PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond

Abstract

Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are approved for BRCA1/2 carriers with HER2-negative breast cancer in the adjuvant setting with a high risk of recurrence as well as the metastatic setting. However, the indications for PARPi are broader for patients with other cancer types (e.g., prostate and ovarian cancer), involving additional biomarkers (e.g., ATM, PALB2, and CHEK) and genomic instability scores. Herein, we summarize the data on PARPi and breast cancer and discuss their use beyond BRCA carriers.

Genetic testing and prognosis of sarcomatoid hepatocellular carcinoma patients

“…Mutations in BRCA1/2 confer high-penetrance susceptibility to breast and ovarian cancers, increasing the risk of developing breast cancer by 49–57% and ovarian cancer by 18–40% ( 55 ). Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are effective against tumors with an impaired ability to repair double-strand DNA breaks, and several FDA-approved PARPi are available for treatment of BRCA1/2 carriers with tumors originating at various sites including breast, ovaries, pancreas and prostate ( 53 , 56 ). However, PARPis used in the clinic remain vulnerable to acquired drug resistance currently, many ongoing clinical trials will evaluate the combination therapy of PARPi and other treatments in breast cancers ( 56 ).…”

“…Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are effective against tumors with an impaired ability to repair double-strand DNA breaks, and several FDA-approved PARPi are available for treatment of BRCA1/2 carriers with tumors originating at various sites including breast, ovaries, pancreas and prostate ( 53 , 56 ). However, PARPis used in the clinic remain vulnerable to acquired drug resistance currently, many ongoing clinical trials will evaluate the combination therapy of PARPi and other treatments in breast cancers ( 56 ). NTRK fusions, encoding TRK fusion proteins, are oncogenic drivers of a wide variety of adult and paediatric tumors.…”

Harnessing Epigenetics for Breast Cancer Therapy: The Role of DNA Methylation, Histone Modifications, and MicroRNA

“…Mutations and polymorphisms in them can lead to abnormal cell growth, which can lead to the development of cancer. Among the genes that are associated with the development and progression of breast cancer, the following are currently listed [ 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]: BRCA1 and BRCA2 genes, which have the best documented association with breast cancer; having a mutation in these genes is responsible for a 50–80% risk of breast cancer and a 45% risk of ovarian cancer before the age of 85—with a mutation in the BRCA1 gene and a 31–56% risk of breast cancer and 11–27% of ovarian cancer in BRCA2 mutation [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]; the PALB2 gene, which is responsible for the repair of damaged DNA; carriers of the defective gene have a 35% risk of developing breast cancer before the age of 70 [ 31 , 32 , 33 , 34 , 35 , 36 ]; the CHEK2 gene, which is responsible for the production of a protein that inhibits tumor growth; women with a mutation in this gene have a twice as high a risk of developing breast cancer compared to the general population [ 37 , 38 , 39 , 40 , 41 , 42 ]; the NBN gene, which encodes a protein regulating the DNA repair process and maintaining chromosome stability [ 43 , 44 , 45 , 46 , ...…”

Therapy of BRCA-associated metastatic breast cancer. Efficacy and safety of talazoparib in the real-world clinical practice

“…22 МЕДИЦИНСКИЙ СОВЕТ 2022;16(22): [21][22][23][24][25][26][27][28][29] Таргетная терапия ВВЕДЕНИЕ До 10% больных раком молочной железы (РМЖ) являются носителями наследственных мутаций, приводящих к потере функции генов, участвующих в репарации ДНК и активации контрольных точек клеточного цикла [1,2]. Мутации, нарушаю щие функции двух важнейших генов, ответственных за репарацию ДНК и развитие РМЖ -BRCA1 и BRCA2, обнаруживаются не менее чем у 5% больных РМЖ.…”

“…Подтверждено значимое преимущество ингибиторов PARP над режимами химиотерапии по выбору врача. Высокая частота объективных ответов, значимое увеличение времени без прогрессирования (ВБП) вне зависимости от линии терапии и подтипа опухоли при удовлетворительной переносимости и сохранении высокого качества жизни обосновали применение ингибиторов PARP в качестве приоритетной опции терапии BRCA-ассоциированного Her2-негативного мРМЖ (HER2-gBRCAm + мРМЖ) [22,23].…”