Clinical application of PARP inhibitors in breast cancer / 国际肿瘤学杂志

Poly adenosine diphosphate ribose polymerase (PARP) inhibitors lead to synthetic lethality in homologous recombination repair-deficient (HRD) tumors by inhibiting DNA damage repair. Two PARP inhibitors, olaparib and talazoparib, have been approved for the salvage treatment of breast cancer susceptibility gene (BRCA) mutation, human epidermal growth factor receptor 2 (HER2) negative advanced breast cancer, and adjuvant treatment of early breast cancer. PAPR inhibitor single agent shows good antitumor activity and controllable safety. A number of clinical studies on PAPR inhibitors combined with chemotherapy, radiotherapy, antiangiogenic therapy and immunotherapy are being carried out. The indications of PARP inhibitors also extend from BRCA mutation to HRD, from ovarian cancer and breast cancer to other solid tumors, promising to benefit more patients in the future.

Tertiary Prevention of Ovarian Cancer After PARP Inhibitor Therapy / 肿瘤防治研究

The tertiary prevention approaches of ovarian cancer include whole-person care, training of the patients to cooperate with physicians in the periods of treatment and follow-up, training program of the qualified surgeons, and recognition of biological behavior changes of relapse after PARPi therapy. Surgery remains the cornerstone in the management of ovarian cancer, but the role of surgery after PARPi remains unknown. Recently, the US FDA withdrew the indication of three PARP inhibitors in the treatment of recurrent ovarian cancer with ≥3 lines of chemotherapy because of their ≥30% increased death risk. Thus, we should pay more attention to the biological recurrence and chemoresistance caused by PARP inhibitors and post-progression survival in ovarian cancer.

Análise de impacto orçamentário dos inibidores de PARP no tratamento de manutenção em primeira linha de pacientes com câncer de ovário avançado, gBRCA mutado, sob a perspectiva do sistema de saúde suplementar brasileiro / Budget impact analysis of PARP inhibitors in the first line maintenance treatment of patients with advanced, gBRCA mutated, ovarian cancer, from the perspective of the Brazilian supplementary health system

Objetivo: O presente artigo visa disponibilizar aos gestores da saúde dados sobre o impacto orçamentário da incorporação dos inibidores de PARP (iPARPs) para o tratamento de primeira linha de manutenção de câncer de ovário avançado, gBRCA mutado, sob a perspectiva do sistema de saúde suplementar. Métodos: Adotou-se o método epidemiológico, tendo como comparador a vigilância ativa em um horizonte temporal de cinco anos. Foram considerados apenas os custos de tratamento medicamentoso na análise, utilizando o pressuposto conservador de que os custos da vigilância ativa são nulos. Além disso, construiu-se uma análise de sensibilidade determinística. Resultados: O impacto orçamentário dos iPARPs na população-alvo em todo o sistema foi de R$ 78,1 milhões em cinco anos acumulados. A análise de sensibilidade apontou que o resultado doimpacto orçamentário varia de R$ 54,6 milhões a R$ 101,6 milhões. A taxa de difusão da tecnologia e os parâmetros epidemiológicos foram os que exerceram a maior influência na variabilidade dos resultados. Conclusão: Os dados sugerem que a incorporação dos iPARPs na população selecionada gera um impacto orçamentário gerenciável.

Objective: The objective was to calculate the budget impact of PARP inhibitors (iPARPs) incorporation for the first-line maintenance treatment of advanced mutated gBRCA ovarian cancer from the perspective of the supplementary health system. Methods: We adopted the epidemiological method, with active surveillance as the comparator in a time horizon of five years. We considered only drug treatment's cost, using a conservative approach in which the costs with active surveillance are null. In addition, we developed a deterministic sensitivity analysis. Results: The budget impact of iPARPs on the target population was R$ 78.1 million in five years. The sensitivity analysis showed that the result of the budget impact ranges from R$ 54.6 million to R$ 101.6 million. The market share evolution and the epidemiological parameters had the highest impact on the result's variability. Conclusion: These data suggest that the incorporation of iPARPs in the selected population generates a manageable budget impact

BRCA mutations: Implications of genetic testing in ovarian Cancer

Ovarian cancer (OC) is one of the most lethal gynecological cancers with a 5?year survival rate that ranges from 30% to 40%. Breast cancer genes (BRCA1 and BRCA2) play a key role in maintaining genomic stability. Mutations in BRCA1/2 genes lead to the accumulation of double?strand breaks, resulting in tumorigenesis. The risk of developing OC in women with BRCA1 and BRCA2 mutations is 39% and 11%, respectively, by 70 years of age. BRCA1/2 mutation testing is thus important to identify women at greatest risk of developing OC in addition to its impact on diagnosis, prognosis, and targeted therapy. Genetic testing is required to identify the BRCA mutations and thus select patients who can benefit from polyadenosine diphosphate (ADP)杛ibose polymerase (PARP) inhibitor therapy. Tumor BRCA mutation testing can detect both germline and somatic mutations allowing implementation of preventive strategies on a broader population. Various international guidelines recommend BRCA1/2 mutation genetic testing in all OC patients irrespective of age and family history. This review focuses on the role of BRCA mutation testing in OC

