Editor's Note: Circulating tumor DNA (ctDNA) is a novel liquid biopsy method that detects tumor-specific DNA mutations in the blood of breast cancer patients, helping to identify high-risk patients prone to recurrence and metastasis. Its prognostic value has been confirmed in multiple studies. At the 2024 ASCO conference, a study (Abstract LBA507) further analyzed the MonarchE study population, confirming that ctDNA testing has predictive value for recurrence risk in HR+/HER2-, lymph node-positive high-risk early-stage breast cancer patients. Oncology Frontier invited Professor Qiang Liu from Sun Yat-sen Memorial Hospital, Sun Yat-sen University  to provide an introduction and commentary.

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Oncology Frontier: Could you share the prognostic value of ctDNA for HR+/HER2-, lymph node-positive high-risk early-stage breast cancer in the MonarchE study?

Professor Qiang Liu: On June 3rd, 2024, the ASCO conference presented data from study LBA507. This study analyzed the prognostic value of ctDNA testing and dynamics in the adjuvant treatment of HR+/HER2-, lymph node-positive high-risk early-stage breast cancer within the MonarchE study. The 5-year results of the MonarchE study were released at the 2023 ESMO conference, showing that patients receiving abemaciclib combined with endocrine therapy (abemaciclib + ET group) had a 5-year IDFS (invasive disease-free survival) rate with an absolute benefit of 7.6% compared to endocrine therapy alone, with a relative risk reduction of 32% in IDFS events (83.6% vs. 76.6%, HR 0.680, 95% CI: 0.599-0.772).

Currently, CDK4/6 inhibitors for high-risk early-stage HR+/HER2- breast cancer patients have become standard for intensified adjuvant treatment. Despite the MonarchE study showing a 7.6% absolute benefit in 5-year IDFS, a significant portion of patients still do not see improved survival. Differentiating truly high-risk patients remains a clinical and research challenge. In this context, LBA507 analyzed samples from a selected patient subgroup in the MonarchE study (n=1397; abemaciclib + ET group, n=685; ET group, n=712). Blood samples were collected before the study treatment (baseline) and at 3, 6, or 24 months post-treatment, using personalized, tumor-informed Signatera ctDNA testing (Natera, Inc), with whole-exome sequencing (WES) performed on matched primary tumor and normal tissue.

Among the 1397 patients, 65% (n=910) had sufficient plasma samples for ctDNA testing and tumor tissue WES (ctDNA cohort). The IDFS event rate in the MonarchE ITT population was 18%, while the ctDNA cohort, enriched for those with IDFS events, had a 27% IDFS event rate (23% in the abemaciclib + ET group [101/438]; 31% in the ET group [146/472]).

In the ctDNA cohort of 910 patients, 83% (758 patients) had consistently negative ctDNA results during the study, with only 15% experiencing IDFS events. Conversely, 87% of patients with positive ctDNA experienced IDFS events. This indicates that ctDNA can identify high-risk patients.

At baseline, 70 patients (7.7%) had positive ctDNA, with 56 of these patients (80%) experiencing IDFS events. Among 34 patients with consistently positive ctDNA, all experienced IDFS events, while 10 out of 24 patients (42%) with converted negative ctDNA still experienced IDFS events. This suggests that even if ctDNA converts from positive to negative, vigilance is still required. Further analysis showed that 82 patients with negative baseline ctDNA who turned positive during treatment had a 93% IDFS event rate. Detecting ctDNA at any point during the 24-month study period indicated poor prognosis.

Minimal Residual Disease (MRD) typically refers to the presence of residual tumor cells after effective treatment, undetectable by conventional imaging tools (CT, MRI, PET-CT), but detectable through molecular techniques like ctDNA. Positive ctDNA indicates ongoing or recurring tumor presence. The average time from positive ctDNA detection to clinical imaging-detected metastasis is 9-19 months, suggesting a window for more aggressive and effective treatment to prevent recurrence.

The retrospective analysis of study LBA507 indicates that:

1. ctDNA testing can significantly identify patients with truly high recurrence risk.
2. Positive or persistently positive ctDNA results indicate ineffective current treatment and the need for timely regimen changes. For HR+/HER2- patients, due to slower tumor progression, we have more time for intensified, individualized treatment to improve outcomes.

Overall, LBA507 is the largest ctDNA testing study conducted on HR+/HER2- breast cancer patients, systematically revealing that ctDNA status can reflect individual tumor recurrence risk to some extent. I believe that as ctDNA testing costs decrease and processes standardize, its clinical application will become more widespread, helping us provide more precise and personalized treatment options for patients.