First-line PARP inhibitor maintenance treatment in ovarian carcinoma for older adult women: a review of the current literature.

Ovarian cancer (OC) is the leading cause of death in women with gynecological cancers. Its diagnosis is more likely in advanced ages, with the older population being the most seen in consultations. Poly(ADP-ribose) inhibitors (PARPi) have changed OC clinical practice and evolution, showing great benefit. However, there is a lack of evidence of PARPi in elderly population that can impact the therapeutic decision and the safety/efficacy. It is necessary to avoid age as limiting factor in PARPis prescription. We conducted a review of the most relevant randomized phase III trials of maintenance PARPi after first-line treatment of advanced OC. We observed the lack of a single criterion for considering older patients, varying among trials. There is a benefit of PARPis in different populations. However, PARPi effect on quality of life is not reported, something of great relevance considering their vulnerability. Measures are needed to benefit older patients to better adapt PARPi treatment.

Prevalence of DNA-Repair Gene mutations in Mexican men with prostate cancer.

INTRODUCTION AND OBJECTIVE: Mexico reported 26,742 new cases of prostate cancer in 2020. Different risk factors have been identified in the pathogenesis of prostate cancer. Among them, genetic factors and alterations or mutations in specific genes have been described in different ethnic groups worldwide. The aim of our study is to report the prevalence of germline DNA-repair gene mutations in Mexican patients with prostate cancer. MATERIAL AND METHOD: We performed germline genetic testing in 50 patients with localized prostate cancer and 50 patients with metastatic prostate cancer. Demographic, clinical, and histopathological data were collected. RESULTS: Thirty-seven germline mutations were identified in 32 patients. The most commonly affected genes were ATM in 6%, followed by FANCA (5%), and ATR (4%). BRCA2 mutations were identified in 3%. The frequency of mutations was higher in the metastatic group. DISCUSSION AND CONCLUSION: The results of our study show different mutations from those reported in different populations or regions. The use of PARP inhibitors is indicated in patients with germline mutations, specifically BRCA2, showing improvement in overall survival and progression free survival. To our knowledge, this is the first study reporting the prevalence of mutations in DNA-repair genes in Mexican patients with prostate cancer.

A Comprehensive Analysis of the Effect of A>I(G) RNA-Editing Sites on Genotoxic Drug Response and Progression in Breast Cancer.

Dysregulated A>I(G) RNA editing, which is mainly catalyzed by ADAR1 and is a type of post-transcriptional modification, has been linked to cancer. A low response to therapy in breast cancer (BC) is a significant contributor to mortality. However, it remains unclear if there is an association between A>I(G) RNA-edited sites and sensitivity to genotoxic drugs. To address this issue, we employed a stringent bioinformatics approach to identify differentially RNA-edited sites (DESs) associated with low or high sensitivity (FDR 0.1, log2 fold change 2.5) according to the IC50 of PARP inhibitors, anthracyclines, and alkylating agents using WGS/RNA-seq data in BC cell lines. We then validated these findings in patients with basal subtype BC. These DESs are mainly located in non-coding regions, but a lesser proportion in coding regions showed predicted deleterious consequences. Notably, some of these DESs are previously reported as oncogenic variants, and in genes related to DNA damage repair, drug metabolism, gene regulation, the cell cycle, and immune response. In patients with BC, we uncovered DESs predominantly in immune response genes, and a subset with a significant association (log-rank test p < 0.05) between RNA editing level in LSR, SMPDL3B, HTRA4, and LL22NC03-80A10.6 genes, and progression-free survival. Our findings provide a landscape of RNA-edited sites that may be involved in drug response mechanisms, highlighting the value of A>I(G) RNA editing in clinical outcomes for BC.

Análise de custo de sequência de tratamento de câncer de ovário avançado, HRD/ BRCAwt, sob a perspectiva do sistema de saúde suplementar brasileiro / Cost Analysis of advanced ovarian cancer treatment sequence, HRD/BRCAwt from the Brazilian supplementary healthcare system perspective