Management of human epidermal growth factor receptor 2杗egative metastatic breast cancer: Role of poly adenosine diphosphate (ADP?ribose) polymerase inhibitors

Human epidermal growth factor receptor 2 (HER2)?negative subset is the most heterogeneous group of metastatic breast cancers (MBCs) as it includes both hormone receptor (HR)?positive and HR?negative breast cancer (or TNBC), which have different therapies and treatment challenges. Though endocrine therapy (ET) remains the treatment backbone in HR?positive HER2?negative cases, about 40% of the patients show intrinsic or acquired resistance to ET due to multiple mechanisms. Combining different therapies such as ET and other targeted therapies with or without chemotherapy fails to give continued benefit, unlike cyclin?dependent kinase (CDK) 4/6 inhibitors that have shown a great benefit. TNBC has conventionally been treated ineffectively with systemic chemotherapy. Recently, poly (ADP?ribose) polymerase inhibitors (PARPi) have emerged for HER2?negative breast cancer (BC) patients, including TNBC. Olaparib and talazoparib have recently been approved in germline BRCA?mutated (gBRCAm) HER2?negative MBC. Additionally, ongoing trials of PARPi in combination with various therapies are expected to provide more and better treatment options for gBRCAm HER2?negative breast cancer.

A review on mechanisms of resistance to PARP inhibitors

Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP?ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA?associated cancers, especially high?grade OC and breast cancers. They lead to synthetic lethality in BRCA?mutated cells by stalling the replication forks in homologous recombination?deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA?associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance

Cáncer de mama triple negativo: terapias sistémicas actuales y experiencia local / Triple negative breast cancer: current systemic therapy and local experience

Resumen El cáncer de mama (CM) es la principal causa de muerte por cáncer en mujeres chilenas. Es una enfermedad heterogénea, en la cual se han identificado cuatro subtipos básicos, determinados según características clínicas, histológicas y moleculares, los que se relacionan a estrategias terapéuticas. El CM triple negativo (CMTN) se caracteriza por su agresividad, recaída temprana y mayor tendencia a presentarse en etapas avanzadas. Frecuentemente afecta a mujeres jóvenes o con antecedentes familiares de CM u ovario. La única terapia sistémica aprobada para el CMTN es la quimioterapia; sin embargo, recientemente terapias moleculares con inhibidores de puntos de control inmune e inhibidores de la poli-adenosina difosfato ribosa polimerasa, han mostrado eficacia en pacientes seleccionados, y se han agregado al arsenal terapéutico para CMTN. Dada la aparición de estas nuevas estrategias, parece relevante entender la heterogeneidad de esta enfermedad, los mecanismos de acción de las nuevas terapias, resultados clínicos y criterios de selección de pacientes para terapias moleculares. Presentamos una revisión de la terapia sistémica actual del CMTN.

Breast cancer is the leading cause of cancer death in Chilean women and worldwide. It is a heterogeneous disease and four different subtypes have been identified based on clinical, histological and molecular features, which correlate with different treatment tumor sensitivity. Triple negative breast cancer is characterized by its aggressiveness, early relapse, and a greater tendency to present in advanced stages. It frequently affects young women, with cancer family history, especially breast or ovarian cancer. The approved systemic therapy for triple negative breast cancer is chemotherapy; however, recently, targeted therapies with checkpoint inhibitors and polyadenosine diphosphate ribose polymerase inhibitors have been shown to be effective in selected patients and have been added to the therapeutic arsenal for triple negative breast cancer. Given the appearance of these new strategies, it seems relevant to understand the heterogeneity of this disease, the mechanisms of action behind new therapies, clinical results, and the criteria to select patients for molecular therapies. We present a review of the current systemic therapy of this breast cancer subtype.

Progress in the application of poly ADP-ribose polymerase inhibitors in tumor radiotherapy / 中华放射医学与防护杂志

The poly ADP-ribose polymerase (PARP) is a class of nuclear enzymes highly expressed in eukaryotic cells and plays a key role in DNA damage repair. In recent years, PARP inhibitors have shown great potential in tumor therapy, and several PARP inhibitors have been approved by the FDA for maintenance therapy of a variety of cancers. PARP inhibitors mainly inhibit PARP enzymes and PARP trapping, resulting in the persistence of DNA single strand breaks, which are converted to double strand breaks during DNA replication. Studies have shown that PARP inhibitors not only have a significant anti-tumor effect, but also have a synergistic effect with radiotherapy. This paper reviewed the potential theoretical basis of PARP inhibitor combined with radiotherapy, summarized the recent progress of preclinical and clinical research on PARP inhibitors in tumor radiotherapy, sorted out the urgent problems in this field, and looked into the application prospect of PARP inhibitors in anti-tumor therapy.

