Navigating the Hype: Perspective on Circulating Tumor DNA in Breast Cancer

Breast cancer is common, affecting 1 in 8 women and accounting for nearly 30% of cancer diagnoses annually in women in the United States. What people often don't know is that the cure rate for early-stage breast cancer is high, with 92% of people alive at five years from the time of their diagnosis. As a practicing medical oncologist, my mission is to balance two often-conflicting goals: utilizing the most advanced tools to save lives while ensuring I do not cause unnecessary harm through overtreatment or premature intervention.
"How ctDNA and Liquid Biopsies Could Transform Breast Cancer Care," the cover article in this season’s issue of CURE, is an insightful foray into the realm of a highly advanced technology to identify cancer recurrence early, while balancing the tension of added anxiety and unknown risks.

What is ctDNA, or circulating tumor DNA, and why is everyone talking about it? Tumors shed small fragments of genetic material (DNA) in the blood. I explain this to patients as the tumor’s fingerprints or discarded crumbs. This information is shed specifically by cancer cells. Using next-generation sequencing, we can now identify and quantify ctDNA in blood. ctDNA are short fragments of 50 to 200 base pairs that circulate in the blood and can persist for minutes to hours. Many factors can affect the presence of ctDNA, including tumor volume, vascularity, disease sites and specific tumor types. Some tumors may shed more ctDNA than others.

Historically, a person diagnosed with an early-stage cancer would complete a staging evaluation, understanding where the cancer started and whether it has learned to travel to somewhere else in the body. In people with early-stage breast cancer, for example, the cancer started in the breast and stayed in the breast; surgical resection is often curative. Based on risk factors, we may recommend chemotherapy, estrogen blockade and radiation after surgery in an effort to reduce the risk of recurrence. We then monitor patients with routine imaging (CT scans, mammograms) to identify recurrence early.

A liquid biopsy may act like a high-powered molecular "stethoscope," picking up these DNA fragments at levels far below what can be discerned on an image.

This technology is currently being used in two primary ways:

1. Detecting minimal residual disease: Checking for "microtraces" of cancer left behind after surgery or chemotherapy.

2. Tracking mutations: Identifying specific genetic changes (like the ESR1 mutations) that tell us a tumor has become resistant to hormone therapy.

Is earlier detection always better? Lead-time bias can be a real issue when looking at liquid biopsy. When we assess new tests for breast cancer, we have to make sure the test is actually moving the finish line further away — i.e., letting people live longer and not just starting the clock earlier. What we strive for is a test that helps us improve the outcome, cure the disease and not just appear as though people are living longer because we identified recurrence earlier.

I also worry about "molecular anxiety." We all have heard of "scanxiety," the anxiety that accompanies the result of a scan or picture. We are now also dealing with "molecular anxiety" accompanying the results of these novel liquid biopsy tests. We are always hoping for a negative test. A true negative is reassuring; however, a false negative result may be falsely reassuring. What if that test itself was nondiagnostic? What we seek are the true positive results, real recurrence of the cancer, which may help us change treatments or monitor more closely.

What concerns patients and me the most are false positives (i.e., identification of ctDNA when there is in fact no recurrence of the cancer). Thankfully, this is rare.

It's important for patients to understand that although these tests are revolutionary, they are not yet perfect. A negative test does not always mean the cancer is gone; it may just mean the amount of ctDNA is below the test’s limit of detection. As the technology improves, the limits of detection have improved as well, but we are still not at 100% sensitivity and specificity for these assays.

Remember, a positive test might pick up cells that the immune system may have cleared naturally — i.e., "false positives" that may lead to the risk of overtreatment. 

There also remains a significant issue of cost, access and equity around these new molecular tests. Testing for ctDNA is not yet part of our universal National Comprehensive Cancer Network Guidelines. Many insurance companies will not cover these tests, leaving patients with significant out-of-pocket expenses. Major academic research centers may have access to these novel tools through research protocols, whereas patients in rural areas may be left behind.

For Dr. Demetria Smith-Graziani, a breast medical oncologist at the Emory Winship Cancer Institute and a member of the CURE advisory board, the conclusion is clear: ctDNA is a tool in progress and may not yet be ready for prime time. For patients curious about the technology, her advice is rooted in transparency: "Understand the uncertainty, weigh the financial cost, and, whenever possible, participate in the research that will eventually turn these ‘unanswered questions’ into life-saving protocols."