Persistent ctDNA Correlates With Disease Recurrence in HR+/HER2– Early Breast Cancer

Detection of circulating tumor DNA (ctDNA) with the Signatera^TM assay was associated with disease recurrence in patients with hormone receptor (HR)–positive, HER2-negative, node-positive, high-risk early breast cancer at 24 months post-randomization to treatment with adjuvant abemaciclib (Verzenio) and endocrine therapy, according to an analysis of data from the phase 3 monarchE trial (NCT03155997) presented at the 2023 San Antonio Breast Cancer Symposium.¹

Using existing whole exome sequencing (WES), researchers looked at 178 patient samples from the monarchE trial who were treated with abemaciclib and had invasive disease-free survival (IDFS) from either 0 or 24 months of treatment. Using the WES data, up to 16 genetic variants were selected for each patient with recurrence events seen in patients positive for somatic mutations or oncogenic mutations.

At baseline of the pilot subset, 10 patients were ctDNA positive, with that number growing to 42 patients at 24 months–all having disease recurrence. Of the 108 patients without disease recurrence, 3 were ctDNA positive at baseline. Looking at the patients who were ctDNA positive at baseline, 7 remained ctDNA positive at 24 months with a median duration of ctDNA detection at baseline to disease recurrence of 27 months (range, 25-43). For patients found to still be ctDNA positive from baseline to 24 months, median duration of ctDNA detection at baseline to disease recurrence was 3 months (range, 1-19) from the 2-year mark.

Of the 35 patients who became ctDNA positive at 24 months, all had an IDFS event, which occurred after a median of 5 months (range, 0-25) before disease recurrence in this group. Further, of the 133 patients who were persistently ctDNA negative at 0 and 24 months, 28 had disease recurrence, which according to the researchers, presents an opportunity to improve ctDNA detection with more frequent testing and timing in terms of drawing samples to active therapy. Patterns who experienced recurrence also appeared in the 24- to 36-month range after treatment overall, with many ctDNA positive patients recurring in the 0- to 12-month range. These data confirmed the technical feasibility of the Signatera assay in this population, according to the researchers.

“This pilot subset was enriched for IDFS events compared to the total monarchE population, but excluded patients who experienced an IDFS event within the 2-year treatment,” explained Stephanie L. Graff, MD, an oncologist at the Legorreta Cancer Center at Brown University, Lifespan Cancer Institute, during a presentation of the data. “All [of the patients] had received adjuvant chemotherapy and began endocrine therapy prior to randomization.”

The open-label, randomized, phase 3 monarchE trial found that adjuvant abemaciclib with endocrine therapy reduced the risk of patient’s disease recurrence and the benefit was sustained at 4 years of follow-up in an interim analysis.²

At the median follow-up of 42 months (interquartile range, 37-47) median IDFS was not reached in either the combination or endocrine therapy alone group, but the previous IDFS benefit was sustained (hazard ratio [HR], 0.66; 95% CI, 0.58-0.76, P < .0001). At 4 years an absolute difference of 6.4% was seen between these groups with an IDFS rate of 85.8% (95% CI, 84.2%-87.3%) in the abemaciclib plus endocrine therapy group compared with 79.4% (95% CI, 77.5%-81.1%). In the combination arm, 157 patients of the 2808 patients who received abemaciclib and endocrine therapy died vs 173 patients of the 2829 patients given just endocrine therapy (HR 0.93; 95% CI, 0.75-1.15, P = 0.50).²

At 5 years, the IDFS benefit was still sustained in an intent-to-treat population reducing the risk of invasive disease by 32% (HR, 0.68; 95% CI, 0.599-0.772) and a 5-year IDFS rate of 83.6% in the combination group compared with 76.0% with endocrine therapy alone.3 Distant relapse-free survival (DRFS) was also maintained at 5 years, reducing risk for DRFS by 32.5% (HR, 0.675; 95% CI, 0.588-0.774), with a 5-year DRFS rate of 86.0% vs 79.2%, respectively, found between the study arms.

The trial consisted of patients with hormone receptor-positive, HER2-negative, node-positive, early breast cancer who were at high-risk of disease recurrence with an ECOG performance status of 1. Patients were randomized 1:1 to receive either physician’s choice standard-of-care endocrine therapy alone or combined with 150 mg of abemaciclib given orally twice a day for 2 years.

Findings from this initial study showed that the most common grade 3 to 4 adverse events were neutropenia (19.6%), leukopenia (11.4%), and diarrhea (7.8%).² Serious AEs occurred in 15.5% of patients on the combination therapy compared with 9.1% who just received endocrine therapy, and there were 2 treatment-related deaths in the study arm.

“A future planned analysis of an expanded cohort, reflective of the intention-to-treat population and including additional time points within the 2-year treatment period, will further define how ctDNA dynamics may identify patients at high risk of recurrence,” Graff said.¹

References

1. Loi S, Johnston S, Arteaga C, et al. Results from a pilot study exploring ctDNA detection using a tumor-informed assay in the monarchE trial of adjuvant abemaciclib with endocrine therapy in HR+, HER2-, node-positive, high-risk early breast cancer. Presented at the 2023 San Antonio Breast Cancer Symposium; San Antonio, TX; December 5-8, 2023. PS06-01.
2. Johnston S, Toi M, O’Shaughnessy J, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncl. 2023;24(1):P77-90. doi:10.1016/S1470-2045(22)00694-5
3. Harbeck N, Rastogi P, O’Shaughnessy J, et al. Adjuvant abemaciclib plus endocrine therapy for HR+, HER2-, high-risk early breast cancer: Results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes. Ann Onc. 2023;34(S2):S1255-S1256. doi:10.1016/j.annonc.2023.10.007