Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer, often with poor outcomes. Currently, follow-up for TNBC consists of physical exams and annual breast imaging, with additional scans only if symptoms appear. This approach may delay the detection of the cancer coming back until the disease is advanced.

A promising new technique is the detection of circulating tumor DNA (ctDNA)-in the blood. Studies suggest ctDNA may identify cancer recurrence months before it becomes visible on scans or causes symptoms. However, it is unknown whether detecting recurrence earlier can actually help patients live longer or feel better.

The EINSTEIN-TNBC trial is a study aiming to evaluate the feasibility of ctDNA-guided surveillance for patients with TNBC after surgery.

Thirty participants will be randomized to either:

Standard of care (routine physical exams and annual breast imaging), or Active surveillance (standard of care plus ctDNA testing, with imaging investigations if ctDNA is detected).

This study will assess the feasibility of conducting a ctDNA-based monitoring trial in this patient population.

If feasible, EINSTEIN-TNBC will lay the foundation for a larger future clinical trial to determine whether earlier detection of metastatic TNBC can improve survival and quality of life.

Background:

Triple-negative breast cancer (TNBC) is associated with poor clinical outcomes. In patients with stage II-III TNBC treated with neoadjuvant therapy in the KEYNOTE-522 trial, almost one-third of patients with residual disease died at 5 years. Yet, standard-of-care (SOC) surveillance after curative therapy consists of routine breast imaging and physical examination, with additional imaging performed only upon development of symptoms suggestive of disease recurrence. Given the ability of circulating tumor DNA (ctDNA) to detect metastatic recurrence at its earlier stages, even prior to detection using conventional imaging, it is possible that early detection and intervention for molecular relapse of TNBC may improve patients' outcomes. This pilot trial evaluates the feasibility of a future phase III randomized controlled trial (RCT), which would evaluate whether ctDNA-based surveillance and subsequent early intervention may improve patients' outcomes including overall survival (OS).

Methods:

This is a multi-center, pilot randomized trial conducted at 3 Canadian cancer centers: Sunnybrook Odette Cancer Centre, Princess Margaret Cancer Centre, and William Osler Health System. Inclusion Criteria: 1) Age ≥18; 2) Biopsy-proven invasive TNBC; 3) T2-4/N0 OR T1c-4/N1-3 disease at initial diagnosis; 4) Residual disease (RCB 2 or 3) after curative-intent neoadjuvant chemo(-immuno)therapy. Exclusion Criteria: 1) Inability to provide informed consent; 2) Prior invasive breast cancer; 3) Another malignancy which may interfere with assessment of clinical outcomes; 4) Current pregnancy; 5) Creatinine clearance <45 mL/min. Post-operatively, participants are randomized 1:1 to 'active surveillance' and SOC surveillance. 'Active surveillance' consists of serial ctDNA measurements (specific assay currently embargoed but will be presented) every 3 months for 1 year post-operatively; ctDNA positivity will trigger imaging investigations (i.e. CT chest/abdomen/pelvis with contrast, bone scan, and MRI brain with contrast) every 3 months until detection of overt MBC. Overt MBC will be treated as per SOC. Primary endpoints: 1) Recruitment rate; 2) Proportion of eligible patients approached who agree to participate; 3) Proportion of randomized patients who complete 1 year of follow-up. Secondary Endpoints: 4) MBC incidence; 5) Correlation of ctDNA findings with imaging results; 6) Number and types of diagnostic and/or therapeutic interventions; 7) Quality of life (EORTC QLQ BN20); 8) Patient anxiety (NCI PRO-CTCAE); 9) ctDNA turnaround time; 10) invasive disease-free survival (iDFS); 11) OS; 12) Perceptions of medical oncologists regarding their experience using ctDNA as a monitoring tool.

Inclusion Criteria:

• Men or women aged 18 and over
• Biopsy proven invasive triple negative breast cancer (defined here as estrogen receptor <10%, progesterone receptor <10%, human epidermal growth factor receptor 2 (HER2) negative status, with HER2 status being defined as per ASCO/CAP guidelines)
• T2-4/N0 (>2 cm primary breast cancer as assessed clinically or on imaging in the absence of nodal involvement) OR T1c-4/N1-3 disease (>10mm with fine needle aspirate or core biopsy confirming nodal involvement is required)
• Residual disease (RCB 2 or 3) on surgical specimen after completion of neoadjuvant chemo(-immuno)therapy

Exclusion Criteria:

• Inability to provide informed consent. Participants who require translators are allowed to enroll
• Prior history of invasive breast cancer -Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the detection of BC recurrence on a liquid biopsy (patients with a history of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and carcinoma-in-situ of cervix are permitted to participate)-
• Pregnant patients are not permitted
• Creatinine clearance <45 mL/min using the Cockcroft-Gault equation.

Radiologists interpreting imaging will be blinded to liquid biopsy results.