Recruiting women with ductal carcinoma in situ to a randomised controlled trial: lessons from the LORIS study.

BACKGROUND: The LOw RISk DCIS (LORIS) study was set up to compare conventional surgical treatment with active monitoring in women with ductal carcinoma in situ (DCIS). Recruitment to trials with a surveillance arm is known to be challenging, so strategies to maximise patient recruitment, aimed at both patients and recruiting centres, were implemented. METHODS: Women aged ≥ 46 years with a histologically confirmed diagnosis of non-high-grade DCIS were eligible for 1:1 randomisation to either surgery or active monitoring. Prior to randomisation, all eligible women were invited to complete: (1) the Clinical Trials Questionnaire (CTQ) examining reasons for or against participation, and (2) interviews exploring in depth opinions about the study information sheets and film. Women agreeing to randomisation completed validated questionnaires assessing health status, physical and mental health, and anxiety levels. Hospital site staff were invited to communication workshops and refresher site initiation visits to support recruitment. Their perspectives on LORIS recruitment were collected via surveys and interviews. RESULTS: Eighty percent (181/227) of eligible women agreed to be randomised. Over 40% of participants had high anxiety levels at baseline. On the CTQ, the most frequent most important reasons for accepting randomisation were altruism and belief that the trial offered the best treatment, whilst worries about randomisation and the influences of others were the most frequent most important reasons for declining. Most women found the study information provided clear and useful. Communication workshops for site staff improved knowledge and confidence but only about half said they themselves would join LORIS if eligible. The most common recruitment barriers identified by staff were low numbers of eligible patients and patient preference. CONCLUSIONS: Recruitment to LORIS was challenging despite strategies aimed at both patients and site staff. Ensuring that recruiting staff support the study could improve recruitment in similar future trials. TRIAL REGISTRATION: ISRCTN27544579, prospectively registered on 22 May 2014.

Patients' views and experiences on the supported self-management/patient-initiated follow up pathway for breast cancer.

PURPOSE: To explore patients' expectations and experience of Supportive Self-Management (SSM)/ Patient Initiated Follow Up (PIFU) following breast cancer treatments over a 12-month period. METHODS: In total, 32/110 (29%) patient participants in the PRAGMATIC (Patients' experiences of a suppoRted self-manAGeMent pAThway In breast Cancer) study were interviewed at baseline, 3, 6, 9 and 12 months. Interviews in this sub-study used a mix-methods approach to explore understanding of the pathway, confidence in self-management, triggers to seek help and/or re-engage with the clinical breast team and impact of the COVID-19 pandemic. Responses to pre-assigned categories were summarised as counts/ percentages and collated in tabular or graphic format. Free responses were recorded verbatim and reviewed using framework analysis. RESULTS: Participants regarded the SSM/PIFU pathway as a way to save time and money for them and the National Health Service (NHS) (14/32; 44%) and as a means of assuming responsibility for their own follow-up (18/32; 56%). Most maintained (very/somewhat) confidence in managing their BC follow-up care (baseline 31/32, 97%; 12 months 29/31, 93%). During the year, 19% (5/26) stopped endocrine therapy altogether because of side effects. Qualitative analysis revealed general satisfaction with SSM/PIFU and described the breast care nurses as reassuring and empathic. However, there was a lingering anxiety about identifying signs and symptoms correctly, particularly for those with screen-detected cancers. There was also uncertainty about who to contact for psychological support. The COVID-19 pandemic discouraged some participants from contacting the helpline as they did not want to overburden the NHS. CONCLUSIONS: The results show that during the first year on the SSM/PIFU pathway, most patients felt confident managing their own care. Clinical teams should benefit from understanding patients' expectations and experiences and potentially modify the service for men with BC and/or those with screen-detected breast cancers.

Talking about Risk, UncertaintieS of Testing IN Genetics (TRUSTING): development and evaluation of an educational programme for healthcare professionals about BRCA1 & BRCA2 testing.

