A Systematic Review of the Molecular Mechanisms Involved in the Association Between PCOS and Endometrial and Ovarian Cancers.

Polycystic ovary syndrome (PCOS), a major cause of female infertility, affects 4%-20% of reproductive-age women. Metabolic and hormonal alterations are key features of PCOS, potentially raising the risk of endometrial (EC) and ovarian (OVCA) cancers. This systematic review aims to summarise the proposed molecular mechanisms involved in the association between PCOS and EC or OVCA.

DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications.

The DNA damage response (DDR) is a network of proteins that coordinate DNA repair and cell-cycle checkpoints to prevent damage being transmitted to daughter cells. DDR defects lead to genomic instability, which enables tumour development, but they also create vulnerabilities that can be used for cancer therapy. Historically, this vulnerability has been taken advantage of using DNA-damaging cytotoxic drugs and radiotherapy, which are more toxic to tumour cells than to normal tissues.

Challenges in PARP inhibitor therapy: A case of Olaparib-induced liver injury and successful rechallenge with Niraparib.

Olaparib, the first-in-class poly ADP-ribose polymerase (PARP) inhibitor, is approved for first line maintenance treatment in platinum-sensitive FIGO stage 3 and 4 high grade serous ovarian cancer (HGSOC) associated with a deleterious BRCA mutation. We report a case involving a 70-year-old female who experienced significant CTCAE Grade 4 hepatocellular injury after initiating first line maintenance Olaparib for Stage 3C HGSOC. Her liver injury resolved upon discontinuation of Olaparib but promptly recurred upon rechallenge.

Targeted and Shallow Whole-Genome Sequencing Identifies Therapeutic Opportunities in p53abn Endometrial Cancers.

Purpose: Shallow whole-genome sequencing (sWGS) can detect copy-number (CN) aberrations. In high-grade serous ovarian cancer (HGSOC) sWGS identified CN signatures such as homologous recombination deficiency (HRD) to direct therapy. We applied sWGS with targeted sequencing to p53abn endometrial cancers to identify additional prognostic stratification and therapeutic opportunities.

Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study.

Purpose: Early results from the phase II MEDIOLA study (NCT02734004) in germline BRCA1- and/or BRCA2-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) showed promising efficacy and safety with olaparib plus durvalumab. We report efficacy and safety of olaparib plus durvalumab in an expansion cohort of women with gBRCAm PSROC (gBRCAm expansion doublet cohort) and two cohorts with non-gBRCAm PSROC, one of which also received bevacizumab (non-gBRCAm doublet and triplet cohorts).

Patients And Methods: In this open-label, multicenter study, PARP inhibitor-naïve patients received olaparib plus durvalumab treatment until disease progression; the non-gBRCAm triplet cohort also received bevacizumab.

Prevalence of mutations in common tumour types in Northern England and comparable utility of national and international Trial Finders.

Purpose: Tumour genomic profiling is of increasing importance in early phase trials to match patients to targeted therapeutics. Mutations vary by demographic group; however, regional differences are not characterised. This was investigated by comparing mutation prevalence for common cancers presenting to Newcastle Experimental Cancer Medicine Centre (ECMC) to The Cancer Genome Atlas (TCGA) and utility of trial matching modalities.

Efficacy and safety of rucaparib treatment in patients with BRCA-mutated, relapsed ovarian cancer: final results from Study 10.

Background: Study 10, a four-part Phase 1/2 study, evaluated oral rucaparib monotherapy in patients with advanced solid tumours. Here we report the final efficacy and safety results in heavily pretreated patients with ovarian cancer who received rucaparib in Study 10 Parts 2A and 2B.

Methods: Parts 2A and 2B (Phase 2 portions) enrolled patients with relapsed, high-grade, platinum-sensitive or platinum-resistant, BRCA-mutated ovarian cancer who had received 2-4 (Part 2A) or 3-4 (Part 2B) prior chemotherapies.

Differences in Durability of PARP Inhibition by Clinically Approved PARP Inhibitors: Implications for Combinations and Scheduling.

Six PARP inhibitors (PARPi) are approved for cancer therapy as monotherapy agents in daily or twice-daily continuous dosing schedules to maintain the necessary continuous suppression of PARP activity. Continuous PARP inhibition is required for single-agent anticancer activity. To investigate if such intense schedules are necessary, we determined the durability of PARP inhibition up to 72 h after a 1 h pulse of 1 µM of five of the approved PARPi, rucaparib, olaparib, niraparib, talazoparib and pamiparib, in IGROV-1 and ES-2 (human ovarian cancer) cells.

The Role of ATR Inhibitors in Ovarian Cancer: Investigating Predictive Biomarkers of Response.

Ataxia telangiectasia and Rad-3 related kinase (ATR) signals DNA lesions and replication stress (RS) to the S and G2/M checkpoints and DNA repair pathways making it a promising target to exploit the dysregulated DNA damage response in cancer. ATR inhibitors (ATRi) are under clinical investigation as monotherapy and in combination with other anticancer agents. Molecular determinants of sensitivity to ATRi are common in ovarian cancer, suggesting the therapeutic potential of ATRi.

