Tumors of female reproductive systemTumors of female reproductive systemОпухоли женской репродуктивной системы1994-40981999-8627Publishing House ABV Press70310.17650/1994-4098-2020-16-1-55-64MAMMOLOGY. REVIEWSМАММОЛОГИЯ. ОБЗОРНЫЕ СТАТЬИPARP1 inhibitors in breast cancer therapy. Mechanism of action and clinical useИнгибиторы PARP1 в терапии рака молочной железы. Механизм действия и клиническое применениеhttps://orcid.org/0000-0002-6763-920XDolgashevaD. S.ДолгашеваД. C.
Russian Federation

Дарья Сергеевна Долгашева

normikus.18.97@gmail.comhttps://orcid.org/0000-0002-9657-9058PevznerA. M.ПевзнерА. М.
Russian Federation
https://orcid.org/0000-0001-8815-2786IbragimovaM. K.ИбрагимоваМ. К.
Russian Federation
https://orcid.org/0000-0002-0714-8927LitvyakovN. V.ЛитвяковН. В.
Russian Federation
https://orcid.org/0000-0001-7419-4512TsyganovM. M.ЦыгановМ. М.
Russian Federation
Oncology Research Institute, Tomsk National Medical Research Center of the Russian Academy of SciencesНаучно-исследовательский институт онкологии ФГБНУ «Томский национальный исследовательский медицинский центр Российской академии наук»National Tomsk State Research UniversityФГАОУ ВО «Национальный исследовательский Томский государственный университет»0906202016155640906202009062020https://ojrs.abvpress.ru/ojrs/article/view/703

It is known that currently PARP inhibitors are actively used in the treatment of tumors of the female reproductive system. A large number of studies have been presented demonstrating the effectiveness of PARP inhibitors in the treatment of BRCA-associated ovarian cancer. It was found that mutations in the BRCA1 and BRCA2 genes are also characteristic of breast cancer (BC). However, PARP inhibitors are rarely used in clinical practice in the treatment of BC. So far, only olaparib has become the first PARP inhibitor approved for the treatment of metastatic BC. This review presents data over the past ten years showing the high efficiency of PARP inhibitors in the treatment of malignant neoplasms of the mammary gland. In 7 of 28 studies analyzed, positive results were achieved with combined treatment with chemotherapeutic drugs and PARP inhibitors. So, for example, in two studies in the treatment of BRCA-associated BC, the response to treatment in patients was 72.5–73.2 %. Thus, PARP inhibitors are of great interest and are of practical value in the treatment of patients with BC.

Известно, что в настоящее время ингибиторы PARP активно применяются при лечении опухолей женской репродуктивной системы. Было представлено огромное количество исследований, доказывающих эффективность PARP-ингибиторов в терапии BRCA-ассоциированного рака яичников. Установлено, что мутации в генах BRCA1 и BRCA2 характерны и для рака молочной железы (РМЖ). Однако ингибиторы PARP редко применяются в клинической практике при лечении РМЖ. На данный момент только олапариб стал первым ингибитором PARP, одобренным для лечения метастатического РМЖ. В представленном обзоре приведены данные за последние 10 лет, показывающие высокую эффективность PARP-ингибиторов при лечении злокачественных новообразований молочной железы. В 7 из 28 проанализированных исследований положительные результаты были достигнуты при комбинированном лечении химиотерапевтическими препаратами и ингибиторами PARP. Так, например, в 2 работах при лечении BRCA-ассоциированного РМЖ ответ на терапию у пациенток составил 72,5–73,2 %. Таким образом, ингибиторы PARP представляют большой интерес и имеют практическую ценность при лечении больных РМЖ.

