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ctDNA Circulating tumour DNA is a subset of cell-free DNA (cfDNA) that is released into the bloodstream from tumour cells. ctDNA carries genetic and epigenetic information specific to cancer, making it a valuable tool for non-invasive cancer diagnostics, monitoring, and research. It provides insights into tumour biology, treatment response, and disease progression.
Recently, there have been a few posts by bladder cancer patients that their oncologists prescribed ctDNA analysis to determine the course of their treatment.
Case 1
A patient was diagnosed with MIBC (T2, N0.M0) with lymph node negative and no metastasis. The patient received neoadjuvant chemotherapy(NAC) and proceeded with a radical cystectomy (RC). The patent’s oncologist trended ctDNA results by Signatera during NAC chemotherapy. The first ctDNA was measured prior to NAC and ctDNA level was 0.02. The 2nd ctDNA was measured after the first two rounds of NAC and ctDNA level was 0.00. Oklahoma, USA
Case 2
A patient was diagnosed with MIBC (T2B) in June 2023. NAC was avoided due to kidney problems. Proceeded with RC in September, 2023. Opdivo (Nivolumab) immunotherapy was started. The ctDNA was 0.15 before Opdivo started, then went up to 0.33 after the first dose of Opdivo, so platinum based chemotherapy was suggested in spite of kidney issue or start PADCEV & Keytruda. The patient seeked a second opinion. Opdivo immunotherapy was continued. After 5 months of Opdivo treatment, ctDNA became negative. Tennessee, USA.
In case 1, the patient did not qualify for adjuvant immunotherapy Nivolumab after radical cystectomy because MIBC (T2, N0.M0) is not considered as high risk. Conventional follow up is periodic imaging such as CT scan or MRI to detect recurrence / metastasis. The oncologist prescribed period ctDNA to detect recurrence early. The cdDNA analysis tool is Signature by Natera. Signatera is tissue-informed ctDNA analysis. It analyses tissue from patient’s bladder cancer obtained during RC, and determines 16 genomic biomarkers which are associated with patients bladder cancer. Then ctDNAs obtained from the patient’s blood are compared with 16 genomic biomarkers obtained from the cancer tissue to determine recurrence.
In case 2, the patient qualified for Nivolumab as adjuvant therapy after radical cystectomy because the patients MIBC (T2B) was considered as high risk but the patient did not qualify for neoadjuvant chemotherapy due to kidney problem. The oncologist prescribed periodic ctDNA analysis to determine if Nivolumab is working for the patient or stops working. In this case, the oncologist chose to use Guardant360 by Guardant Health to detect the effectiveness of Nivolumab treatment by periodically doing ctDNA analysis by Guardant360. Guardant360 is tissue-free ctDNA analysis and it does not require a patient’s analysis based upon the patient’s cancer tissue. Instead, Guardant360 uses a patient’s blood and can analyse up to 85 different gene abnormalities and compare with known bladder cancer associated gene abnormalities and determine recurrence.
Insurance coverage
According Netra’s site, Signatera is covered by Medicare for MIBC in the adjuvant and recurrence monitoring setting.
According to Guardant Health, the test is the “first blood-only liquid biopsy test for monitoring molecular response to immune checkpoint inhibitors covered by Medicare for beneficiaries with metastatic or inoperable solid tumours who are on an immune checkpoint inhibitor therapy. Note that Nivolumab, Pembrolizumab and Avelumab are immune checkpoint inhibitor based immunotherapy which have been approved to treat bladder cancer in Canada.
I cannot find article whether Health Canada has approved or even if it is reviewing ctDNA analysis such as Signature or Guardant360 . But interestingly, Lifelab which I use for blood test and other tests is now offering Signatera for CDN$ 4,500.
Incidentally, I became aware of circulating DNA or ctDNA in November 2017 when I was diagnosed with NMIBC. I was attending a BCC patients education seminar which was held in Vancouver. Dr. Alexander Wyatt of UBC gave a talk on ctDNA. It was a complex subject and I only vaguely member colorful bar chats. If I recall correctly, BCC donated $50K to Dr. Wyatt’s research on ctDNA on bladder cancer. I have found a few research papers on ctDNA analysis in bladder cancers by Dr. Wyatt’s team. Below are two such research papers.
Liquid Biopsy-Analysis of Circulating Tumor DNA (ctDNA) in bladder cancer – 2018
Emerging data suggests that ctDNA analysis will augment the management of patients with bladder cancer (BC) . Our review summarizes recent progress and preliminary data supporting clinical utility of ctDNA in BC. In particular, we highlight the remarkable potential for ctDNA to aid disease surveillance across different stages of BC and the power of ctDNA to provide insights into the metastatic BC genome in real-time.
Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification on metastatic bladder cancer. – 2021 Nature communications. Below are extracts from the Abstract of the article.
Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers
Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in metastatic urothelial carcinoma (mUC) is reliable and practical, and mitigates against disease under sampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC
Incidentally, a debated was held during the 2024 EAU annual conference held in Paris in April, this year. The title of the report on the debate was published on UroToday. Rapid Fire Debate 4: Patient with MIBC After Radical Cystectomy – Can We Use ctDNA to Guide Decisions on Adjuvant Chemo/IO? What About urinary tumor (utDNA) for Bladder Sparing After NAC? Dr. Peter Black participated in the debate. Do Google search on the title to find the article.
