ctDNA Detection and CCR5 Inhibition Show Promise in Triple-Negative Breast Cancer
New research highlights circulating tumor DNA as a prognostic tool in early-stage triple-negative breast cancer, while leronlimab demonstrates long-term survival signals in heavily pretreated metastatic patients through CCR5 receptor blockade.
Circulating tumor DNA (ctDNA) detection is emerging as a powerful prognostic tool in early-stage triple-negative breast cancer (TNBC), though its role in guiding treatment decisions remains under investigation. Meanwhile, novel mechanisms of CCR5 inhibition show potential for enhancing immune checkpoint responses in metastatic disease.
In the neoadjuvant setting, the phase 2 I-SPY2 study (NCT01042379) evaluated 138 patients with stage II to III triple-negative breast cancer. The study demonstrated that early ctDNA clearance during neoadjuvant therapy was a strong predictor of achieving a pathologic complete response (pCR) and was associated with superior distant recurrence-free survival (DRFS). However, 11 patients had pCR in the group with early ctDNA clearance, but 8 patients did not.
The phase 2 PREDICT-DNA (TBCRC 040) trial (NCT07069595), which aimed to determine the negative predictive value (NPV) of ctDNA for pCR in patients with TNBC and HER2-positive disease who were intended to undergo standard chemotherapy, failed to meet its primary end point of an NPV greater than 90%. Despite this, patients with TNBC who were ctDNA negative after neoadjuvant therapy were 10 times less likely to experience recurrence compared with those with detectable ctDNA, independent of their pCR status. Patients who cleared ctDNA by the preoperative time point did extremely well compared with those who didn't, with a hazard ratio of 9.6.
Although ctDNA assays can detect molecular residual disease (MRD) earlier than imaging, no studies have yet shown that acting on a positive result improves outcomes or that de-escalating therapy based on a negative test is safe, so routine use remains limited to clinical trials. Trials including I-SPY2 and PREDICT-DNA demonstrate that ctDNA clearance correlates with improved pCR and recurrence outcomes, but ctDNA status alone is not yet reliable enough to guide treatment selection.
In metastatic TNBC, leronlimab, a humanized monoclonal antibody targeting the CCR5 receptor, is being evaluated for its ability to modulate the tumor immune microenvironment. Data presented at the AACR Immuno-Oncology Conference, held February 18-21, 2026 in Los Angeles, California, explored mechanisms of immune checkpoint resistance in TNBC and offered insight into how CCR5 blockade may enhance responses to immune checkpoint inhibitors (ICIs).
Across multiple TNBC patient gene expression datasets, CCR5 expression correlated with elevated cytotoxic T-lymphocyte signatures and T-cell exhaustion profiles, identifying immune states potentially amenable to CCR5 inhibition. PD-L1 and PD1, the abundance of which correlates with improved response to immune checkpoint therapies, was increased by leronlimab. In cell culture and histology analyses, CCR5 inhibition with leronlimab increased the abundance of PD-L1 in breast cancer cells. In Rhesus monkeys, leronlimab induced PD1 in T cells.
CCR5 activity was associated with the secretion of immunosuppressive mediators from triple-negative breast cancer cells, [sB7-H3 (CD276), BAFF (sTNFSF13B), and sTyro3], which were significantly reduced following leronlimab treatment.
In a pooled retrospective clinical analysis of 28 heavily pretreated patients with metastatic triple-negative breast cancer from three clinical trials, leronlimab demonstrated a favorable safety profile with no therapy-limiting toxicities, and 5 of 28 patients (17.9%) remain alive after a median follow-up of more than 63 months.