A large component of the tumor microenvironment in breast cancer consists of cancer-associated fibroblasts (CAFs), a cell type which can influence tumor progression, angiogenesis and therapy resistance. Receptors on CAF are activated by ligands secreted from tumor cells resulting in establishment of a malignant paracrine crosstalk, supporting the tumor as a whole. Preclinical data suggests a specific role for tumor cell-secreted Platelet-derived growth factor-CC (PDGF-CC) in maintaining the triple-negative breast cancer (TNBC) phenotype through paracrine activation of PDGFR (Platelet-derived growth factor receptor) on CAFs. Inhibition of CAF PDGFR in preclinical TNBC breast tumor models resulted in tumors converting into a luminal ER subtype, with subsequent response to endocrine therapy. Imatinib, a PDGFR inhibitor, was tested in the preclinical setting leading to comparable results. To establish a proof-of-principle concerning if ER expression can be induced in patients, imatinib will be given to TNBC patients before surgery to analyze expression of ER before and after treatment.
The study is a window-of-opportunity phase II, single center clinical trial investigating the efficacy and feasibility of short term imatinib (400 mg per day for 10 days) for early TNBC patients planned for surgery, who are not eligible for neoadjuvant chemotherapy. The primary endpoint is to determine changes in ER expression before and after imatinib treatment by analyzing the diagnostic biopsy and the surgical specimen. If ER expression changes from 0% to 2% or more, or ER is changed from 1-9% to either ≥10% or at least 2% increase combined with a significant increase in luminal gene transcripts, the primary endpoint is met. Secondary endpoints include determining safety of short-term imatinib and assessing blood and tissue markers such as ctDNA (circulating tumorDNA), immune cell markers and analyses of activity in luminal gene expression programs. Thirty-five patients will be recruited with an interim analysis planned after recruitment of 20 patients. The study is now open for inclusion.
NCT05722795.
Vastra Gotalandsregionen/Department of Oncology, Gothenburg, Sweden.
Mats Paulsson Foundation, Cancera Foundation, The Swedish Cancer Society, Göran Grosskopf and Region Skåne ALF.
All authors have declared no conflicts of interest.