Значение герминальной BRCA-мутации при формировании опухолевого микроокружения Эффективность PARP-ингибирования в поздней линии терапии метастатического кастрационно-резистентного рака предстательной железы

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

TREATMENT OF HEAD AND NECK SQUAMOUS CELL CARCINOMA ACCORDING ON THE SPECIFIC MOLECULAR FEATURES OF THE TUMOR (A LITERATURE REVIEW)

Despite the achieved progress in radiotherapy, chemotherapy, and surgery, head and neck squamous cell carcinoma (HNSCC) still remains the sixth most common cause of death from cancer worldwide. The division of HNSCC into 2 large groups with different survival rates is a significant achievement made during the last decades in cancer research and treatment of head and neck cancer. In 45 % – 90 % of cases, oropharyngeal squamous cell carcinoma is presumably associated with human papillomavirus (HPV). A recent whole-exome sequencing study on HNSCC helped to develop new principles of treatment that will allow to increase the effectiveness of conventional therapy. The study demonstrated that inactivating mutations in the p53 gene trigger carcinogenesis. The majority of tumors have such mutations that inactivate the p53 tumor suppressor gene. According to the results of sequencing, HPV-positive and HPV-negative tumors have completely different mutation profiles. Intratumoral heterogeneity should be taken into account when implementing new treatment approaches. We present an overview of studies published between 1989 and 2014. Current review briefly describes molecular mechanisms of carcinogenesis in HNSCC in the light of genetic and biochemical features of the tumor, paying particular attention to the most significant scientific achievements in this field. Moreover, we outline the advancements of wholeexome sequencing in HNSCC and give an overview of recent studies devoted to new therapeutic approaches. The process of carcinogenesis in HNSCC is often initiated by tumor suppressors. In this case, the development of target-based drugs is problematic. Target therapy focused on the ways of tumor growth suppression is a much more serious challenge than inhibition of oncogenic signals, because it requires reactivation of tumor suppressors and restoration of their functions, which is more difficult than conventional chemical and biological blockage. Poor survival of patients with HNSCC, which is usually associated with a small size of recurrent tumors, their latent growth, and localization in various anatomical areas, shows that there is an urgent need for developing new therapeutic approaches for the disease. The study was aimed to analyze specific molecular features of head and neck tumors and to explore the opportunities of providing personalized care for these patients

Human papillomavirus-associated oropharyngeal carcinoma: trends in epidemiology and methods for detecting the virus in tumors

Oropharyngeal squamous cell carcinoma has been traditionally associated with tobacco and alcohol consumption. Nevertheless, latter 30 years have shown squamous cell carcinoma (OPSCC) incidence stagnation and increasing, despite the decrease in smoking prevalence. The incidence was recognized among white men of middle age, often non-smokers or former smokers in the investigations with smoking cessation data. It differs from traditional patient with OPSCC, older men, heavy smoker or alcohol drinker. The incidence of OPSCC is increased due human papilloma virus (HPV) infection. The infection transition is associated with sex and oro-genital contact may lead to HPV-infection of oropharynx and oral cavity. There are multiple types of HPV, but the majority of OPSCC is associated with HPV 16 type. Epidemiology of HPV-associated OPSCC, HPV-infection of oral cavity and/or oropharynx and HPV detection are discussed in the review