Evolution of the CDK4/6 inhibitor abemaciclib: from palliative to adjuvant therapy. Clinical experience with abemaciclib in patients with hormone-receptor-positive, HER2-negative breast cancer

Introduction. Cyclin-dependent kinase 4/6 inhibitors are indicated in endocrine therapy for the treatment of hormone receptorpositive, HER2-negative, advanced, or metastatic breast cancer. In the recent past, abemaciclib made its debut as a combinatorial partner for adjuvant therapy in hormone-dependent breast cancer. This article demonstrates the analysis of our own experience of introducing abemaciclib into clinical practice.Aim. The aim of the study was to evaluate the preliminary results of treatment of patients with hormone receptor-positive HER2-negative metastatic breast cancer using abemaciclib outside the framework of clinical trials, in the real clinical practice of an oncological dispensary.Materials and methods. A retrospective analysis of the results of treatment was carried out in 27 patients who were prescribed abe-maciclib in various regimens and lines from April 2021 to January 2022 in the conditions of routine practice in the Krasnodar region.Results and discussion. Analysis of the total population of 27 patients at a median follow-up of 8 months showed that the median PFS was not reached. The one-year PFS was 68.8%. Treatment outcomes were independent of prescribing abemaciclib to treat baseline metastatic disease or breast cancer progression after previous radical treatment (p = 0.60). The PFS did not depend on the expression of progesterone receptors in the tumor tissue (p = 0.326) and the proliferative activity index Ki-67 (p = 0.618). Patients who received no more than 2 lines of previous drug treatment for a history of metastatic breast cancer had the greatest benefit from abemaciclib therapy (p = 0.001).Conclusions. Despite a relatively difficult group of patients (96% of patients with visceral metastases), abemaciclib has demonstrated efficacy and safety. The effectiveness did not depend on the analyzed factors: Ki-67, the level of expression of progesterone receptors, the type of metastatic disease (de novo metastatic or progressive breast cancer). In view of the best results, it is advisable to prescribe abemaciclib in the early lines of therapy

Induction of ovarian steroidogenesis as an additional potential risk factor for progression in premenopausal patients with hormone-receptor-positive breast cancer receiving tamoxifen as adjuvant therapy

Introduction. Patients with hormone-receptor-positive (HR+) breast cancer (BC) over 40 years old who take tamoxifen are not subject to mandatory castration. However this cohort of patients is not homogeneous.Aim. The present study is aimed at studying the features of ovarian steroidogenesis in perimenopausal breast cancer patients receiving adjuvant hormone therapy (HT) with tamoxifen.Materialy and methods. The study included 82 patients aged 42 to 53 years with GH+BC who received HT with tamoxifen 20 mg daily. Within 9 months from the start of HT in patients, the levels of estradiol and follicle-stimulating hormone in the peripheral blood were studied every 3 months.Results. In 66.7% of patients who received chemotherapy (CT), the development of amenorrhea was noted. Half of the patients in the HT-only group demonstrated amenorrhea. Oligomenorrhea was observed in 20.8% and 16.7% in each group, respectively. The incidence of amenorrhea in women treated with chemotherapy was higher (OR 2.02; 95% CI: 0.73-5.67), but the differences were not statistically significant (p = 0.1766). In the general cohort, in 15.7-16.8% of patients, the level of estradiol exceeded 251 pg / ml - the upper limit of the norm of the follicular phase of the menstrual cycle. Differences between groups in the incidence of estradiol levels > 251 pg/ml were statistically significant (p = 0.0293). 3.4-5.6% of patients in the total cohort (depending on the period of observation) had an estradiol level > 649 pg / ml, which corresponded to the highest ovulatory value.Conclusions. Against the background of HT with tamoxifen in some perimenopausal patients hyperestrogenism is observed which indicates the implementation of the effect of induction of ovarian steroidogenesis and can be considered as an additional potential risk factor for the progression of HR+BC. Amenorrhea after CT is not a reliable marker of ovarian suppression

Эффективность и безопасность комбинации ленватиниба и эверолимуса у больных диссеминированным раком почки, прогрессирующим на фоне антиангиогенной таргетной терапии: второй анализ данных российского многоцентрового наблюдательного исследования

