Ask the Experts About Circulating Tumor DNA in the Management of Cancer

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The Personalized Medicine Foundation and CancerConnect are pleased to provide patients and caregivers the opportunity to ask questions about the role of Circulating Tumor DNA (ctDNA) in the Management of Cancer. We have put together a panel of leading cancer experts to answer questions and publish a forum for the exchange of information.​

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John Strickler, M.D., Associate Professor of Medicine, Associate Director Clinical Research – GI Oncology, Co-Leader, Duke Cancer Institute Molecular Tumor Board, Duke University

Daniel H. Ahn, D.O., M.S.,Assistant Professor of Medicine, Division of Hematology/Medical Oncology, Lead of GI Oncology Translational Research Disease Working Group, Board of Directors Member, ACCRU consortium

Cancer is caused by genetic mutations, and these mutations can be detected by measuring circulating tumor DNA, or ctDNA, in the blood. Detection of ctDNA allows for personalized cancer surveillance based on an individual’s unique set of tumor mutations.

Traditionally, the most common way to detect the presence of cancer has been through the use of imaging techniques like computerized tomography (CT) scan, magnetic resonance imaging (MRI), and positron emission tomography (PET). However, these imaging tools are limited in their ability to detect molecular residual disease (MRD), or very small traces of cancer in the body. ctDNA can be detected in the blood long before it appears on a CT or MRI scan.

Knowing if there are traces of cancer present in your body can help your oncologist decide:

  • Your best initial treatment
  • If you are responding to treatment
  • If further cancer treatment needs to be considered
  • If there are signs that the cancer has returned or progressed

What is circulating tumor DNA (ctDNA)?

Circulating tumor DNA (ctDNA) is 150–200-base-pair fragments of DNA, which originate from cancer cells and are present in the bloodstream or other body fluids.

How is ctDNA different than cfDNA?

Cell-free DNA (cfDNA) is all the DNA in the bloodstream including germline DNA and tumor DNA. ctDNA is the portion of cfDNA that is derived specifically from the tumor.

How can ctDNA help manage cancer?

There are currently four clinical applications of ctDNA to guide precision medicine in patients with cancer:

  • Detection of minimal residual disease (MRD) following surgery.
  • Monitoring the treatment response in the metastatic setting.
  • Identifying genomic drivers of therapeutic sensitivity and resistance.
  • Guiding treatment strategies to overcome resistance to treatment.

How is ctDNA used for the management of early-stage cancers?

Across all stages of surgically removed cancer, detection of ctDNA following surgery is a strong predictor of cancer recurrence. The detection of ctDNA could lead clinicians to intensify therapy in certain situations. Conversely, the absence of ctDNA could provide an opportunity to minimize surveillance or adjuvant treatment.

How is ctDNA used for the management of metastatic cancer?

ctDNA can be used to monitor treatment response, identify genomic drivers of treatment sensitivity or resistance, or identify new therapies that could overcome genomic drivers of treatment resistance.

When should ctDNA be collected?

Both tissue and blood samples are required initially to build the ctDNA test. Once the test is built, only blood samples are required for the periodic follow-up tests performed to monitor for MRD or recurrence. Since DNA assays require ctDNA shedding into the bloodstream, the performance of ctDNA assays is improved when blood is collected after—rather than during—active chemotherapy.

What is the procedure for ordering a ctDNA test?

Currently ctDNA testing must be requested by a provider so the test can be sent to the company performing the test. Patients cannot order this test. Only a physician can order the test.

Is ctDNA different from NGS testing?

“Next Generation Sequencing,” or “NGS” is a platform that allows simultaneous testing of multiple molecular targets. NGS testing can be performed on tumor tissue or blood (ctDNA).

If my doctor orders NGS testing on tumor tissue, will ctDNA testing also be performed?

Not always - ctDNA is typically a separate test and will usually not be ordered together with NGS testing unless specifically requested. Providers and hospitals use a variety of different companies to perform DNA testing. Some companies, like Natera perform both ctDNA and NGS testing, while others do not.

Does insurance pay for ctDNA testing?

Each insurance company is different. Medicare has begun paying for ctDNA testing with Signatera™ for Stage II-III colon cancer. For questions or financial assistance, individuals can contact Natera’s Patient Coordinators.

Phone: 650.489.9050 Fax: 650.412.1962

Email: signaterapc@natera.com

Patient-Submitted Questions

What tests are routinely ordered on colon cancer tissue removed during surgery?

DNA mismatch repair deficiency (MMR): Approximately 15% of stage I-III colorectal cancer diagnoses arise from the microsatellite instability (MSI) pathway, which is a consequence of deficient DNA mismatch repair (MMR). Deficient MMR (dMMR) can develop from an inherited germline mutation in a MMR gene (MLH1, MSH2, MSH6, PMS2)—Lynch Syndrome, for example—or, more commonly, can be due to epigenetic inactivation of the MLH1 gene and the CpG island methylator phenotype (CIMP). dMMR tumors are associated with a better stage-adjusted overall survival compared to proficient MMR (pMMR) tumors. MMR status may also be predictive for benefit from adjuvant chemotherapy and the type of chemotherapy patients will receive.

If I already had my cancer removed, can tissue from the surgery be obtained for ctDNA testing?

Most patients who have a cancer removed will have had tissue stored, which will be available for additional testing, including tumor somatic profiling, or to develop tumor-informed cell-free DNA profiling for MRD ctDNA assessment.

In tumor-informed assays, the primary tumor is sequenced to identify the patient-specific genomic alterations, upon which the primers for ctDNA testing in the plasma are designed to be based. Tumor-agnostic assays rely on a panel of preselected primers designed to detect known genomic alterations and epigenetic signatures relevant to CRC.

Are clinical trials available evaluating ctDNA testing?

Numerous clinical trials are currently underway to validate the role of ctDNA in selecting patients for adjuvant chemotherapy by addressing several questions:

  • Can adjuvant chemotherapy be omitted in patients who have no detectable ctDNA after surgery (treatment de-escalation)?
  • Could treatment escalation help in patients with detectable, post-operative ctDNA?
  • Does the clearance of ctDNA with adjuvant chemotherapy result in a cure?
  • Is ctDNA a predictive biomarker for treatment efficacy?
  • What is the best strategy to treat patients who continue to have detectable ctDNA after adjuvant chemotherapy?
The Ask The Expert Series is made possible by support from The Personalized Medicine Foundation, Incyte Oncology, Abbvie, and CancerConnect. The "Ask The Expert" series is not medical advice nor is it a substitute for your doctor. It should serve as a guide to facilitate access to additional information and enhancement of a shared decision making process with your treating physician.
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