The ATR inhibition by Elimusertib enhances the radiosensitivity of MDA-MB-231 triple negative breast cancer in vitro.

PURPOSE: DNA damage response (DDR) is the principal mechanism regulating genomic stability and cell cycle checkpoint activation by coordinating DNA repair and apoptotic pathways. Ataxia telangiectasia and Rad3-related protein (ATR) play a significant role in the DDR due to its capability to detect a wide spectrum of DNA damage. Therefore, targeting DDR, specifically ATR, is a promising therapeutic strategy in cancer treatment. Furthermore, the inhibition of ATR sensitizes cancer cells to radiotherapy (RT). Herein, we, for the first time, investigated the synergistic effects of Elimusertib (BAY-1895344) as a highly potent selective ATR inhibitor with RT combination in triple-negative breast cancer (TNBC), in vitro. METHODS: MDA-MB-231 TNBC cells were firstly treated with different concentrations of Elimusertib for 24 h and then exposed to 4 and 8 Gy of X-ray irradiation. After post-irradiation for 72 h, WST-1, Annexin V, cell cycle, acridine orange/propidium iodide, mitochondria staining and western blot analysis were conducted. RESULTS: Our findings showed that 4 Gy irradiation and lower doses (especially 2 and 4 nM) of Elimusertib combination exerted a considerable anticancer activity at 72 h post-irradiation through apoptotic cell death, marked nuclear and mitochondrial damages and the suppression of ATR-Chk1 based DDR mechanism. CONCLUSION: ATR inhibition by Elimusertib in combination with RT may be a promising new treatment strategy in the treatment of TNBC. However, further experiments should be performed to elucidate the underlying molecular mechanisms of the therapeutic efficacy of this combination treatment and its association with DNS repair mechanisms in TNBC, in vitro and in vivo.

Fluence map analyzer reduces low dose volume in locally advanced post mastectomy breast cancer patients.

Multi-leaf collimator dose leakage in intensity-modulated radiotherapy (IMRT) plans causes higher low dose volume which increases the long-term risks of radiotherapy. We have developed Fluence Map Analyzer (FMA) program that suggests the ideal field geometry to reduce low dose volume in locally advanced breast cancer IMRT plans. In this comparative experimental study, FMA has been applied to standard IMRT plans (STD-IMRT) of randomly selected 15 left and 15 right-sided locally advanced breast cancer patients. All patients underwent a modified radical mastectomy. The chest wall, IMN, axillary, and supraclavicular lymph nodes are included in planning target volume (PTV). The heart, lungs, contralateral breast, and medulla spinalis were delineated as organs at risk (OARs). Two sets of plans, namely STD-IMRT and FMA-IMRT, were generated for each patient. The dosimetric analysis was performed using dose-volume histogram (DVH) and standard evaluation parameters of PTV and OARs. No differences could be observed among the two techniques for PTV coverage. However, FMA-IMRT plans achieved significantly lower V5volumes and mean doses of the heart, lungs, contralateral breast, and body contours. FMA-IMRT used a smaller number of sub-fields and fewer monitor units (MU). FMA automizes the field geometry determination process for locally advanced breast cancer IMRT planning while reducing low dose volume significantly.

The impact of the field width on VMAT plan quality and the assessment of half field method.

PURPOSE: The goal of this work is to investigate the field width dependence of the volumetric modulated arc therapy (VMAT) plan quality and to propose a half field method to irradiate large volumes effectively with VMAT. MATERIALS AND METHODS: We compared four different VMAT methods; namely three full field (3ff), four full field (4ff), three half field (3hf), four half field (4hf). To evaluate the impact of the field width on VMAT plan quality, 12 different size PTVs were created in the virtual phantom and treatment plans generated for each PTV were compared. The effectiveness of our half field method was tested using computed tomography (CT) data of 10 nasopharyngeal carcinoma patients. RESULTS: In the virtual phantom study, organs at risk (OAR) mean dose, the maximum point dose, and Homogeneity Index (HI) were found to be field width dependent. Conformation Number (CN) was not significantly affected. In the clinical study, 4hf plans obtained statistically significant dose reduction at brainstem (P < 0.001), right parotid (P = 0.034), oral cavity (P < 0.001), larynx (P = 0.003), cochlea (P = 0.017), lips (P = 0.024), and Body-PTV (P = 0.04) compared to 4ff plans. CONCLUSION: Our results indicate that VMAT plan quality is dependent on the field width. Half field VMAT method, with the help of reduced field width, shows a clear advantage for the irradiation of large size targets compared to traditionally used full field VMAT plans.