Table 4 Prospective interventional clinical trials using ctDNA MRD monitoring randomizing patients to escalate treatment after curative surgery

From: Use of ctDNA in early breast cancer: analytical validity and clinical potential

Clinical trial identification number and name

Key inclusion and patients enrolled or planned

ctDNA assay used and frequency of ctDNA analysis during the screening period

Treatment escalation in ctDNA-positive patients without metastatic disease on imaging

Key outcomes

Status and results published (if present)

NCT03145961, c-TRAK TN89

N = 161 enrolled

High-risk resected TNBC

Tumor-informed

ddPCR

Randomization 2:1 to pembrolizumab or observation (protocol amendment closed the observation group)

Co-primary endpoints

• ctDNA detection rate

• Sustained ctDNA clearance rate on pembrolizumab

Completed

Detect recurrence

• Specificity 99.8%

• Sensitivity not reported. 7 patients relapsed without ctDNA detection

• High proportion of ctDNA-positive patients had metastatic disease on imaging

• High rate of treatment refusal

• None cleared ctDNA on pembrolizumab

NCT04915755, ZEST trial98,117

N = 800 (planned)

Stage I–III HR + /HER2- gBRCA or TNBC after curative treatment

Tumor-informed

SignateraTM

Frequency of ctDNA analysis is different depending on the time elapsed since surgery

Randomization 1:1 to niraparib or placebo (in two cohorts depending if gBRCA or wtBRCA)

Primary outcomes related to treatment tolerance

Terminated by the sponsor

• Higher than expected ctDNA-positive patients had metastatic disease on imaging

NCT04567420, DARE118,119

N = up to 1000 (expected)

Stage II-III High-risk ER+ ( ≥ 10%) /HER2- on standard adjuvant ET

Tumor-informed

SignateraTM

Testing during routine clinical visits (recommended every 4–6 months)

Randomization to palbociclib-fulvestrant or standard adjuvant endocrine therapy

Co-primary endpoints

• Incidence of ctDNA detection

• Effect of Palbociclib plus fulvestrant on RFS

Recruiting,

• Update (2023) N = 542 enrolled screening period

• 37 ctDNA-positive

• 10 with metastatic disease on imaging

• 22 randomized

NCT03285412, LEADER part II120,121

N = 120 (expected)

T1c-T4c, any N, ER+ ( ≥ 10%) /HER2- on adjuvant ET

Tumor-informed

SignateraTM

No information on the timing of ctDNA testing

Randomization to ribociclib and ET or standard adjuvant ET

• Rate of ctDNA clearance

• DFS

Recruiting

• Update (2023) N = 191 enrolled screening period

• 17 ctDNA-positive

• 4 with metastatic disease on imaging

• 12 randomized

NCT04985266, TRAK-ER122

N = 1100 (expected)

High-risk ER+ ( ≥ 10%) /HER2- on standard adjuvant endocrine therapy

Tumor-informed

RaDaRTM

Every 3 months for up to 3 years

Randomization to palbociclib-fulvestrant or standard adjuvant ET

• Incidence of positive ctDNA result during surveillance

• Effect of Palbociclib plus fulvestrant on RFS

Recruiting

NCT05512364, TREAT-ctDNA Elacestrant123

N = 220 (expected)

High-risk ER+ ( ≥ 10%) /HER2- on standard adjuvant endocrine therapy

Tumor-informed

RaDaRTM

ctDNA tested at multiple timepoints

Randomization to elacestrant or standard adjuvant ET

• Effect of elacestrant on DMFS

• ctDNA elimination rate at month 1

Recruiting

  1. ctDNA circulating tumor DNA, ddPCR digital drop polymerase chain reaction, DFS disease-free survival, DMFS distant metastasis free survival, ER + estrogen receptor-positive, ET endocrine therapy, gBRCA germline pathogenic BRCA mutation, HER2 human epidermal growth factor receptor 2, N number of patients, NGS next-generation sequencing, RFS relapse-free survival, TNBC triple-negative breast cancer, VAF variant allele frequency, wtBRCA absence of germline pathogenic BRCA mutation.
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