Introduction. The presence of a germinal BRCA mutation occurs in 3–4% of all breast cancer (BC) patients with various biological subtypes, but significantly with a high frequency in patients with a triple negative biological subtype (in 10–20% of cases). For the treatment of patients with HER2-negative metastatic breast cancer associated with gBRCA mutation, the effectiveness of biologically targeted drugs from the group of PARP inhibitors (olaparib and talazoparib) has been proven.Purpose. Comparison of the results of our experience with the use of talazoparib in patients with HER2-gBRCA+ + mBC with the data of the EMBRACA registration study.Materials and methods. As part of the multicenter compassionate use program (CUP) with the support of Pfizer, 24 patients with HER2-negative metastatic gBRCA-associated mutation metastatic breast cancer (HER2-gBRCA+ breast cancer) received biologically targeted therapy with the PARP inhibitor talazoparib at a standard oral dose of 1 mg per day for vital indications . The average age of patients with HER2-gBRCAm+ breast cancer was 50 years (29–90 years).Results. Objective response (OR) was registered in 29% of cases, disease control (OR+stabilization) – in 71% of cases. The median progression-free survival (PFS) was 6.5 months (95% CI [3–10]). Objective response, disease control, and median PFS were evaluated depending on the biological subtype, the number of lines of previous therapy, and the presence of platinum-containing agents in the anamnesis.Objective response and disease control were evaluated depending on the biological subtype: in patients with ER+HER2-mBC versus patients with triple negative subtype, OR was 33% vs 22%, and disease control was 83% vs 61%, respectively. In the presence of < 3 vs ≥ 3 lines of therapy for metastatic disease in the anamnesis, OR was 31% vs 12.5%, disease control – 75% vs 50% of cases, respectively. In the presence or absence of platinum-containing agents in the anamnesis, OR was observed in 22% vs 33% of cases, and disease control – 67% vs 67%, respectively.In patients with the luminal subtype versus patients with the triple negative subtype, the PFS was 9 months vs 5 months, respectively (HR = 0.705; 95% CI [0.231–2.147]; p = 0.5208). Median PFS in the presence of <3 vs ≥3 lines of therapy for metastatic disease in the anamnesis was 9 months vs 4 months, respectively (HR = 4,216; 95% CI [1,334–13,327]; p = 0.0056). In the presence or absence of platinum-containing agents in previous lines of therapy 5 months vs 9.5 months, respectively (HR =1.484; 95% CI [0.48–4.582]; p = 0.4750).During the treatment with talazoparib adverse events of the 3rd-4th grades were observed in 5 patients (20,8%). These include moderate and severe anemia in 3 patients (12.5%), thrombocytopenia in 1 patient (4%), and neutropenia in 1 patient (4%). The majority of patients (79,5%), which received talazoparib, did not require dose adjustment. The need to reduce the dose to 0.75 mg was noted in 3 patients (12.5%), to 0.5 mg – in 2 patients (8%). Hemotransfusion was performed in 3 patients. For effective therapy safety management regular monitoring of blood parameters is necessary.Conclusion. Thus, targeted therapy with talazoparib is an effective treatment option for HER2-gBRCA+ mBC.
Часто недержание мочи после выполнения радикальной простатэктомии (РПЭ) регистрируют в первые 2-6 мес после оперативного вмешательства. В целях сокращения периода инконтиненции разработаны и усовершенствованы различные хирургические методы, направленные на сохранение и восстановление структур, участвующих в механизме удержания мочи. Цель работы-оценить эффективность применения оригинального метода формирования уретроцистоанастомоза в раннем восстановлении функции удержания мочи.
Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new targeted therapy considering limited chemotherapy options. KRAS mutations are the most frequent molecular alterations in CRC. However, there are no approved K-Ras targeted therapies for these tumors yet. GSK-3β is demonstrated to be a critically important kinase for the survival and proliferation of K-Ras–dependent pancreatic cancer cells. In this study, we tested combinations of standard-of-care therapy and 9-ING-41, a small molecule inhibitor of GSK-3β, in CRC cell lines and patient-derived tumor organoid models of CRC. We demonstrate that 9-ING-41 inhibits the growth of CRC cells via a distinct from chemotherapy mechanism of action. Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41–treated CRC cells. Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras–dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC.
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