Co-Targeting of DTYMK and PARP1 as a Potential Therapeutic Approach in Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, with no standardized treatment for advanced disease. Based on preliminary bioinformatical analyses DTYMK and PARP1 were selected as potential therapeutic targets. High levels of both proteins were detected in uveal melanoma cells and correlated with increased tumor growth and poor prognosis. In vitro tests on MP41 (BAP1 positive) and MP46 (BAP1 negative) cancer cell lines using inhibitors pamiparib (PARP1) and Ymu1 (DTYMK) demonstrated significant cytotoxic effects. Combined treatment had synergistic effects in MP41 and additive in MP46 cell lines, reducing cell proliferation and inhibiting the mTOR signaling pathway. Furthermore, the applied inhibitors in combination decreased cell motility and migration speed, especially for BAP1-negative cell lines. Our hypothesis of the double hit into tumoral DNA metabolism as a possible therapeutic option in uveal melanoma was confirmed since combined targeting of DTYMK and PARP1 affected all tested cytophysiological parameters with the highest efficiency. Our in vitro findings provide insights into novel therapeutic avenues for managing uveal melanoma, warranting further exploration in preclinical and clinical settings.

BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance.

PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood.We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials.Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene's reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations.

The PARP1 selective inhibitor saruparib (AZD5305) elicits potent and durable antitumor activity in patient-derived BRCA1/2-associated cancer models.

BACKGROUND: Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance. METHODS: Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi. RESULTS: AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (> 386 days vs. 90 days). Mechanistically, AZD5305 induced more replication stress and genomic instability than the PARP1/2 inhibitor olaparib in PARPi-sensitive tumors. All tumors at progression with either PARPi (39/39) showed increase of HRR functionality by RAD51 foci formation. The most prevalent resistance mechanisms identified were the acquisition of reversion mutations in BRCA1/BRCA2 and the accumulation of hypomorphic BRCA1. AZD5305 did not sensitize PDXs with acquired resistance to olaparib but elicited profound and durable responses when combined with carboplatin or ceralasertib in 3/6 and 5/5 models, respectively. CONCLUSIONS: Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option.

Mechanism and rational combinations with GP-2250, a novel oxathiazine derivative, in ovarian cancer.

BACKGROUND: GP-2250, a novel analog of taurultam (TRLT), has emerged as a potent anti-neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP-2250 using in vitro and in vivo models. METHODS: We carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse-phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP-2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP-2250 alone and in combination with standard-of-care drugs (e.g., paclitaxel, cisplatin, topotecan, and poly ADP-ribose polymerase [PARP] inhibitors). RESULTS: We investigated the cytotoxic effect of GP-2250 in 10 ovarian cancer cell lines and found GP-2250 combined with a PARP inhibitor had the greatest synergy. RPPA revealed that GP-2250 inhibited hypoxia-inducible factor-1α, AKT, and mammalian target of rapamycin (mTOR) activation and expression. High-resolution mass spectrometry revealed that hexokinase2 activity and protein expression were significantly reduced by GP-2250 exposure. Furthermore, GP-2250 reduced glycolysis and ATP synthesis in cancer cells. An in vivo pharmacodynamic experiment using the OVCAR8 mouse model demonstrated that 500 mg/kg GP-2250 was effective in downregulating AKT and mTOR activation and expression. In the in vivo therapy experiment using an orthotopic mouse model, a combination of GP-2250 with either PARP inhibitors or bevacizumab showed a significant reduction of tumor weights and nodules compared to those treated with a vehicle, control IgG groups, or monotherapy groups. CONCLUSIONS: Taken together, our data indicate that GP-2250 exerts profound effects on tumor metabolism and, in combination with PARP inhibitors or bevacizumab, showed promising anti-tumor efficacy. These findings could have implications for the clinical development of GP-2250.

53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer.