Objetivo: Estimar o custo da sequência de tratamento considerando as terapias com niraparibe e bevacizumabe, respectivamente, como terapias de manutenção de 1L e 2L para pacientes com câncer de ovário (CO) epitelial com deficiência de recombinação homóloga (HRD) e BRCA selvagem (BRCAwt) em um horizonte temporal de cinco anos, sob a perspectiva do sistema de saúde suplementar brasileiro. Métodos: Foi desenvolvido um modelo de sobrevida particionado com três transições de estados de saúde, considerando os seguintes regimes em 1L e 2L, respectivamente: carboplatina + paclitaxel seguido de terapia de manutenção com niraparibe; carboplatina + gencitabina + bevacizumabe seguido pela continuação de bevacizumabe. As posologias em bula e as curvas de sobrevida livre de progressão dos respectivos estudos pivotais em cada uma das linhas terapêuticas foram utilizadas na análise, e o custo de tratamento foi calculado a partir da lista oficial de preços de medicamentos da CMED de abril de 2023. Resultados: O custo em 1L e 2L foi de BRL 868.830 e BRL 403.407, totalizando BRL 1.272.237 em um horizonte temporal de cinco anos, com 2,28 e 0,52 anos de vida livre de progressão, respectivamente, na 1L e 2L, com o total de 2,8 anos. Conclusões: O resultado da análise de custo de sequência de tratamento de câncer de ovário HRD/BRCAwt apresentou um custo total estimado de BRL 1.272.237, com 2,8 anos de vida livre de progressão. Essa análise contribui no entendimento dos custos e da eficácia esperada com o uso da terapia de manutenção de niraparibe em 1L e bevacizumabe em 2L em um horizonte temporal de cinco anos.

Objective: To estimate the cost of the treatment sequence, considering the maintenance therapies niraparib and bevacizumab, respectively, as maintenance therapies in 1L and 2L for patients with epithelial ovarian cancer with homologous recombination deficiency (HRD) and BRCA wild-type (BRCAwt) over a 5-year time horizon from the perspective of the Brazilian supplementary health system. Methods: A partitioned survival model was developed with three health state transitions, considering the following regimens in the 1L and 2L, respectively: carboplatin + paclitaxel followed by maintenance therapy with niraparib; carboplatin + gemcitabine + bevacizumab followed by the continuation of bevacizumab. The product's label and progression-free survival curves from the respective pivotal studies in each of the therapeutic lines were used in the analysis and the cost of treatment was calculated using as a reference the official CMED drug price list from April 2023. Results: The cost in 1L and 2L was BRL 868,830 and BRL 403,407, totaling BRL 1,272,237 over a 5-year period, with 2.28 and 0.52 years of progression-free survival, respectively in 1L and 2L, with a total of 2.8 years. Conclusions: The result of the analysis of the cost of the treatment sequence of ovarian cancer HRD/BRCAwt presented an estimated total cost of 1,272,237 with 2.8 year of progression-free survival. This analysis contributes to understand the expected cost and effectiveness with the use of maintenance therapy niraparib in 1L and bevacizumab in 2L over a 5-year time horizon.

A Benchmark of In-House Homologous Recombination Repair Deficiency Testing Solutions for High-Grade Serous Ovarian Cancer Diagnosis.

Homologous recombination deficiency (HRD) has become an important prognostic and predictive biomarker for patients with high-grade serous ovarian cancer who may benefit from poly-ADP ribose polymerase inhibitors (PARPi) and platinum-based therapies. HRD testing provides relevant information to personalize patients' treatment options and has been progressively incorporated into diagnostic laboratories. Here, we assessed the performance of an in-house HRD testing system deployable in a diagnostic clinical setting, comparing results from two commercially available next-generation sequencing (NGS)-based tumor tests (SOPHiA DDMTM HRD Solution and AmoyDx® (HRD Focus Panel)) with the reference assay from Myriad MyChoice® (CDx). A total of 85 ovarian cancer samples were subject to HRD testing. An overall strong correlation was observed across the three assays evaluated, regardless of the different underlying methods employed to assess genomic instability, with the highest pairwise correlation between Myriad and SOPHiA (R = 0.87, p-value = 3.39 × 10-19). The comparison of the assigned HRD status to the reference Myriad's test revealed a positive predictive value (PPV) and negative predictive value (NPV) of 90.9% and 96.3% for SOPHiA's test, while AmoyDx's test achieved 75% PPV and 100% NPV. This is the largest HRD testing evaluation using different methodologies and provides a clear picture of the robustness of NGS-based tests currently offered in the market. Our data shows that the implementation of in-house HRD testing in diagnostic laboratories is technically feasible and can be reliably performed with commercial assays. Also, the turnaround time is compatible with clinical needs, making it an ideal alternative to offer to a broader number of patients while maintaining high-quality standards at more accessible price tiers.

Triple-negative breast cancer: from none to multiple therapeutic targets in two decades.

