How ctDNA and Liquid Biopsies Could Transform Breast Cancer Care

For many patients diagnosed with early-stage breast cancer, the clinical road map feels relatively predictable: surgery, perhaps radiation or chemotherapy and the hope for a cure. But for Amy Ferris, a consulting and information technology (IT) professional in Austin, Texas, that standard map was missing a critical detour.

What began as a routine stage 1 breast cancer diagnosis in late 2023 at the age of 53 was radically redefined not by traditional imaging, but by a liquid biopsy, a circulating tumor DNA (ctDNA) test that uncovered what was otherwise invisible to her oncology team.

A ‘blinding’ discovery

Following two surgeries to remove what appeared to be localized stage 1 breast cancer, Ferris met with her oncologist and reviewed the surgical pathology, which showed clear margins and no lymph node involvement. A Signatera ctDNA test told a different story.

“She talked me through all the stage 1 things, and then she left the Signatera for last,” Ferris says. “She said, ‘There’s this test ... it came back positive. I feel like we should go looking and do some imaging.’ ”

That “looking” led to a startling discovery: The cancer had already spread to Ferris’ liver. The diagnosis was immediately elevated to stage 4. For Ferris, the revelation was “blinding,” a sharp contrast to the initial staging that had suggested a simpler journey.

Dr. Allison E. Gorrebeeck, a medical oncologist at Texas Oncology, recalls the pivotal moment Ferris entered her care and began navigating the complexities of her diagnosis. Although ctDNA is well validated for detecting cancer at levels far lower than traditional imaging, Gorrebeeck notes that it remains a point of debate because it is not yet an established part of the universal standard of care.

“There is a question we have yet to prove: that detecting this at these low levels is going to actually change the outcome or impact what we do with therapy,” she explains, highlighting the professional caution that often accompanies such a rapid technological shift.

In Ferris’ case, the decision to utilize the technology was driven by patient advocacy rather than routine protocol. “Amy got this test because she asked for it because she had read about it, and it certainly changed her story,” Gorrebeeck says.

This revelation fundamentally altered her treatment strategy and prognosis, allowing Gorrebeeck to monitor the disease’s evolution in real time and know precisely “when it is time to move on to the next treatment.”

Drawing a parallel to hematologic cancers of the blood, where minimal residual disease (MRD) — the tiny traces of cancer that may remain in the bloodstream after surgery or chemotherapy and are detectable via a simple blood draw — monitoring has been a staple for years, Gorrebeeck sees ctDNA as the future of solid tumor management. “It may be able to better guide us in tumor biology and help us to know when to be more aggressive in treatment, and maybe also we will have data someday to say when we can be less aggressive in treatment,” she concludes.

For decades, breast cancer monitoring has relied on the visible: the lump felt during an examination, the shadow on a mammogram or the “hot spot” on a PET scan. However, a new frontier in oncology is moving beyond what the eye can see.

ctDNA is transforming the landscape for patients with breast cancer and survivors, offering a window into the body’s molecular environment that was previously inaccessible.

A specialized tool for high-risk detection

Dr. Alexis Ann LeVee, a breast medical oncologist with UCLA Health and a member of the CURE advisory board, emphasizes that although the term “ctDNA” is broad, its applications are becoming highly specialized. In the early-stage setting, physicians use ctDNA to monitor MRD.

“When we see circulating tumor DNA in the blood, that does signal an increased risk of recurrence,” LeVee explains.

At the CURE Educated Patient Breast Cancer Summit, held earlier this year during the Miami Breast Cancer Conference, Dr. W. Fraser Symmans, a professor in the Department of Pathology at The University of Texas MD Anderson Cancer Center, provided a comprehensive overview of how this technology is reshaping breast cancer care, explaining that tumors are highly vascularized from their earliest stages, leading them to release various signals into the bloodstream.

The industry has largely pivoted toward ctDNA because it is more frequent in the blood and, crucially, can be amplified in a laboratory setting. “That tiny needle in the haystack can be amplified and detected,” Symmans noted during a presentation at the summit.

LeVee highlights the particular value of ctDNA in early-stage triple-negative breast cancer, an aggressive subtype. Following neoadjuvant (presurgical) treatment, ctDNA clearance is a strong predictor of a pathologic complete response — the disappearance of all signs of cancer. On the other hand, for patients with residual disease, a positive ctDNA test indicates a significantly higher risk of recurrence.

However, LeVee cautions that we are still in a “research” phase for many applications using ctDNA. “Right now, we don’t quite know how to act on these positive ctDNA test results,” she notes, pointing to ongoing trials that are investigating whether early intervention for ctDNA positivity improves long-term survival.

Evolving evidence: Recent data findings in breast cancer

Recent studies, reported on by CURE at curetoday.com, highlight how ctDNA is moving from a prognostic tool to a guide for surgical and systemic interventions.