53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks, thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination in BRCA1-deficient cells. Consequently, BRCA1-mutant tumors, typically sensitive to PARP inhibitors (PARPi), become resistant in the absence of 53BP1. Here, we demonstrate that the 'leaky' DNA end resection in the absence of 53BP1 results in increased micronuclei and cytoplasmic double-stranded DNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer cells, and impedes tumor growth. Loss of 53BP1 correlates with a response to immune checkpoint blockade (ICB) and improved overall survival. Immunohistochemical assessment of 53BP1 in two malignancies, high grade serous ovarian cancer and pancreatic ductal adenocarcinoma, which are refractory to ICBs, reveals that lower 53BP1 levels correlate with an increased adaptive and innate immune response. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Therefore, we conclude that 53BP1 is critical for tumor immunogenicity and underpins the response to ICB. Our results support including 53BP1 expression as an exploratory biomarker in ICB trials for malignancies typically refractory to immunotherapy.

Iron: The Secret Ingredient Breaking PARPi Resistance.

PARP inhibitors (PARPi) are used as a first-line treatment option for cancers with BRCA1/2 mutations, yet a significant number of patients show a limited response to these agents. In the present study, Lei and colleagues demonstrate that PARPi promote increased ferroptosis sensitivity and this can be exploited therapeutically to improve the response to PARPi, marking an important therapeutic concept to exploit ferroptosis-based strategies in clinical settings. See related article by Lei et al., p. 1476 (2).

Targeted Nanocarrier-Based Drug Delivery Strategies for Improving the Therapeutic Efficacy of PARP Inhibitors against Ovarian Cancer.

The current focus of ovarian cancer (OC) research is the improvement of treatment options through maximising drug effectiveness. OC remains the fifth leading cause of cancer-induced mortality in women worldwide. In recent years, nanotechnology has revolutionised drug delivery systems. Nanoparticles may be utilised as carriers in gene therapy or to overcome the problem of drug resistance in tumours by limiting the number of free drugs in circulation and thereby minimising undesired adverse effects. Cell surface receptors, such as human epidermal growth factor 2 (HER2), folic acid (FA) receptors, CD44 (also referred to as homing cell adhesion molecule, HCAM), and vascular endothelial growth factor (VEGF) are highly expressed in ovarian cancer cells. Generation of active targeting nanoparticles involves modification with ligands that recognise cell surface receptors and thereby promote internalisation by cancer cells. Several poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are currently used for the treatment of high-grade serous ovarian carcinomas (HGSOC) or platinum-sensitive relapsed OC. However, PARP resistance and poor drug bioavailability are common challenges, highlighting the urgent need to develop novel, effective strategies for ovarian cancer treatment. This review evaluates the utility of nanoparticles in ovarian cancer therapy, with a specific focus on targeted approaches and the use of PARPi nanocarriers to optimise treatment outcomes.

Application of PARP inhibitors combined with immune checkpoint inhibitors in ovarian cancer.

The advent of polyadenosine diphosphate ribose polymerase inhibitors (PARPi) has brought about significant changes in the field of ovarian cancer treatment. However, in 2022, Rucaparib, Olaparib, and Niraparib, had their marketing approval revoked for third-line and subsequent therapies due to an increased potential for adverse events. Consequently, the exploration of new treatment modalities remains imperative. Recently, the integration of PARPi with immune checkpoint inhibitors (ICIs) has emerged as a potential remedy option within the context of ovarian cancer. This article offers a comprehensive examination of the mechanisms and applications of PARPi and ICIs in the treatment of ovarian cancer. It synthesizes the existing evidence supporting their combined use and discusses key considerations that merit attention in ongoing development efforts.

DNA-Damaging Therapies in Patients With Prostate Cancer and Pathogenic Alterations in Homologous Recombination Repair Genes.

