Abstract PS06-02: Circulating tumor DNA (ctDNA) monitoring of estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) high risk breast cancer during adjuvant endocrine therapy

Abstract Background: ctDNA monitoring during adjuvant endocrine therapy provides an opportunity to detect molecular relapse before clinically apparent recurrence. The rate and dynamics of ctDNA positivity and the frequency of asymptomatic but imaging detectable metastatic disease at the time of ctDNA detection remain unknown in high-risk ER+/HER2- breast cancers. We present results of ctDNA positivity rates in 508 and imaging results in ctDNA+ patients from a prospective, multicenter, randomized ctDNA surveillance and intervention trial, DARE (NCT04567420). Patients and methods: Patients receiving adjuvant endocrine therapy for > 6 months but < 7 years, with either (i) risk of recurrence > 15% calculated by PREDICT, RSPC, or CTS5, or (ii) > 4 positive axillary lymph nodes, or (iii) primary tumor > 5 cm, or (iv) 1-3 positive nodes with grade 3 histology, or > 3 cm tumor, or Oncotype Dx RS > 26, MammaPrint high risk, EndoPredict > 4, Prosigna score > 60 were eligible for ctDNA surveillance with the SignateraTM assay (Natera Inc.) every 4-6 months during routine follow up visits. ctDNA+ patients underwent systemic staging with imaging and randomized to continuation of adjuvant therapy versus switching to fulvestrant plus palbociclib if there was no evidence of distant metastatic disease. The primary objectives are to assess the incidence of ctDNA positivity in the surveillance phase and to assess if palbociclib plus fulvestrant improves relapse-free survival in 100 randomized patients. This is an updated, protocol-driven interim report to determine if screening eligibility criteria needs to be revised to keep randomization rate > 15% of the screened population. Results: The trial is open at 15 sites and enrolled 508 patients between May 2021 and June 2023; 882 plasma ctDNA tests were performed successfully in 364 patients (72%). The most common reason for failure to generate a personalized ctDNA assay was insufficient tissue submitted, 78% of failed tests were due to preanalytical failure, the technical failure rate was 22%. Thirty patients, 8.2% of those with results available, had >1 positive ctDNA result, the overall positivity rate across all assays was 3.4% (n=30/882). Patient characteristics are shown in the table (not all patients have complete data), 47% of ctDNA+ cases had >4 + lymph nodes. ctDNA positivity rate in the first test was 3.8%, and anytime ctDNA detection rate among those with serial testing was 7.2%. Among ctDNA+ patients, the first ctDNA draw was positive in 23 of 30 cases (77%) with 36.5 months median time (range 6-102 months) from surgery to testing. Using 12 months interval brackets from surgery to 1st ctDNA positivity, annual detection rates were 2,3% (1/44), 8.5% (7/82), 10.8% (9/83), 7.5% (4/53), 13,2% (5/38), and 6.2% (4/64), at 1st, 2nd, 3rd, 4th and > 5th year post-surgery, respectively, due to small sample sizes, 95% confidence broadly overlap. Five ctDNA+ patients (16.7%) had asymptomatic, imaging-detectable metastatic disease, 22 ctDNA+ patients were randomized, the goal is to accrue a total of 100 patients. Conclusions: ctDNA surveillance of ER+/HER2- breast cancers during adjuvant endocrine therapy indicate 8.3% detection rate at patient level and 3.4% at assay level. Serial screening increases detection rates as 23% of positive ctDNA tests occurred after an initial negative result. 83% of ctDNA+ patients had true molecular relapse without imaging detectable metastatic disease. Eligibility for screening on the trial is now restricted to patients with >4 + lymph nodes, randomization is open for any patients who are ctDNA+ including routine commercial screening. Table of patient characteristics with ctDNA result (n=364) ctDNA+ (n=30) Age < 50 29% 23% Age >50 71% 77% PR + 78% 73% PR - 7% 17% HER2 IHC negative 79% 77% Grade 1 8% 7% Grade 2 53% 50% Grade 3 29% 37% T 1 19% 17% T2 43% 43% T3 27% 27% T4 2% 7% 0 +nodes 12% 12% 1 +node 24% 10% 2 +nodes 15% 13% 3 +nodes 8% 13% >4 +nodes 0 47% Citation Format: Lajos Pusztai, Ekaterina Kalashnikova, Evthokia Hobbs, Ursa Brown-Glaberman, Monica Mita, Paula Klein, Fengting Yan, Sima Ehsani, Wajeeha Razaq, Alison Stopeck, Manali Bhave, Michelle Loch, Sagar Sardesai, Evanthia Roussos Torres, Mark Burkard, Femi Okubanjo, Eric Gauthier, Angel Rodriguez, Minetta Liu, Peter Kabos. Circulating tumor DNA (ctDNA) monitoring of estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) high risk breast cancer during adjuvant endocrine therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS06-02.