and progress. The TRACERx study involves the collection and analysis of tumor tissue samples and liquid biopsies (blood samples) from patients with early-stage NSCLC at multiple time points during their treatment journey. By studying these samples, we can monitor the genetic alterations in tumors over time, identify the emergence of drug-resistant subclones, and understand the mechanisms behind cancer recurrence and metastasis. The findings from the TRACERx study have the potential to inform the development of new treatment strategies, improve patient outcomes, and guide the design of future clinical trials targeting the specific genetic changes driving lung cancer.

Discovery:

Circulating tumor DNA (ctDNA) has emerged as a promising biomarker in cancer management, particularly in early-stage adenocarcinoma. By detecting and profiling residual tumor cells after curative intent therapy, ctDNA can help identify high-risk patients and inform treatment strategies. Dr. Swanton’s research group has demonstrated that preoperative ctDNA detection is prognostic in early-stage adenocarcinoma, with chromosomal instability acting as a predictor of ctDNA detection in non-small cell lung cancer (NSCLC). These findings suggest that management strategies for high-risk early-stage adenocarcinomas, based on preoperative ctDNA detection, are currently inadequate and require innovation. Postoperative ctDNA detection has been shown to predict impending NSCLC relapse, supporting the need for assessment of early treatment escalation in high-risk populations. Enhanced ctDNA surveillance techniques could help identify high-risk patients, allowing for timely intervention and improved treatment outcomes.

In addition to its prognostic value, ctDNA has inspired the development of new bioinformatic tools for cancer research. ECLIPSE is one such tool, enabling accurate estimation of subclonal cancer cell fractions in low-tumor-fraction ctDNA samples. This method has revealed that ctDNA can provide insight into clonal structures from different surgically excised tissue sites, capturing additional heterogeneity at relapse. Patients with multiple metastatic dissemination events (polyclonal dissemination) experienced a more aggressive disease course, highlighting the potential clinical value of determining metastatic dissemination patterns using ctDNA analysis.

Circulating tumor DNA is poised to change the landscape of (neo)adjuvant trial designs. By measuring subclonal expansion in preoperative plasma, ctDNA analysis may enable the prediction of future metastatic subclones. This offers the possibility for early intervention, potentially targeting and eradicating such clones months or even years before relapse. As ctDNA continues to gain prominence in cancer research and treatment, it is expected to play an increasingly vital role in guiding personalized treatment strategies and improving patient outcomes.

In summary, ct DNA has the potential to revolutionize early-stage adenocarcinoma treatment by providing crucial prognostic information, enabling the development of new bioinformatic tools, and guiding (neo)adjuvant trial designs. As research on ctDNA continues to advance, it will likely play a critical role in the future of personalized cancer treatment and management.

For more information:

Nature 2023 4/13

https://www.nature.com/articles/s41586-023-05776-4

Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

Dr. Swanton’s website:

https://www.crick.ac.uk/research/labs/charles-swanton

https://www.crick.ac.uk/research/find-a-researcher/charles-swanton