New insights for gynecological cancer therapies: from molecular mechanisms and clinical evidence to future directions.

Advanced and recurrent gynecological cancers lack effective treatment and have poor prognosis. Besides, there is urgent need for conservative treatment for fertility protection of young patients. Therefore, continued efforts are needed to further define underlying therapeutic targets and explore novel targeted strategies. Considerable advancements have been made with new insights into molecular mechanisms on cancer progression and breakthroughs in novel treatment strategies. Herein, we review the research that holds unique novelty and potential translational power to alter the current landscape of gynecological cancers and improve effective treatments. We outline the advent of promising therapies with their targeted biomolecules, including hormone receptor-targeted agents, inhibitors targeting epigenetic regulators, antiangiogenic agents, inhibitors of abnormal signaling pathways, poly (ADP-ribose) polymerase (PARP) inhibitors, agents targeting immune-suppressive regulators, and repurposed existing drugs. We particularly highlight clinical evidence and trace the ongoing clinical trials to investigate the translational value. Taken together, we conduct a thorough review on emerging agents for gynecological cancer treatment and further discuss their potential challenges and future opportunities.

Germline and somatic testing for ovarian Cancer: An SGO clinical practice statement.

Germline and somatic genetic testing have become critical components of care for people with ovarian cancer. The identification of germline and somatic pathogenic variants as well as homologous recombination deficiency can contribute to the prediction of treatment response, prognostic outcome, and suitability for targeted agents (e.g. poly (ADP-ribose) polymerase (PARP) inhibitors). Furthermore, identifying germline pathogenic variants can prompt cascade genetic testing for at-risk relatives. Despite the clinical benefits and consensus recommendations from several organizations calling for universal genetic testing in ovarian cancer, only about one third of patients complete germline or somatic genetic testing. The members of the Society of Gynecologic Oncology (SGO) Clinical Practice Committee have composed this statement to provide an overview of germline and somatic genetic testing for patients with epithelial ovarian cancer, focusing on available testing modalities and options for care delivery.

Inhibition of Poly(ADP-ribose) Polymerase Sensitizes [177Lu]Lu-DOTAGA.(SA.FAPi)2-Mediated Radiotherapy in Triple-Negative Breast Cancer.

Fibroblast activation protein (FAP) is highly expressed in many tumor types and constitutes a promising target for tumor-specific delivery of therapeutic radionuclides. [177Lu]Lu-DOTAGA.(SA.FAPi)2 is a novel radiopharmaceutical based on a novel bidentate inhibitor of FAP that is excreted more slowly than its monomeric counterparts. Still, the efficacy of radiotherapy is mitigated by cascades of DNA damage repair signaling in tumor cells including those via Poly(ADP-ribose) polymerase (PARP). We hereby aimed to evaluate the efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2 in combination with a PARP inhibitor, Olaparib, in the 4T1 murine triple negative breast cancer (TNBC) model. The therapeutic efficacy was visualized using 18F-FDG and [68Ga]Ga-FAPI-04 positron emission imaging/computer tomography (PET/CT). Our results demonstrated that Olaparib suppressed BALB/3T3 fibroblasts in vitro and sensitized the efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2 in mice bearing 4T1 tumors via enhancement of DNA damage. Treatment-associated toxicity was tolerable with only mild leukopenia. Therefore, the combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and Olaparib is a feasible treatment against TNBC.

The Poly (ADP-ribose) polymerase inhibitor olaparib and pan-ErbB inhibitor neratinib are highly synergistic in HER2 overexpressing epithelial ovarian carcinoma in vitro and in vivo.

