Highlights
The plasmaMATCH trial demonstrated that circulating tumor DNA (ctDNA) testing provides 93 percent sensitivity compared to contemporaneous tissue biopsies, enabling rapid and accurate genotyping for advanced breast cancer patients.
Targeted therapies for rare HER2 and AKT1 mutations showed clinically relevant activity, validating these as actionable targets when identified via liquid biopsy.
Low baseline ctDNA levels are strongly associated with improved progression-free survival (PFS) and higher objective response rates (ORR), particularly in triple-negative breast cancer (TNBC).
Undetectable ctDNA levels after just one cycle of treatment (C2D1) serve as a robust surrogate for treatment response, with an 86 percent ORR observed in patients who achieved ctDNA clearance.
Introduction: The Liquid Biopsy Revolution in Breast Cancer
The management of advanced breast cancer has long been hampered by the spatial and temporal heterogeneity of metastatic disease. While tissue biopsies remain the gold standard for diagnosis, they are invasive, often difficult to repeat, and may not fully capture the evolving genomic landscape of a patient’s cancer under the pressure of systemic therapy. The emergence of liquid biopsies, specifically the analysis of circulating tumor DNA (ctDNA), offers a minimally invasive alternative for genomic profiling. However, beyond simple mutation detection, the quantitative aspects of ctDNA—its baseline concentration and how it changes during treatment—have remained areas of intense investigation. The plasmaMATCH trial represents a landmark effort to not only validate the diagnostic utility of ctDNA but also to understand its prognostic and predictive power in the context of mutation-directed therapy.
Study Design: The plasmaMATCH Platform Trial
The plasmaMATCH trial (NCT03182634) was a multicentre, multicohort, phase 2a platform trial conducted across 18 hospitals in the United Kingdom. The trial was designed to evaluate the clinical validity of ctDNA testing and its ability to guide treatment in patients with histologically confirmed advanced breast cancer who had progressed after at least one line of prior therapy.
The study utilized a unique platform design where patients were screened via ctDNA testing and then assigned to one of five parallel treatment cohorts based on identified mutations:
Cohort A: ESR1 Mutations
Patients with ESR1 mutations were treated with high-dose intramuscular fulvestrant (500 mg).
Cohort B: HER2 Mutations
Patients with HER2 mutations received the pan-HER tyrosine kinase inhibitor neratinib. Estrogen receptor-positive patients in this cohort also received standard-dose fulvestrant.
Cohort C: AKT1 Mutations (ER+)
Patients with AKT1 mutations and ER-positive disease were treated with the AKT inhibitor capivasertib in combination with fulvestrant.
Cohort D: AKT1/PTEN Mutations (ER-)
Patients with AKT1 mutations and ER-negative disease or those with PTEN mutations received capivasertib monotherapy.
Cohort E: Triple-Negative Breast Cancer (TNBC)
This cohort explored the combination of the PARP inhibitor olaparib and the ATR inhibitor ceralasertib in patients with TNBC, regardless of specific mutation status, though dynamics were closely tracked.
The primary endpoint for each cohort was the confirmed objective response rate (ORR). Longitudinal blood samples were collected at baseline (Cycle 1 Day 1, C1D1) and before the start of the second cycle (Cycle 2 Day 1, C2D1) to assess ctDNA dynamics using error-corrected targeted sequencing panels (Guardant360 and GuardantOMNI).
Analytical and Clinical Validity of ctDNA Testing
The initial findings from the plasmaMATCH trial provided compelling evidence for the diagnostic accuracy of ctDNA. Among 1,034 patients with available results, the agreement between digital PCR (dPCR) and targeted sequencing was exceptionally high, ranging from 96 percent to 99 percent. When compared to tissue sequencing, ctDNA testing demonstrated an overall sensitivity of 93 percent, which rose to 98 percent when contemporaneous biopsies were used.
This high level of concordance suggests that ctDNA can effectively replace the need for repeat tissue biopsies in many clinical scenarios, offering a faster and less invasive route to identifying actionable mutations such as HER2 or AKT1. The rapid turnaround time of liquid biopsy is particularly beneficial for patients with late-stage disease who require timely treatment adjustments.
Therapeutic Impact: Outcomes of Mutation-Directed Therapy
The trial’s results regarding the efficacy of targeted therapies were mixed but largely positive for specific cohorts. Cohorts B (HER2) and C (AKT1/ER+) met their primary endpoints. In Cohort B, 25 percent of patients (5 of 20) achieved a confirmed response, while in Cohort C, 22 percent (4 of 18) responded. These findings validate HER2 and AKT1 mutations as viable therapeutic targets in breast cancer when identified through ctDNA.
Conversely, Cohorts A (ESR1) and D (AKT1/ER- or PTEN) did not meet their target response rates. In Cohort A, the ORR was only 8 percent, suggesting that while ESR1 mutations are common, high-dose fulvestrant monotherapy may not be sufficient to overcome resistance in all cases. In Cohort D, the ORR was 11 percent, indicating a need for more refined targeting or combination strategies for AKT/PTEN alterations in ER-negative settings.
