Circulating Tumor DNA in Breast Cancer Q&A
What is Circulating Tumor DNA?
Circulating tumor DNA is essentially DNA that cancer cells shed into the blood stream as they die. There is a lot of interest in using circulating tumor DNA to assess for MRD (molecular residual disease), and identify people who have or may be at risk for a future recurrence. Ultimately, the big question is can we use ctDNA to utilize treatments to prevent or delay a recurrence? Can outcomes be changed in patients who have a positive ctDNA test?
Is ctDNA in breast cancer ready for prime time use?
As exciting as this technology is, we do not know yet what to do with the results and there are potential harms to doing ctDNA testing (Signatera from Natera is one assay to check for ctDNA but there are others out there that exist as well from different companies such as Guardant). Let’s walk through this in more detail.
Let’s say that a patient has completed active therapy for breast cancer (typically, we think of active therapy as surgery, chemotherapy and radiation - longer term treatments such as endocrine therapy or anti HER2 therapy typically fall into the maintenance category) and gets a test done at some point after that to look for ctDNA. If that test detects the presence of ctDNA, typically that will prompt a scan to look for cancer. If that scan (and subsequent biopsies as needed) confirm a recurrence, then that patient starts on treatment. What we do not know at this time is “does starting that treatment at that point versus at a later time point (when perhaps they developed symptoms prompting a scan) improve long term outcomes” or did that patient simply start treatment earlier with possibly increased side effects but without a long term benefit in survival.
On the other hand, what happens if the ctDNA is detected but the scans are negative. This is where the biggest questions lie and here’s where we really do not know what to do. There can be false positives (positive test without actual recurrence in future) or false negatives (negative test but patient does recur in future) but there is a high likelihood that a positive ctDNA will result in a clinical recurrence (seen on imaging) at some point in the future. We do not yet know what to do in this “in between period.” We do not have data yet on treatments we can offer to intervene (and whether these treatments will be effective) and this waiting can create severe anxiety and fear, without a possible intervention.
What about the ZEST Trial?
The ZEST Trial was just presented at the 2024 San Antonio Breast Cancer Symposium. The trial asked the question: can adding niraparib (a PARP inhibitor) to patients with triple negative breast cancer or BRCA mutated hormone receptor positive breast cancer with a positive ctDNA test and no radiological evidence of disease prevent or delay a recurrence? They allowed patients with stage I-III disease to enroll who had completed standard therapy (could have still be on pembrolizumab for TNBC or endocrine therapy for HR+).
Unfortunately, the study was terminated due to very low numbers of patients with a positive ctDNA and half of the patients who had a positive ctDNA already had radiologic evidence of disease. 1901 patients were enrolled into the study. Only 147 patients (7.7%) had a positive ctDNA and only 40 (after excluding those who were ineligible or who had positive scans) were able to be randomized to be assigned to the niraparib arm or placebo arm of the study. Because the numbers were so small, they could not do any statistical analyses but they showed a numerical approval in niraparib approving the recurrence free interval (time to recurrence). Patients on niraparib (18 patients) had a recurrence free interval of 11.4 months versus 5.4 months in those on placebo (22 patients) but it’s just too small of a population to draw any conclusions and these small numbers have a wide margin of error.
When I shared this information on Instagram, many questions came up about the ZEST trial and ctDNA in general so let’s answer some of them.
Is ctDNA used the same way in different cancers? No, there are different recommendations for using ctDNA depending on the type of cancer and the studies that have been done and results of those studies. While we can learn from data in other cancer types, we cannot necessarily extrapolate from cancer types and say that because ctDNA is used in this way in colon cancer, for example, then we can use the same way in breast cancer.
Would a more sensitive ctDNA assay produce different results? Potentially. It is possible that a more sensitive assay identify more patients but we need to test this before being able to say for certain.
