Tumors of female reproductive systemTumors of female reproductive systemОпухоли женской репродуктивной системы1994-40981999-8627Publishing House ABV Press93410.17650/1994-4098-2022-18-1-54-65MAMMOLOGY. CLINICAL CASEМАММОЛОГИЯ. КЛИНИЧЕСКИЙ СЛУЧАЙCauses of resistance to PARP inhibitors and ways to overcome it. Case report of aggressive BRCA-related breast cancerПричины резистентности к PARP-ингибированию и возможности ее преодоления. Клинический случай агрессивного течения BRCA-ассоциированного рака молочной железыStukanA. I.СтуканьА. И.
Russian Federation

Anastasiya Igorevna Stukan 

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

 

Анастасия Игоревна Стукань 

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

 

jolie86@bk.ruGoryainovaA. Yu.ГоряиноваА. Ю.
Russian Federation

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

 

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

SharovS. V.ШаровС. В.
Russian Federation

146 Dimitrova St., Krasnodar 350040, Russia

350040 Краснодар, ул. Димитрова, 146

GoncharovaO. A.ГончароваО. А.
Russian Federation

146 Dimitrova St., Krasnodar 350040, Russia

350040 Краснодар, ул. Димитрова, 146

KhachmamukZ. K.ХачмамукЗ. К.
Russian Federation

146 Dimitrova St., Krasnodar 350040, Russia

350040 Краснодар, ул. Димитрова, 146

DurovV. V.ДуровВ. В.
Russian Federation

146 Dimitrova St., Krasnodar 350040, Russia

350040 Краснодар, ул. Димитрова, 146

Clinical Oncology Dispensary No. 1, Ministry of Health of Krasnodar RegionГБУЗ «Клинический онкологический диспансер № 1» Министерства здравоохранения Краснодарского краяKuban State Medical UniversityФГБОУ ВО «Кубанский государственный медицинский университет»08052022181546507052022https://ojrs.abvpress.ru/ojrs/article/view/934

PARP inhibitors. However, in clinical practice, despite the proven antitumor efficacy of drugs, acquired resistance to PARP inhibitors leads to difficulties in selecting further therapy due unknown resistance mechanisms and absence of algorithm of action. Despite the various mechanisms of resistance to PARP inhibitors, the choice of subsequent combination therapy after the detection of resistance to PARP inhibitors should be based on an understanding of these mechanisms and the existence of heterogeneous metastatic process. At the same time, it is very important to study the molecular and genetic characteristics of the disease at each stage of progression, which will help to identify the cause of resistance and select the optimal treatment strategy. It seems that liquid biopsy of circulating tumor DNA, detection of circulating tumor cells, circulating microRNA or exosomes may be more suitable methods of molecular diagnostics than repeated biopsies. Currently, there are data on the identification of two types of resistance to PARP inhibitors: mechanisms independent and dependent on the BRCA1/2 gene and homologous DNA recombination repair (HRR) mechanisms. Strategies for using combinations of different therapeutic regimens in conjunction with PARP inhibitors are very promising options for preventing treatment resistance in view of the increasing number of patients with similar clinical course of the disease.

In the presented clinical case, BRCA1-associated triple-negative breast cancer demonstrates an aggressive clinical course in case of adjuvant chemotherapy absence. Using the example of a clinical case, the effectiveness of therapy with the PARP inhibitor olaparib in disseminated BRCA1-mutated breast cancer, including those with brain metastases, was confirmed. At the same time, against the background of good tolerance and сlinical efficacy especially in the case of brain metastases, the use of the PARP inhibitor olaparib is a worthy alternative to chemotherapeutic regimens. The selection of subsequent therapy after a PARP inhibitor requires a balanced approach, taking into account the possible causes of crossresistance with chemotherapy regimens.

На сегодняшний день опции терапии BRCA-ассоциированного рака молочной железы существенно расширились с появлением нового класса препаратов – PARP-ингибиторов. Однако, несмотря на доказанную противоопухолевую эффективность препаратов, в клинической практике приобретенная резистентность к PARP-ингибиторам приводит к затруднениям в подборе дальнейшей терапии ввиду отсутствия понимания причин резистентности и алгоритма действий. Несмотря на различные механизмы резистентности к PARP-ингибиторам, выбор последующей комбинированной терапии после выявления резистентности к PARP-ингибиторам должен основываться на понимании этих механизмов и существовании гетерогенности метастатического процесса. При этом весьма важно изучать молекулярно-генетические характеристики заболевания на каждом этапе прогрессирования, что поможет выявить причину резистентности и подобрать оптимальную стратегию лечения. Вероятно, выполнение жидкостной биопсии по циркулирующей опухолевой дНК, детекция циркулирующих опухолевых клеток, циркулирующей микроРНК или экзосом могут быть более подходящими методами молекулярной диагностики, чем повторные биопсии. В настоящий момент есть данные о выявлении 2 типов резистентности к PARP-ингибиторам, включающих причины, не зависящие и зависящие от гена BRCA1/2 и механизма репарации путем гомологичной рекомбинации дНК (HRR). стратегии использования комбинаций различных терапевтических режимов совместно с PARP-ингибиторами являются весьма обнадеживающими опциями для предупреждения резистентности к терапии ввиду все возрастающего числа пациентов с подобным клиническим течением заболевания.

В представленном клиническом случае BRCA1-ассоциированный тройной негативный рак молочной железы демонстрирует агрессивное клиническое течение при отказе от адъювантной химиотерапии. также описана эффективность терапии PARP-ингибитором олапарибом при диссеминированном BRCA1-мутированном раке молочной железы, в том числе с метастазами в головной мозг. При этом на фоне хорошей переносимости и контроля над заболеванием, особенно в случае метастазов в головной мозг, применение PARP-ингибитора олапариба составляет достойную альтернативу химиотерапевтическим режимам. Подбор последующей терапии после PARP-ингибитора требует взвешенного подхода именно с учетом возможных причин перекрестной резистентности с химиотерапевтическими режимами.

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