Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis.

IntroductionEffective treatments for hormone-receptor-positive (HR(+)) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population.MethodsBOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR(+) advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints.ResultsFinal study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38-0.54); log-rank P < 0.0001; central review: 11.0 versus 4.1 months, respectively; hazard ratio = 0.38 (95% confidence interval 0.31-0.48); log-rank P < 0.0001] in the overall population and in all prospectively defined subgroups, including patients with visceral metastases, [corrected] and irrespective of age. The incidence and severity of adverse events were consistent with those reported at the interim analysis and in other everolimus trials.ConclusionThe addition of everolimus to exemestane markedly prolonged PFS in patients with HR(+) advanced BC with disease recurrence/progression following prior NSAIs. These results further support the use of everolimus plus exemestane in this patient population. ClinicalTrials.gov #NCT00863655

Introducing the DizzyQuest: an app-based diary for vestibular disorders

BACKGROUND Most questionnaires currently used for assessing symptomatology of vestibular disorders are retrospective, inducing recall bias and lowering ecological validity. An app-based diary, administered multiple times in daily life, could increase the accuracy and ecological validity of symptom measurement. The objective of this study was to introduce a new experience sampling method (ESM) based vestibular diary app (DizzyQuest), evaluate response rates, and to provide examples of DizzyQuest outcome measures which can be used in future research. METHODS Sixty-three patients diagnosed with a vestibular disorder were included. The DizzyQuest consisted of four questionnaires. The morning- and evening-questionnaires were administered once each day, the within-day-questionnaire 10 times a day using a semi-random time schedule, and the attack questionnaire could be completed after the occurrence of a vertigo or dizziness attack. Data were collected for 4~weeks. Response rates and loss-to-follow-up were determined. Reported symptoms in the within-day-questionnaire were compared within and between patients and subgroups of patients with different vestibular disorders. RESULTS Fifty-one patients completed the study period. Average response rates were significantly higher than the desired response rate of \textgreater 50% (p \textless 0.001). The attack-questionnaire was used 159 times. A variety of neuro-otological symptoms and different disease profiles were demonstrated between patients and subgroups of patients with different vestibular disorders. CONCLUSION The DizzyQuest is able to capture vestibular symptoms within their psychosocial context in daily life, with little recall bias and high ecological validity. The DizzyQuest reached the desired response rates and showed different disease profiles between subgroups of patients with different vestibular disorders. This is the first time ESM was used to assess daily symptoms and quality of life in vestibular disorders, showing that it might be a useful tool in this population

Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers. Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks). Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup. Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer

Arable weed seeds as indicators of regional cereal provenance: a case study from Iron Age and Roman central-southern Britain

The ability to provenance crop remains from archaeological sites remains an outstanding research question in archaeology. Archaeobotanists have previously identified the movement of cereals on the basis of regional variations in the presence of cereal grain, chaff and weed seeds (the consumer–producer debate), and weed seeds indicative of certain soil types, principally at Danebury hillfort. Whilst the former approach has been heavily criticised over the last decade, the qualitative methods of the latter have not been evaluated. The first interregional trade in cereals in Britain is currently dated to the Iron Age hillfort societies of the mid 1st millennium bc. Several centuries later, the development of urban settlements in the Late Iron Age and Roman period resulted in populations reliant on food which was produced elsewhere. Using the case study of central-southern Britain, centred on the oppidum (large fortified settlement) and civitas capital of Silchester, this paper presents the first regional quantitative analysis of arable weed seeds in order to identify the origin of the cereals consumed there. Analysis of the weed seeds which were present with the fine sieve by-products of the glume wheat Triticum spelta (spelt) shows that the weed floras of samples from diverse geological areas can be separated on the basis of the soil requirements of individual taxa. A preliminary finding is that, rather than being supplied with cereals from the wider landscape of the chalk region of the Hampshire Downs, the crops were grown close to Late Iron Age Silchester. The method presented here requires further high quality samples to evaluate this conclusion and other instances of cereal movement in the past