PURPOSE: Outcomes data for DNA-damaging therapeutics for men with prostate cancer (PC) and non-BRCA1/2 homologous recombination repair (HRR) mutations are limited. We evaluated outcomes by HRR alteration in men with PC treated with poly(ADP-ribose)polymerase inhibitors (PARPi) and/or platinum chemotherapy. METHODS: Retrospective data from the PROMISE consortium were used. Clinical outcomes differences were assessed between patients with BRCA1/2 mutations (cohort A) and those with HRR mutations without direct BRCA complex interaction (cohort B: ATM, CDK12, CHEK1, CHEK2, and FANCL). Outcomes in patients with HRR mutations with direct BRCA complex interaction were also explored (cohort C: RAD51B/C/D, RAD54L2, BARD1, GEN1, PALB2, FANCA, and BRIP1). RESULTS: One hundred and forty-six patients received PARPi (cohort A: 94, cohort B: 45, cohort C: 7) and 104 received platinum chemotherapy (cohort A: 48, cohort B: 44, cohort C: 10). PSA50 response rate to PARPi was higher in cohort A (61%) than cohort B (5%), P < .001. Median clinical/radiographic progression-free survival (crPFS) with PARPi in cohort A was significantly longer than in cohort B: 15.9 versus 8.7 months, P = .005. PSA50 response rate to platinum therapy was higher in cohort A (62%) than in cohort B (32%), P = .024, although crPFS was not significantly different. PSA50 response rate to PARPi and platinum was 40% and 32%, respectively, in cohort C. In multivariable analysis, cohort A had significantly improved overall survival and crPFS compared with cohort B with PARPi but not platinum chemotherapy. CONCLUSION: Patients with BRCA1/2-mutated PC had significantly improved outcomes to PARPi but not platinum chemotherapy compared with those with HRR mutations without direct BRCA complex interaction.

PARP enzymes and mono-ADP-ribosylation: advancing the connection from interferon-signalling to cancer biology.

ADP-ribosyltransferases of the PARP family encompass a group of enzymes with variegated regulatory functions in cells, ranging from DNA damage repair to the control of cell-cycle progression and immune response. Over the years, this knowledge has led to the use of PARP1/2 inhibitors as mainstay pharmaceutical strategies for the treatment of ovarian, pancreatic, prostate and breast cancers, holding mutations in genes encoding for proteins involved in the DNA repair mechanisms (synthetic lethality). Meanwhile, the last decade has witnessed significant progress in comprehending cellular pathways regulated by mono-ADP-ribosylation, with a huge effort in the development of novel selective compounds to inhibit those PARPs endowed with mono-ADP-ribosylation activity. This review focuses on the progress achieved in the cancer field, delving into most recent findings regarding the role of a subset of enzymes - the interferon-stimulated PARPs - in cancer progression.

Tolerability of the niraparib individualized starting dose in the PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib first-line maintenance therapy.

PURPOSE: To explore safety and tolerability parameters for the niraparib individualized starting dose (ISD) in patients with newly diagnosed advanced ovarian cancer that responded to platinum-based chemotherapy who participated in the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016). METHODS: The PRIMA protocol was amended so newly enrolled patients received an ISD based on baseline body weight/platelet count. In this ad hoc analysis, the timing, duration, and resolution of the first occurrence of common any-grade hematologic (thrombocytopenia, anemia, neutropenia) and nonhematologic (nausea, asthenia/fatigue, constipation, insomnia, hypertension) treatment-emergent adverse events (TEAEs) were evaluated by treatment arm in the ISD safety population (data cutoff, November 17, 2021; median follow-up, 3.5 years). RESULTS: Of 733 randomized patients, 255 were enrolled after the ISD protocol amendment and received ≥ 1 dose of study treatment (niraparib, 169; placebo, 86). In the niraparib arm, median times to first events were 22.0-35.0 days for hematologic TEAEs and 7.0-56.0 days for nonhematologic TEAEs. First events resolved in ≥ 89.8% of patients for hematologic TEAEs; for nonhematologic TEAEs, resolution rates ranged from 55.3% (insomnia) to 86.0% (nausea). Median durations of first hematologic TEAEs were ≤ 16.0 days, but for first nonhematologic TEAEs ranged from 18.0 days (nausea) to 134.0 days (insomnia). CONCLUSION: The niraparib ISD was generally well tolerated and TEAEs were manageable. Common hematologic and nonhematologic TEAEs occurred early and first events of hematologic TEAEs had a short duration (≈ 2 weeks) and a high resolution rate. These findings support close monitoring immediately following niraparib initiation and may help inform patient expectations for niraparib safety.

Clinical Response to Olaparib in a Patient With Leptomeningeal Carcinomatosis in Newly Diagnosed Breast Cancer With Germline BRCA2 Mutation.

