В работе была проанализирована отечественная и зарубежная литература, в которой рассматривается фармакогенетический подход к лечению рака молочной железы, а также приведены результаты клинических исследований, в которых показана роль молекулярно-генетических маркеров в эффективности терапии рака молочной железы. Известно, что аллельные варианты генов могут иметь различное влияние на эффективность лекарственных веществ. Фармакогенетическое значение имеют любые как наследуемые (герминальные), так и случайные (соматические) изменения в геноме пациенток. Как правило, для оценки эффективности и токсичности лекарственных веществ используются наследуемые генетические варианты, в то же время, случайные мутации, а также другие известные для опухолевого генома изменения используются при выборе схемы лечения и создания задела для увеличения эффективности терапии. Одним из перспективных и стремительно развивающихся направлений современной фармакологии является адресная доставка лекарственных препаратов к опухоли. В обзоре обобщаются новые актуальные разработки в области направленного транспорта лекарственных веществ в опухолевую ткань. This review analyzed Russian and international studies focusing on the pharmacogenetic approach to treatment of breast cancer. Also, the authors presented results of clinical studies, which showed the role of molecular genetic markers in the efficacy of breast cancer therapy. Allelic variants of different genes have been shown to exert different influences on drug effects. Both inherited and somatic changes in the patient’s genome are pharmacogenetically significant. Inherited genetic variants are generally used for evaluating efficacy and toxicity of drugs while somatic mutations and other known changes in tumor cells are used primarily for selection of treatment and creation of a base for enhancing the effectiveness of therapy. A promising and rapidly developing field of modern pharmacology is targeted delivery of drugs to the tumor. This review summarized state-of-the-art knowledge of new developments in transport of drugs to tumor tissue.
Цель. Изучение связи полиморфных маркеров генов репарации ДНК ERCC2 (rs13181), ERCC5 (rs17655), транспортного белка ABCB1 (rs1045642, rs2032582) с клиническим ответом и степенью патоморфологической регрессии (ПР) опухоли у беременных женщин с онкологическими заболеваниями после ХТ препаратами платины.
Background. Breast cancer is the most common cancer among women. Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, in which there are no special targets for therapy. Therefore chemotherapy is still leading treatment for TNBC including the regiments with platinum drugs.Aim. To study the association of polymorphic markers of the genes XRCC1 (rs25487), ERCC5 (rs17655), TP53 (rs1042522), CDKN1A1 (rs1801270) with progression-free survival (PFS) and overall survival (OS) of TNBC patients after platinum-based neoadjuvant chemotherapy.Materials and methods. Polymorphic markers of the XRCC1, ERCC5, CDKN1A and TP53 genes were studied in blood samples of 67 patients with stage II–III TNBC by real-time polymerase chain reaction with fluorescent allele-specific probes. The results of determining the markers were compared with PFS and OS using the Kaplan–Meyer method and the log-rank-test.Results. The association was found for the polymorphic marker rs25487 of the XRCC1 gene with PFS (carrying the T/T genotype was associated with a decrease of median PFS: 15.6 months versus 34.3 months, p = 0.013) and OS (carrying the T allele was associated with a decrease of median OS: 24.3 months versus 34.6 months, p = 0.041) without depending on the BRCA status. For the polymorphic marker rs17655 of the ERCC5 gene, significant difference in PFS was obtained in the period from 15.4 to 60.0 months of follow-up (the carrier of the C allele was associated with a decrease of median PFS: 20.0 months versus 35.2 months, p = 0.035). When considering the genotypes of the polymorphic marker of the ERCC5 gene differences were revealed between patients with the C/C genotype (M = 15.9 months) and two other genotypes (M = 33.6 months), p = 0.039. For the polymorphic marker rs1801270 of the CDKN1A gene significant differences in PFS were obtained in the period from 15.4 to 60.0 months of follow-up (for carriers of allele A, a decrease in median PFS was observed: 16.6 months versus 32.0 months, p = 0.046). For the polymorphic marker of the TP53 gene (rs1042522) a tendency to decrease OS for carriers of the C/C genotype was found seems promising for further study.Conclusion. The association of the studied polymorphic markers of the genes XRCC1 (rs25487), ERCC5 (rs17655) and CDKN1A (rs1801270) with PFS was revealed in patients with TNBC. Association with OS was obtained for the polymorphic marker of the XRCC1 gene (rs25487). These data may allow for further validation to individualize the treatment of this category of patients.