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting

Immunosenescence and lymphomagenesis

One of the most important determinants of aging-related changes is a complex biological process emerged recently and called \u201cimmunosenescence\u201d. Immunosenescence refers to the inability of an aging immune system to produce an appropriate and effective response to challenge. This immune dysregulation may manifest as increased susceptibility to infection, cancer, autoimmune disease, and vaccine failure. At present, the relationship between immunosenescence and lymphoma in elderly patients is not defined in a satisfactory way. This review presents a brief overview of the interplay between aging, cancer and lymphoma, and the key topic of immunosenescence is addressed in the context of two main lymphoma groups, namely Non Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL). Epstein Barr Virus (EBV) plays a central role in the onset of neoplastic lymphoproliferation associated with immunological changes in aging, although the pathophysiology varies vastly among different disease entities. The interaction between immune dysfunction, immunosenescence and Epstein Barr Virus (EBV) infection appears to differ between NHL and HL, as well as between NHL subtypes

Everolimus Plus Exemestane in Postmenopausal Patients with HR+ Breast Cancer: BOLERO-2 Final Progression-Free Survival Analysis

INTRODUCTION: Effective treatments for hormone-receptor-positive (HR(+)) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population. METHODS: BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR(+) advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints. RESULTS: Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38–0.54); log-rank P < 0.0001; central review: 11.0 versus 4.1 months, respectively; hazard ratio = 0.38 (95% confidence interval 0.31–0.48); log-rank P < 0.0001] in the overall population and in all prospectively defined subgroups, including patients with visceral metastases, patients with recurrence during or within 12 months of completion of adjuvant therapy, and irrespective of age. The incidence and severity of adverse events were consistent with those reported at the interim analysis and in other everolimus trials. CONCLUSION: The addition of everolimus to exemestane markedly prolonged PFS in patients with HR(+) advanced BC with disease recurrence/progression following prior NSAIs. These results further support the use of everolimus plus exemestane in this patient population. ClinicalTrials.gov #NCT00863655. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12325-013-0060-1) contains supplementary material, which is available to authorized users

The Prospective Dutch Colorectal Cancer (PLCRC) cohort: real-world data facilitating research and clinical care

Real-world data (RWD) sources are important to advance clinical oncology research and evaluate treatments in daily practice. Since 2013, the Prospective Dutch Colorectal Cancer (PLCRC) cohort, linked to the Netherlands Cancer Registry, serves as an infrastructure for scientific research collecting additional patient-reported outcomes (PRO) and biospecimens. Here we report on cohort developments and investigate to what extent PLCRC reflects the “real-world”. Clinical and demographic characteristics of PLCRC participants were compared with the general Dutch CRC population (n = 74,692, Dutch-ref). To study representativeness, standardized differences between PLCRC and Dutch-ref were calculated, and logistic regression models were evaluated on their ability to distinguish cohort participants from the Dutch-ref (AU-ROC 0.5 = preferred, implying participation independent of patient characteristics). Stratified analyses by stage and time-period (2013–2016 and 2017–Aug 2019) were performed to study the evolution towards RWD. In August 2019, 5744 patients were enrolled. Enrollment increased steeply, from 129 participants (1 hospital) in 2013 to 2136 (50 of 75 Dutch hospitals) in 2018. Low AU-ROC (0.65, 95% CI: 0.64–0.65) indicates limited ability to distinguish cohort participants from the Dutch-ref. Characteristics that remained imbalanced in the period 2017–Aug’19 compared with the Dutch-ref were age (65.0 years in PLCRC, 69.3 in the Dutch-ref) and tumor stage (40% stage-III in PLCRC, 30% in the Dutch-ref). PLCRC approaches to represent the Dutch CRC population and will ultimately meet the current demand for high-quality RWD. Efforts are ongoing to improve multidisciplinary recruitment which will further enhance PLCRC’s representativeness and its contribution to a learning healthcare system