Case of LMC in a BRCA2-mutated breast cancer patient shows clinical improvement with Olaparib therapy.

PARP inhibitor therapy in patients with IDH1 mutated cholangiocarcinoma.

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) missense mutations occur at a frequency of 10%-15% in intrahepatic cholangiocarcinoma (iCCA). IDH1 mutations result in accumulation of (R)-2-hydroxyglutarate, an oncometabolite that leads to DNA hypermethylation and impairment of homologous recombination (HR). Impairment of HR results in a "BRCAness" phenotype which may confer sensitivity to poly(ADP ribose) polymerase (PARP) inhibition. METHODS: We conducted a retrospective cohort review to identify patients with advanced, IDH1 mutated iCCA treated with a PARP inhibitor (PARPi) at the University of Michigan between 2018 and 2023. Patients are described with respect to prior lines of therapy, response to platinum-based chemotherapy, and progression-free survival (PFS) and overall survival (OS) from the time of PARPi initiation. RESULTS: Between 2018 and 2023 we identified 40 patients with IDH1 mutated iCCA of which 6 patients were treated with a PARPi as monotherapy or in combination with an ATR inhibitor or anti-PD-1 immune checkpoint inhibitor. Majority of patients (n = 5) carried an IDH1 R132C mutation per tissue-based next generation sequencing. All patients had previously received at least one line of cisplatin-based systemic therapy for advanced disease prior to treatment with PARPi. PFS and OS from time of PARPi initiation ranged from 1.4 to 18.5 months and 2.8 to 42.4 months, respectively. Best response on PARPi therapy included 2 partial responses. CONCLUSION: This is the first case series to describe PARPi treatment in IDH1 mutated iCCA. Results underscore the limitation of PARPi monotherapy, potentially support combined PARPi therapies, and highlight a need for effective treatment options for patients with IDH1 mutated iCCA.

PARP Inhibitors in Brain Metastases from Epithelial Ovarian Cancer through a Multimodal Patient Journey: Case Reports and Literature Review.

Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Brain metastasis (BM) is quite an uncommon presentation. However, the likelihood of central nervous system (CNS) metastasization should be considered in the context of disseminated disease. The therapeutic management of BMs is an unmet clinical need, to date. We identified, across different cancer centers, six cases of both BRCA wild-type and BRCA-mutated EOCs spreading to the CNS. They presented either with a single brain lesion or with multiple lesions and most of them had intracranial-only disease. All cases received Poly-ADP ribose polymerase inhibitor (PARPi) maintenance, as per clinical practice, for a long time within a multimodal treatment approach. We also provide an insight into the available body of work regarding the management of this intriguing disease setting, with a glimpse of future therapeutic challenges. Despite the lack of unanimous guidelines, multimodal care pathways should be encouraged for the optimal disease control of this unfortunate patient subset. Albeit not being directly investigated in BM patients, PARPi maintenance is deemed to have a valuable role in this setting. Prospective research, aimed to implement worthwhile strategies in the multimodal patient journey of BMs from EOC, is eagerly awaited.

Dynamic immunoediting by macrophages in homologous recombination deficiency-stratified pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, notably resistant to existing therapies. Current research indicates that PDAC patients deficient in homologous recombination (HR) benefit from platinum-based treatments and poly-ADP-ribose polymerase inhibitors (PARPi). However, the effectiveness of PARPi in HR-deficient (HRD) PDAC is suboptimal, and significant challenges remain in fully understanding the distinct characteristics and implications of HRD-associated PDAC. We analyzed 16 PDAC patient-derived tissues, categorized by their homologous recombination deficiency (HRD) scores, and performed high-plex immunofluorescence analysis to define 20 cell phenotypes, thereby generating an in-situ PDAC tumor-immune landscape. Spatial phenotypic-transcriptomic profiling guided by regions-of-interest (ROIs) identified a crucial regulatory mechanism through localized tumor-adjacent macrophages, potentially in an HRD-dependent manner. Cellular neighborhood (CN) analysis further demonstrated the existence of macrophage-associated high-ordered cellular functional units in spatial contexts. Using our multi-omics spatial profiling strategy, we uncovered a dynamic macrophage-mediated regulatory axis linking HRD status with SIGLEC10 and CD52. These findings demonstrate the potential of targeting CD52 in combination with PARPi as a therapeutic intervention for PDAC.