INTRODUCTION: Ovarian cancer (OC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical efficacy of the Poly (ADP-ribose) polymerase (PARP) inhibitor (olaparib) and the pan-ErbB inhibitor (neratinib) as single agents and in combination in ovarian cancer cell lines and xenografts with variable HER2 expression. METHODS: In vitro cell viability with olaparib, neratinib, and their combination was assessed using flow-cytometry based assays against a panel of OC primary cell lines with variable HER2 expression. Immunoblotting experiments were performed to elucidate the mechanism of activity and synergism. The in vivo antitumor activity of the olaparib/neratinib combination versus single agents was tested in HER2 positive xenograft OC models. RESULTS: HER2 + OC cell lines demonstrated higher sensitivity to olaparib and neratinib when compared to HER2 negative tumors (i.e., IC50: 2.06 ± 0.33 µM vs. 39.28 ± 30.51 µM, p = 0.0035 for olaparib and 19.42 ± 2.63 nM vs. 235.0 ± 165.0 nM, p = 0.0035 for neratinib). The combination of olaparib with neratinib was more potent when compared to single-agent olaparib or neratinib both in vitro and in vivo, and demonstrated synergy in all primary HER2 + OC models. Western blot experiments showed neratinib decreased pHER2/neu while increased Poly(ADP-ribose) (PAR) enzymatic activity; olaparib increased pHER2/Neu expression and blocked PAR activatio. Olaparib/neratinib in combination decreased both pHER2/Neu as well as PAR activation. CONCLUSION: The combination of olaparib and neratinib is synergistic and endowed with remarkable preclinical activity against HER2+ ovarian cancers. This combination may represent a novel therapeutic option for ovarian cancer patients with HER2+, homologous recombination-proficient tumors resistant to chemotherapy.

Clinical Application of Poly(ADP-Ribose) Polymerase (PARP) Inhibitors in Ovarian Cancer.

The treatment of ovarian cancer has remained a clinical challenge despite high rates of initial response to platinum-based chemotherapy. Patients are generally diagnosed at an advanced stage with significant disease burden, which portends to worse survival outcomes. Deficiencies in the homologous recombination (HRD) DNA damage repair (DDR) pathway and mutations in the BRCA1/2 genes have been found in ovarian carcinomas. Moreover, patients with these specific molecular aberrations have demonstrated sensitivity and thus improved response to poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. The results of various clinical trials exploring the use of PARPi in different populations of ovarian cancer patients have shown impressive survival and response outcomes. With expanding indications, the use of PARPi has thus changed the landscape of ovarian cancer treatment. In this chapter, we will describe the different settings of PARPi treatment-frontline maintenance therapy, maintenance therapy for patients with recurrent platinum-sensitive disease, and treatment in the recurrent setting-and discuss treatment considerations and management of toxicities, as well as offer thoughts on future directions.

Combining Poly (ADP-Ribose) Polymerase (PARP) Inhibitors with Chemotherapeutic Agents: Promise and Challenges.

Better understanding of molecular drivers and dysregulated pathways has furthered the concept of precision oncology and rational drug development. The role of DNA damage response (DDR) pathways has been extensively studied in carcinogenesis and as potential therapeutic targets to improve response to chemotherapy or overcome resistance. Treatment with small molecule inhibitors of PARP has resulted in clinical response and conferred survival benefit to patients with ovarian cancer, BRCA-mutant breast cancer, HRD-deficient prostate cancer and BRCA-mutant pancreatic cancer, leading to US Food and Drug Administration (FDA) approvals. However, the observed clinical benefit with single agent PARP inhibitors is limited to few tumor types within the relevant genetic context. Since DDR pathways are essential for repair of damage caused by cytotoxic agents, PARP inhibitors have been evaluated in combination with various chemotherapeutic agents to broaden the therapeutic application of this class of drugs. In this chapter, we discuss the combination of PARP inhibitors with different chemotherapeutics agents, clinical experience to date, lessons learnt, and future directions for this approach.

Clinical Use of PARP Inhibitors in BRCA Mutant and Non-BRCA Mutant Breast Cancer.

The use of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of patients with germline BRCA mutations (gBRCAm) and breast cancer, both in the early and advanced settings, is a success of genomically-directed treatment. These agents have been shown to be associated with longer progression-free survival when compared to standard chemotherapy, with an acceptable toxicity profile. A recent randomized trial demonstrated improved survival with the use of olaparib for 2 years compared to placebo in patients with early-stage high risk gBRCAm associated breast cancer. Ongoing research efforts are focused on identifying patients beyond those with BRCA1/2 or PALB2 mutations who may benefit from PARP inhibitors, exploring the overlapping mechanisms of resistance between platinum and PARP inhibitors and developing agents with less toxicity that will allow combinational strategies.

Cost-effectiveness of poly-(ADP-ribose) polymerase (PARP)-inhibitors for the maintenance treatment after responding to first- and second-line chemotherapy in advanced ovarian cancer.