e12556 Background: Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. There are no special targets for neoadjuvant therapy of TNBC, and leading treatment for TNBC is chemotherapy including the regiments with platinum drugs. The aim of the work was to study the relationship between the polymorphic markers rs25487 of the XRCC1 gene, rs17655 of the ERCC5 gene, rs1042522 of the TP53 gene, rs1801270 of the CDKN1A1 gene with progression-free (PFS) and overall survival (OS) in patients with TNBC after platinum-based neoadjuvant chemotherapy. Methods: The work includes 67 TNBC patients with II-III stage of disease. The samples of blood of patients were collected before chemotherapy. All patients received platinum-based neoadjuvant chemotherapy (docetaxel or paclitaxel in combination with carboplatin/cisplatin). Data on the carriage of mutations in the BRCA 1/2 genes were obtained from medical institutions. DNA was isolated from samples of blood and polymorphic markers of the XRCC1, ERCC5, CDKN1A and TP53 genes were analyzed by real-time PCR with fluorescent allele-specific probes on CFX96 (Bio-Rad). The results were compared the clinical data (PFS and OS) using the Kaplan-Meyer method and the log-rank test. Results: The median follow-up time was 27.6 (minimum 6.4 – maximum 66.9) months. There was an association between carrying the T/T genotype of the polymorphic marker rs25487 of the XRCC1 gene and a decrease of median PFS (15.6 months versus 34.3 months, p = 0.013). The carriage of T allele of this marker was associated with a decrease of median OS (24.3 months versus 34.6 months, p = 0.041). These relationships for the XRCC1 marker were observed without depending on the BRCA status. Significant difference in PFS was obtained for the polymorphic marker rs17655 of the ERCC5 gene in the period from 15.0 to 60.0 months of follow-up. The decrease of median PFS was observed in carriers of the C allele (20.0 months versus 35.2 months, p = 0.035). The differences were more pronounced for carriers of the C/C genotype: the median PFS for carriers of C/C and two other genotypes was 15.9 and 33.6 months, respectively ( p = 0.039). A decrease in median PFS was observed for carriers of allele A of the polymorphic marker rs1801270 of the CDKN1A gene in the period from 15.0 to 60.0 months of follow-up: 16.6 months versus 32.0 months, p = 0.046. A tendency to decrease OS for carriers of the C/C genotype of the polymorphic marker rs1042522 of the TP53 gene was found. Conclusions: We revealed a relationship between the polymorphic markers rs25487 of the XRCC1 gene, rs17655 of the ERCC5 gene, and rs1801270 of the CDKN1A1 gene with PFS in patients with TNBC, as well as a relationship between the polymorphic marker rs25487 of the XRCC1 gene and OS. These data need further validation and may allow individualizing the treatment of patients with TNBC.
