Abstract
Simple SummaryDisseminated tumor cells (DTCs) present in the bone marrow of breast cancer patients are an indicator of minimal residual disease and micrometastatic spread. These cells can already be found at the earliest disease stages and are associated with poorer outcomes. In preclinical models, neoadjuvant chemotherapy was shown to promote micrometastatic spread. The aim of this large single-center retrospective study was to compare the frequency and prognostic significance of DTC detection between patients treated with neoadjuvant chemotherapy and treatment-naive patients.Preclinical data suggest that neoadjuvant chemotherapy (NAT) may promote micrometastatic spread. We aimed to compare the detection rate and prognostic relevance of disseminated tumor cells (DTCs) from the bone marrow (BM) of patients with early-stage breast cancer (EBC) after NAT with that of therapy-naive EBC patients. DTCs were identified from BM samples, collected during primary surgery. Patients who received NAT were compared to patients who received chemotherapy after surgery. In total, 809 patients were analyzed. After NAT, 45.4% of patients were DTC-positive as compared to 19.9% of patients in the adjuvant chemotherapy group (p < 0.001). When sampled in patients who had undergone NAT, the detection of DTCs in the BM was significantly increased (OR: 3.1; 95% confidence interval (CI): 2.1–4.4; p < 0.001). After NAT, DTC-positive patients with ≥2 DTCs per 1.5 × 106 mononuclear cells in their BM had an impaired disease-free survival (HR: 4.8, 95% CI: 0.9–26.6; p = 0.050) and overall survival (HR: 4.2; 95% CI: 1.4–12.7; p = 0.005). The higher rate of DTC-positive patients after NAT as compared to a treatment-naive comparable control cohort suggests that NAT supports tumor cell dissemination into the bone marrow. DTC positivity in BM predicted relapse in various distant organs, implying that tumor cell dissemination was not restricted to the bone marrow.
Highlights
Breast cancer is the most common type of cancer in women in the western world.Despite modern treatment, the disease may recur at distant sites even in patients without lymph node involvement and small tumors that have been completely removed
We aimed to compare the proportion and prognostic relevance of disseminated tumor cells (DTCs) positivity when bone marrow (BM) was sampled after neoadjuvant chemotherapy (NAT) with the proportion and prognostic relevance of DTC positivity when BM was sampled before adjuvant chemotherapy
Only when we looked at patients with higher numbers of DTCs in their bone marrow (≥2 DTCs/1.5 × 106 mononuclear cells) after the completing NAT were we able to confirm a poorer prognosis in the neoadjuvant group too (Figure 1C,D)
Summary
The disease may recur at distant sites even in patients without lymph node involvement and small tumors that have been completely removed. This implies that the disease spreads early and remains in a dormant state, a phenomenon called minimal residual disease (MRD) [1]. While pCR is usually defined as the absence of any invasive tumor residuals in the breast or lymph nodes following NAT, scoring systems such as the CPS + EG score (clinical-pathologic Scoring System incorporating estrogen receptor-negative disease and nuclear grade 3 tumor pathology) use a pre-treatment clinical stage as well as post-NAT pathologic stage, nuclear grade, and the estrogen receptor status to estimate prognosis [6]. The monitoring of MRD might help to improve risk stratification after NAT [7]
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