Cancer is essentially a disease of DNA, which is the blueprint of what makes us each unique individuals. Mutations, which are alterations in DNA, lead to mutant proteins that cause cellular changes resulting in cancer. While we now have effective therapies against some mutant proteins, the ability to detect cancer mutations for clinical use has only recently become feasible. A relatively new area of cancer research is to figure out how to best detect mutations in a patient with cancer using blood. We and others have pioneered the use of “liquid biopsies” for the detection of cancer.
All cells in the body “shed” their DNA into the bloodstream. We still do not understand the function of this free-floating DNA, and they may just be cellular waste products. However, despite knowing this, only recently have we been able to analyze this cell-free DNA (cfDNA) in the blood using newer technologies.
These technologic breakthroughs help us detect cancer DNA molecules in the bloodstream. Our lab at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins presented the first proof-of-principle studies that circulating plasma tumor DNA (ptDNA) could be detected in patients with even early stage breast cancer—opening the possibility of using liquid biopsies to guide clinical decisions.
A liquid biopsy refers to either assessing circulating tumor cells in patients with cancer, or evaluating ptDNA in cancer patients. Here we are using ptDNA for our liquid biopsy studies due to superior sensitivity and specificity. Liquid biopsies with ptDNA can be more sensitive than traditional tissue biopsies, and do not require any invasive procedure other than a blood draw. It has been described as medicine’s new stethoscope, I would agree. It is a “game-changer” because it allows for not only detecting cancer mutations, but is also quantitative, allowing doctors to assess how much cancer a patient has based on the level of ptDNA. It also affords the opportunity for serial measurements and monitoring, and importantly, is a virtual “biopsy” of all sites of cancer rather than a single tissue biopsy. This is because the blood serves as a reservoir for all cancer sites and is clinically meaningful since we know that different sites of cancer can harbor different mutations even within the same patient.
Using a liquid biopsy may help us in three areas: metastatic disease, early stage breast cancer and primary screening. For patients with metastatic breast cancer, liquid biopsy may enable us to find mutated genes for which we may have targeted therapies. Liquid biopsies can also reveal drug-resistant genes, allowing clinicians to change therapies earlier than what is currently possible with conventional CT scans. Additionally, assessing ptDNA is quantitative. Currently, to treat metastatic breast cancer, we start a new therapy, wait two to three months, and then obtain a CT scan to see if the new therapy has worked.
By using non-invasive liquid biopsies, we may be able to assess whether a new therapy is working after one week rather than two to three months. This is because we can quantify ptDNA and see whether the levels in the blood are decreasing—potentially improving outcomes for patients with this faster assessment.
For early stage breast cancers that we hope to cure, ptDNA is also a potentially powerful tool to help guide management decisions. Under the current standard of care, most patients receive additional therapies such as chemotherapy and hormone therapy to improve our chances. However, 60 to 70 percent of patients do not need these additional therapies as they are already cured after surgery.
The current unmet need is that we cannot tell which patients are cured after surgery and which patients are ultimately going to relapse. Based on our earlier studies, we believe that assessing ptDNA via liquid biopsies can tell us who is and who is not cured after surgery and/or chemotherapy.
The idea is simple. After every treatment (e.g. surgery, radiation, chemotherapy, hormone therapy), we can draw a tube of blood and see whether the patient still has ptDNA, which indicates residual microscopic breast cancer. If the blood test is negative, we consider the patient cured. However, if positive, the patient moves on to the next therapy, and we again assess ptDNA after the therapy. This idea may appear bold, but our early work (and now verified by others) shows that it is feasible. Moreover, we have initiated a multi-institutional national prospective trial to test this hypothesis, and hope to obtain definitive data in the next five years.
Finally, liquid biopsies can serve as a general screening tool along with mammography. An abnormal mammogram leads to uncertainty, but combining mammography with a liquid biopsy yields more specific information, since ptDNA is only present in cancerous and precancerous lesions. This approach may enable health care providers to recommend biopsy sooner, so we can detect cancer earlier—giving us greater odds of curing it.
Content courtesy of Ben Ho Park, M.D., Ph.D., Professor of Oncology at the Johns Hopkins University School of Medicine, Associate Dean for Postdoctoral Affairs and Associate Director for Research Training and Education at the Johns Hopkins Kimmel Cancer Center. The content was reproduced with permission of the office of Marketing and Communications for Johns Hopkins Medicine International. Additional reuse and reprinting is not allowed. The information aims to educate readers and is not a substitute for consultation with a physician.