The Launch of the DARE Study in ER+/HER2– High-Risk Breast Cancer

Dr Pusztai on the Launch of the DARE Study in ER+/HER2– High-Risk Breast Cancer

Lajos Pusztai, MD, DPhil, professor of medicine, Medical Oncology, co-leader, Genetics, Genomics and Epigenetics, Yale Cancer Center, discusses the phase 2 DARE trial (NCT04567420) evaluating circulating tumor DNA (ctDNA)-guided second-line adjuvant therapy for patients with high-risk, stage II-III, estrogen receptor (ER)-positive, HER2-negative breast cancer, highlighting the importance of researching ctDNA utility in this patient population.

, investigators presented data on the use of ctDNA detection as an indicator of disease relapse. Pusztai begins by noting that the DARE study utilizing ctDNA monitoring is likely the most extensive trial of its kind. During the screening phase of the DARE trial, 542 patients were enrolled, with over 1120 ctDNA assays conducted. The median surveillance period was approximately 2 years. Out of these assays, 37 showed ctDNA-positive results, indicating a 3.3% assay positivity rate and an 8.9% positivity rate at the patient level, Pusztai explains, adding that these outcomes aligned with expectations given the rarity of recurrences and the high sensitivity and specificity of the assays. 

The ctDNA assays work by identifying relapses before clinical manifestation, Pusztai expands. Of the 37 patients with ctDNA positivity, 47% had more than 4 positive nodes, and 47% exhibited grade 3 disease or higher. Additionally, 31% of patients had T3 disease or larger and 10 patients had metastatic disease (27%), while the rest did not. Notably, earlier ctDNA studies used archived blood without concurrent imaging to show ctDNA positivity, but this trial revealed that a majority of patients in who tested ctDNA positive were imaging negative, indicating a state of minimal residual disease or molecular relapse, Pusztai emphasizes.

This research is important because of its potential implications on clinical practice, he continues. Pusztai explains that if results from the trial show that implementing this tool early and using it to guide therapy only introduces additional inconvenience and cost without enhancing recurrence-free survival, the tool may be valuable but lack meaningful clinical relevance. Conversely, a positive study outcome, ideally confirmed by independent trials, could be beneficial to the treatment paradigm, he adds. Successfully avoiding subsequent recurrence by introducing a second-line adjuvant treatment, potentially with modern endocrine regimens, would reshape treatment approaches, Pusztai states.

The DARE trial serves as an exploratory step, signaling the need for a large, definitive randomized trial with registrational intent in the future. These initial studies represent a foundational phase in uncovering the clinical utility of ctDNA monitoring, Pusztai concludes.

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Lajos Pusztai, MD, DPhil, discusses the phase 2 DARE trial evaluating circulating tumor DNA-guided second-line adjuvant therapy for patients with high-risk, stage II-III, estrogen receptor-positive, HER2-negative breast cancer, highlighting the importance of researching ctDNA utility in this patient population.


Dr Graff on the Relation Between ctDNA Positivity and Disease Recurrence in HR+/HER2– Breast Cancer

Stephanie L. Graff, MD, director, breast oncology, Lifespan Cancer Institute, assistant professor of medicine, Warren Alpert Medical School, co-leader, Breast Cancer Translational Research Disease Group, Brown University’s Legorreta Cancer Center, discusses findings from a pilot study exploring the association between disease recurrence and circulating tumor DNA (ctDNA) positivity in patients with hormone receptor (HR)–positive, HER2-negative, node-positive, high-risk, early breast cancer who have received adjuvant treatment of abemaciclib (Verzenio) and endocrine therapy.

This pilot study aimed to assess the technical feasibility of ctDNA detection using the Signatera™ assay in a subset of patients from the phase 3 monarchE trial (NCT03155997). The study analyzed samples from 178 patients, 84 of whom had been treated with abemaciclib and endocrine therapy, Graff begins. Although the study was enriched for invasive disease-free survival (IDFS) events, patients who experienced an IDFS event within the 2-year treatment window were ineligible for enrollment, she explains. Patients who received adjuvant chemotherapy and began endocrine therapy prior to randomization were included on the study. 

Primary tumors from these patients underwent whole exome sequencing, providing a comprehensive genomic profile. The Signatera ctDNA assay was developed for each patient based on up to 16 variants detected by whole exome sequencing from the baseline tumor sample, Gradd states. The ctDNA detection aimed to assess the presence and clearance of ctDNA during and after treatment.

 elucidated disease recurrence dynamics, she continues. Among the 10 patients who were ctDNA-positive at baseline, 42 became positive at 24 months, and all patients experienced disease recurrence. Three of the 108 patients who did not experience disease recurrence were ctDNA-positive at baseline. Persistence of ctDNA positivity from baseline to 24 months was observed in 7 patients, with a median duration of 27 months (range, 25-43) from baseline to recurrence, Graff elucidates.

Additionally, 35 patients became ctDNA-positive at 24 months, all of whom experienced an IDFS event after a median of 5 months prior to disease recurrence. The median duration of ctDNA detection at baseline to disease recurrence was 3 months (range, 1-19) in patients who remained ctDNA positive at 24 months, she expands

Overall, results from this study validated the feasibility of the Signatera assay, and potential prognostic significance of ctDNA detection in patients with HR–positive, HER2-negative breast cancer in the adjuvant setting. This pilot study is integral for understanding the technical aspects and utility of ctDNA detection as a potential biomarker for monitoring treatment response and disease recurrence in patients with high-risk early breast, receiving adjuvant abemaciclib and endocrine therapy. Results from the analysis may contribute to ongoing precision medicine efforts in breast cancer and improve long-term outcomes through innovative approaches like ctDNA monitoring.

Stephanie L. Graff, MD,  discusses findings from a pilot study exploring the association between disease recurrence and circulating tumor DNA  positivity in patients with hormone receptor–positive, HER2-negative, node-positive, high-risk, early breast cancer who have received adjuvant treatment of abemaciclib and endocrine therapy.
 

Detection of circulating tumor DNA (ctDNA) with the Signatera

 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 

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.

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, 

 < .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, 

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%).

 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.

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.

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. 

. 2023;24(1):P77-90. doi:10.1016/S1470-2045(22)00694-5

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. 

. 2023;34(S2):S1255-S1256. doi:10.1016/j.annonc.2023.10.007

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Detection of circulating tumor DNA with the Signatera assay was associated with disease recurrence in patients with hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer at 24 months post-randomization to treatment with adjuvant abemaciclib and endocrine therapy.

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