Актуальность. Для современной клинической онкологии одной из важнейших целей является развитие персонифицированного подхода в лечении онкологических пациентов. Это связано с высоким уровнем токсичности химиотерапевтических лекарственных средств. Ключевыми препаратами, использующимися в схемах химиотерапии при раке яичников, являются производные платины, сочетающие высокую эффективность и столь же высокую токсичность. Это делает актуальным поиск маркеров чувствительности к данной группе препаратов. Целью данной работы было изучение статуса полиморфных маркеров генов XRCC1, ERCC2 и CDKN1A и их связи с длительностью времени без прогрессирования (ВБП), которое является суррогатным клиническим маркером чувствительности к производным платины при раке яичника. Материалы и методы. В исследование были включены 26 больных распространенным раком яичника (II-IV стадии), у которых до начала химиотерапии, при первичной циторедуктивной операции, был произведен забор образцов опухолевой ткани. После операции все больные получили стандартную химиотерапию с использованием паклитаксела и препаратов платины. Из образцов опухолевой ткани выделяли ДНК с помощью набора Diatom DNA Prep 400 (Россия). Определение статуса полиморфных маркеров Gln399Arg гена XRCC1, Lys751Gln гена ERCC2 и Ser31Arg гена CDKN1A проводили методом ПЦР-ПДРФ и подтверждением результата методом ПЦР в реальном времени с последующим анализом кривых плавления продукта ПЦР. Статус маркеров был сопоставлен с длительностью ВБП. Результаты. Нами выявлена тенденция к большей продолжительности ВБП при наличии аллеля Gln маркера Gln399Arg гена XRCC1 (медиана ВБП составляла 14,1 мес. у больных с наличием аллеля Gln в сравнении с 10,9 мес. в подгруппе больных с отсутствием аллеля Gln, р = 0,095). В подгруппе больных, которым была проведена оптимальная циторедуктивная операция, носительство минорного аллеля Arg маркера Ser31Arg гена СDKN1A ассоциировалось с уменьшением медианы ВБП (19,1 и 12,8 мес. при отсутствии и наличии аллеля Arg соответственно, р = 0,035). Вывод. Выявлена взаимосвязь статуса полиморфных маркеров генов XRCC1 и CDKN1A с длительностью ремиссии после платиносодержащей химиотерапии рака яичника, что делает целесообразным дальнейшее изучение данных молекулярно-генетических факторов на более репрезентативной группе больных раком яичника. Background: The most important goal of current clinical oncology is personalized treatment primarily due to high toxicity of chemotherapeutic drugs. The key drugs used in chemotherapy of ovarian cancer are platinum derivatives, which are both highly effective and highly toxic. Therefore, searching for sensitivity markers for this group of drugs is very relevant. The aim of this work was to study polymorphic markers of XRCC1 and ERCC2 DNA repair genes and the cell cycle regulation gene, CDKN1A, and their relationship with progression-free survival time (PFS), which is a surrogate clinical marker for sensitivity of ovarian cancer to platinum drugs. Materials and methods. The study included 26 patients with advanced ovarian cancer (stage II-IV). Tumor samples were withdrawn from patients before the onset of chemotherapy, during the primary cytoreductive surgery. After surgery, all patients received a standard chemotherapy with paclitaxel and platinum drugs. DNA was isolated from tumor tissue samples using a Diatom DNA Prep 400 kit (Isogen, Russia). The polymorphic markers, Gln399Arg of the XRCC1 gene, Lys751Gln of the ERCC2 gene, and Ser31Arg of the CDKN1A gene were analyzed by PCR-RFLP and real-time PCR melting curves analysis as a reference. The marker status was compared with the duration of PFS. Results. A tendency towards longer duration of PFS was observed in the presence of the Gln allele of Gln399Arg XRCC1 marker (median PFS, 14.1 months in patients with the Gln allele vs. 10.9 months in the subgroup without the Gln allele; p = 0.095). In the subgroup with optimal cytoreductive surgery, carrying the minor Arg allele of the CDKN1A gene Ser31Arg marker was associated with duration of PFS. In the presence of the minor Arg allele, the PFS duration after platinum-containing chemotherapy was statistically significantly decreased (median PFS, 19.08 months in the absence of Arg allele vs. 12.82 months in the presence of Arg allele, p = 0.035). Conclusion. Polymorphic markers of XRCC1 and CDKN1A genes were found to be related with remission duration after platinum-containing chemotherapy of ovarian cancer. This suggests advisability of further studies of these molecular genetic factors on a representative group of patients with ovarian cancer.
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