• Retrospective data from the I-SPY trial suggest that ctDNA could eventually help surgeons decide the extent of lymph node removal. By predicting “nodal burden” via a blood test, doctors might identify which patients can safely skip invasive axillary lymph node dissections, thereby reducing the risk of side effects like lymphedema, or swelling of the limbs.
• A study conducted by Natera and the University of Pittsburgh focused on patients aged 70 and older who chose primary endocrine therapy rather than surgery and found that the Signatera test can accurately monitor these patients.
• In the metastatic setting, researchers are using serial liquid biopsies every three months to catch ESR1 mutations — genetic changes that allow a tumor to become resistant to standard hormone therapy. The trial found that switching patients to camizestrant (an oral selective estrogen receptor degrader) upon detecting the mutation, rather than waiting for a scan to show progression, prolonged the time patients remained on their first-line treatment.
• Data from the plasmaMATCH trial showed that baseline ctDNA levels could predict a patient’s response to targeted therapy. Patients with low or undetectable ctDNA after just four weeks of treatment consistently had better outcomes and longer progression-free survival, or the time a patient lives without their disease spreading and worsening.
• The Cancer Vaccine Coalition, through a strategic partnership with the V Foundation for Cancer Research, announced a $1 million grant toward a phase 2 study at The University of Texas MD Anderson Cancer Center, the INTERCEPT-HER2 clinical trial, which will involve researchers utilizing ctDNA to determine which patients will receive a therapeutic cancer vaccine designed to train the immune system to recognize and destroy remaining cancer cells before they can spread.

Bridging the gap: Dr. Sucharu Prakash on access and equity

Although the technology is advancing rapidly, Dr. Sucharu Prakash, Medical Director of Quality Services for Texas Oncology, is focused on ensuring these innovations reach patients outside of major academic centers. He describes ctDNA as a “game changer” that acts like a “stethoscope for the blood.”

“In cardiology, we can listen to the heart and hear murmurs,” Prakash says. “Similarly, we can now check a patient’s blood to detect tiny amounts of cancer DNA way before any symptoms come on or disease shows up on a CT or PET scan.”

However, Prakash highlights significant hurdles for those in rural areas who may live hours from a designated cancer center. “Texas has the largest rural population in the country,” he notes, emphasizing that Texas Oncology is working to “mandate or recommend” consistent diagnostic testing across all its locations, regardless of ZIP code.

Prakash also acknowledges the divisiveness within the medical community regarding ctDNA. Some oncologists are hesitant because the technology is not yet included in the National Comprehensive Cancer Network (NCCN) guidelines.

“We doctors are circumspect; we’re sometimes slow to adopt new technology,” he admits. But he argues that if a patient today could benefit from a personalized approach, either by escalating therapy to catch a recurrence early or de-escalating to avoid toxic side effects, providers have a duty to stay updated on the latest data.

From physician to patient: Dr. Alexea M. Gaffney-Adams’ lived experience

Perhaps no one understands the promise and paradox of ctDNA better than Dr. Alexea M. Gaffney-Adams, a physician with Stony Brook Medicine and a stage 3 breast cancer survivor. Diagnosed at age 37, Gaffney-Adams has navigated the complexities of treatment as a provider and a patient, eventually enrolling in the DARE clinical trial.

The DARE trial monitors high-risk survivors for recurrence using the Signatera test. For Gaffney-Adams, the test offers a level of sensitivity that traditional tumor markers never could. “Even though I had a very large tumor and local metastasis, none of my tumor markers were positive or elevated,” she shares. “But this is something I can rely on.”

Gaffney-Adams describes a unique molecular anxiety that comes with liquid biopsies, a feeling similar to scan anxiety while waiting for results. Yet she finds profound peace of mind in the trial’s proactive nature. “If this was to be positive, it’s the earliest possible positive result I can have,” she says. “We’re no longer shooting in the dark.”

The power of molecular monitoring

In Ferris’ case, the test didn’t just change her diagnosis; it saved her from a treatment plan that would have focused on the wrong target. “We would have gone forward treating the breast cancer, like radiating my breast while I was dying of the cancer in my liver,” she says.

Over the last two and a half years, Ferris has watched her ctDNA levels fluctuate in real time, acting as a molecular mirror for how her body responds to various treatments, including CDK4/6 inhibitors. When side effects like pneumonitis forced her to pause medication, the test accurately reflected the status of her disease.

Managing the ‘30% rule’

Living with a stage 4 diagnosis requires a profound mental shift. Ferris describes a learning process of “riding with the unknown.” To manage the emotional weight, she implemented what she calls her “30% rule.”

“I’ll let [the anxiety] creep up to like 30%,” she jokes. “But at the beginning, it was like 500% and mind-blowing. Somehow your brain finds a way to handle the unknown and almost celebrate it.”

Today, Ferris is a proactive advocate, encouraging other patients to ask about liquid biopsies. She views the technology as a necessary “different angle” on disease management, providing a level of personalization that traditional bloodwork cannot match.

For Ferris, the “random whim” of her husband — who had heard of the technology through his own work in IT — to ask for the test has made all the clinical difference. As she focuses on organizing family photos and spending time with her children, she remains profoundly aware of the invisible clock that ctDNA helped reset.

“I feel like I’ve had 2.5 years of bonus time so far,” Ferris says. “In any other scenario, in another century or without this test, I would be gone by now. I’m just really grateful.”

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