ctDNA and cfDNA in Breast Cancer: What “Low Shedding” Means
A plain-language guide to ctDNA and cfDNA in breast cancer, including low shedding across lobular, HER2-positive, triple-negative, and ER/PR-positive disease.
ctDNA testing can support treatment planning and monitoring in metastatic breast cancer.
A negative liquid-biopsy result does not always mean there is no active cancer. It may mean the tumour sheds too little DNA into blood for detection.
Contents
Overview
Circulating tumour DNA, or ctDNA, testing is increasingly used in breast-cancer care. It is especially useful in metastatic disease.
A liquid biopsy may identify targetable mutations. It may also help monitor treatment response or track progression over time.
ctDNA is the tumour-derived fraction of total cell-free DNA, or cfDNA, found in blood. The amount available for testing depends on the assay. It also depends on how much DNA the tumour releases into the bloodstream.
This distinction matters. A low or negative ctDNA result does not always mean there is no active cancer.
It can mean the tumour sheds very little DNA. It can mean the tumour fraction falls below the assay’s detection limit. The cancer’s biology can also make blood-based detection harder at that time point.
ctDNA versus cfDNA
cfDNA describes all fragmented DNA circulating in plasma. It includes DNA released from normal tissues and tumour cells.
ctDNA is the cancer-specific subset of cfDNA. It carries tumour-related changes such as mutations, copy-number alterations, and other genomic features. Some of these changes may be clinically actionable.
Because ctDNA is only one component of the total cfDNA pool, cfDNA can be measurable when ctDNA is not. A liquid biopsy may therefore find little or no ctDNA despite a measurable amount of total cfDNA.
Liquid-biopsy results need clinical context. Imaging, symptoms, pathology, and tissue-based testing remain important parts of interpretation.
What “low shedding” means
“Low shedding” usually describes tumours that release relatively little tumour DNA into circulation. ctDNA levels can vary with tumour burden, metastatic site, growth rate, treatment effect, and intrinsic subtype.
Low shedding matters most when a test is negative. FoundationOne Liquid CDx and similar assays analyse cfDNA from plasma.
When tumour fraction is low, false-negative results become more likely. The blood sample may not contain enough tumour-derived material for confident detection.
A negative liquid biopsy cannot independently exclude active or progressing cancer.
This is particularly important when imaging, symptoms, or prior tissue findings suggest otherwise.
Lobular breast cancer
Low shedding is a growing area of interest in metastatic invasive lobular carcinoma, or mILC. Diffuse growth patterns and often slower biology may reduce the amount of ctDNA available in blood compared with more proliferative disease.
A 2025 prospective study used personalised serial ctDNA testing in people with mILC. ctDNA was detectable in many participants.
Changes over time tracked treatment response and progression.
In that study, falling or stable ctDNA during treatment often aligned with clinical benefit on imaging. Rising ctDNA was associated with a greater likelihood of progression.
People who remained ctDNA-negative during follow-up had very good short-term outcomes. However, a ctDNA-negative result still needs caution. Low-shedding tumours may be underrepresented in blood-based assays.
ER/PR-positive disease
Hormone receptor-positive disease, especially HR-positive/HER2-negative disease, can show lower ctDNA levels than more aggressive subtypes. This may reduce blood-based detection sensitivity in some settings.
ctDNA remains useful in ER/PR-positive breast cancer. In metastatic disease, assays may detect alterations such as PIK3CA or ESR1.
These findings can influence treatment selection. They can also identify potential resistance mechanisms.
Lower shedding makes negative results less straightforward to interpret. Serial testing may sometimes offer more information than one isolated blood draw.
Clinicians often interpret ctDNA with imaging and tissue results. Blood testing should not stand alone when tumour shedding may be low.
HER2-positive disease
HER2-positive breast cancer is biologically active and has effective targeted treatment options. In metastatic disease, ctDNA testing may capture genomic changes over time.
Across breast cancer, ctDNA analysis can identify targetable alterations. It can also complement tissue testing when repeat tissue biopsy is difficult or unsafe.
The important point is not that every HER2-positive tumour sheds heavily. Tumour fraction and assay sensitivity can still limit ctDNA detection.
This is especially relevant when disease burden is low or treatment is working well.