The introduction of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of women with epithelial ovarian cancers (EOC) has radically changed the treatment in maintenance setting after responding to first- and second-line chemotherapy. The aim of this paper was to assess the pharmacological costs of PARP inhibitors (olaparib, niraparib, rucaparib and veliparib) in maintenance treatment after responding to first-line chemotherapy in EOC. Incremental cost-effectiveness ratio (ICER) was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (progression-free survival (PFS)). We have considered the pivotal phase III randomized controlled trials (RCTs). Three different populations were considered: the overall population, patients with germline BRCA mutation (gBRCA) and homologous recombination deficiency (HRD) patients non-gBRCA mutation. Three thousand four hundred and twenty patients and 1209 patients were considered in maintenance treatment after responding to first- and second-line chemotherapy in EOC, respectively. At the actual price, the treatment with PARP inhibitors is not cost-effective in maintenance treatment after responding to first-line and second-line chemotherapy in EOC. A reduction in pharmacological costs is mandatory.

Hematological disorders after salvage PARPi treatment for ovarian cancer: Cytogenetic and molecular defects and clinical outcomes.

Inhibitors of poly(ADP-ribose) polymerase (PARPi) are increasingly employed as salvage therapy in epithelial ovarian cancer (EOC), but cytotoxic drug exposure along with PARP inhibition may favor development of hematological disorders. In our study, of 182 women with EOC treated with PARPi, 16 (8.7%) developed therapy-related myeloid neoplasms (t-MNs), with 12 cases of myelodysplasia and 4 of acute myeloid leukemia. All experienced persistent cytopenia after PARPi discontinuation. Seven patients had del(5q)/-5 and/or del(7q)/-7, nine had a complex karyotype and TP53 mutations, recently reported as risk factor for t-MNs in EOC post-PARPi, were found in 12 out of 13 tested patients. Four patients had a rapid and fatal outcome, one had stable disease, eleven underwent induction therapy, followed by allogeneic hematopoietic cell transplantation in seven. Three of these 11 patients experienced refractory disease, and 8 had complete remission. During a 6.8 months (range 2.3-49) median observation time, 3 out of 16 patients were alive, with one surviving patient free of both solid and hematological tumors. Ten patients died because of leukemia, two because of transplant-related events, one from heart failure. Five more patients experienced persistent cell blood count abnormalities following PARPi discontinuation, without reaching MDS diagnostic criteria. A customized Myelo-panel showed clonal hematopoiesis in all five patients. These findings confirm the actual risk of t-MNs in EOC patients after chemotherapy and prolonged PARPi therapy. The management of these patients is complex and outcomes are extremely poor. Careful diagnostic procedures are strongly recommended whenever unusual cytopenias develop in patients receiving PARPi therapy.

Selective PARP1 inhibitors, PARP1-based dual-target inhibitors, PROTAC PARP1 degraders, and prodrugs of PARP1 inhibitors for cancer therapy.

Poly ADP-ribose polymerase (PARP) plays a critical role in many cellular processes such as DNA damage repair, gene transcription and cell apoptosis. Therefore, targeting PARP represents a promising strategy for cancer therapy. To date, numerous small molecule PARP1 inhibitors have been identified, but many of them suffer from limited clinical efficacy and serious toxicity. Hence, PARP1 inhibitor-based combination therapies, and other PARP1 modulators (e.g. PROTAC degraders, dual acting agents) have attracted great attention with significant advancements achieved in the past few years. In this review, we overviewed the recent progress on PARP1-based drug discovery with a focus on PARP1 inhibitor-based drug combination therapy and other PARP1-targeting strategies (e.g. selective PARP1 inhibitors, PARP1-based dual-target inhibitors, PROTAC PARP1 degraders, and prodrugs of PARP1 inhibitors). In addition, we also summarized the reported co-crystal structures of PARP1 inhibitors in complex with their target proteins as well as the binding interactions. Finally, the challenges and future directions for PARP-based drug discovery in cancer therapy are also discussed in detail.