How many negative tests do you need to say that you will not experience a breast cancer recurrence? It’s not a number of tests. Ultimately, it depends on your individual risk of recurrence and if that risk is more likely to be early (such as we see with a triple negative breast cancer) versus a later recurrence (what we see with a HR+ breast cancer), for example. It’s more over the period of time that has lapsed compared to number of tests. Remember, that there can be false positives as well as false negatives.
What are some of the ongoing other ctDNA studies in breast cancer? Here are some ongoing trials. In TNBC, we have the ASPRIA study (https://clinicaltrials.gov/study/NCT04434040) , which is atezolizumab + sacituzumab govitecan (Trodelvy) for patients with TNBC who test positive for ctDNA and the PERSEVERE study which is testing different interventions (https://clinicaltrials.gov/study/NCT04849364). In HER2+, we have the KAN-HER2 trial, which is looking at adding neratinib to ado trastuzumab emtansine (Kadcyla) (https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS620). In hormone receptor positive, there are several studies including DARE, LEADER, TRAK-ER and TREAT-ctDNA which are all evaluating different interventions. You can get information on all of these trials at Clinicaltrials.gov and see if they are enrolling/recruiting patients as well as the available locations. I am hopeful some of these trials will help us answer many of the ongoing questions about ctDNA.
Why didn’t the study require that more participants be ctDNA positive before it began? The ZEST trial included participants with stage I-III disease who would be tested ctDNA and if positive (with negative scans), then the patients would be either assigned to the placebo group versus niraparib group. Because the trial didn’t select for a higher risk population (and allowed stage I patients who are at a lower risk of recurrence compared to stage 2 or 3 disease), they had a low number of patients who ended up testing positive for ctDNA. This was not what they had expected initially. We will see if future trials are more selective in terms of the patient population.
I hope this information was helpful! Wishing you a wonderful holiday season and looking forward to bringing you more content via Substack in 2025! Share with a friend or family member who may find this information helpful.
Great article! More and more patients are asking about ctDNA testing, and it’s on us to help them understand both the benefits and the limitations. I’ve started incorporating it into my practice, sometimes a bit earlier than guidelines might suggest, because in certain cases, that extra piece of information can completely change the course of treatment. Like any new technology, it’s not just about having the tool—it’s about using it wisely and working with our patients to navigate these complex decisions together.
Recently, my wife was diagnosed with stage IB triple-negative breast cancer (TNBC), invasive ductal carcinoma, grade 3/3. She has just started the ACT regimen with Keytruda. Her oncologist explained that imaging will be used to determine if her 2 cm tumor has begun to shrink. Despite having undergone five mammograms, including screening, diagnostic, and 3D tomography, none of them detected the tumor. However, both ultrasound and MRI revealed the tumor, with slight discrepancies in size between the two technologies. There is no indication of metastasis or lymph node involvement.
We have expressed interest in circulating tumor DNA (ctDNA) testing even if it is considered experimental, but the oncologist stated that imaging is the standard protocol. While I understand the importance of following protocol, I struggle to comprehend why an additional method of observation would not be encouraged—especially since we have repeatedly offered to pay out of pocket. Wouldn’t ctDNA testing provide a complementary way to monitor progress during and after treatment, particularly given the neoadjuvant approach?
We are strongly advocating for ctDNA testing, as well as Galectin-3 (Gal-3) staining of the remaining biopsy samples, to better monitor circulating tumor load. Could ctDNA testing potentially show a reduction in tumor burden before changes become visible on imaging? Additionally, the Gal-3 test, while based on research from smaller studies, might offer insights into the efficacy of Keytruda. This science suggests that Gal-3 staining could guide the selection of immunotherapy drugs, should adjustments become necessary. The data surrounding Gal-3 staining is compelling and indicates it could help refine treatment decisions.
I believe these two additional metrics—ctDNA and Gal-3 staining—could play a critical role in preventing micro-metastases and potential tumor seeding. By providing the oncology team with more detailed tools, they could adjust the treatment plan, potentially incorporating another platinum-class immunosuppressant if needed.
As an aside, I do trust our oncology team. However, I feel there are additional avenues worth exploring to ensure the best possible treatment regimen.