Objective. The primary endpoint was progression-free survival; secondary endpoints included overall survival, objective response rate and duration, tumor control rate and duration, as well as safety profile of lenvatinib with everolimus in consecutive patients with advanced renal cell carcinoma who had disease progression after targeted antiangiogenic therapy.Materials and methods. This observational study included 129 consecutive patients with metastatic renal cell carcinoma resistant to targeted antiangiogenic therapy. The median age was 60 years; a male to female ratio was 3.1:1. Twenty-seven patients (20.9 %) had ECOG performance status of 2—4. The majority of study participants (n = 127; 98.4 %) had multiple metastases. Tumor lesions were located in >1 organ in 104 cases (80.6 %). The primary tumor was removed in 110 (85.3 %), including 39 (30.2 %) patients undergone cytoreductive surgery. Seventy patients (54.2 %) had earlier received more than one line of therapy. Upon enrollment, there were 13 IMDC favourable-risk patients (10.1 %), 86 IMDC intermediate-risk patients (66.6 %), and 29 IMDC poor-risk patients (22.5 %). In one patient (0.8 %), the IMDC risk was not estimated. All patients received lenvatinib at a dose of 18 mg/day and everolimus at a dose of 5 mg/day. The median follow-up was 10.5 (1—30) months.Results. Median progression-free survival was 14.9 (11.9—17.9) months; overall survival was 19.9 (15.2—24.6) months. The objective response rate was 17.0 % (median duration 9.7 (2.8—16.5) months); tumor control rate was 72.9 % (median duration 10.0 (2.5—17.5) months). Adverse events were observed in 112patients (86.8 %) with grade III—IVadverse events registered in 27participants (20.9 %). Five participants (3.9 %) needed inpatient treatment of adverse events; one patient (0.8 %) died due to adverse events. Adverse events required treatment discontinuation in 4 patients (3.1 %), treatment interruption in 35 patients (27.1 %), and dose reduction in 33 patients (25.6 %).Conclusion. The results of the secondary analysis in the ROSLERCM observational study confirmed the results obtained earlier on the efficacy and safety of the lenvatinib plus everolimus combination in the second- and subsequent-line therapy for advanced renal cell carcinoma resistant to targeted antiangiogenic therapy in consecutive Russian patients.Цель. Первичной конечной точкой являлась беспрогрессивная выживаемость, вторичными — общая выживаемость, частота и длительность ответа на лечение и контроля над опухолью, а также профиль безопасности комбинации ленватиниба и эверолимуса у неотобранных пациентов с распространенным почечно-клеточным раком, прогрессирующим после антиангиогенной таргетной терапии.Материалы и методы. В наблюдательное исследование последовательно включены 129 больных диссеминированным почечноклеточным раком, резистентным к антиангиогенной таргетной терапии. Медиана возраста — 60 лет, соотношение мужчин и женщин — 3,1:1. Соматический статус расценен как ECOG 2—4у 27 (20,9 %) больных. У127 (98,4 %) пациентов имелись множественные метастазы. Опухолевые очаги локализовались в >1 органе в 104 (80,6 %) случаях. Первичная опухоль удалена у 110 (85,3 %) больных, в 39 (30,2%) наблюдениях — с циторедуктивной целью. Ранее >1 линии предшествующей терапии получали 70 (54,2 %) больных. На момент включения в исследование к группе благоприятного прогноза по шкале IMDC относились 13 (10,1 %), промежуточного — 86 (66,6 %), неблагоприятного — 29 (22,5 %) больных; группа прогноза не определена у 1 (0,8 %) пациента. Всем больным назначали ленватиниб 18мг/сут с эверолимусом 5мг/сут. Медиана наблюдения за всеми пациентами составила 10,5 (1—30) мес. Результаты. Медиана беспрогрессивной выживаемости достигла 14,9(11,9—17,9) мес, общей выживаемости — 19,9(15,2—24,6) мес. Частота объективного ответа составила 17,0 % (медиана длительности — 9,7(2,8—16,5) мес), частота контроля над опухолью — 72,9 % (медиана длительности — 10,0 (2,5—17,5) мес). Нежелательные явления зарегистрированы у 112 (86,8 %), в том числе, III—IV степеней тяжести — у 27 (20,9 %) больных. Госпитализация для коррекции нежелательных явлений потребовалась в 5 (3,9 %) случаях, 1 (0,8 %) пациент умер из-за нежелательных явлений. Нежелательные явления послужили причиной отмены терапии в 4 (3,1 %), перерыва в лечении — в 35 (27,1 %), редукции дозы — в 33 (25,6 %) случаях.Заключение. Результаты второго анализа наблюдательного исследования ROSLERCM подтвердили ранее полученные результаты применения комбинации ленватиниба с эверолимусом во 2-й и последующих линиях терапии распространенного почечно-клеточного рака, рефрактерного к антиангиогенному лечению, у неотобранных российских больных

Role of Hydrogen Bonding in Photoinduced Electron–Proton Transfer from Phenols to a Polypyridine Ru Complex with a Proton-Accepting Ligand

Electron–proton transfer (EPT) from phenols to a triplet metal-to-ligand charge transfer (MLCT)-excited Ru polypyridine complex containing an uncoordinated nitrogen site, <b>1­(T)</b>, can be described by a kinetic model that accounts for the H-bonding of <b>1­(T)</b> to phenol, <b>1­(T)</b> to solvent, and phenol to solvent. The latter plays a major role in the kinetic solvent effect and commonly precludes simultaneous determination of the EPT rate constant and <b>1­(T)</b>-phenol H-bonding constant. A number of these quantities previously reported for similar systems are shown to be in error due to inconsistent data analysis. Control experiments replacing either <b>1­(T)</b> by its structural isomer with a sterically screened nitrogen site or phenol by its H-bonding surrogate, trifluoroethanol, and the observation of negative activation enthalpies for the overall reactions between <b>1­(T)</b> and phenols lend support to the proposed model and provide evidence for the formation of a precursor H-bonded complex between the reactants, which is a prerequisite for EPT