Rising ctDNA to Tailor Endocrine Therapy Switch in Patients With ER+/HER2- Metastatic Breast Cancer.

Rationale:

In patients with metastatic breast cancer, fragments of tumor DNA called "circulating tumor DNA" or "ctDNA" can be detected in the blood. When the level of ctDNA increases, it often means that treatment is no longer effective and that the disease is likely to progress. Previous studies have shown that quickly changing hormone therapy as soon as a specific genetic anomaly (ESR1 mutation) is detected in the blood can improve outcomes for breast cancer patients. This monitoring also allows for earlier action against cells that are resistant to treatment. However, this mutation is only present in about 4 out of 10 women, which limits the use of this method to only some patients.

Unlike previous approaches that targeted only the ESR1 mutation, the TAILORswitch study will assess a change in treatment following an increase in ctDNA, even in the absence of mutation, and before any other signs of disease progression. This change will include a new oral hormone therapy (camizestrant) combined with a targeted treatment that has shown benefits in cases of resistance (abemaciclib). This approach aims to intervene earlier in order to prevent disease progression.

In summary, TAILORswitch explores a new way to personalize treatment, using more sensitive blood monitoring tools to improve quality of life and patient outcomes.

Objectives:

The primary objective of this trial is to demonstrate the efficacy of switching to camizestrant-abemaciclib combination therapy in patients with hormone-dependent metastatic breast cancer (ER+ HER2-) receiving targeted therapy combined with hormone therapy as first-line treatment, in cases where ctDNA levels increase without other signs of disease progression (clinical or radiological).

Secondary objectives include:

* The efficacy, safety, and tolerability of the treatment switch * The safety and feasibility of reducing the number of imaging exams in patients undergoing ctDNA monitoring every 3 months (optional substudy).

Trial Design:

TAILORswitch is a multi-step phase 3 randomized trial. Step 1 involves recruiting 370 patients with advanced or metastatic hormone-dependent breast cancer who are receiving CDK4/6 inhibitor and aromatase inhibitor therapy as their first treatment.

Optional: some patients included in Step 1 will be offered to participate in a sub-study to evaluate imaging follow-up de-escalation. These patients will be allocated in of the following groups:

* Group A: maintenance of standard imaging every 3 to 4 months. * Group B: reduction to imaging once per year at most, with a return to the standard frequency in case of clinical, radiological, biological, or ctDNA-based signs of progression.

Step 2 involves patients who are initially eligible and show an increase in ctDNA levels without radiological progression. These patients will be allocated to one of the following groups:

* Group experimental: switch to the combination of camizestrant + abemaciclib until progression. * Group control: continuation of standard treatment (AI + CDK4/6i) until progression.

The recruitment period is 30 months, with the aim of including 156 patients in Step 2. Each participant will be followed for 30 months after inclusion.