A negative liquid biopsy does not exclude clinically meaningful HER2-driven disease. It may simply mean that the plasma sample contained insufficient tumour DNA at collection.
Triple-negative breast cancer
Triple-negative breast cancer, or TNBC, tends to have higher ctDNA levels than HR-positive/HER2-negative disease. This likely reflects its more proliferative and biologically aggressive behaviour.
This can make ctDNA attractive for monitoring treatment response and residual risk. Dynamic changes may be easier to detect in blood.
Research discussed by the Breast Cancer Research Foundation found higher ctDNA levels in TNBC at every measured time point. Early ctDNA clearance during treatment was associated with favourable response patterns in TNBC.
Even in TNBC, ctDNA is not a perfect marker. Blood findings still need to be interpreted alongside the wider clinical picture.
What a negative liquid biopsy may mean
A negative ctDNA report can have several explanations. The right interpretation depends on the clinical setting.
It may reflect:
Low tumour burden.
Effective treatment.
Intrinsically low tumour shedding.
Disease at sites that are less represented in plasma.
Technical limits caused by very low tumour fraction.
For patients, a “nothing showed up” result is not always bad news. It is also not always definitive reassurance.
In a low-shedding context, a negative report may fit with slower or controlled disease. It should not independently rule out progression or replace imaging and clinical assessment.
How this may help in practice
For people using tests such as FoundationOne Liquid CDx, the useful question is often not simply whether the report is positive or negative. The key question is how the result fits with breast-cancer subtype, recent scans, symptoms, and treatment course.
Serial trends can sometimes be more useful than a one-off result. This is especially true in lobular or hormone receptor-positive disease, where low shedding may reduce the value of a single blood draw.
Liquid biopsy is one part of the picture, not a stand-alone answer.
A positive result may identify a treatment option. It may also provide an early sign of change.
A negative result may still require repeat testing, imaging, or tissue biopsy. The next step depends on the wider clinical picture.
Conclusion
ctDNA testing is a useful and rapidly evolving tool in breast cancer. Its performance is shaped by biology as much as technology.
TNBC tends to shed more ctDNA. Hormone receptor-positive disease often sheds less.
HER2-positive disease can still be limited by low tumour fraction. Metastatic lobular cancer may be especially prone to low-shedding patterns that complicate interpretation.
ctDNA and cfDNA are not the same thing. A negative blood test does not mean the same thing across all breast-cancer subtypes.
Liquid-biopsy results are most meaningful beside imaging, pathology, symptoms, and treatment response over time.
Related pages
Liquid Biopsy for HER2-Positive Resistance: HER2-specific guide to what ctDNA may detect or miss during treatment resistance.
Blood Biopsy Trial — Getting Ahead of Treatment Resistance: HR-positive/HER2-negative guide to serial ctDNA monitoring for emerging ESR1 mutations.
FGFR1 Amplification in ER+ Breast Cancer: Why an ER-positive FGFR1 amplification signal may fluctuate or disappear on a later blood draw.
References
Foldi J, et al. Personalized Circulating Tumor DNA Testing for Detection of Progression and Treatment Response Monitoring in Patients With Metastatic Invasive Lobular Carcinoma of the Breast. JCO Precision Oncology. 2025.
Davis AA, et al. Circulating tumour DNA characterisation of invasive lobular carcinoma in patients with metastatic breast cancer. NPJ Breast Cancer. 2022.
Magbanua MJM, et al. The clinical significance and biology of circulating tumor DNA in breast cancer. 2023.
Panet F, et al. Use of ctDNA in early breast cancer: analytical validity and clinical potential. 2024.
Woodhouse R, et al. Clinical and analytical validation of FoundationOne Liquid CDx. 2020.
Foundation Medicine. When it comes to ctDNA, tumour fraction matters.
Roche Diagnostics. FoundationOne Liquid CDx technical information.
Breast Cancer Research Foundation. 2023 Breast Cancer ctDNA Study.
Breast Cancer Network Australia. HER2-positive breast cancer.
Ajjawi I, et al. Prognostic Value of Circulating Tumor DNA in HR+/HER2- Breast Cancer. 2025.
This information is for education only. It is not medical advice, diagnosis, or treatment. Discuss test results and treatment decisions with your oncology team.
© 2026 Abbey Mitchell. All rights reserved. Please share by URL rather than copying page text.
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