Biomarkers of neoadjuvant dalpiciclib in patients with operable HER2-negative luminal B breast cancer in the DANCER trial.

600 Background: DANCER (NCT05640778) was a circulating tumor DNA (ctDNA)-directed, single-arm, phase II trial investigating the clinical activity of dalpiciclib combined with aromatase inhibitors as a neoadjuvant regimen for operable human epidermal growth factor receptor 2 (HER2)-negative luminal B breast cancer. Although a high complete cell cycle arrest (CCCA) rate (primary endpoint) of 86.7% (26/30) was achieved at 2 weeks (T1), some patients showed suboptimal clinical responses after neoadjuvant therapy. This underscores the importance of identifying biomarkers predictive of response to CDK4/6 inhibitors. Methods: Plasma samples collected at baseline (T0), T1, mid-therapy (T2), surgery (S), and postoperatively (PO) underwent ctDNA and Olink proteomic analyses. Tumor tissues obtained at T0, T1, and S were assessed for somatic variation profiling, immunohistochemical markers and MammaPrint index. Patients achieving CCCA at both T1 and S with a concurrent objective response by MRI at S were classified as Good Responders (GRs, n = 15); others were Moderate Responders (MRs, n = 15). Results: The baseline clinicopathological features of the patients were balanced between the GR and MR groups. Compared to MRs, the GRs at S exhibited significantly lower residual cancer burden (RCB) scores, preoperative endocrine prognostic index (PEPI) scores, histological tumor grades, Ki67 expressions, and CA153 levels. Additionally, GRs demonstrated significantly higher Miller-Payne grades, tumor-infiltrating lymphocyte levels, and tumor shrinkage rates. In terms of biomarkers, GRs had a higher rate of ctDNA clearance at and prior to T2 (100.0% vs 54.5%; p = 0.045), as well as higher levels of plasma CCL4 ( p = 0.029), plasma CCL19 ( p = 0.020), immunohistochemical pRb ( p = 0.044), and immunohistochemical CDK4 ( p = 0.034). Furthermore, GSTM1 demonstrated a significant shift in its copy number pattern after treatment at S, with five previously detected baseline deletions no longer being identified and five de novo amplifications emerging ( p = 0.007). Lack of early ctDNA clearance was also significantly associated with RCB class of III and PEPI score of ≥ 4. Besides, MammaPrint high-risk patients showed a significant increase in RCB and PEPI scores vs. low-risk patients. Conclusions: Patients with operable HER2-negative luminal B breast cancer who exhibit early ctDNA clearance, MammaPrint low-risk status, GSTM1 deletion, increased pRb/CDK4 expression, and higher plasma CCL4/CCL19 levels may derive substantial benefit from neoadjuvant dalpiciclib therapy. Clinical trial information: NCT05640778 .