BACKGROUND: Mainstreaming of germline testing demands that all healthcare professionals have good communication skills, but few have genetic testing and counselling experience. We developed and evaluated educational workshops-Talking about Risk & UncertaintieS of Testing IN Genetics (TRUSTING). Contents included: presentations and exercises, an interview with a geneticist about BRCA testing, screening and prevention implications, filmed interactions between surgeons, a genetic counsellor and geneticists with a fictitious family (proband had a BRCA2 pathogenic variant with triple-negative breast cancer, her older sister-BRCA2 heterozygous, and cousin-negative for BRCA2 variant). METHODS: Twenty-one surgeons, 5 oncologists, 18 nurses and 9 genetic counsellors participated. Knowledge (18 item MCQ), communication skills (responses to 6 questions from proband and relatives) and self-confidence (discussing 9 genetic testing issues) were assessed pre- and post workshop. RESULTS: Knowledge scores improved significantly post workshop (mean change = 7.06; 95% confidence interval (CI) 6.37-7.74; P < 0.001), as did communication (mean change = 5.38; 95% CI 4.37-6.38; P < 0.001) and self-confidence (P < 0.001). DISCUSSION: Healthcare professionals' knowledge and self-confidence when discussing the risks and uncertainties in genetics are often poor. TRUSTING workshops significantly enhanced attendees' navigation of communication difficulties encountered and will be rolled out more widely.

The development and initial evaluation of the Diarrhoea Management Diary (DMD) in patients with metastatic breast cancer.

PURPOSE: Chemotherapy-induced diarrhoea (CID) is a common, but often underreported problem in patients with breast cancer that has a profound effect on quality of life. It is best measured from a patient's perspective, but tools are limited. The aim of this study was to develop and evaluate the Diarrhoea Management Diary (DMD), a self-report measure to assess CID, use of self-management strategies and treatment adherence. METHODS: The DMD was constructed using an iterative process of instrument development: concept elicitation (literature review), item generation and reduction (cognitive debriefing), and pilot testing in the target population. After translation into eight languages, the DMD was used in an international randomised trial for women receiving lapatinib and capecitabine for metastatic breast cancer with or without prophylactic octreotide. Patterns of missing data and sensitivity to change were examined. RESULTS: The understandability and completeness of the 8-item DMD was confirmed in cognitive interviews and pilot testing. Practicability of the DMD was evaluated in 62 women with metastatic breast cancer (median age 57). Up to 68% reported CID at any given time-point, and 19% had diarrhoea at each time-point. Patients also described efficacy of different strategies for diarrhoea management. Missing data were associated with study discontinuation. DMD missing item response was 0.9%. Sensitivity to change was good at most assessment points. CONCLUSIONS: Although further psychometric testing is recommended, initial evaluation of the DMD showed good content validity and practicability in international research with cancer patients.

Patients' and partners' views of care and treatment provided for metastatic castrate-resistant prostate cancer in the UK.

OBJECTIVE: Documentations of the experiences of patients with advanced prostate cancer and their partners are sparse. Views of care and treatment received for metastatic castrate-resistant prostate cancer (mCRPC) are presented here. METHODS: Structured interviews conducted within 14 days of a systemic therapy for mCRPC starting and 3 months later explored the following: treatment decisions, information provision, perceived benefits and harms of treatment, and effects of these on patients' and partners' lives. RESULTS: Thirty-seven patients and 33 partners recruited from UK cancer centres participated. The majority of patients (46%) reported pain was their worst symptom and many wanted to discuss its management (baseline-50%; 3 months-33%). Patients and partners believed treatment would delay progression (>75%), improve wellbeing (33%), alleviate pain (≈12%) and extend life (15% patients, 36% partners). At 3 months, most men (42%) said fatigue was the worst treatment-related side effect (SE), 27% experienced unexpected SEs and 54% needed help with SEs. Most patients received SE information (85% written; 75% verbally); many additionally searched the Internet (33% patients; 55% partners). Only 54% of patients said nurse support was accessible. CONCLUSION: Pain and other symptom management are not optimal. Increased specialist nurse provision and earlier palliative care links are needed. Dedicated clinics may be justified.

Enhancing decision-making about adjuvant chemotherapy in early breast cancer following EndoPredict testing.