Please read the following with a big grain of salt. There may be errors, especially in numbers. Please pose any question.
Galleri : Blood-based multi-cancer early detection (MCED) by GRAIL
Illumina, Inc. is the largest and leading manufacturer of DNA sequencing equipment in the world. Recently, Illumina spin off its DNA analysis division GRAIL as a separate company. GRAIL started in 2016 focusing detection of multiple cancers analyzing cell free DNA in blood. Later GRAIL named such blood-based multi-cancer early detection (MCED) as “Galleri”.
Though previously mentioned Signatera (tissue informed)ctDNA testing and Guardant 360 (tissue uninformed)ctDNA testing both analyze DNAs obtained from fragments of tumour in blood, Galleri analyses DNAs obtained from fragments of tumour and normal cells in blood. Also though Signatera and Guardant 360 ctDNA test analyze abnormal genes, Galleri compares pattern of DNA methylations to patterns of DNA methylations of persons with no cancer and persons with various cancers to determine if the client has cancer or not, and if cancer, it will tell what cancer it is.
I have thought that accumulation of abnormality in specific genes in DNA – genetic abnormality would cause cancer. This is true, but recently I learned that epigenetic abnormality can cause cancer also. I understand Epi means above or upon, so epigenetic means above genetic. For example, even a tumour suppressor gene, i.e. TP53 is normal in DNA, methylation can silence the gene from transcription resulting in not synthesizing p53 protein. There are about 28 million sites in the human genome, where methylation can happen. GRAIL has accumulated data of methylation from over 1 million sites in DNA from non cancer persons and persons with cancer, and analyzed patterns of methylation of various cancers and normal tissues. Galleri will compare a client’s DNA methylation patterns vs GRAIL’s database of methylation patterns. Figures of methylation patterns of person with no cancer and with lung cancer are shown. Blue indicates unmethylated sites and red indicates methylated sites. So, if Galleri test for the pattern of a client DNA methylation of the particular section of the DNA that is similar to the pattern of the lung cancer, Galleri can raise a red flag for that particular section of DNA as a possible sign of cancer. Grail’s site says Galleri uses AI – machine learning for this pattern recognition process.
“tinyurl.com/bddfe8vf”
The Galleri test has not been cleared or approved by FDA. The Galleri test received FDA Breakthrough Device Designation in 2019. Based upon Grail’s own studies, the Galleri test has shown a low false-positive rate of 0.5% (detects a cancer signal when no cancer is present). A true-positive rate ( detects cancer signal when a specific cancer is present) is about 50% in average for 50+ cancer types, but its accuracy goes up to 67% for 12 major cancers, including bladder cancer. The Galleri test data came from 20,000 participants at more than 140 clinical study sites. UHN/UT and Princess Margaret Cancer Centre in Toronto was listed as the test site in Canada. In November, 2023, the US Food and Drug Administration (FDA) approved an Investigational Device Exemption study to determine whether the Galleri blood test can reduce late-stage cancer diagnoses for cancers that don’t have traditional screening approaches. The blood test, which has been sold in the US since 2021, is not currently FDA approved, but Grail is hoping that interim data from its study will help the test secure premarketing authorization from the FDA. Note that the current price of Grail test is US$949. The study will track outcomes in as many as 50,000 Medicare beneficiaries who will receive annual Galleri tests alongside routine medical care compared with a matched group who will only receive usual care. Participants will include individuals from racial and ethnic minorities, and seniors from historically underserved communities.
Furthermore, National Health Service (NHS) in UK and Grail has been conducting a very large three year study NHS-Galleri trial to find out how Galleri MCED test for UK citizens between the ages over 50 and 77 years old will benefit not only to UK citizen but also to UK healthcare system – NHS. Already 140,000 UK citizens had participated.
NHS England has reviewed preliminary data from the first year of the NHS-Galleri trial and did not find them compelling enough to justify proceeding straight away with a large-scale pilot program of the test in NHS clinical practice, while we await the final results of the trial. Committing to accelerate implementation of the test in the NHS at scale would have been an exceptional step, requiring exceptional data after just one year, and while what we have seen is very promising, the data so far do not support moving at such a fast pace.
As planned at the outset of the trial, the results will be used by the UK National Screening Committee to consider whether the Galleri test could play a role in a national cancer screening program. We think that NHS patients should be the first to benefit from new technologies, and we want to be ready to make the test available to an increasing number of people rapidly if the final trial results show evidence of significant benefit for patients.
A similar study (PATHFINDER 2) in the US with UHN in Toronto started in 2021 involving with 35,000 participants who are 50 years or older. The primary completion date in Feb, 2026.
Referenced sites
Grail home site, Galleri home site, NHS site, various research papers on methylation and cancer, Youtube on Methylation, ChatGTP, my daughters biology, bio-chemistry, cell biology text books.
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