FLT1 activation in cancer cells promotes PARP-inhibitor resistance in breast cancer.

Acquired resistance to PARP inhibitors (PARPi) remains a treatment challenge for BRCA1/2-mutant breast cancer that drastically shortens patient survival. Although several resistance mechanisms have been identified, none have been successfully targeted in the clinic. Using new PARPi-resistance models of Brca1- and Bard1-mutant breast cancer generated in-vivo, we identified FLT1 (VEGFR1) as a driver of resistance. Unlike the known role of VEGF signaling in angiogenesis, we demonstrate a novel, non-canonical role for FLT1 signaling that protects cancer cells from PARPi in-vivo through a combination of cell-intrinsic and cell-extrinsic pathways. We demonstrate that FLT1 blockade suppresses AKT activation, increases tumor infiltration of CD8+ T cells, and causes dramatic regression of PARPi-resistant breast tumors in a T-cell-dependent manner. Moreover, PARPi-resistant tumor cells can be readily re-sensitized to PARPi by targeting Flt1 either genetically (Flt1-suppression) or pharmacologically (axitinib). Importantly, a retrospective series of breast cancer patients treated with PARPi demonstrated shorter progression-free survival in cases with FLT1 activation at pre-treatment. Our study therefore identifies FLT1 as a potential therapeutic target in PARPi-resistant, BRCA1/2-mutant breast cancer.

Challenges and future perspectives for the use of temozolomide in the treatment of SCLC.

Small-cell lung cancer (SCLC), accounting for 10-20 % of all lung tumors, represents the most aggressive high-grade neuroendocrine carcinoma. Most patients are diagnosed with extensive-stage SCLC (ES-SCLC), with brian metastases identified in âˆ¼ 80 % of cases during the disease cours, and the prognosis is dismal, with a 5-year survival rate of less than 5 %. Current available treatments in the second-line setting are limited, and topotecan has long been the only FDA-approved drug in relapsed or refractory ES-SCLC, until the recent approval of lurbinectedin, a selective inhibitor of RNA polymerase II. Temozolomide (TMZ) is an oral alkylating agent, which showed single-agent activity in SCLC, particularly among patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Several studies have revealed the synergistic activity of temozolomide with poly-ADP-ribose polymerase (PARP) inhibitors, that prevent repair of TMZ-induced DNA damage. This review focuses on the rationale for the use of TMZ in ES-SCLC and provides an overview of the main trials that have evaluated and are currently investigating its role, both as a single-agent and in combinations, in relapse or refractory disease.

Predictors of long-term progression-free survival in patients with ovarian cancer treated with niraparib in the PRIMA/ENGOT-OV26/GOG-3012 study.

OBJECTIVE: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study. METHODS: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA/homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021). RESULTS: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1- and BRCA2-mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions). CONCLUSIONS: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy. TRIAL REGISTRATION NUMBER: NCT02655016.

[Mutation frequency of homologous recombination repair genes in prostate adenocarcinomas]. / A homológ rekombinációs hibajavító rendszer szomatikus génmutációinak vizsgálata prosztata-adenokarcinómában, újgenerációs szekvenálással.

The best predictive marker for the expected efficacy of PARP inhibitor therapy is mutations in BRCA1/2 or other homologous recombination repair genes. These tests are part of routine molecular pathology diagnostics. Among 281 patients with prostate adenocarcinoma, somatic pathogenic mutations in one of these genes were identified in 21.4% of patients. In 28.5% of the patients, the test was unsuccessful; the main limitation of successful testing was the age of the paraffin blocks and low DNA concentration. In the case of BRCA1/2 testing, the success rate was significantly reduced for samples older than 5 years, while in tests involving a broader set of homologous recombination repair genes, the success rate was significantly reduced for samples older than 2 years. Therefore, it is very important to test high-risk prostate cancers at the time of primary diagnosis, and probably also liquid biopsy testing of circulating tumor DNA will play an important role in safe diagnosis in the near future.