Poly(ADP-ribose) Polymerase (PARP) is Critically Involved in Liver Ischemia/Reperfusion-injury.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) is a DNA-repairing enzyme activated by extreme genomic stress, and therefore is potently activated in the remnant liver suffering from ischemia after surgical resection. However, the impact of PARP on post-ischemic liver injury has not been elucidated yet. MATERIALS AND METHODS: We investigated the impact of PARP on murine hepatocyte/liver injury induced by hypoxia/ischemia, respectively. RESULTS: PJ34, a specific inhibitor of PARP, markedly protected against hypoxia/reoxygenation (H/R)-induced cell death, though z-VAD-fmk, a pan-caspase inhibitor similarly showed the protective effect. PJ34 did not affect H/R-induced caspase activity or caspase-mediated cell death. z-VAD-fmk also did not affect the production of PAR (i.e., PARP activity). Therefore, PARP- and caspase-mediated cell death occurred in a mechanism independent of each other in H/R. H/R immediately induced activation of PARP and cell death afterwards, both of which were suppressed by PJ34 or Trolox, an antioxidant. This suggests that H/R-induced cell death occurred redox-dependently through PARP activation. H/R and OS induced nuclear translocation of apoptosis inducing factor (AIF, a marker of parthanatos) and RIP1-RIP3 interaction (a marker of necroptosis), both of which were suppressed by PJ34. H/R induced PARP-mediated parthanatos and necroptosis redox-dependently. In mouse experiments, PJ34 significantly reduced serum levels of AST, ALT & LDH and areas of hepatic necrosis after liver ischemia/reperfusion, similar to z-VAD-fmk or Trolox. CONCLUSION: PARP, activated by ischemic damage and/or oxidative stress, may play a critical role in post-ischemic liver injury by inducing programmed necrosis (parthanatos and necroptosis). PARP inhibition may be one of the promising strategies against post-ischemic liver injury.

Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer.