breast cancerPARP1inhibitorschemotherapytreatment effectprogression-free survivalрак молочной железыPARP1ингибиторыхимиотерапияэффект лечениявыживаемость без прогрессированияThe work was supported by the Russian Science Foundation grant No. 19-75-00027 “Study of the somatic status of BRCA1 gene in breast tumors for personalized treatment”.Работа поддержана грантом РНФ № 19-75-00027 «Исследование соматического статуса гена BRCA1 в опухоли молочной железы для персонализированного назначения лечения».De Murcia J.M., Ricoul M., Tartier L. et al. Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse. EMBO J 2003;22(9):2255–63. DOI: 10.1093/emboj/cdg206.Citarelli M., Teotia S., Lamb R.S. Evolutionary history of the poly-(ADP-ribose) polymerase gene family in eukaryotes. BMC Evol Biol 2010;10(1):308. DOI: 10.1186/1471-2148-10-308Hassa P.O., Haenni S.S., Elser M. et al. Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going? Microbiol Mol Biol Rev 2006;70(3):789–829. DOI: 10.1128/MMBR.00040-05.Piskunova T.S., Yurova M.N., Zabezhinski M.A. et al. Poly-(ADP-ribosa)-polymerase – the relationships with life span and carcinogenesis. Uspekhi gerontologii = Advances in Gerontology 2007;20(2):82–90. (In Russ.).Пискунова Т.C., Юрова М.Н., Забежинский М.А. и др. Поли-(АДФ-рибоза)-полимераза – связь с продолжительностью жизни и канцерогенезом. Успехи геронтологии 2007;20(2):82–90.Efremova A.S., Shram S.I., Myasoedov N.F., Doxorubicin causes transient activattion of protein poly-ADF-ribosylation in H9c2 cardiomyocytes. Doklady Akademii nauk = Reports of the Academy of Sciences 2015;464(6):745–9. (In Russ.). DOI: 10.7868/S0869565215300246.Ефремова А.С., Шрам С.И., Мясоедов Н.Ф. Доксорубицин вызывает временную активацию процесса поли-АДФ-рибозилирования белков в клетках H9c2. Доклады Академии наук 2015;464(6):74–9. DOI: 10.7868/S0869565215300246.Chiarugi A., Moskowitz M.A. PARP-1 a perpetrator of apoptotic cell death? Science 2002;297(5579):200–1. DOI: 10.1126/science.1074592.Langelier M.F., Pascal J.M. PARP-1 mechanism for coupling DNA damage detection to poly-(ADP-ribose) synthesis. Curr Opin Struc Biol 2013;23(1):134–43. DOI: 10.1016/j.sbi.2013.01.003.Alkhatib H.M., Chen D., Cherney B. et al. Cloning and expression of cDNA for human poly-(ADP-ribose) polymerase. Proc NAS 1987;84(5):1224–8. DOI: 10.1073/pnas.84.5.1224.Konecny G.E., Kristeleit R.S. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Brit J Cancer 2016;115(10):1157–73. DOI: 10.1038/bjc.2016.311.Ramus S.J., Gayther S.A. The contribution of BRCA1 and BRCA2 to ovarian cancer. Mol Oncol 2009;3(2):138–50. DOI: 10.1016/j.molonc.2009.02.001.Neuhausen S.L., Ozcelik H., Southey M.C. et al. BRCA1 and BRCA2 mutation carriers in the Breast Cancer Family Registry: an open resource for collaborative research. Breast Cancer Res Treat 2009;116(2):379–86. DOI: 10.1007/s10549-008-0153-8.Ledermann J.A. PARP inhibitors in ovarian cancer. Ann Oncol 2016;27(1):40–4. DOI: 10.1093/annonc/mdw094.Ledermann J., Harter P., Gourley C. et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. New Engl J Med 2012;366(15):1382–92. DOI: 10.1056/NEJMoa1105535.Mirza M.R., Monk B.J., Herrstedt J. et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. New Engl J Med 2016;375(22):2154–64. DOI: 10.1056/NEJMoa1611310.Balasubramaniam S., Beaver J.A., Horton S. et al. FDA approval summary: rucaparib for the treatment of patients with deleterious BRCA mutation-associated advanced ovarian cancer. Clin Cancer Res 2017;23(23):7165–70. DOI: 10.1158/1078-0432.CCR-17-1337.Malone K.E., Daling J.R., Doody D.R. et al. Prevalence and predictors of BRCA1 and BRCA2 mutations in a populationbased study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res 2006;66(16):8297–308. DOI: 10.1158/0008-5472.CAN-06-0503.Tutt A., Robson M., Garber J.E. et al. Oral poly-(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010;376(9737):235–44. DOI: 10.1016/S0140-6736(10)60892-6.Kaufman B., Shapira-Frommer R., Schmutzler R.K. et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33(3):244–50. DOI: 10.1200/JCO.2014.56.2728.Robson M., Im S.A., Senkus E. