cabazitaxel and Triple-Negative-Breast-Neoplasms

The GENEVIEVE study compared the pathological complete response (pCR) rate (ypT0/is ypN0/+) in patients with operable human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) treated with either cabazitaxel or paclitaxel.. GENEVIEVE was a prospective, multicentre, randomised, open-label, phase II study comparing the efficacy and the safety of four 3-weekly cycles cabazitaxel versus 12 weeks of paclitaxel given as neoadjuvant treatment. Primary end-point was the pCR rate defined as the complete absence of invasive carcinoma on histological examination of the breast irrespective of lymph node involvement (ypT0/is, ypN0/+) after the taxane treatment. Patients could receive an anthracycline-based therapy thereafter.. Overall, 333 patients were randomised and started treatment with 74.7% and 83.2% of patients completing treatment in the cabazitaxel and paclitaxel arms, respectively. Patients in cabazitaxel arm had a significantly lower pCR rate compared to the paclitaxel arm (1.2% versus 10.8%; p = 0.001). A total of 42 (25.3%) patients in the cabazitaxel arm and 17 (10.2%) in the paclitaxel arm had at least one serious adverse event (p < 0.001). Dose reductions were observed in 9.6% patients in the cabazitaxel arm compared to 11.4% in the paclitaxel arm (p = 0.721). Main reason for dose reductions was non-haematological toxicities in 3.0% versus 7.8% (p = 0.087), respectively.. The GENEVIEVE study showed no short-term effect of cabazitaxel in triple-negative or luminal B/HER2-negative primary BC, while there seemed to be no differences in drug exposure and patient compliance between the two arms.. ClinicalTrials.gov NCT01779479.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Biomarkers, Tumor; Breast Neoplasms; Chemotherapy, Adjuvant; Drug Administration Schedule; Female; Germany; Humans; Mastectomy; Medication Adherence; Middle Aged; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Staging; Paclitaxel; Prospective Studies; Receptor, ErbB-2; Taxoids; Time Factors; Treatment Outcome; Triple Negative Breast Neoplasms; Young Adult

Limited therapeutic options are available for triple-negative breast cancer (TNBC), emphasizing an urgent need for more effective treatment approaches. The development of strategies by targeting tumor-associated macrophages (TAMs) to stimulate their ability of Programmed Cell Removal (PrCR) provides a promising new immunotherapy for TNBC treatment.. CD47 is a critical self-protective "don't eat me" signal on multiple human cancers against macrophage immunosurveillance. Using human and mouse TNBC preclinical models, we evaluated the efficacy of PrCR-based immunotherapy by blocking CD47. We performed high-throughput screens on FDA-approved anti-cancer small molecule compounds for agents potentiating PrCR and enhancing the efficacy of CD47-targeted therapy for TNBC treatment.. We showed that CD47 was widely expressed on TNBC cells and TAMs represented the most abundant immune cell population in TNBC tumors. Blockade of CD47 enabled PrCR of TNBC cells, but the efficacy was not satisfactory. Our high-throughput screens identified cabazitaxel in enhancing PrCR-based immunotherapy. A combination of CD47 blockade and cabazitaxel treatment yielded a highly effective treatment strategy, promoting PrCR of TNBC cells and inhibiting tumor development and metastasis in preclinical models. We demonstrated that cabazitaxel potentiated PrCR by activating macrophages, independent of its cytotoxicity toward cancer cells. When treated with cabazitaxel, the molecular and phenotypic signatures of macrophages were polarized toward M1 state, and the NF-kB signaling pathway became activated.. The combination of CD47 blockade and macrophage activation by cabazitaxel synergizes to vastly enhance the elimination of TNBC cells. Our results show that targeting macrophages is a promising and effective strategy for TNBC treatment.

Topics: Animals; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; CD47 Antigen; Cell Line, Tumor; Databases, Genetic; Drug Synergism; Female; Humans; Macrophage Activation; Mice; Mice, Inbred BALB C; Mice, Knockout; NF-kappa B; Phagocytosis; Phenotype; RAW 264.7 Cells; Signal Transduction; Taxoids; Triple Negative Breast Neoplasms; Tumor Microenvironment; Tumor-Associated Macrophages; Xenograft Model Antitumor Assays

Topics: Animals; Cell Line, Tumor; Humans; I-kappa B Kinase; Mice; RNA, Small Interfering; Taxoids; Triple Negative Breast Neoplasms