Observational study finds low ctDNA levels associated with improved treatment outcomes in breast cancer — Evidence Review

Scientists at the Institute of Cancer Research, London have developed a blood test that can help predict how well patients with advanced breast cancer will respond to specific treatments. Previous studies generally agree that lower circulating tumor DNA (ctDNA) levels are associated with better treatment outcomes and that ctDNA monitoring can guide therapy choices.

• Several studies in both advanced and early-stage breast cancer consistently report that lower or undetectable ctDNA levels, both before and during treatment, correlate with a higher likelihood of treatment response and longer progression-free survival, supporting the findings of the new study 1 2 4 5.
• Research in other cancers (such as lung, colorectal, and melanoma) also demonstrates that early changes in ctDNA levels can predict therapeutic efficacy and survival outcomes, suggesting this approach is broadly applicable to monitoring treatment effectiveness 11 12 13 14 15.
• While ctDNA shows promise as a predictive biomarker, some studies highlight the need for further research to validate its use in personalizing treatment, particularly regarding its role in guiding therapy changes and its predictive value compared to other blood-based markers 4 8 9.

Study Overview and Key Findings

Predicting which breast cancer treatment will work best for an individual remains a major clinical challenge, especially as available therapies and cancer subtypes diversify. The new study addresses this gap by trialing a non-invasive blood test that measures ctDNA in patients with advanced breast cancer, aiming to forecast treatment response before and shortly after therapy begins. Unlike traditional assessments that rely on imaging or tissue biopsies, this liquid biopsy could enable clinicians to make more personalized, timely, and potentially effective treatment decisions.

Property	Value
Organization	Institute of Cancer Research, London, Breast Cancer Now, Cancer Research UK, NIHR Biomedical Research Centre at the Royal Marsden NHS foundation trust
Authors	Dr Iseult Browne, Prof Nicholas Turner
Population	Patients with advanced breast cancer
Sample Size	167 patients
Methods	Observational Study
Outcome	ctDNA levels and treatment response
Results	Low ctDNA levels linked to better treatment outcomes.

Literature Review: Related Studies

To assess how the new findings fit within the broader scientific context, we searched the Consensus database, which contains over 200 million research papers. The following search queries were used:

1. ctDNA levels breast cancer treatment outcomes
2. blood test predict breast cancer therapy
3. low ctDNA levels treatment efficacy correlation

Summary Table of Related Study Topics and Key Findings

Topic	Key Findings
How do ctDNA levels relate to treatment response and survival in breast cancer?	- Lower or undetectable ctDNA levels before and during treatment are associated with better response rates and longer progression-free survival or overall survival in both early and advanced breast cancer 1 2 4 5. - Persistence of detectable ctDNA during therapy predicts poor response and higher risk of recurrence 1 4 5.
Can early changes in ctDNA guide or optimize therapy decisions?	- Early ctDNA dynamics (suppression or clearance) after one or two treatment cycles can serve as a surrogate marker for treatment efficacy and may inform early adaptation of therapy 2 5. - Personalized ctDNA monitoring can potentially improve the selection of effective therapies and reduce unnecessary treatment 1 2.
How do blood-based biomarkers compare to ctDNA for predicting breast cancer outcomes?	- Other blood-based indices, such as neutrophil-to-lymphocyte ratio (NLR) and metabolic biomarkers, can also predict treatment response and prognosis but are less specific to tumor genetics than ctDNA 8 9 10. - Combined approaches using ctDNA with other blood biomarkers may further refine risk stratification 8 9 10.
Is ctDNA monitoring predictive in other cancers and/or therapy types?	- Studies in colorectal, lung, and melanoma cancers confirm that early decreases in ctDNA are linked to better treatment response and survival, indicating a broader applicability of ctDNA monitoring 11 12 13 14 15. - Undetectable ctDNA levels often correlate with durable and prolonged treatment benefits 11 14.

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How do ctDNA levels relate to treatment response and survival in breast cancer?

The new study's findings that low or undetectable ctDNA levels are linked to better treatment response and longer disease control in advanced breast cancer are strongly supported by previous research. Multiple studies have shown that ctDNA levels, measured at baseline and during treatment, correlate with pathologic response, relapse risk, and survival in both early and advanced disease settings.