Safety and Efficacy of Dostarlimab in Patients With Recurrent/Advanced Non-small Cell Lung Cancer: Results from Cohort E of the Phase I GARNET Trial.

Background: Dostarlimab is an anti-programmed cell death protein-1 antibody being evaluated in recurrent/advanced solid tumors, including non-small cell lung cancer (NSCLC), in the ongoing Phase I, multi-center, open-label, 2-part (dose escalation and cohort expansion) GARNET study (NCT02715284).

Materials And Methods: Here, we report an interim analysis of patients with recurrent/advanced NSCLC who progressed following platinum-based chemotherapy. Patients received dostarlimab (500 mg IV every 3 weeks [Q3W] for Cycles 1-4, then 1000 mg Q6W) until disease progression or unacceptable toxicity for > 2 years.

Tipping Growth Inhibition into Apoptosis by Combining Treatment with MDM2 and WIP1 Inhibitors in p53 Uterine Leiomyosarcoma.

As there is no optimal therapeutic strategy defined for women with advanced or recurrent uLMS, there is an urgent need for the discovery of novel, targeted approaches. One such area of interest is the pharmacological inhibition of the MDM2-p53 interaction with small-molecular-weight MDM2 inhibitors. Growth inhibition and cytotoxic assays were used to evaluate uLMS cell line responses to MDM2 inhibitors as single agents and in combination, qRT-PCR to assess transcriptional changes and Caspase-Glo 3/7 assay to detect apoptosis.

Pharmacokinetics and safety of rucaparib in patients with advanced solid tumors and hepatic impairment.

Purpose: The poly(ADP-ribose) polymerase inhibitor rucaparib is approved for the treatment of patients with recurrent ovarian and metastatic castration-resistant prostate cancer; however, limited data are available on its use in patients with hepatic dysfunction. This study investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of rucaparib in patients with advanced solid tumors.

Methods: Patients with normal hepatic function or moderate hepatic impairment according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were enrolled and received a single oral dose of rucaparib 600 mg.

Genomic, Transcriptomic, and Functional Alterations in DNA Damage Response Pathways as Putative Biomarkers of Chemotherapy Response in Ovarian Cancer.

Defective DNA damage response (DDR) pathways are enabling characteristics of cancers that not only can be exploited to specifically target cancer cells but also can predict chemotherapy response. Defective Homologous Recombination Repair (HRR) function, e.g.

Integration of computer-aided automated analysis algorithms in the development and validation of immunohistochemistry biomarkers in ovarian cancer.

In an era when immunohistochemistry (IHC) is increasingly depended on for histological subtyping, and IHC-determined biomarker informing rapid treatment choices is on the horizon; reproducible, quantifiable techniques are required. This study aimed to compare automated IHC scoring to quantify 6 DNA damage response protein markers using a tissue microarray of 66 ovarian cancer samples. Accuracy of quantification was compared between manual H-score and computer-aided quantification using Aperio ImageScope with and without a tissue classification algorithm.

Characterisation of Ovarian Cancer Cell Line NIH-OVCAR3 and Implications of Genomic, Transcriptomic, Proteomic and Functional DNA Damage Response Biomarkers for Therapeutic Targeting.

In order to be effective models to identify biomarkers of chemotherapy response, cancer cell lines require thorough characterization. In this study, we characterised the widely used high grade serous ovarian cancer (HGSOC) cell line NIH-OVCAR3 using bioinformatics, cytotoxicity assays and molecular/functional analyses of DNA damage response (DDR) pathways in comparison to an ovarian cancer cell line panel. Bioinformatic analysis confirmed the HGSOC-like features of NIH-OVCAR3, including low mutation frequency, TP53 loss and high copy number alteration frequency similar to 201 HGSOCs analysed (TCGA).

First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor.

Background: This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor.

Methods: E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50-800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines.

Enteric Type Bartholin Gland Adenocarcinoma: An Unusual Variant of a Rare Neoplasm.

Vulval cancer is rare. With Bartholin gland carcinomas representing <5% of all vulval carcinomas they present both diagnostic and management challenges. There are a small number of cases in the literature describing Bartholin gland carcinomas with unusual histology which necessitates the need to explore the possibility of metastases from elsewhere.

Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations?

The DNA damage response (DDR) machinery is responsible for detecting DNA damage, pausing the cell cycle and initiating DNA repair. Ataxia telangiectasia and Rad3-related (ATR) protein is a key kinase at the heart of the DDR, responsible for sensing replication stress (RS) and signalling it to S and G2/M checkpoints to facilitate repair. In cancer, loss of G1 checkpoint control and activation of oncogenes that drive replication, result in cancer cells more likely to enter S phase with increased RS.

Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer.

Purpose: Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody-drug conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623).

Antitumor activity of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy in patients with platinum-sensitive, relapsed, -mutated, high-grade ovarian cancer, and an update on safety.

Objective: To report results from an integrated efficacy and safety analysis supporting the European Commission's approval of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy treatment for relapsed, platinum-sensitive, -mutated ovarian cancer.

Methods: Efficacy was analyzed in platinum-sensitive patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who had high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer and a deleterious or mutation and received two or more prior chemotherapies (including two or more platinum-based therapies). The primary end point was investigator-assessed, confirmed objective response rate (visit cut-off: April 10, 2017).