RESUMO
Immune checkpoint inhibitors utilize the immune system to kill cancer cells and are now widely applied across numerous malignancies. Pembrolizumab has two breast-specific indications in triple-negative disease. Currently, programmed death ligand-1 (PD-L1) expression on tumor and surrounding immune cells is the only validated predictive biomarker for immune checkpoint inhibitors (ICIs) in breast cancer; however, it can be imprecise. Additional biomarkers are needed to identify the patient population who will derive the most benefit from these therapies. The tumor immune microenvironment contains many biomarker candidates. In tumor cells, tumor mutational burden has emerged as a robust biomarker across malignancies in general, with higher burden cancers demonstrating improved response, but will need further refinement for less mutated cancers. Preliminary studies suggest that mutations in breast cancer gene 2 (BRCA-2) are associated with increased immune infiltration and response to ICI therapy. Other genomic alterations are also being investigated as potential predictive biomarkers. In immune cells, increased quantity of tumor-infiltrating lymphocytes and CD8+ cytotoxic T cells have correlated with response to immunotherapy treatment. The role of other immune cell phenotypes is being investigated. Peripherally, many liquid-based biomarker strategies such as PD-L1 expression on circulating tumor cells and peripheral immune cell quantification are being studied; however, these strategies require further standardization and refinement prior to large-scale testing. Ultimately, multiple biomarkers utilized together may be needed to best identify the appropriate patients for these treatments.
RESUMO
Trastuzumab deruxtecan has been shown to have responses in heavily pretreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, the safety of this medication in patients with severe liver dysfunction and untreated or symptomatic central nervous system metastases is unknown. We describe a patient with metastatic HER2-positive breast cancer with liver failure and leptomeningeal metastases who was treated with dose-reduced trastuzumab deruxtecan. With treatment, the patient's hyperbilirubinemia resolved and she demonstrated a response on imaging. She was dose-escalated to full dose with minimal adverse events.
RESUMO
The GLI1 oncogene and p53 tumor suppressor gene function in an inhibitory loop that controls stem cell and tumor cell numbers. Since GLI1 and p53 both interact with the coactivator TATA Binding Protein Associated Factor 9 (TAF9), we hypothesized that competition between these transcription factors for TAF9 in cancer cells may contribute to the inhibitory loop and directly affect GLI1 function and cellular phenotype. We showed that TAF9 interacts with the oncogenic GLI family members GLI1 and GLI2 but not GLI3 in cell-free pull-down assays and with GLI1 in rhabdomyosarcoma and osteosarcoma cell lines. Removal of the TAF9-binding acidic alpha helical transactivation domain of GLI1 produced a significant reduction in the ability of GLI1 to transform cells. We then introduced a point mutation into GLI1 (L1052I) that eliminates TAF9 binding and a point mutation into GLI3 (I1510L) that establishes binding. Wild-type and mutant GLI proteins that bind TAF9 showed enhanced transactivating and cell transforming activity compared with those that did not. Therefore, GLI-TAF9 binding appears important for oncogenic activity. We then determined whether wild-type p53 down-regulates GLI function by sequestering TAF9. We showed that p53 binds TAF9 with greater affinity than does GLI1 and that co-expression of p53 with GLI1 or GLI2 down-regulated GLI-induced transactivation, which could be abrogated using mutant forms of GLI1 or p53. This suggests that p53 sequesters TAF9 from GLI1, which may contribute to inhibition of GLI1 activity by p53 and potentially impact therapeutic success of agents targeting GLI-TAF9 interactions in cancer.