• Lower pre-treatment or on-treatment ctDNA levels have consistently predicted higher rates of treatment response and longer progression-free or overall survival in breast cancer patients 1 2 4 5.
• Persistent or rising ctDNA during therapy is associated with poor outcomes, including lower likelihood of complete response and increased risk of recurrence 1 4 5.
• These findings are robust across breast cancer subtypes, including triple-negative and hormone receptor-positive/HER2-negative disease 1 3.
• The new study extends these observations to advanced disease and reinforces the potential of ctDNA as a practical non-invasive biomarker for guiding therapy 1 2 4 5.

Can early changes in ctDNA guide or optimize therapy decisions?

Evidence from clinical trials and observational studies suggests that early measurement of ctDNA dynamics—such as ctDNA clearance after a treatment cycle—can serve as an actionable marker for modifying treatment strategies. The current study's approach of testing ctDNA at baseline and after four weeks aligns with this literature.

• Early suppression or clearance of ctDNA after initiation of therapy reliably predicts improved outcomes, supporting timely adjustments to treatment plans 2 5.
• Personalized ctDNA monitoring can help identify non-responders early, allowing consideration of alternative therapies or enrollment in clinical trials 1 2.
• These strategies can potentially minimize exposure to ineffective treatments and reduce unnecessary side effects 1 2 5.
• Ongoing trials are investigating whether ctDNA-guided therapy changes translate to improved survival and quality of life 2.

How do blood-based biomarkers compare to ctDNA for predicting breast cancer outcomes?

Beyond ctDNA, several blood-based markers—such as inflammatory indices and metabolic biomarkers—have been investigated for their prognostic and predictive value in breast cancer. While these can provide additional information, ctDNA remains the most specific indicator of tumor burden and genetic changes.

• Peripheral blood-derived indices like NLR, PLR, and PNI are associated with response to therapy and survival, but their predictive power is generally lower than that of ctDNA 8 9.
• Recent multi-omic studies suggest that metabolic biomarkers, such as inosine and uridine, may also help predict treatment response, particularly in triple-negative breast cancer 10.
• Combining ctDNA with other blood biomarkers may enhance risk stratification and personalize therapy decisions 8 9 10.
• The new study supports a growing trend toward integrated liquid biopsy approaches in breast cancer management 8 9 10.

Is ctDNA monitoring predictive in other cancers and/or therapy types?

The prognostic and predictive value of ctDNA is not limited to breast cancer. Studies in metastatic lung, colorectal, and melanoma cancers demonstrate that early reductions in ctDNA levels are associated with better response rates and longer survival, indicating that ctDNA monitoring could serve as a universal tool for tracking treatment efficacy.

• In lung and colorectal cancers, early drops in ctDNA during immunotherapy or chemotherapy predict objective response and prolonged survival 11 12 13 15.
• Patients with metastatic melanoma who achieve undetectable ctDNA on treatment experience durable clinical benefit and improved survival 14.
• These cross-cancer findings reinforce the validity of ctDNA as an early, non-invasive marker for therapeutic efficacy 11 12 13 14 15.
• The new study's focus on breast cancer adds to a growing body of evidence supporting the implementation of ctDNA monitoring in diverse cancer types 11 12 13 14 15.

Future Research Questions

While the new study strengthens the case for ctDNA-guided treatment selection in advanced breast cancer, several important questions remain. Further research is needed to confirm the clinical utility of ctDNA monitoring, optimize its integration into standard care, and address potential limitations such as tumor heterogeneity and assay sensitivity.

Research Question	Relevance
Does ctDNA-guided therapy adaptation improve overall survival in advanced breast cancer?	Determining whether changing treatment based on early ctDNA results leads to better survival outcomes is critical for validating clinical adoption 2 4.
How do ctDNA-based tests perform across different breast cancer subtypes?	Examining test accuracy and predictive value in various subtypes (e.g., triple-negative vs. hormone receptor-positive) will clarify generalizability and clinical relevance 3 10.
Can combining ctDNA with other blood biomarkers improve treatment prediction in breast cancer?	Integrated approaches may enhance predictive power and allow for more precise, individualized treatment strategies 8 9 10.
What are the optimal timing and frequency of ctDNA monitoring for treatment assessment?	Defining the best time points and intervals for ctDNA testing will maximize its utility and cost-effectiveness in clinical practice 1 2 5.
What are the limitations of ctDNA testing in detecting minimal residual disease or predicting late recurrence?	Understanding technical and biological limitations will help refine ctDNA assays and ensure accurate interpretation of negative results 1 4 5.