Triple-negative breast cancers (TNBCs) are more likely to occur in younger patients and have a poor prognosis. They are highly heterogeneous tumors consisting of different molecular subtypes. The only common characteristic among them is the absence of targets for endocrine therapy and human epidermal growth factor receptor 2 (HER2) blockade. In the past two decades, there has been an increased understanding of these tumors from a molecular perspective, leading to their stratification according to new therapeutic strategies. TNBC has ushered breast carcinomas into the era of immunotherapy. The higher frequency of germline BRCA mutations in these tumors enables targeting this repair defect by drugs like PARP inhibitors, resulting in synthetic lethality in neoplastic cells. Additionally, we have the identification of new molecules to which this generation of smart drugs, such as antibody-drug conjugates (ADCs), are directed. In this review, we will discuss the trajectory of this knowledge in a systematic manner, presenting the molecular bases, therapeutic possibilities, and biomarkers.

RAD50 Deficient in a Breast Cancer Model Predicts Sensitivity to PARP Inhibitors.

BACKGROUND: Breast and ovarian tumors with pathogenic variants in BRCA1 or BRCA2 genes are more sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi) treatment than wildtype tumors. Pathogenic variants in non-BRCA1/2 homologous recombination repair genes (HRR) also concede sensitivity to PARPi treatment. RAD50 participates in the Mre11-RAD50-Nbn (MRN) complex of the HRR pathway and plays an important role in DNA repair. OBJECTIVE: The objective of this study is to evaluate whether RAD50 protein deficiency modulates the PARPi response in breast cancer cell lines. METHODS: T47D breast cancer cell line was modified using small interfering RNA and CRISPR/Cas9 technology, to knockout the RAD50 gene. PARPi response (niraparib, olaparib and rucaparib alone or in combination with carboplatin), in T47D and T47D-edited clones, was evaluated by cell viability, cell cycle, apoptosis and protein expression analyses. RESULTS: Treatment with niraparib and carboplatin exerted a synergistic effect on T47D-RAD50 deficient cells and an antagonistic effect on T47D cells parental. Cell cycle analysis demonstrated an increase in the G2/M population in cells treated with niraparib or rucaparib alone or in combination with carboplatin. T47D-RAD50 deficient cells treated with rucaparib and carboplatin exhibited twofold levels in late apoptosis, also showing differences in PARP activation. All T47D RAD50 deficient clones treated with niraparib or rucaparib combined with carboplatin, or rucaparib alone showed increased levels of H2AX phosphorylation. CONCLUSIONS: T47D RAD50 deficient cells treated with PARP inhibitors alone or in combination with carboplatin showed cell cycle arrest in the G2/M phase, leading to death by apoptosis. Thus, RAD50 deficiency may be a good biomarker for predicting PARPi response.

Deoxycytidine kinase (dCK) inhibition is synthetic lethal with BRCA2 deficiency.

BRCA2 is a well-established cancer driver in several human malignancies. While the remarkable success of PARP inhibitors proved the clinical potential of targeting BRCA deficiencies, the emergence of resistance mechanisms underscores the importance of seeking novel Synthetic Lethal (SL) targets for future drug development efforts. In this work, we performed a BRCA2-centric SL screen with a collection of plant-derived compounds from South America. We identified the steroidal alkaloid Solanocapsine as a selective SL inducer, and we were able to substantially increase its potency by deriving multiple analogs. The use of two complementary chemoproteomic approaches led to the identification of the nucleotide salvage pathway enzyme deoxycytidine kinase (dCK) as Solanocapsine's target responsible for its BRCA2-linked SL induction. Additional confirmatory evidence was obtained by using the highly specific dCK inhibitor (DI-87), which induces SL in multiple BRCA2-deficient and KO contexts. Interestingly, dCK-induced SL is mechanistically different from the one induced by PARP inhibitors. dCK inhibition generates substantially lower levels of DNA damage, and cytotoxic phenotypes are associated exclusively with mitosis, thus suggesting that the fine-tuning of nucleotide supply in mitosis is critical for the survival of BRCA2-deficient cells. Moreover, by using a xenograft model of contralateral tumors, we show that dCK impairment suffices to trigger SL in-vivo. Taken together, our findings unveil dCK as a promising new target for BRCA2-deficient cancers, thus setting the ground for future therapeutic alternatives to PARP inhibitors.

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

Expert consensus to optimize the treatment of elderly patients with luminal metastatic breast cancer.

