Cancer UrologyCancer UrologyОнкоурология1726-97761996-1812Publishing House ABV Press151910.17650/1726-9776-2021-17-3-85-94DIAGNOSIS AND TREATMENT OF URINARY SYSTEM TUMORS. PROSTATE CANCERДИАГНОСТИКА И ЛЕЧЕНИЕ ОПУХОЛЕЙ МОЧЕПОЛОВОЙ СИСТЕМЫ. Рак предстательной железыGerminal BRCA-mutation significance in the tumor microenvironment formation Efficacy of PARP inhibition in late-line therapy of metastatic castration-resistant prostate cancerЗначение герминальной BRCA-мутации при формировании опухолевого микроокружения Эффективность PARP-ингибирования в поздней линии терапии метастатического кастрационно-резистентного рака предстательной железыhttps://orcid.org/0000-0002-0698-7710StukanA. I.СтуканьА. И.
Russian Federation

Anastasiya Igorevna Stukan

146 Dimitrova St., Krasnodar 350040; 4 Mitrofana Sedina St., Krasnodar 350063

Анастасия Игоревна Стукань

350063 Краснодар, ул. Митрофана Седина, 4; 350040 Краснодар, ул. Димитрова, 146

jolie86@bk.ruhttps://orcid.org/0000-0001-7127-7945GoryainovaA. Yu.ГоряйноваА. Ю.
Russian Federation

146 Dimitrova St., Krasnodar 350040; 4 Mitrofana Sedina St., Krasnodar 350063

350063 Краснодар, ул. Митрофана Седина, 4; 350040 Краснодар, ул. Димитрова, 146

RigerN. A.РигерН. А.
Russian Federation

146 Dimitrova St., Krasnodar 350040

350040 Краснодар, ул. Димитрова, 146

https://orcid.org/0000-0002-8715-2992SharovS. V.ШаровС. В.
Russian Federation

146 Dimitrova St., Krasnodar 350040; 4 Mitrofana Sedina St., Krasnodar 350063

350063 Краснодар, ул. Митрофана Седина, 4; 350040 Краснодар, ул. Димитрова, 146

ShatokhinaA. S.ШатохинаА. С.
Russian Federation

146 Dimitrova St., Krasnodar 350040

350040 Краснодар, ул. Димитрова, 146

ChukhrayO. Yu.ЧухрайО. Ю.
Russian Federation

146 Dimitrova St., Krasnodar 350040

350040 Краснодар, ул. Димитрова, 146

https://orcid.org/0000-0003-3041-520XAndreevD. V.АндреевД. В.
Russian Federation

146 Dimitrova St., Krasnodar 350040; 4 Mitrofana Sedina St., Krasnodar 350063

350063 Краснодар, ул. Митрофана Седина, 4; 350040 Краснодар, ул. Димитрова, 146

Clinical Oncologic Dispensary No. 1ГБУЗ Клинический онкологический диспансер № 1Kuban State Medical University, Ministry of Health of RussiaФГБОУ ВО Кубанский государственный медицинский университет» Минздрава РоссииKuban State Medical University, Ministry of Health of RussiaФГБОУ ВО Кубанский государственный медицинский университет Минздрава РоссииKuban State Medical University, Ministry of Health of RussiaФГБОУ ВО Кубанский государственный медицинский университет Минздрава России1111202117385941011202110112021https://oncourology.abvpress.ru/oncur/article/view/1519

