The use of circulating tumour DNA (ctDNA) in managing operable breast cancer (BC) has faced hurdles due to mixed results from various studies. A recent study aimed to determine the prognostic value of ctDNA is in predicting outcomes for patients with operable non-metastatic BC.
Methods
The study involved a systematic review and meta-analysis that searched PubMed/Medline, Embase, and CENTRAL databases, as well as conference proceedings. The outcomes assessed were detection with disease-free survival (DFS) and overall survival (OS) in patients with stage I-III BC.
Results
Overall, 57 studies were included and 5,779 patients met the inclusion criteria. Univariate analyses showed that ctDNA detection was associated with worse DFS at baseline after neoadjuvant therapy and during follow-up. In addition, ctDNA detection was linked to worse OS post-neoadjuvant therapy and during follow-up. Multivariate analyses rendered consistent results. Notably, the hazard ratios were higher when ctDNA was detected at the end of neoadjuvant therapy or during follow-up, especially for primary tumour-informed assays.
The sensitivity and specificity of this prognostic marker for BC recurrence ranged from 0.31-1.0 and 0.7-1.0, respectively. The average lead time from ctDNA detection to visible recurrence was 10.81 months (ranging 0-58.9 months).
It was inferred that ctDNA detection has high specificity for predicting BC relapse. Studies evaluating ctDNA in early breast cancer had mixed results. However, this meta-analysis found that ctDNA detection consistently indicates a higher risk of BC recurrence and death. The findings confirmed that the presence of ctDNA predicted poorer disease-free survival and overall survival in patients with operable BC, particularly when detected after treatment – using primary tumour-informed assays.
This increased risk is especially notable when ctDNA is detected after treatment using tumour-informed assays. ctDNA detection can predict metastasis about 11 months before its clinical diagnosis – with up to 100% specificity.
Discussion
In metastatic BC, ctDNA is used to detect molecular changes for targeted treatments. Early studies suggested that ctDNA detection at baseline or follow-up predicted higher relapse risk. This prompted further research. This meta-analysis––which includes a significantly larger dataset than previous studies––confirms that patients with detectable ctDNA consistently have a worse prognosis. The risk is notably higher when ctDNA is detected after neoadjuvant or adjuvant therapy, indicating possible treatment resistance.
The timing of ctDNA assessment during follow-up varied among studies, and some patients with positive ctDNA results might have missed imaging assessments. This makes it unclear whether ctDNA detected during follow-up indicates minimal residual disease or undiagnosed asymptomatic metastases.
Ongoing studies like LEADER, TRAK-ER, and DARE aim to assess whether early intervention based on ctDNA detection can improve outcomes. The MiRaDoR study explores treatment efficacy by monitoring minimal residual disease using ctDNA in early BC patients.
There is no consensus on the best strategy for detecting ctDNA in early BC. Tumor-agnostic assays do not require prior knowledge of tumour characteristics, while tumour-informed assays track specific mutations identified through tumour tissue sequencing. Tumour-informed assays may be more sensitive for detecting known mutations, especially in patients with localized disease.
The findings indicated that patients with ctDNA detected by tumour-informed assays had a higher risk of recurrence and death compared to those with non-tumour-informed assays.
While our results provide valuable insights, they must be interpreted with caution due to the diversity of ctDNA methodologies, patient populations, tumour characteristics, and timing of ctDNA evaluation in the included studies. Future research should focus on standardising ctDNA assessment methods and further exploring its potential to guide treatment strategies in BC.
Keywords: Circulating Tumour DNA, Breast Cancer Prognosis, ctDNA Detection, Disease-Free Survival, Overall Survival, Tumour-Informed Assays, Breast Cancer Recurrence
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