The Prognostic Significance of Baseline ctDNA Levels
A critical secondary analysis of the plasmaMATCH data focused on the quantitative levels of ctDNA at baseline. Researchers found that baseline ctDNA levels were a significant prognostic factor. In Cohort E (TNBC), low baseline ctDNA levels were associated with a dramatically longer progression-free survival (HR 0.33; P = 0.001) and a significantly higher ORR (40 percent vs. 9.7 percent; P = 0.02).
In the combined targeted cohorts (A through D), a similar though slightly weaker trend was observed, with low baseline levels correlating with improved PFS (HR 0.60; P = 0.03). This association between baseline ctDNA and response was further validated in the independent PEARL study. These data suggest that high baseline ctDNA levels may reflect not just a higher tumor burden, but a more aggressive tumor biology or shared mechanisms of resistance that make the cancer less responsive to targeted interventions.
On-Treatment Dynamics: The Power of Early Clearance
Perhaps the most clinically transformative finding from the recent plasmaMATCH analysis is the impact of early ctDNA dynamics. By comparing ctDNA levels at C1D1 and C2D1 (after only one cycle of therapy), researchers could identify which patients were likely to benefit long-term.
In Cohorts A-D, the suppression of ctDNA below the median level by C2D1 was predictive of better outcomes (HR 0.47; P = 0.001). However, the most striking results were seen in patients who achieved complete ctDNA clearance (undetectable levels) at C2D1. In Cohort E, patients with undetectable ctDNA at C2D1 had a staggering ORR of 86 percent, compared to only 11 percent in those with detectable ctDNA (P = 0.01). The hazard ratio for PFS in this group was 0.25 (P = 0.01).
Interestingly, in Cohort E, six out of seven patients who achieved undetectable ctDNA were wild-type for BRCA1, BRCA2, and PALB2. This suggests that ctDNA dynamics can identify responders even in groups where traditional genomic markers might not predict success. Early clearance appears to be a robust, cross-therapy surrogate for clinical benefit.
Safety and Adverse Event Profile
The safety profiles varied across the different treatment cohorts, reflecting the diverse mechanisms of the drugs used. In Cohort A (fulvestrant), the most common grade 3-4 adverse event was an increase in gamma-glutamyltransferase (16 percent). In Cohort B (neratinib), diarrhea was the primary concern, with grade 3-4 events occurring in 25 percent of patients, despite the use of prophylactic anti-diarrheals.
Cohort C (capivasertib + fulvestrant) saw fatigue as a notable side effect (22 percent), and Cohort D (capivasertib monotherapy) reported rash in 26 percent of patients. There was one treatment-related death in Cohort C due to grade 4 dyspnoea. Overall, the toxicities were consistent with the known profiles of these agents, but they highlight the need for careful monitoring in a heavily pre-treated population.
Expert Commentary and Clinical Implications
The plasmaMATCH trial provides a blueprint for the future of precision oncology in breast cancer. The high sensitivity of ctDNA testing for actionable mutations supports its adoption into routine clinical practice for rapid genotyping. More importantly, the data on ctDNA dynamics offer a potential shift in how we evaluate treatment efficacy.
Traditionally, clinicians wait 2-3 months for the first radiological assessment (RECIST) to determine if a treatment is working. The plasmaMATCH data suggest that a blood test taken just three to four weeks into treatment could provide an earlier and perhaps more accurate signal of response. If a patient fails to show significant ctDNA suppression by the second cycle, it may indicate primary resistance, allowing for an earlier switch to alternative therapies and sparing the patient unnecessary toxicity.
However, some limitations remain. While ctDNA clearance is a strong positive predictor, the lack of clearance does not always mean treatment failure, and the thresholds for ‘significant suppression’ may vary by drug class and tumor subtype. Further prospective trials are needed to determine if changing therapy based solely on ctDNA dynamics improves overall survival.
Conclusion
The plasmaMATCH trial confirms that ctDNA is a powerful tool for both selecting and monitoring therapy in advanced breast cancer. Baseline ctDNA levels provide important prognostic context, while early on-treatment dynamics serve as a highly sensitive indicator of therapeutic response. As liquid biopsy technology continues to evolve, the integration of quantitative ctDNA monitoring into clinical workflows promises to refine our approach to personalized medicine, ensuring that the right patient receives the right treatment at the right time.
Funding and ClinicalTrials.gov
The plasmaMATCH trial was funded by Cancer Research UK, AstraZeneca, and Puma Biotechnology. The trial is registered with ClinicalTrials.gov (NCT03182634), the European Clinical Trials database (EudraCT2015-003735-36), and the ISRCTN registry (ISRCTN16945804).
References
1. Turner NC, Kingston B, Kilburn LS, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol. 2020;21(10):1296-1308. doi:10.1016/S1470-2045(20)30444-7
2. Browne IM, Pascual J, Cutts RJ, et al. The Prognostic and Predictive Impact of ctDNA Levels in Patients with Advanced Breast Cancer Enrolled on the plasmaMATCH Trial. Clin Cancer Res. 2026;32(1):148-158. doi:10.1158/1078-0432.CCR-24-0651
