Breast cancer (BC) is the most common female cancer and the first leading cause of cancer death in women. Luminal phenotypes represent about 70% of this disease. Treatment for metastatic hormone-dependent HER2-negative breast cancer in most cases involves various lines of endocrine therapy since their sequential use improves overall and relapse-free survival while maintaining a high quality of life. Disease progression during such therapy may be associated with the development of primary or secondary resistance to the treatment. The reason for the secondary resistance is both a mutation of receptors for steroid hormones and activation of new signaling pathways. The study of these mechanisms has led to the creation of highly effective drug combinations for the treatment of hormone-positive HER2-negative metastatic breast tumors. To date, clinical trials of three agents from the group of cyclin-dependent kinases has been developed and successfully completed: palbociclib, ribociclib and abemaciclib. These agents in combination with non-steroidal aromatase inhibitors or estrogen receptor antagonists in randomized clinical trials increased direct treatment efficacy, overall survival and progression-free survival rates. Clinical case of a menopausal patient with metastatic hormone-positive HER2-negative breast cancer with visceral metastases who received successive chemotherapy and a combination of the highly selective oral kinase inhibitor CDK4\6 ribocyclib with the aromatase inhibitor letrozole allowed to achieve a response to therapy for 27 months with CR for 8 months. The safety profile was satisfactory; side effects included grade 2 neutropenia, grade 1 arthralgia, grade 1 hyperglycemia and grade 1 increase in urea which did not had an adverse effect on the patient's quality of life.
The purpose of this study was to research the effectiveness of molecular genetic tests based on the determination of the rs4673 CYBA polymorphism (c.242C>T) and the level of paraoxonase 1 (PON1) in the blood plasma of patients with breast cancer (BC) for predicting and diagnosing anthracycline-mediated cardiotoxicity (AMC). The genotyping of rs4673 CYBA (c.242C>T) and the study of the PON1 level in the blood plasma of 280 patients of the Caucasian type with a histologically verified diagnosis of breast cancer, who received complex treatment on the basis of the National Medical Research Center of Oncology, were carried out. Based on the results of observation for at least 8 months, two groups were identified: group 1 (257 people) without diagnosed cardiovascular changes; group 2 (23 people) - patients with subacute and early chronic AMC. It was found that carriers of the rs4673 polymorphism increase the likelihood of developing AMC by 6.8 times (p = 0.001). In the blood plasma of both groups of patients, an increase in the level of PON1 was described after the fourth course compared to the initial level (group 1 - p = 0.036, group 2 - p = 0.048). The level of the studied enzyme was higher in the blood plasma of patients with diagnosed AMC compared with patients without cardiovascular complications (before chemotherapy - p = 0.001, after the fourth course - p = 0.023). The test based on the measurement of the concentration of PON1 in the blood plasma of patients after the fourth course of chemotherapy was distinguished by high quality metrics: sensitivity - 100%, specificity - 70.8%, area under the ROC-curve (AUC) - 0.825 with a threshold level of PON1 equal to 2, 9 ng/μL. The presence of the T/T genotype caused a high level of PON1 in the blood plasma after the fourth course of chemotherapy (p = 0.012). The results of our work are of undoubted practical importance, since they allow us to obtain data on the prognosis and diagnosis of a patient in a short time, which can later be verified using clinical and instrumental methods.
Ростов-на-Дону 2 Больница Christiana Care, г. Ньюарк, штат Делавэр, США РЕЗЮМЕ Ингибиторы иммунных контрольных точек, нацеленные на запрограммированный лиганд гибели клеток PD-L1, стали крупным прорывом в лечении многих онкологических заболеваний. Ниволумаб -это антитело, избирательно блокирующее рецептор PD-1 на поверхности цитотоксических Т-клеток для предотвращения подавления регуляции иммунного ответа. Известно, что ингибиторы иммунных контрольных точек могут вызывать так называемые иммуноопосредованные нежелательные явления, в том числе со стороны эндокринной системы. Сахарный диабет 1 типа является одним из тяжелых редких и потенциально опасных для жизни иммуноопосредованных нежелательных явлений, встречающихся менее чем у 1 % пациентов, получающих лечение ингибиторами иммунных контрольных точек. Хотя общая частота сахарного диабета 1 типа, связанного с ингибитором PD-1, относительно низка, тем не менее он имеет молниеносное течение и может представлять потенциальную угрозу для жизни пациентов, если не будут проведены своевременная диагностика и лечение. Поскольку ингибиторы PD-1 широко используются для лечения многих злокачественных заболеваний, осложнения в виде диабета 1 типа должны привлекать внимание врачей. Кроме того, нельзя не учитывать тот факт, что в ходе лечения врачи должны помогать пациентам лучше распознавать симптомы гипергликемии или диабетического кетоацидоза, что требует тщательного наблюдения за ними во время лечения, регулярного мониторинга уровня глюкозы в плазме крови, оперативного выявления и правильной диагностики и лечения диабета.
The development of a new direction in anticancer medical therapy – the use of immune checkpoint inhibitors targeting PD-1/ PD-L1 and CTLA-4 – has significantly changed the approach to tumor treatment in the last few years. The PD1 blocker nivolumab in major registered clinical trials improved overall survival, including in metastatic melanoma, with a favorable toxicity profile. However, its efficacy in patients with brain metastases from melanoma was poorly studied, since the inclusion criteria for most clinical trials do not envisage recruiting such patients. The immune-mediated toxicity of immune checkpoint inhibitors is currently well enough studied. However, cases of cutaneous toxicity are quite rare and present certain difficulties for differential diagnosis and treatment. This article presents two cases of effective nivolumab treatment in patients with generalized BRAFwt and BRAFmut cutaneous melanoma. The first case is of interest due to the presence of brain metastases in the patient. Nivolumab therapy helped achieving complete regression of intracranial metastases with the long-term effect. The second case, in addition to effective treatment, demonstrates a rare manifestation of skin toxicity – vitiligo on the face and upper extremities.
Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms. The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein‑4 (CTLA‑4) and programmed cell death protein‑1 (PD‑1). Immune checkpoint inhibitors (ICI), which were broadly applied for melanoma treatment in the past decade, can unleash anti-tumor immune responses and result in melanoma regression. Patients responding to the ICI treatment showed long-lasting remission or disease control status. However, a large group of patients failed to respond to this therapy, indicating the development of resistance mechanisms. Among them are intrinsic tumor properties, the dysfunction of effector cells, and the generation of immunosuppressive tumor microenvironment (TME). This review discusses achievements of ICI treatment in melanoma, reasons for its failure, and promising approaches for overcoming the resistance. These methods include combinations of different ICI with each other, strategies for neutralizing the immunosuppressive TME and combining ICI with other anti-cancer therapies such as radiation, oncolytic viral, or targeted therapy. New therapeutic approaches targeting other immune checkpoint molecules are also discussed.
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