Title
A Randomized, Phase II Trial of Circulating Tumor DNA-Guided Second Line Adjuvant Therapy for High Residual Risk, Stage II-III, Estrogen Receptor Positive, HER2 Negative Breast Cancer (DARE)

Description
Surveillance population and ctDNA screening (up to 1000 patients): Clinically high risk, stage II-III, ER positive, HER2-, breast cancer patients who are currently receiving adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen are eligible for ctDNA screening if they meet any one of the following criteria for high risk for recurrence: (i) predicted risk of distant recurrence or death equal to or greater than 15% calculated by PREDICT, RSPC, or CTS5 (for late recurrence), (ii) four or more positive axillary lymph nodes or ipsilateral supraclavicular involvement regardless of tumor size, (iii) primary tumor equal to or greater than 5 centimeters regardless of nodal status, (iv) patients with 1-3 positive nodes, regardless of tumor size are eligible if at least one of the following is also true: grade 3 histology, greater than or equal to 3 cm tumor size, high molecular risk score (i.e. Oncotype Dx Recurrence score(RS) > 26, MammaPrint high risk, EndoPredict > 4, Prosigna score > 60).
In order to start ctDNA surveillance, patients must be currently receiving endocrine therapy and have completed at least 6 months, but no more than 7 years and with at least 3 more years of planned adjuvant endocrine therapy of treatment without distant recurrence. Prior adjuvant CDK4/6 therapy is allowed, but at least 12 months must have elapsed since completing CDK4/6 therapy and enrolling into ctDNA surveillance on this study. However, participants in the PENELOPE and PALLAS clinical trials are not eligible.
For screening, patients will undergo Signatera testing during routine follow up clinic visits. The current ASCO/NCCN breast cancer practice guidelines recommend follow up visits every 4 to 6 months at the treating physician's discretion. The investigators anticipate that screening positivity rates will be the highest in patients between years 1-5 after initial diagnosis, based on the annual hazard rates of recurrence in ER positive breast cancer. However, since up to 50% of all recurrences occur after 5 years of follow-up, the investigators allow starting ctDNA screening up to 7 years after starting adjuvant endocrine therapy if a patient meets criteria for high risk.

Objective
Primary Outcome Measures:

Surveillance/ctDNA screening Phase [ Time Frame: enrollment ]


Primary objective of the ctDNA screening (surveillance) phase is to assess the incidence of ctDNA detection (i.e. ctDNA positivity) in patients with ER positive HER2 negative breast cancer who are receiving standard of care adjuvant endocrine therapy but remain high risk for recurrence.


Therapeutic Phase [ Time Frame: through study completion, an average of 6 years ]


Primary objective of the therapeutic randomized phase is to assess whether palbociclib plus fulvestrant improves relapse-free survival compared to standard of care adjuvant endocrine therapy in patients with ER+/HER2 negative breast cancer with detectable ctDNA in the plasma but without evidence of metastatic disease on imaging.


Secondary Outcome Measures:


Secondary Objective 1: Feasibility- correlation between clinically apparent metastatic or local disease and positive ctDNA result. [ Time Frame: enrollment ]


Estimate proportion of patients who have clinically apparent metastatic or local disease (i.e. imaging positive) at the time of first positive ctDNA result.



Secondary Objective 2: Efficacy- assess the ability of positive ctDNA results to predict clinical relapse. [ Time Frame: through study completion, an average of 6 years ]


Assess the statistical correlation between ctDNA clearance, clinical relapse and the time to relapse in the control arm of the study.



Secondary Objective 3: Efficacy- assess whether ctDNA clearance is associated with improved relapse free survival and overall survival. [ Time Frame: through study completion, an average of 6 years ]


Assess the statistical correlation between ctDNA clearance, relapse free survival and overall survival in the treatment arm of the study.



Secondary Objective 4: Efficacy- assess the efficacy of the combination arm, palbociclib plus fulvestrant compared to the control arm. [ Time Frame: through study completion, an average of 6 years ]


Compare the statistical correlation between ctDNA clearance, relapse free survival and overall survival in the two arms of the study.



Secondary Objective 5: Safety and Tolerability- number of participants with treatment-related adverse event as assed by CTCAE V5.0. [ Time Frame: through study completion, an average of 6 years ]


To assess the tolerability and safety of treatments.

Treatment Experimental: Arm A
Palbociclib/Fulvestrant Combination
Drug: Palbociclib
4 week cycles
Other Name: IBRANCE
Drug: Fulvestrant
4 week cycles
Other Name: Faslodex

Active Comparator: Arm B
Adjuvant Therapy
Drug: Adjuvant Therapy
Standard of Care
Other Name: Standard of Care

Key Eligibility For full study eligibility, please see this study's ClinicalTrials.gov record.


Applicable Disease Sites
Breast

Participating Institutions
UW Health 1 S. Park Medical Center; UW Health Eastpark Medical Center; UW Health University Hospital