Most patients diagnosed with luminal metastatic breast cancer (MBC) who are seen in oncology consultations are elderly. MBC in elderly patients is characterized by a higher percentage of hormone receptor (HR) expression and a lower expression of human epidermal growth factor receptor 2 (HER2). The decision regarding which treatment to administer to these patients is complex due to the lack of solid evidence to support the decision-making process. The objective of this paper is to review the scientific evidence on the treatment of elderly patients with luminal MBC. For this purpose, the Oncogeriatrics Section of the Spanish Society of Medical Oncology (SEOM), the Spanish Breast Cancer Research Group (GEICAM) and the SOLTI Group appointed a group of experts who have worked together to establish consensus recommendations to optimize the treatment of this population. It was concluded that the chronological age of the patient alone should not guide therapeutic decisions and that a Comprehensive Geriatric Assessment (CGA) should be performed whenever possible before establishing treatment. Treatment selection for the elderly population should consider the patient's baseline status, the expected benefit and toxicity of each treatment, and the impact of treatment toxicity on the patient's quality of life and functionality.

BRCAness as a Biomarker of Susceptibility to PARP Inhibitors in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most common primary brain cancer. GBMs commonly acquire resistance to standard-of-care therapies. Among the novel means to sensitize GBM to DNA-damaging therapies, a promising strategy is to combine them with inhibitors of the DNA damage repair (DDR) machinery, such as inhibitors for poly(ADP-ribose) polymerase (PARP). PARP inhibitors (PARPis) have already shown efficacy and have received regulatory approval for breast, ovarian, prostate, and pancreatic cancer treatment. In these cancer types, after PARPi administration, patients carrying specific mutations in the breast cancer 1 (BRCA1) and 2 (BRCA2) suppressor genes have shown better response when compared to wild-type carriers. Mutated BRCA genes are infrequent in GBM tumors, but their cells can carry other genetic alterations that lead to the same phenotype collectively referred to as 'BRCAness'. The most promising biomarkers of BRCAness in GBM are related to isocitrate dehydrogenases 1 and 2 (IDH1/2), epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN), MYC proto-oncogene, and estrogen receptors beta (ERß). BRCAness status identified by accurate biomarkers can ultimately predict responsiveness to PARPi therapy, thereby allowing patient selection for personalized treatment. This review discusses potential biomarkers of BRCAness for a 'precision medicine' of GBM patients.

Novel combinatorial strategies for boosting the efficacy of immune checkpoint inhibitors in advanced breast cancers.

The year 2019 witnessed the first approval of an immune checkpoint inhibitor (ICI) for the management of triple negative breast cancers (TNBC) that are metastatic and programmed death ligand (PD)-L1 positive. Extensive research has focused on testing ICI-based combinatorial strategies, with the ultimate goal of enhancing the response of breast tumors to immunotherapy to increase the number of breast cancer patients benefiting from this transformative treatment. The promising investigational strategies included immunotherapy combinations with monoclonal antibodies (mAbs) against human epidermal growth factor receptor (HER)-2 for the HER2 + tumors versus cyclin-dependent kinase (CDK)4/6 inhibitors in the estrogen receptor (ER) + disease. Multiple approaches are showing signals of success in advanced TNBC include employing Poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, MEK inhibitors, phosphatidylinositol 3­kinase (PI3K)/protein kinase B (AKT) signaling inhibitors or inhibitors of adenosine receptor, in combination with the classical PD-1/PD-L1 immune checkpoint inhibitors. Co-treatment with chemotherapy, high intensity focused ultrasound (HIFU) or interleukin-2-ßÉ£ agonist have also produced promising outcomes. This review highlights the latest combinatorial strategies under development for overcoming cancer immune evasion and enhancing the percentage of immunotherapy responders in the different subsets of advanced breast cancers.

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.

PARP Inhibitors as Therapeutic Options for Tyrosine Kinase-dependent Leukemia: A Review.

The idea of utilizing poly-ADP-ribose polymerase inhibitors (PARPi) as therapeutics for cancer has grown in popularity since its original approval for clinical usage in treatment of BRCA DNA repair-associated-mutated ovarian cancer. In this study, we evaluated experimental data regarding in vitro studies utilizing PARPi as a treatment for tyrosine kinase (TK)-dependent leukemia. Studies from 2015 to 2019 were compiled and the ones with most relevant TK pathways and PARP inhibition were analyzed. PARPi showed activity against many leukemia cell lines and samples from patients with primary leukemia, especially when combined with other signaling pathway inhibitor drugs, improving upon the hypothesis that the utilization of PARPi has potential as a new therapeutic approach in treatment of primary leukemia and TK-dependent leukemia.

Landscape of Germline Mutations in DNA Repair Genes for Breast Cancer in Latin America: Opportunities for PARP-Like Inhibitors and Immunotherapy.

