Abstract
There is limited knowledge on the benefit of the α-subunit–specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor–positive (ER+) HER2− and triple-negative ...breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2− and TNBC. In the intention-to-treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival HR 0.24; 95% confidence interval (CI), 0.083–0.67, P = 0.0065. Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078–0.60, P = 0.003).
Significance:
Alpelisib monotherapy displayed efficacy in heavily pretreated ER+ breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting.
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Pragmatic trials evaluating complex health interventions often compare them to usual care. This comparator should resemble care as provided in everyday practice. However, usual care can differ for ...the same condition, between patients and practitioners, across clinical sites and over time. Heterogeneity within a usual care arm can raise methodological and ethical issues. To address these it may be necessary to standardise what usual care entails, although doing so may compromise a trial's external validity. Currently, there is no guidance detailing how researchers should decide the content of their usual care comparators. We conducted a methodology review to summarise current thinking about what should inform this decision.
MEDLINE, Embase, CINAHL and PsycINFO were searched from inception to January 2022. Articles and book chapters that discussed how to identify or develop usual care comparators were included. Experts in the field were also contacted. Reference lists and forward citation searches of included articles were screened. Data were analysed using a narrative synthesis approach.
One thousand nine hundred thirty records were identified, 1611 titles and abstracts screened, 112 full texts screened, and 16 articles included in the review. Results indicated that the content of a usual care comparator should be informed by the aims of the trial, existing care practices, clinical guidelines, and characteristics of the target population. Its content should also be driven by the trial's requirements to protect participants, inform practice, and be methodologically robust, efficient, feasible and acceptable to stakeholders. When deciding the content of usual care, researchers will need to gather information about these drivers, balance tensions that might occur when responding to different trial objectives, and decide how usual care will be described and monitored in the trial.
When deciding the content of a usual care arm, researchers need to understand the context in which a trial will be implemented and what the trial needs to achieve to address its aim and remain ethical. This is a complex decision-making process and trade-offs might need to be made. It also requires research and engagement with stakeholders, and therefore time and funding during the trial's design phase.
PROSPERO CRD42022307324.
Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by ...which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.
Metastatic breast cancer remains incurable. Next-generation sequencing (NGS) offers the ability to identify actionable genomic alterations in tumours which may then be matched with targeted ...therapies, but the implementation and utility of this approach is not well defined for patients with metastatic breast cancer.
We recruited patients with advanced breast cancer of any subtype for prospective targeted NGS of their most recent tumour samples, using a panel of 108 breast cancer-specific genes. Genes were classified as actionable or non-actionable using the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) guidelines.
Between February 2014 and May 2019, 322 patients were enrolled onto the study, with 72% (n = 234) of patients successfully sequenced (n = 357 samples). The majority (74%, n = 171) of sequenced patients were found to carry a potentially actionable alteration, the most common being a PIK3CA mutation. Forty-three percent (n = 74) of patients with actionable alterations were referred for a clinical trial or referred for confirmatory germline testing or had a change in therapy outside of clinical trials. We found alterations in AKT1, BRCA2, CHEK2, ESR1, FGFR1, KMT2C, NCOR1, PIK3CA and TSC2 to be significantly enriched in our metastatic population compared with primary breast cancers. Concordance between primary and metastatic samples for key driver genes (TP53, ERBB2 amplification) was > 75%. Additionally, we found that patients with a higher number of mutations had a significantly worse overall survival.
Genomic profiling of patients with metastatic breast cancer can have clinical implications and should be considered in all suitable patients.
Precise control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development and frequently corrupted in cancer. By coupling a cell ...surface readout of bivalent MHC class I gene expression with whole-genome CRISPR-Cas9 screens, we identify specific roles for MTF2-PRC2.1, PCGF1-PRC1.1 and Menin-KMT2A/B complexes in maintaining bivalency. Genetic loss or pharmacological inhibition of Menin unexpectedly phenocopies the effects of polycomb disruption, resulting in derepression of bivalent genes in both cancer cells and pluripotent stem cells. While Menin and KMT2A/B contribute to H3K4me3 at active genes, a separate Menin-independent function of KMT2A/B maintains H3K4me3 and opposes polycomb-mediated repression at bivalent genes. Release of KMT2A from active genes following Menin targeting alters the balance of polycomb and KMT2A at bivalent genes, facilitating gene activation. This functional partitioning of Menin-KMT2A/B complex components reveals therapeutic opportunities that can be leveraged through inhibition of Menin.
Comorbid mental health problems have been shown to have an adverse effect on the quality of life of people with common eye disorders. This study aims to assess whether symptoms of anxiety and/or ...depression are more prevalent in people with age-related macular degeneration (AMD) than in people without this condition.
A systematic search of electronic databases (Medline, CINAHL, EMBASE, PsycINFO) from inception to February 2012 was conducted to identify studies of AMD populations which measured symptoms of anxiety and/or depression. Reference checking of relevant articles was also performed. Data on the study setting, prevalence and how anxiety and depression were measured were extracted from the papers. Critical appraisal was performed using the Critical Appraisal Skills Programme (CASP) tools.
A total of 16 papers were included in the review, from an original search result of 597. The prevalence estimates, taken from nine cross-sectional and cohort studies, ranged from 15.7%-44% for depressive symptoms and 9.6%-30.1% for anxiety symptoms in people with AMD. The seven case-control studies found that people with AMD were more likely to experience symptoms of depression compared with those without AMD, but not more likely to experience symptoms of anxiety.
Overall, the evidence suggests that symptoms of depression are more prevalent amongst AMD populations than anxiety symptoms. The heterogeneity of the studies included in this review means that it is difficult to draw strong conclusions as to the true estimates of depression and anxiety symptoms in AMD populations and prevented formal meta-analysis. Further research which specifies clinical anxiety and gives clear definitions as to the type of AMD being investigated is required.
The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown ...efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.
Poetic Inquiry erlaubt eine Annäherung an die zahlreichen Facetten des Selbst, aus deren Zusammenspiel Verstehen möglich wird. Dennoch sehen wir uns als Forschende, auch wenn wir kreative ...Untersuchungsmethoden nutzen, immer wieder veranlasst, spezifische Anteile unserer Identität zu ignorieren. Persönliches in unserer Forschung anzuerkennen ist unbequem, einige würden auch sagen: irrelevant. Ich hingegen erachte es als außerordentlich bedeutsam, da es zugleich das Multiple, Fluide, sich Überschneidende und oft auch Widersprüchliche von Subjektivität fassbar macht. Als Wissenschaftler/innen haben die meisten von uns bereits irgendwann um die je eigene Situierung im Forschungsprozess gerungen, anderen steht es noch bevor. Auch wenn die Kämpfe, die wir dann mit uns führen, unterschiedlich sein mögen, ist ihnen ein gewisses Unbehagen gemeinsam. In diesem Beitrag greife ich auf Poetic Inquiry zurück, um das Unbehagen und die Verunsicherung verstehen zu können, die ich erlebte, als ich mich – gerade Mutter geworden – wieder meiner Forschungsarbeit zuwendete. Auf diese Weise bleibt meine eigene Geschichte nicht isoliert, sondern wird Teil eines breiteren Dialogs über Unbehagen, Unsicherheit und die Möglichkeit, sich sowohl als Forscher/in als auch als Person im Forschungsprozess zu situieren.
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