Progress of PARP inhibitors in breast cancer / 肿瘤研究与临床

PARP inhibitors are a kind of anticancer drugs approved for the clinical treatment of ovarian cancer and primary peritoneal cancer on the basis of the strategy of synthetic lethality. With the publication of two phase Ⅲ clinical trials results, the indications for PARP inhibitors have been expanded to advanced breast cancer with germline BRCA-1/2 mutations. However, the current exploration of PARP inhibitors in breast cancer is still at early stage. This article summarizes the anticancer mechanism of PARP inhibitors and new advances in treatment of breast cancer.

Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management

Ovarian cancer patients with homologous recombination deficiencies exhibit specific clinical behaviors, and improved responses to treatments, such as platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors, have been observed. Germline mutations in the BRCA 1/2 genes are the most well-known mechanisms of homologous recombination deficiency. However, other mechanisms, such as germline and somatic mutations in other homologous recombination genes and epigenetic modifications, have also been implicated in homologous recombination deficiency. The epidemiology and implications of these other mechanisms need to be better understood to improve the treatment strategies for these patients. Furthermore, an evaluation of various diagnostic tests to investigate homologous recombination deficiency is essential. Comprehension of the role of homologous recombination deficiency in ovarian cancer also allows the development of therapeutic combinations that can improve the efficacy of treatment. In this review, we discuss the epidemiology and management of homologous recombination deficiency in ovarian cancer patients.

Research progress of PARP inhibitors in ovarian cancer / 中国生化药物杂志

Ovarian cancer is one of the highest mortality rate of gynecologic malignant tumors. Chemotherapy can improve the survival rate of the traditional ovary. In recent years, PARP [poly(ADP-ribose)polymerase]inhibitors in breast cancer susceptibility gene (breast cancer susceptibility gene, BRCA) mutations in patients with ovarian cancer can significantly improve the disease-free survival, may change the prognosis of patients with ovarian cancer. This part of PARP [poly(ADP-ribose)polymerase] inhibitors, inhibiting the repairment of DNA damage in tumor cell, causing DNA damage accumulation, eventually killing tumor cells.In breast cancer susceptibility gene 1 (breast cancer susceptibility gene1, BRCA1)/BRCA2 mutation patients with ovarian cancer, PARP inhibitors and BRCA mutation of the synthetic lethal effect provides a new direction for the development of anti-cancer drugs. Now, many highly selective and sensitive PARP inhibitors have been developed and applied in clinical trials.Although PARP inhibitor monotherapy can produce a therapeutic effect in BRCA mutation in patients with ovarian cancer, but the clinical application is still used in combination with other chemotherapy or radiotherapy. This review is focused on the recent progress in clinical trials of PARP inhibitors in combination with common chemotherapeutic agents.

Research progress in synthetic lethality targeting DNA repair defects / 肿瘤

The concept of synthetic lethality is defined as a genetic interaction of two non-allelic and non-lethal genes that when mutated simultaneously results in cell death, which has been proposed as a potential way to develop novel antitumor approaches. A new therapeutic approach targeting DNA repair defective genes may remarkably promote the antitumor efficacy based on the mechanism of tumorigenesis induced by DNA repair defects. Previous studies have demontrated that BRCA1 (breast cancer susceptibility gene 1)/BRCA2 or PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene mutation with PARP [poly(ADP-ribose) polymerase] inhibitors could lead to killing effect in cancer cells; deletion of MSH2 (mutS homolog 2) gene with inhibiton of proofreading activity of DNA polβ (polymerase β) and the deletion of MLH1 (mutL homolog 1) gene with inhibiton of proofreading activity of DNA polγ could both lead to killing effect in cancer cells with MMR (mismatch repair) deficiency. PINK1 (PTEN-induced putative kinase 1) may be a potential therapeutic target for the treatment of MMR-deficient cancers with deletion of MSH2, MLH1 or MSH6 gene based on the theory of synthetic lethality. This review descibes the synthetic lethality associated with DNA repair defects. Copyright © 2013 by TUMOR.

Advances in research of PARP inhibitors in combination with chemotherapeutic agents in the treatment of malignant tumors / 肿瘤

In recent years, synthetic lethality of PARP [poly (ADP-ribose) polymerase] inhibition in cancers with BRCA1 (breast cancer susceptibility gene 1) and BRCA2 mutations appears to provide a novel, efficient and safe antitumor strategy. It was hypothesized that the mechanism underlying this new antitumor strategy was the inhibition of DNA damage repair leading to cell death. Since the synthetic lethality was confirmed in breast cancer cells by PARP inhibitor intervention, many highly selective and sensitive PARP inhibitors have been developed and applied in clinical trials. Although the effectiveness of PARP inhibitor used as a single agent can be reached in breast cancer and ovarian cancer with BRCA1 / BRCA2 mutation, it is generally advised to use PARP inhibitors in combination with chemotherapeutic agents or radiation therapy. This review is focused on the recent progress in clinical antitumor therapy with PARP inhibitors in combination with common chemotherapeutic agents. Copyright © 2013 by TUMOR.