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) genes are present in about 50% of cases of hereditary breast cancer. Proteins encoded by these genes are key players in DNA repair by homologous recombination (HR). Advances in next generation sequencing and gene panels for breast cancer testing have generated a large amount of data on gene variants implicated in hereditary breast cancer, particularly in genes such as PALB2, ATM, CHEK2, RAD51, MSH2, and BARD1. These genes are involved in DNA repair. Most of these variants have been reported for Caucasian, Jewish, and Asian population, with few reports for other communities, like those in Latin American (LA) countries. We reviewed 81 studies from 11 LA countries published between 2000 and 2019 but most of these studies focused on BRCA1/2 genes. In addition to these genes, breast cancer-related variants have been reported for PALB2, ATM, CHEK2, BARD1, MLH1, BRIP1, MSH2, NBN, MSH6, and PMS2 genes. Some of these variants are unique to LA populations. This analysis may contribute to enhance breast cancer variant characterization, and thus to find therapies and implement precision medicine for LA communities.

Genomic-Based Therapy of Gynecologic Malignancies.

This paper will review the current status of genomic-based therapy of gynecologic malignancies. The routine "standard-of-care" delivery of targeted therapeutics based on the presence of specific molecular biomarkers in the management of the gynecologic malignancies has been delayed compared to the substantial progress made in several other tumor types. However, relatively recently reported and rather robust phase 3 trial data have confirmed a potentially major role for PARP inhibitors as both active treatment and maintenance therapy of advanced ovarian cancer. Further, data demonstrating the presence of a specific molecular phenotype (micro-satellite ( instability high - MSI-H) is a valid biomarker for the potential clinical utility of checkpoint inhibitor immunotherapy has relevance for all gynecologic malignancies, and particularly in the setting of metastatic or recurrent endometrial cancer. CONCLUSIONS: The introduction of PARP inhibitors into the oncology armamentarium has substantially impacted standard-of-care strategies in the management of ovarian cancer. It is anticipated that the results of ongoing and future trials will further define the role of genomic-based therapy in ovarian cancer and other gynecologic malignancies.

DNA Repair Proteins as Therapeutic Targets in Ovarian Cancer.

Epithelial ovarian cancer is a serious public health problem worldwide with the highest mortality rate of all gynecologic cancers. The current standard-of-care for the treatment of ovarian cancer is based on chemotherapy based on adjuvant cisplatin/carboplatin and taxane regimens that represent the first-line agents for patients with advanced disease. The DNA repair activity of cancer cells determines the efficacy of anticancer drugs. These features make DNA repair mechanisms a promising target for novel cancer treatments. In this context a better understanding of the DNA damage response caused by antitumor agents has provided the basis for the use of DNA repair inhibitors to improve the therapeutic use of DNA-damaging drugs. In this review, we will discuss the functions of DNA repair proteins and the advances in targeting DNA repair pathways with special emphasis in the inhibition of HRR and BER in ovarian cancer. We focused in the actual efforts in the development and clinical use of poly (ADPribose) polymerase (PARP) inhibitors for the intervention of BRCA1/BRCA2-deficient ovarian tumors. The clinical development of PARP inhibitors in ovarian cancer patients with germline BRCA1/2 mutations and sporadic high-grade serous ovarian cancer is ongoing. Some phase II and phase III trials have been completed with promising results for ovarian cancer patients.

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.

Genetics of triple-negative breast cancer: Implications for patient care.

Patients with triple-negative breast cancer (TNBC), defined as lacking expression of the estrogen and progesterone receptors (ER/PR) and amplification of the HER2 oncogene, often have a more aggressive disease course than do patients with hormone receptor-positive breast cancer, including higher rates of visceral and central nervous system metastases, early cancer recurrences and deaths. Triple-negative breast cancer is associated with a young age at diagnosis and both African and Ashkenazi Jewish ancestry, the latter due to three common founder mutations in the highly penetrant cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2). In the past decade, there has been a surge both in genetic testing technology and in patient access to such testing. Advances in genetic testing have enabled more rapid and less expensive commercial sequencing than could be imagined only a few years ago. Massively parallel, next-generation sequencing allows the simultaneous analysis of many different genes. Studies of TNBC patients in the current era have revealed associations of TNBC with mutations in several moderate penetrance breast cancer susceptibility genes, including PALB2, BARD1, BRIP1, RAD51C and RAD51D. Interestingly, many of these genes, like BRCA1/2, are involved in homologous recombination DNA double-stranded repair. In this review, we summarize the current understanding of pathogenic germline gene mutations associated with TNBC and the early detection and prevention strategies for women at risk of developing this high-risk breast cancer subtype. Furthermore, we discuss recent the advances in targeted therapies for TNBC patients with a hereditary predisposition, including the role of poly (ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2 mutation-associated breast cancers.