Therapy delay due to COVID-19 pandemic among European women with breast cancer: prevalence and associated factors.

PURPOSE: This study investigates the impact of the COVID-19 pandemic on breast cancer (BC) care, analyzing treatment delays and factors associated with them. METHODS: This retrospective cross-sectional study analyzed data from the Oncology Dynamics (OD) database. Surveys of 26,933 women with BC performed between January 2021 and December 2022 in Germany, France, Italy, the United Kingdom, and Spain were examined. The study focused on determining the prevalence of treatment delays due to the COVID-19 pandemic, considering factors such as country, age group, treating facility, hormone receptor status, tumor stage, site of metastases, and Eastern Cooperative Oncology Group (ECOG) status. Baseline and clinical characteristics were compared for patients with and without therapy delay using chi-squared tests, and a multivariable logistic regression analysis was conducted to explore the association between demographic and clinical variables and therapy delay. RESULTS: The present study found that most therapy delays lasted less than 3 months (2.4%). Factors associated with higher risk of delay included being bedridden (OR 3.62; 95% CI 2.51-5.21), receiving neoadjuvant therapy (OR 1.79; 95% CI 1.43-2.24) compared to adjuvant therapy, being treated in Italy (OR 1.58; 95% CI 1.17-2.15) compared to Germany or treatment in general hospitals and non-academic cancer facilities (OR 1.66, 95% CI 1.13-2.44 and OR 1.54; 95% CI 1.14-2.09, respectively) compared to treatment by office-based physicians. CONCLUSION: Addressing factors associated with therapy delays, such as patient performance status, treatment settings, and geographic location, can help guide strategies for improved BC care delivery in the future.

Asymmetric Centriole Numbers at Spindle Poles Cause Chromosome Missegregation in Cancer.

Chromosomal instability is a hallmark of cancer and correlates with the presence of extra centrosomes, which originate from centriole overduplication. Overduplicated centrioles lead to the formation of centriole rosettes, which mature into supernumerary centrosomes in the subsequent cell cycle. While extra centrosomes promote chromosome missegregation by clustering into pseudo-bipolar spindles, the contribution of centriole rosettes to chromosome missegregation is unknown. We used multi-modal imaging of cells with conditional centriole overduplication to show that mitotic rosettes in bipolar spindles frequently harbor unequal centriole numbers, leading to biased chromosome capture that favors binding to the prominent pole. This results in chromosome missegregation and aneuploidy. Rosette mitoses lead to viable offspring and significantly contribute to progeny production. We further show that centrosome abnormalities in primary human malignancies frequently consist of centriole rosettes. As asymmetric centriole rosettes generate mitotic errors that can be propagated, rosette mitoses are sufficient to cause chromosome missegregation in cancer.

Pharmacological Inhibition of Centrosome Clustering by Slingshot-Mediated Cofilin Activation and Actin Cortex Destabilization.

Centrosome amplification is a hallmark of virtually all types of cancers, including solid tumors and hematologic malignancies. Cancer cells with extra centrosomes use centrosome clustering (CC) to allow for successful division. Because normal cells do not rely on this mechanism, CC is regarded as a promising target to selectively eradicate cells harboring supernumerary centrosomes. To identify novel inhibitors of CC, we developed a cell-based high-throughput screen that reports differential drug cytotoxicity for isogenic cell populations with different centrosome contents. We identified CP-673451 and crenolanib, two chemically related compounds originally developed for the inhibition of platelet-derived growth factor receptor ß (PDGFR-ß), as robust inhibitors of CC with selective cytotoxicity for cells with extra centrosomes. We demonstrate that these compounds induce mitotic spindle multipolarity by activation of the actin-severing protein cofilin, leading to destabilization of the cortical actin network, and provide evidence that this activation is dependent on slingshot phosphatases 1 and 2 but unrelated to PDGFR-ß inhibition. More specifically, we found that although both compounds attenuated PDGF-BB-induced signaling, they significantly enhanced the phosphorylation of PDGFR-ß downstream effectors, Akt and MEK, in almost all tested cancer cell lines under physiologic conditions. In summary, our data reveal a novel mechanism of CC inhibition depending on cofilin-mediated cortical actin destabilization and identify two clinically relevant compounds interfering with this tumor cell-specific target. Cancer Res; 76(22); 6690-700. ©2016 AACR.

MAP1S controls microtubule stability throughout the cell cycle in human cells.

Summary Understanding the molecular basis for proper cell division requires a detailed functional analysis of microtubule (MT)-associated proteins. MT-associated protein 1S (MAP1S), the most ubiquitously expressed MAP1 family member, is required for accurate cell division. Here, using quantitative analysis of MT plus-end tracking, we show that MAP1S knockdown alters MT dynamics throughout the cell cycle. Surprisingly, MAP1S downregulation results in faster growing, yet short-lived, MTs in all cell cycle stages and in a global loss of MT acetylation. These aberrations correlate with severe defects in the final stages of cell division. In monopolar cytokinesis assays, we demonstrate that MAP1S guides MT-dependent initiation of cytokinesis. Our data underline the key role of MAP1S as a global regulator of MT stability and demonstrate a new primary function of MAP1S to regulate MT dynamics at the onset of cytokinesis.

A novel microtubule inhibitor 4SC-207 with anti-proliferative activity in taxane-resistant cells.

Microtubule inhibitors are invaluable tools in cancer chemotherapy: taxanes and vinca alkaloids have been successfully used in the clinic over the past thirty years against a broad range of tumors. However, two factors have limited the effectiveness of microtubule inhibitors: toxicity and resistance. In particular, the latter is highly unpredictable, variable from patient to patient and is believed to be the cause of treatment failure in most cases of metastatic cancers. For these reasons, there is an increasing demand for new microtubule inhibitors that can overcome resistance mechanisms and that, at the same time, have reduced side effects. Here we present a novel microtubule inhibitor, 4SC-207, which shows strong anti-proliferative activity in a large panel of tumor cell lines with an average GI50 of 11 nM. In particular, 4SC-207 is active in multi-drug resistant cell lines, such as HCT-15 and ACHN, suggesting that it is a poor substrate for drug efflux pumps. 4SC-207 inhibits microtubule growth in vitro and in vivo and promotes, in a dose dependent manner, a mitotic delay/arrest, followed by apoptosis or aberrant divisions due to chromosome alignment defects and formation of multi-polar spindles. Furthermore, preliminary data from preclinical studies suggest low propensity towards bone marrow toxicities at concentrations that inhibit tumor growth in paclitaxel-resistant xenograft models. In summary, our results suggest that 4SC-207 may be a potential anti-cancer agent.