Circulating tumor (ct)DNA monitoring of ER+/HER2- high-risk breast cancer during adjuvant endocrine therapy.
Lajos Pusztai, Carly Bess Scalise, Ekaterina Kalashnikova, Ursa Brown Glaberman, Sima Ehsani, Alison Stopeck, Manali Bhave, Alexandra Dos Santos Zimmer, Evanthia T. Roussos Torres, Paula Klein, Sagar Sardesai, Fengting Yan, Marina N. Sharifi, Peter Kabos, Wajeeha Razaq, Michelle Marie Loch, Angel Rodriguez, Minetta C. Liu
Abstract
1010 Background: ctDNA monitoring during adjuvant endocrine therapy is an opportunity to detect molecular relapse before clinically apparent recurrence. ctDNA positivity rates, dynamics and the frequency of asymptomatic imaging-detectable metastatic disease at the time of ctDNA detection remain unknown in high-risk ER+/HER2- BCs. We present ctDNA results from a prospective, multicenter, randomized ctDNA interventional trial, DARE (NCT04567420). Methods: Patients receiving adjuvant endocrine therapy for >6 months but <7 years, with either recurrence risk >15% (PREDICT, RSPC, CTS5), >4 positive axillary lymph nodes, (primary tumor >5 cm, or 1-3 positive nodes with grade 3 histology, or >3 cm tumor, or high molecular risk (Oncotype Dx RS >26, MammaPrint high risk, EndoPredict >4, Prosigna score >60) were eligible for ctDNA surveillance with the Signatera assay (Natera, Inc.) every 6 months. ctDNA+ patients had systemic staging with imaging and if there was no evidence of metastatic disease patients were randomized to switching to fulvestrant + palbociclib (Arm A) or to continuation of adjuvant therapy (Arm B). Negative predictive value (NPV) was calculated for recurrence in the screening group after each ctDNA- test. In randomized patients, early ctDNA dynamics were correlated with recurrence-free survival (RFS) and ctDNA clearance rates were calculated by trial arm. Results: 552 patients had tissue sent for assay design; 494 had ctDNA results; 52 failed WES and/or had incomplete tumor/normal/blood sets; 6 had pending reports. Among patients not randomized, 432 were ctDNA-, of these N=43 had one time point and 389 had >2 ctDNA- result, overall median screening time 27.4 months (0-45.5), 4 ctDNA- patients had recurrence (NPV 100% at 6 months and 99% at 12 months post-testing). Forty patients were randomized, 34 had post-randomization ctDNA result. Randomization rates were 53% and 76% for patients who tested ctDNA-positive on the first screening (N=19) versus those who turned positive in follow up testing (N=15). At any time post-randomization, ctDNA clearance rates were 63% (10/16) in Arm A and 22% (4/18) in Arm B. Among randomized patients, 6 of 9 patients with increased ctDNA levels from the pre-randomization to the 3-month on-treatment recurred (median time to recurrence 4.8 months, range: 3.3-24.3), among those with a decrease in ctDNA post-treatment only 1 of 6 experienced recurrence at 10.3 months (HR: 5.3, 95% CI: 1.1-53, p=0.04). Conclusions: This study demonstrates the ability of ctDNA to identify breast cancer patients at high risk of relapse for randomization in a prospective, multicenter, randomized clinical trial. Patients with serially ctDNA- results during surveillance had 99% RFS after a median f/u of 27.4 months. Interim analysis revealed higher clearance rates in Arm A compared to patients randomized to Arm B. Early on treatment ctDNA dynamics is prognostic of patient outcomes. Clinical trial information: NCT04567420 .