OBJECTIVE: Chemotherapy side-effects can be substantial. There is increasing recognition that some oestrogen receptor positive (ER +ve), human epidermal growth factor receptor 2 negative (HER2 -ve) patients with breast cancer derive no benefit from chemotherapy and experience only iatrogenic harm. Gene expression profiling tests help refine recurrence risk and likely chemotherapy benefit. EndoPredict® is one such test, which classifies risks of distant recurrence as low or high in patients treated with surgery and adjuvant endocrine therapy alone. We compared treatment decisions pre-test and post-test results, patients' anxiety, decisional conflict, and oncologists' confidence about the decisions made. METHODS: Fourteen oncologists in 7 UK hospitals saw 149 pts judged to have equivocal indications for chemotherapy. Provisional treatment decisions were recorded then reconsidered when EPClin results were available. Pre-test and post-test results, patients completed State/Trait Anxiety Inventories (STAI), and the decisional conflict scale. Oncologists also recorded basic clinical details, their agreement with, and confidence about treatment decisions. RESULTS: Sixty-seven percent patients initially prescribed endocrine alone with high risk result upgraded to endocrine+chemotherapy (E + C); 83% prescribed E + C and had low risk scores, downgraded to E. None of 46 patients initially favouring E alone, who were low risk, changed decisions. Oncologists' confidence about decisions was significantly increased following the results (P = 0.002). Patients with downgraded treatment decisions had significantly lower anxiety scores (P = 0.045); those upgraded had increased scores (P = 0.001). Overall decisional conflict and uncertainty fell significantly post-test (P < 0.022). CONCLUSIONS: EndoPredict scores increased oncologists' and patients' decision-making confidence, generally improving the matching of risk with therapy decisions.

The effect of ovarian cancer screening on sexual activity and functioning: results from the UK collaborative trial of ovarian cancer screening RCT.

BACKGROUND: To examine the impact of multimodal (MMS) and ultrasound (USS) screening on the sexual activity and functioning of 22 966 women in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) RCT. METHODS: Fallowfield's Sexual Activity Questionnaire (FSAQ) was completed prior to randomisation, then annually in a random sample (RS) of women from MMS, USS and control groups. Any women in the study who required repeat screening due to unsatisfactory results formed an Events Sample (ES); they completed questionnaires following an event and annually thereafter. RESULTS: Over time in the RS (n=1339) there was no difference between the MMS and USS groups in sexual activity compared with controls. In the ES there were significant differences between the USS group (n=10 156) and the MMS group (n=12 810). The USS group had lower pleasure scores (mean difference=-0.14, P=0.046). For both groups women who had ⩾2 repeat screens, showed a decrease in mean pleasure scores compared with their annual scores (mean difference=-0.16, P=0.005). Similarly mean pleasure scores decreased following more intensive screens compared with annual screening (mean difference=-0.09, P=0.046). CONCLUSIONS: Ovarian cancer screening did not affect sexual activity and functioning unless a woman had abnormal results and underwent repeated or higher level screening.

Chemotypes sensitivity and predictivity of in vivo outcomes for cytotoxic assays in THLE and HepG2 cell lines.

In the present study, we demonstrate the utility of in vitro ATP depletion assays in both THLE and HepG2 cells for predicting the toxicological outcome in Exploratory Toxicology Studies across 446 Pfizer proprietary compounds. Our results suggest a higher likelihood of selecting suitable compounds for in vivo safety studies by using cytotoxicity assays in multiple cell-lines over a single cell line. In addition, we demonstrate that different cell-lines have different sensitivities to compounds depending on their ionization state, that is, acid, base or neutral. HepG2 cells are more sensitive for basic compounds, whereas THLE cells have a relatively higher sensitivity for the acidic and neutral compounds. These in vitro cytotoxicity assays when combined with physicochemical properties (cLogP >3 and topological polar surface area (TPSA) <75Å(2)), are the most effective means to prioritize compounds having a lower probability of causing adverse events in vivo.

Using an in vitro cytotoxicity assay to aid in compound selection for in vivo safety studies.

Recent publications have demonstrated that using calculated physiochemical properties can help in the design of compounds that have a decreased risk of significant findings in rodent toxicology studies. In this Letter, we extend this concept and incorporate results from a high throughput cytotoxicity assay to help the drug discovery community select compounds for progression into in vivo studies. The results are presented in an easily interpretable odds ratio so that teams can readily compare compounds and progress potential clinical candidates to the necessary rodent in vivo studies.

The computational prediction of genotoxicity.