Metastatic castration-resistant prostate cancer is a difficult problem for a clinical oncologist. In addition, mutations in genes of homologous DNA recombination, including BRCA1/2, suggest an aggressive behavior and therapy resistance. Treatment options for such patients were significantly limited until new drugs - PARP inhibitors have been registered. Nevertheless, there is evidence that BRCA1/2 gene mutations are associated with increased mutational load, neoepitopes formation, increased number of tumor-infiltrating lymphocytes and a response to the immune response checkpoints blockade. Studies have shown that BRCA2-mutated prostate cancer demonstrates high level of immune cells infiltration compared to tumors without mutation, in particular with respect to CD4+, CD8+ and FOXP3+ T-lymphocytes. It should be noted that studies have shown a tendency of CD8+ T-lymphocytes/FOXP3+ T-cells ratio decreasing in BRCA2-mutated tumors. Thus, the mutational status of BRCA2 presumably forms the immune phenotype of prostate cancer with an increase of intratumoral immune cells, but with immunosuppressive properties. At the same time, the use of immune checkpoint blockers in advanced prostate cancer has been unsuccessful in terms of overall survival. Despite the fact that immune checkpoint blocker's efficacy is often associated with a high intracellular CD4+ and CD8+ T lymphocytes, their presence is clearly insufficient for response. Studies showed that PARP inhibitors effect tumor microenvironment significantly. Anti-PD-1/PD-L1 combination with PARP inhibitors is being actively studied due to their properties of modulating the tumor microenvironment. Thus, future immunooncological strategies for primary prostate cancer therapy may include not only an increase in mutational load, but also an impact on the immunosuppressive microenvironment. The article presents clinical cases of 3 brothers, carriers of the germinal BRCA2 c.9371A>T mutation, suffering from prostate cancer with a burdened family history. The disease development under standard therapies was studied and markers of the tumor microenvironment were immunohistochemically evaluated. PARP inhibitor Olaparib efficacy in prostate cancer of older brother in late-line therapy for metastatic castration-resistant disease was analyzed.

Метастатический кастрационно-резистентный рак предстательной железы является сложной проблемой для клинического онколога. Кроме этого, наличие мутации в генах гомологичной рекомбинации ДНК, в том числе BRCA1/2, предполагает агрессивное течение и резистентность к проводимой терапии. До регистрации новой группы препаратов - PARP-ингибиторов - опции лечения таких больных были существенно ограниченны. Тем не менее есть данные о том, что мутации генов BRCA1/2 связаны с повышенной мутационной нагрузкой, образованием неоэпитопов, увеличением количества инфильтрирующих опухоль лимфоцитов и ответом на блокаду контрольных точек иммунного ответа. В исследованиях показано, что BRCA2-мутированный рак предстательной железы обладает высоким уровнем инфильтрации иммунными клетками по сравнению с опухолями без мутации, в частности в отношении Т-лимфоцитов, экспрессирующих CD4, CD8 и FOXP3. Следует отметить, что в исследованиях наблюдалась тенденция к снижению отношения CD8+-Т-лимфоцитов к FOXP3+-Т-клеткам в BRCA2-мутированных опухолях. Таким образом, мутационный статус BRCA2 предположительно формирует иммунный фенотип рака предстательной железы с увеличением количества интратуморальных иммунных клеток, но с иммуносупрессивными свойствами. При этом использование блокаторов контрольных точек иммунитета при распространенном раке предстательной железы до сих пор было в значительной степени безуспешным в отношении показателей общей выживаемости пациентов. Несмотря на то что эффективность блокаторов контрольных точек иммунитета зачастую связана с высоким содержанием внутриопухолевых CD4+- и CD8+-Т-лимфоцитов, их присутствия явно недостаточно для ответа. Как показано в исследованиях, ингибиторы PARP способны оказывать существенное влияние на микроокружение опухоли. Активно изучается комбинация анти-PD-VPD-Lt с ингибиторами PARP за счет их свойств модулирования микроокружения опухоли. Таким образом, будущие онкоиммунологические стратегии первичной терапии рака предстательной железы могут включать не только повышение мутационной нагрузки, но и воздействие на иммуносупрессивное микроокружение. В статье представлены случаи развития рака предстательной железы у 3 братьев, носителей герминальной мутации гена BRCA2 c.9371A>T с отягощенным семейным анамнезом. Изучено клиническое течение заболевания при применении стандартных методов терапии, иммуногистохимически оценены маркеры микроокружения опухоли. Проанализирована эффективность использования PARP-ингибитора олапариба у одного из братьев в поздней линии терапии при метастатическом кастрационно-резистентном заболевании.

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