Blood Test for Tumour DNA Predicts Survival in Advanced Breast Cancer, Major Analysis Finds

A simple blood draw may soon help oncologists peer into the future of patients with advanced breast cancer, according to one of the most comprehensive syntheses of the evidence to date. A team of Danish researchers led by Cæcilie Ottosen and Ea Kragelund of Aarhus University Hospital has completed a systematic review and meta-analysis of 64 studies involving thousands of patients, and the verdict is striking: elevated levels of circulating tumour DNA, or ctDNA, in the bloodstream are consistently associated with shorter progression-free survival and overall survival in advanced breast cancer. The findings, published in Breast Cancer Research and Treatment, provide the strongest quantitative support yet for what many oncologists have long suspected — that fragments of tumour DNA drifting freely in plasma carry real prognostic weight, and that tracking them over time could fundamentally change how treatment decisions are made in metastatic disease.

Circulating tumour DNA is exactly what its name suggests: genetic material shed by tumour cells into the bloodstream as cancer cells die and release their contents. Unlike a traditional tissue biopsy, which captures only a single snapshot of a single tumour site, ctDNA offers a minimally invasive, real-time window into the entire tumour burden across the body. Because it can be sampled repeatedly from a simple vial of blood, it has the theoretical potential to reveal whether a treatment is working long before changes become visible on a CT scan or PET image. That matters enormously in advanced breast cancer, where treatment strategies are evolving rapidly but where decisions about when to switch therapies still rest largely on imaging-based assessments such as the RECIST criteria, which measure tumour size on radiographic scans.

To establish whether ctDNA truly delivers on this promise, the Aarhus team conducted a rigorous search of the Medline, Embase and Cochrane databases covering studies published up to February 2025. They registered the review prospectively in PROSPERO and evaluated the quality of each included study using the Quality in Prognosis Studies tool, a standard instrument designed to guard against bias in prognostic research. From the eligible literature, they extracted hazard ratios — statistical measures that describe how much a biomarker changes the risk of an event such as disease progression or death — along with their 95 percent confidence intervals, and then pooled the results using random-effects models, which account for variability between studies.

The headline numbers are compelling. Across studies encompassing 2,586 patients, elevated ctDNA levels measured at the start of treatment were associated with roughly a doubling of the risk of disease progression, with a pooled hazard ratio of 2.0 for progression-free survival. For overall survival, the association was even stronger: among 2,454 patients, high baseline ctDNA carried a pooled hazard ratio of 2.6, meaning those patients faced more than two and a half times the risk of death compared with patients whose baseline ctDNA was low. In practical terms, a patient walking into the clinic with abundant tumour DNA in her plasma is statistically likely to fare worse than a patient with barely detectable levels, regardless of the treatment she ultimately receives.

Perhaps even more clinically meaningful is what happens to ctDNA during therapy. The meta-analysis found that unfavourable changes in ctDNA levels over the course of treatment — rising concentrations, or a failure to clear the biomarker once therapy begins — were associated with reduced progression-free survival, with a pooled hazard ratio of 2.5 across 710 patients, and reduced overall survival, with a pooled hazard ratio of 2.4 across 154 patients. This dynamic dimension is where ctDNA distinguishes itself from static prognostic markers. A single measurement tells you something about tumour burden; a series of measurements tells you whether the tumour is responding to the drug in real time. In the era of targeted therapies such as CDK4/6 inhibitors and PI3K inhibitors, where treatment sequences are complex and expensive, an early molecular signal of failure could spare patients months of ineffective therapy and its side effects.

The review also examined whether specific genetic alterations detected in ctDNA carry prognostic information of their own. The answer, broadly, is yes — but with caveats. Mutations in genes such as ESR1, the oestrogen receptor gene that frequently evolves resistance to endocrine therapy, and PIK3CA and TP53, both central players in breast cancer biology, were generally associated with less favourable outcomes when detected at baseline. Studies tracking ESR1 mutations in patients treated with fulvestrant and CDK4/6 inhibitors, for example, have repeatedly shown that the emergence of these mutations in plasma heralds clinical progression. However, the authors note that results across the literature were not entirely consistent, reflecting differences in assay methods, patient populations, treatment contexts and the specific variants analysed. The heterogeneity is a reminder that ctDNA is not a single test but a family of technologies, ranging from digital droplet PCR, which hunts for known mutations with exquisite sensitivity, to whole-exome and whole-genome sequencing, which survey the tumour genome more broadly.

Methodologically, the Danish analysis stands out for its scale and discipline. Sixty-four studies is a large evidence base for a prognostic biomarker review, and the use of the QUIPS tool for quality assessment, together with random-effects meta-analysis and formal measures of statistical heterogeneity, follows the highest standards in the field, including the PRISMA 2020 reporting guidelines. The authors also situate their work within a rapidly moving landscape: clinical guidelines from the American Society of Clinical Oncology now recommend testing for ESR1 mutations to guide therapy in hormone receptor-positive metastatic disease, and proposals for ctDNA-based response criteria — sometimes dubbed ctDNA-RECIST — are actively being developed to complement, and perhaps eventually rival, traditional imaging endpoints.

Still, the researchers are careful about what their findings do and do not establish. A strong prognostic association — showing that ctDNA levels predict outcomes — is not the same as demonstrated clinical utility, meaning proof that acting on the biomarker actually improves patients’ lives. That distinction, long emphasised in the biomarker literature, requires prospective interventional trials in which treatment decisions are randomised based on ctDNA results. The review also highlights gaps in the evidence: overall survival data for dynamic ctDNA changes rest on relatively few patients, subgroup analyses by breast cancer subtype were limited by inconsistent reporting, and the field lacks standardisation in how ctDNA is quantified and what thresholds define ‘elevated’ or ‘unfavourable’ change. Until those issues are resolved, ctDNA remains a powerful prognostic signal rather than a validated decision-making tool for every patient.

Even so, the trajectory is unmistakable. The pooled effect sizes reported here — hazard ratios of 2.0 to 2.6 across thousands of patients — place ctDNA among the most robust prognostic biomarkers described in advanced breast cancer. Combined with the growing arsenal of therapies that can be matched to specific mutations found in plasma, the technology points toward a future in which a blood test drawn at diagnosis and repeated throughout treatment provides oncologists with a continuous, molecular readout of the disease. For patients with advanced breast cancer, whose options depend on catching treatment failure early, that future cannot come soon enough. The Danish team’s synthesis does not close the chapter on ctDNA, but it firmly establishes the scientific foundation on which the next generation of trials — and, ultimately, clinical practice — will be built.

Subject of Research: Prognostic value of circulating tumour DNA in advanced breast cancer

Article Title: Circulating tumour DNA and its clinical relevance in predicting progression-free survival and overall survival in patients with advanced breast cancer: a systematic review and meta-analysis

Article References: Circulating tumour DNA and its clinical relevance in predicting progression-free survival and overall survival in patients with advanced breast cancer: a systematic review and meta-analysis. (n.d.). https://doi.org/10.1007/s10549-026-08087-0

Image Credits: AI Generated

DOI: 10.1007/s10549-026-08087-0

Keywords: ctDNA, advanced breast cancer, liquid biopsy, progression-free survival, overall survival, meta-analysis, biomarkers, ESR1 mutations, systematic review, prognosis, precision oncology, treatment monitoring