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. New Engl J Med 2017;377(6):523–33. DOI: 10.1056/NEJMoa1706450.Plummer M., de Martel C., Vignat J. et al. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Global Health 2016;4(9):609–16. DOI: 10.1016/S2214-109X(16)30143-7.Weil M.K., Chen A.P. PARP inhibitor treatment in ovarian and breast cancer. Curr Probl Cancer 2011;35(1):7–50. DOI: 10.1016/j.currproblcancer.2010.12.002.Ahmad A., Robinson A.R., Duensing A. et al. ERCC1-XPF endonuclease facilitates DNA double-strand break repair. Mol Cell Biol 2008;28(16):5082–92. DOI: 10.1128/MCB.00293-08.Shuck S.C., Short E.A.,Turchi J.J. Eukaryotic nucleotide excision repair: from understanding mechanisms to influencing biology. Cell Res 2008;18(1):64–72. DOI: 10.1038/cr.2008.2.Sy S.M., Huen M.S., Chen J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci USA 2009;106(17):7155–60. DOI: 10.1073/pnas.0811159106.O’Shaughnessy J., Osborne C., Pippen J. et al. Efficacy of BSI-201, a poly-(ADPribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial. J Clin Oncol 2009;27(18):3. DOI: 10.1200/jco.2009.27.18_suppl.3.O’Shaughnessy J., Osborne C., Pippen J. et al. Final results of a randomized phase II study demonstrating efficacy and safety of BSI-201, a poly-(ADP-ribose) polymerase (PARP) inhibitor, in combination with gemcitabine/carboplatin (G/C) in metastatic triple negative breast cancer (TNBC). Cancer Res 2009;69(24 Suppl):abstract 3122. DOI: 10.1158/0008-5472.SABCS-09-3122.Isakoff S., Overmoyer B., Tung N. et al. A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. J Clin Oncol 2010;28(15):1019. DOI: 10.1200/jco.2010.28.15_suppl.1019.Moulder S., Mita M., Bradley C. et al. A phase 1b study to assess the safety and tolerability of the PARP inhibitor iniparib (BSI-201) in combination with irinotecan for the treatment of patients with metastatic breast cancer (MBC). Cancer Res 2010;70(24 Suppl):abstract P6-15-01. DOI: 10.1158/0008-5472.SABCS10-P6-15-01.Gelmon K.A., Tischkowitz M., Mackay H. et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011;12(9):852–61. DOI: 10.1016/S1470-2045(11)70214-5.O’Shaughnessy J., Osborne C., Pippen J.E. et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. New Engl J Med 2011;364(3):205–14. DOI: 10.1056/NEJMoa1011418.Isakoff S.J., Overmoyer B., Tung N.M. et al. A phase II trial expansion cohort of the PARP inhibitor veliparib (ABT888) and temozolomide in BRCA1/2 associated metastatic breast cancer. Cancer Res 2011;71(24 Suppl):abstract P3-16-05. DOI: 10.1158/0008-5472.SABCS11-P3-16-05.Tan A., Toppmeyer D., Stein M. et al. Phase I trial of veliparib, (ABT-888), a poly-(ADP-ribose) polymerase (PARP) inhibitor, in combination with doxorubicin and cyclophosphamide in breast cancer and other solid tumors. J Clin Oncol 2011;29(15):3041. DOI: 10.1200/jco.2011.29.15_suppl.3041.Dent R.A., Lindeman G.J., Clemons M. et al. Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first-or second-line treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Res 2013;15(5):R88. DOI: 10.1186/bcr3484.Kaufman B., Shapira-Frommer R., Schmutzler R.K. et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation: An open-label phase II study. J Clin Oncol 2013;31(15):11024. DOI: 10.1200/jco.2013.31.15_suppl.11024.Liu J.F., Tolaney S.M., Birrer M. et al. A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer 2013;49(14):2972–8. DOI: 10.1016/j.ejca.2013.05.020.Telli M.L., Jensen K.C., Vinayak S. et al. Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumor-based measure of genomic instability: PrECOG 0105. J Clin Oncol 2015;33(17):1895–901. DOI: 10.1200/JCO.2014.57.0085.Rodler E.T., Kurland B.F., Griffin M. et al. Phase I study of veliparib (ABT-888) combined with cisplatin and vinorelbine in advanced triple-negative breast cancer and/or BRCA mutation-associated breast cancer. Clin Cancer Res 2016;22(12):2855–64. DOI: 10.1158/1078-0432.CCR-15-2137.Drew Y., Ledermann J., Hall G. et al. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly-(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Brit J Cancer 2016;114(7): 723–30. DOI: 10.1038/bjc.2016.41.Kummar S., Wade J.L., Oza A.M. et al. Randomized phase II trial of cyclophosphamide and the oral poly-(ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer. Invest New Drugs 2016;34(3):355–63. DOI: 10.1007/s10637-016-0335-x.Somlo G., Frankel P.H., Arun B.K. et al. Efficacy of the PARP inhibitor veliparib with carboplatin or as a single agent in patients with germline BRCA1- or BRCA2- associated metastatic breast cancer: California Cancer Consortium Trial NCT01149083. Clin Cancer Res2017;23(15):4066–76. DOI: 10.1158/1078-0432.CCR-16-2714.Somlo G., Frankel P.H., Luu T.H. et al. Efficacy of the PARP inhibitor (PI) ABT-888 (veliparib [vel]) either with carboplatin (carb) or as a single agent followed by post-progression therapy in combination with carb in patients (pts) with BRCA1- or BRCA2-(BRCA)-associated metastatic breast cancer (MBC). J Clin Oncol 2015;33(15):520. DOI: 10.1200/jco.2015.33.15_suppl.520.Robson M.E., Im S.-A., Senkus E. et al. OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). J Clin Oncol 2017;35(18 Suppl):LBA4. DOI: 10.1200/JCO.2017.35.18_suppl.LBA4.Loibl S., O’Shaughnessy J., Untch M. et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol 2018;19(4):497–509. DOI: 10.1016/S1470-2045(18)30111-6.Litton J.K., Rugo H.S., Ettl J. et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. New Engl J Med 2018;379(8):753–63. DOI: 10.1056/NEJMoa1802905.Litton J., Rugo H.S., Ettl J. et al. Abstract GS6-07: EMBRACA: A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician’s choice of therapy in patients with advanced breast cancer and a germline BRCA mutation. Cancer Res 2018;78(4). DOI: 10.1158/1538-7445.SABCS17-GS6-07.Konstantinopoulos P.A., Waggoner S.E., Vidal G.A. et al. TOPACIO/Keynote-162 (NCT02657889): a phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC) – results from ROC cohort. J Clin Oncol 2018;36(15):106. DOI: 10.1200/JCO.2018.36.15_suppl.106.Vinayak S., Tolaney S.M., Schwartzberg L.S. et al. TOPACIO/Keynote-162: Niraparib + pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial. J Clin Oncol 2018;36(15):1011. DOI: 10.1200/JCO.2018.36.15_suppl.1011.Arun B.K., Han H.S., Kaufman B. et al. Abstract PD4-01: First-line veliparib plus carboplatin/paclitaxel in patients with HER2-negative advanced/metastatic gBRCA-associated breast cancer: Planned subgroup analysis from the phase 3 BROCADE3 trial. Am Assoc Cancer Res 2020;80(4 Suppl):abstract PD4-01. DOI: 10.1158/1538-7445.SABCS19-PD4-01.Robson M., Im S.-A., Senkus E. et al. Abstract PD4-03: OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Am Assoc Cancer Res 2020; 80(4 Suppl):abstract PD4-03. DOI: 10.1158/1538-7445.SABCS19-PD4-03.