BACKGROUND: Ovarian cancer is the sixth most common cancer in women world-wide. Epithelial ovarian cancer (EOC) is the most common; three-quarters of women present when disease has spread outside the pelvis (stage III or IV). Treatment consists of a combination of  surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women with advanced disease will relapse. PARP (poly (ADP-ribose) polymerase) inhibitors (PARPi), are a type of anticancer treatment that works by preventing cancer cells from repairing DNA damage, especially in those with breast cancer susceptibility gene (BRCA) variants. PARPi offer a different mechanism of anticancer treatment from conventional chemotherapy. OBJECTIVES: To determine the benefits and risks of poly (ADP-ribose) polymerase) inhibitors (PARPi) for the treatment of epithelial ovarian cancer (EOC). SEARCH METHODS: We identified randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (Central 2020, Issue 10), Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to October 2020), Embase (1990 to October 2020), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials, the National Research Register (NRR), FDA database and pharmaceutical industry biomedical literature. SELECTION CRITERIA: We included trials that randomised women with EOC to PARPi with no treatment, or PARPi versus conventional chemotherapy, or PARPi together with conventional chemotherapy versus conventional chemotherapy alone. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. Two review authors independently assessed whether studies met the inclusion criteria. We contacted investigators for additional data. Outcomes included overall survival (OS), objective response rate (ORR), quality of life (QoL) and rate of adverse events. MAIN RESULTS: We included 15 studies (6109 participants); four (3070 participants) with newly-diagnosed, advanced EOC and 11 (3039 participants) with recurrent EOC. The studies varied in types of comparisons and evaluated PARPi. Eight studies were judged as at low risk of bias in most of the domains. Quality of life data were generally poorly reported. Below we present six key comparisons.  The majority of participants had BRCA mutations, either in their tumour (sBRCAmut) and/or germline (gBRCAmut), or homologous recombination deficiencies (HRD) in their tumours. Newly diagnosed EOC Overall, four studies evaluated the effect of PARPi in newly-diagnosed, advanced EOC. Two compared PARPi with chemotherapy and chemotherapy alone. OS data were not reported. The combination of PARPi with chemotherapy may have little to no difference in progression-free survival (PFS) (two studies, 1564 participants; hazard ratio (HR) 0.82, 95% confidence interval (CI 0).49 to 1.38; very low-certainty evidence)(no evidence of disease progression at 12 months' 63% with PARPi versus 69% for placebo).  PARPi with chemotherapy likely increases any severe adverse event (SevAE) (grade 3 or higher) slightly (45%) compared with chemotherapy alone (51%) (two studies, 1549 participants, risk ratio (RR) 1.13, 95% CI 1.07 to 1.20; high-certainty evidence). PARPi combined with chemotherapy compared with chemotherapy alone likely results in little to no difference in the QoL (one study; 744 participants, MD 1.56 95% CI -0.42 to 3.54; moderate-certainty evidence).  Two studies compared PARPi monotherapy with placebo as maintenance after first-line chemotherapy in newly diagnosed EOC. PARPi probably results in little to no difference in OS (two studies, 1124 participants; HR 0.81, 95%CI 0.59 to 1.13; moderate-certainty evidence) (alive at 12 months 68% with PARPi versus 62% for placebo). However, PARPi may increase PFS (two studies, 1124 participants; HR 0.42, 95% CI 0.19 to 0.92; low-certainty evidence) (no evidence of disease progression at 12 months' 55% with PARPi versus 24% for placebo). There may be an increase in the risk of experiencing any SevAE (grade 3 or higher) with PARPi (54%) compared with placebo (19%)(two studies, 1118 participants, RR 2.87, 95% CI 1.65 to 4.99; very low-certainty evidence), but the evidence is very uncertain. There is probably a slight reduction in QoL with PARPi, although this may not be clinically significant (one study, 362 participants; MD -3.00, 95%CI -4.48 to -1.52; moderate-certainty evidence).  Recurrent, platinum-sensitive EOC Overall, 10 studies evaluated the effect of PARPi in recurrent platinum-sensitive EOC. Three studies compared PARPi monotherapy with chemotherapy alone. PARPi may result in little to no difference in OS (two studies, 331 participants; HR 0.95, 95%CI 0.62 to 1.47; low-certainty evidence) (percentage alive at 36 months 18% with PARPi versus 17% for placebo). Evidence is very uncertain about the effect of PARPi on PFS (three studies, 739 participants; HR 0.88, 95%CI 0.56 to 1.38; very low-certainty evidence)(no evidence of disease progression at 12 months 26% with PARPi versus 22% for placebo). There may be little to no difference in rates of any SevAE (grade 3 or higher) with PARPi (50%) than chemotherapy alone (47%) (one study, 254 participants; RR 1.06, 95%CI 0.80 to 1.39; low-certainty evidence). Four studies compared PARPi monotherapy as maintenance with placebo. PARPi may result in little to no difference in OS (two studies, 560 participants; HR 0.88, 95%CI 0.65 to 1.20; moderate-certainty evidence)(percentage alive at 36 months 21% with PARPi versus 17% for placebo). However, evidence suggests that PARPi as maintenance therapy results in a large PFS (four studies, 1677 participants; HR 0.34, 95% CI 0.28 to 0.42; high-certainty evidence)(no evidence of disease progression at 12 months 37% with PARPi versus 5.5% for placebo). PARPi maintenance therapy may result in a large increase in any SevAE (51%) (grade 3 or higher) than placebo (19%)(four studies, 1665 participants, RR 2.62, 95%CI 1.85 to 3.72; low-certainty evidence). PARPi compared with chemotherapy may result in little or no change in QoL (one study, 229 participants, MD 1.20, 95%CI -1.75 to 4.16; low-certainty evidence). Recurrent, platinum-resistant EOC Two studies compared PARPi with chemotherapy. The certainty of evidence in both studies was graded as very low. Overall, there was minimal information on the QoL and adverse events. AUTHORS' CONCLUSIONS: PARPi maintenance treatment after chemotherapy may improve PFS in women with newly-diagnosed and recurrent platinum-sensitive EOC; there may be little to no effect on OS, although OS data are immature. Overall, this is likely at the expense of an increase in SevAE. It is  disappointing that data on quality of life outcomes  are relatively sparse. More research is needed to determine whether PARPi have a role to play in platinum-resistant disease.

PARP Inhibition and Beyond in BRCA-Associated Breast Cancer in Women: A State-Of-The-Art Summary of Preclinical Research on Risk Reduction and Clinical Benefits.

In mammalian cells, DNA damage response initiates repair by error-free homologous recombination (HRR) or by error-prone non-homologous end joining (NHEJ). DNA damage is detected by PARP proteins that facilitate this repair, both in normal cells and in cancer cells. Cells containing BRCA1/2 mutations have an HRR-deficient repair mechanism which may result in unrepaired one-ended double-strand breaks and stalled replication forks, considered as the most lethal cell damage. Here, we review the state of the art of the role of Poly (ADP-ribose) polymerase (PARP) inhibitors as a precision-targeted anticancer drug in BRCA1/2-mutated female breast cancer. Although knowledge is incomplete, it is assumed that the main role of the archetype PARP1 in the cell nucleus is to detect and adhere to single-strand breaks. This mediates possible damage repair, after which cells may continue replication; this process is called synthetic lethality. As for PARP clinical monotherapy, progression-free survival has been observed using the FDA- and EMA-approved drugs olaparib and talazoparib. In the case of combined drug therapy, a synergy has been demonstrated between veliparib and platinum drugs. Information regarding adverse effects is limited, but hematological effects have been described. However, there is need for multicenter trials, preferably conducted without commercial guidance and funding. Some of the available trials reported resistance to PARP inhibitors. In this review, we also describe the various causes of resistance to PARP inhibitors and research indicating how resistance can be overcome.

