Development of a more SensItive method to predict Breast cancer recurrence after 5-Years of endocrine treatment making use of diagnostic LeukApheresis to detect circulating tumor cells

Rationale: Adjuvant endocrine treatment (ET) for 5 years is standard for patients with primary hormone receptor positive (ER+) breast cancer. However, recurrences still occur, of which more than 50% occur after 5 years ET. Extended adjuvant endocrine therapy (EET), up to 10-15 years, increases disease free survival (DFS). However, there is no robust biomarker predicting late recurrence risk after 5-years ET. The measurement of circulating tumor cells (CTCs) as a reflection of residual disease could possibly serve as such a biomarker. Recent studies showed the prognostic value of CTC enumeration in ER+ lymph node positive (N+) primary breast cancer patients during and after ET. Unfortunately, the classic CTC enumeration method using 7.5 mL of blood is not sensitive enough as disease recurrence also occurred in patients without detectable CTCs. To measure residual disease through more sensitive CTC detection, screening of a larger blood volume is desired. CTC enumeration in 30 mL of blood yielded a higher percentage of patients who had ≥1 CTC than in 7.5 mL of blood, which increases sensitivity and specificity. However, the robustness of this test is weak due to stochastic variation inherent to the low CTC numbers found. A technique to greatly increase the screened blood volume is called Diagnostic Leukapheresis (DLA). During DLA, 2.5-5L of blood is passed through a centrifuge, which isolates peripheral blood mononuclear cells (PBMCs) as well as CTCs from the blood, which is returned to the patient. Preliminary results have shown that this procedure increases the sensitivity of CTC detection substantially by 500-1000. We therefore hypothesize that CTC detection through DLA improves the detection rate among ER+, N+ primary breast cancer who have received 5 years of adjuvant endocrine therapy and will be a promising technique for risk classification in this patient group. Objective: The primary objective of this study is to demonstrate that our DLA-based method is promising enough to detect CTCs in ER+, N+ primary breast cancer patients after 5 years ET. Simultaneously, other methods (CTC detection in 7.5 ml and 30 ml of blood as well as ctDNA detection) will be assessed in this study population and explored how they compare with our DLA-based approach in terms of tumor load detection.

We hypothesize that CTC detection through diagnostic leukapheresis improves the detection rate among ER+, N+ primary breast cancer who have received 5 years of adjuvant endocrine therapy and will be a promising technique for risk classification in this patient group.

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