IMPORTANCE OF THE FIELD: The computational prediction of genotoxicity is important to the early identification of those chemical entities that have the potential to cause carcinogenicity in humans. AREAS COVERED IN THIS REVIEW: The review discusses key scientific developments in the prediction of Ames mutagenicity and in vitro chromosome damage over the past 4 - 5 years. The performance and limitations of computational approaches are discussed in relation to published and internal validation exercises. Their application to the modern drug discovery paradigm is also discussed. WHAT THE READER WILL GAIN: Key highlights of a review of the recent scientific literature for the prediction of Ames mutagenicity and chromosome damage and an appreciation of the factors that limit the predictive performance of in silico systems. TAKE HOME MESSAGE: Current in silico systems perform well in the mutagenicity prediction of the publicly-derived data on which they are based, but their performance outside the applicability domain is considerably lower. We conclude that it is the lack of mechanistic structure-activity relationships and limited access to high quality proprietary data which are holding back computational genotoxicity from reaching higher predictive levels.

Discovery of novel dialkyl substituted thiophene inhibitors of HCV by in silico screening of the NS5B RdRp.

A novel 5,4-dialkyl substituted thiophene was discovered by in silico screening of the 3D polymerase crystal structure (1GX6) that demonstrated single digit micromolar HCV inhibition activity in the replicon assay and dose-dependent inhibition in the replicase complex assay. Subsequently, SAR was explored with a small set of dialkyl and tetrahydro-benzo thiophenes. Since these thiophenes inhibit synthesis of both, single- and double-stranded RNAs, their mechanism of action is distinct from other known HCV inhibitors.

Small molecule inhibitors of E. coli primase, a novel bacterial target.

Bacterial primase is essential for DNA replication in Gram-positive and Gram-negative bacteria. It is also structurally distinct from eukaryotic primases, and therefore an attractive, but under-explored, target for therapeutic intervention. We applied virtual screening to discover primase inhibitors, and subsequently several commercially available analogs of these initial hits showed potent primase inhibition and in vitro antibacterial activity. This work provides a 3D pharmacophore for primase ligands, SAR trends, and leads that can be further optimized.

RNA unrestrained molecular dynamics ensemble improves agreement with experimental NMR data compared to single static structure: a test case.

Nuclear magnetic resonance (NMR) provides structural and dynamic information reflecting an average, often non-linear, of multiple solution-state conformations. Therefore, a single optimized structure derived from NMR refinement may be misleading if the NMR data actually result from averaging of distinct conformers. It is hypothesized that a conformational ensemble generated by a valid molecular dynamics (MD) simulation should be able to improve agreement with the NMR data set compared with the single optimized starting structure. Using a model system consisting of two sequence-related self-complementary ribonucleotide octamers for which NMR data was available, 0.3 ns particle mesh Ewald MD simulations were performed in the AMBER force field in the presence of explicit water and counterions. Agreement of the averaged properties of the molecular dynamics ensembles with NMR data such as homonuclear proton nuclear Overhauser effect (NOE)-based distance constraints, homonuclear proton and heteronuclear (1)H-(31)P coupling constant (J) data, and qualitative NMR information on hydrogen bond occupancy, was systematically assessed. Despite the short length of the simulation, the ensemble generated from it agreed with the NMR experimental constraints more completely than the single optimized NMR structure. This suggests that short unrestrained MD simulations may be of utility in interpreting NMR results. As expected, a 0.5 ns simulation utilizing a distance dependent dielectric did not improve agreement with the NMR data, consistent with its inferior exploration of conformational space as assessed by 2-D RMSD plots. Thus, ability to rapidly improve agreement with NMR constraints may be a sensitive diagnostic of the MD methods themselves.

The impact of informatics and computational chemistry on synthesis and screening.

High-throughput synthesis and screening technologies have enhanced the impact of computational chemistry on the drug discovery process. From the design of targeted, drug-like libraries to 'virtual' optimization of potency, selectivity and ADME/Tox properties, computational chemists are able to efficiently manage costly resources and dramatically shorten drug discovery cycle times. This review will describe some of the successful strategies and applications of state-of-the-art algorithms to enhance drug discovery, as well as key points in the drug discovery process where computational methods can have, and have had, greatest impact.