Running out of time: The case of patient advocacy for ovarian cancer patients' access to PARP inhibitors.

This article analyses patient advocacy for ovarian cancer patients' access to a group of new targeted cancer treatments, so-called poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors. Ovarian cancer is often detected in its advanced stages and has relatively poor survival rates. Based on ethnographic fieldwork with the Gynae Cancer Group, a Swedish patients' group, this article examines ovarian cancer patient advocates' engagement with biomedicine as a rarely considered topic in the social sciences. Adopting a modified version of the science and technology studies perspective on evidence-based activism, I analyse how ovarian cancer patient advocates engage in the 'epistemic activities' of framing, producing and mobilising 'credentialed' and 'experiential' knowledge. I show how patient advocates, alone and together with professionals and the media, engage in epistemic activities to 'act upon' ovarian cancer patients' anticipated limited time and poor prognosis: patient advocates mobilise around PARP inhibitors as offering hope, access to these drugs as an urgent matter and ovarian cancer care as unequal. The article contributes to the sociological literature on novel cancer treatments and patient advocacy through its ethnographic tracing of cancer advocacy tropes and knowledge practices, centred on the temporal figure of 'the patient running out of time'.

Medical Management of newly diagnosed breast cancer in a BRCA1/2 mutation carrier.

Germline BRCA1/2 mutations may be infrequent in unselected breast cancer population but are concentrated in those with triple-negative breast cancer or high-risk family history. Insight into the biology of BRCA mutation is now allowing a targeted therapeutic approach to these carriers with breast cancer. Functional BRCA genes play a critical role in DNA damage repair. Agents such as platinum salts and poly (ADP-ribose) polymerase (PARP) inhibitors exploit this vulnerability of impaired DNA damage repair mechanism in BRCA mutant cancers to leverage therapeutic benefit. Research has demonstrated improved response rates to platinum salts in BRCA-mutated compared with non-BRCA-mutated breast cancer, particularly in the metastatic setting. Additionally, clinical trials of single-agent PARP inhibitors have shown encouraging response rates and progression-free survival in patients with BRCA1/2-mutated breast cancer. In this review, we summarize the medical management of BRCA-associated breast cancer.

The efficacy and safety of the addition of poly ADP-ribose polymerase (PARP) inhibitors to therapy for ovarian cancer: a systematic review and meta-analysis.

BACKGROUND: The purpose of this study was to explore the efficacy and tolerability of poly ADP-ribose polymerase (PARP) inhibitors in patients with ovarian cancer. METHODS: The meta-analysis searched the PubMed, Web of Science, EBSCO, and Cochrane libraries from inception to February 2020 to identify relevant studies. And the main results of this study were long-term prognosis and treatment-related adverse events. RESULTS: The results showed that the addition of PARP inhibitors could significantly prolong progression-free survival (PFS) and overall survival (OS) for patients with ovarian cancer (HR 0.44, 95% CI 0.34-0.53, p < 0.001; HR, 0.79, 95% CI 0.65-0.94, p < 0.001, respectively). In the BRCA 1/2 mutation patients, the HR of PFS was 0.29 (p < 0.001), and the HR was 0.51 (p < 0.001) in the no BRCA 1/2 mutation patients. The HR of PFS was 0.40 (p < 0.001) in the homologous recombination deficiency (HRD) mutation patients, while the HR was 0.80 (p < 0.001) in the no HRD mutation patients. Moreover, the analysis found that the use of PARP inhibitors did not significantly increase the risk of all grade adverse events (AEs) (RR = 1.04, p = 0.16). But the incidence of grade 3 or higher AEs was increased (RR = 1.87, p = 0.002). In general, the AEs were mainly manifested in the blood system. CONCLUSIONS: PARP inhibitors can improve the prognosis of ovarian cancer patients with and without genetic mutations (BRCA 1/2 or HRD). Furthermore, PARP inhibitors were tolerable to patients when added to their current therapy, although it inevitably adds the grade 3 and higher AEs.

BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic-related mutations in BRCA1 associated with an increased risk of ovarian cancer.

BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly(ADP-ribose) polymerase (PARP). Despite a number of small-size hospital-based studies being previously reported, there is not yet, to our knowledge, precise data of BRCA1/2 mutations among Chinese ovarian cancer patients. We performed a multicenter cohort study including 916 unselected consecutive epithelial ovarian cancer (EOC) patients from eastern China to screen for BRCA1/2 mutations using the next-generation sequencing approach. A total of 153 EOC patients were found to carry pathogenic germline mutations in BRCA1/2, accounting for an overall mutation incidence of 16.7% with the predominance in BRCA1 (13.1%) compared with BRCA2 (3.9%). We identified 53 novel pathogenic mutations, among which the c.283_286delCTTG and the c.4573C > T of BRCA1 were both found in two unrelated patients. More importantly, the most common mutation found in this study, c.5470_5477del8 was most likely to be Chinese population-related without an apparent founder origin. This hot-spot mutation was presumably associated with an increased risk of ovarian cancer. Taken together, germline BRCA1/2 mutations were common in Chinese EOC patients with distinct mutational spectrum compared to Western populations. Our study contributes to the current understanding of BRCA1/2 mutation prevalence worldwide. We recommend BRCA1/2 genetic testing to all Chinese women diagnosed with EOC to identify HBOC families, to provide genetic counseling and clinical management for at-risk relatives. Mutation carriers may also benefit from PARP-targeted therapies.

What's new in small cell lung cancer - extensive disease? An overview on advances of systemic treatment in 2016.

Systemic therapy options for small cell lung cancer patients with extensive disease remain poor. After an initial response on first-line therapy, virtually all patients develop disease progression. For those who showed an initial response only few therapy options with low response rates are currently available. Until now, many experimental and targeted agents have failed to yield convincing clinical benefits, and new therapy options are clearly warranted for these patients. In this year's oncological congresses, several new therapy strategies, including checkpoint inhibition, showed promising results in ongoing trials. Furthermore, a potential benefit of new agents targeting DLL3, Aurora A kinase and PARP-inhibitor was reported. In this review we summarize new developments and critically highlight the most important and promising data in the relapsed small cell lung cancer disease.

Circulating Tumor DNA Dynamics Fail to Predict Efficacy of Poly(ADP-ribose) Polymerase/VEGFR Inhibition in Patients With Heavily Pretreated Advanced Solid Tumors.

PURPOSE: Cell-free circulating tumor DNA (ctDNA) has shown its potential as a quantitative biomarker for longitudinal monitoring of response to anticancer therapies. However, ctDNA dynamics have not been studied in patients with heavily pretreated, advanced solid tumors, for whom therapeutic responses can be weak. We investigated whether changes in ctDNA could predict clinical outcomes in such a cohort treated with combined poly(ADP-ribose) polymerase/vascular endothelial growth factor receptor inhibitor therapy. MATERIALS AND METHODS: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC), triple-negative breast cancer (TNBC), small-cell lung cancer (SCLC), or non-small-cell lung cancer (NSCLC) received up to 7 days of cediranib 30 mg orally once daily monotherapy lead-in followed by addition of olaparib 200 mg orally twice daily. Patients had progressed on a median of three previous lines of therapy. Plasma samples were collected before and after cediranib monotherapy lead-in and on combination therapy at 7 days, 28 days, and every 28 days thereafter. ctDNA was quantified from plasma samples using a multigene mutation-based assay. Radiographic assessment was performed every 8 weeks. RESULTS: ctDNA measurements were evaluable in 63 patients. The median baseline ctDNA variant allele fractions (VAFs) were 20%, 28%, 27%, and 34% for PDAC, TNBC, SCLC, and NSCLC, respectively. No association was observed between baseline VAF and radiographic response, progression-free survival, or overall survival (OS). Similarly, no association was found between ctDNA decline and radiographic response or survival. However, an increase in ctDNA at 56 days of combination therapy was associated with disease progression and inferior OS in a landmark analysis. CONCLUSION: ctDNA levels or dynamics did not correlate with radiographic response or survival outcomes in patients with advanced metastatic malignancies treated with olaparib and cediranib.