The impact of TP53 co-mutations in EGFR mutated patients on PFS and OS is controversial. Different classifications of TP53 mutations with respect to functional and potential clinical impact have been ...published. Therefore, we retrospectively analyzed the impact of TP53 co-mutations on ORR, PFS and OS in a cohort of EGFR mutated NSCLC IV patients (UICC 7) using different classifications of TP53 mutations.
75 EGFR mutated NSCLC IV patients homogeneously treated with 1st line EGFR TKI were analyzed for TP53 co-mutations. TP53 mutations were classified according to three different types of classifications. The endpoints ORR, PFS and OS were investigated.
TP53 co-mutations were found in 29/59 patients (49.2%). TP53 co-mutations were a statistically significant independent negative predictive factor for ORR, PFS and OS. TP53 co-mutations were associated with inferior mPFS and mOS: mPFS/mOS 12 vs. 18/24 vs. 42 months for non-disruptive/disruptive mutations vs. WT (
< 0.004)/(
< 0.009), 11 vs. 17/23 vs. 42 months for pathogenic vs. non-pathogenic/WT (
< 0.001)/(
< 0.001), and 7 vs. 12 vs. 18/12 vs. 28 vs. 42 months for exon 8 vs. non-exon 8 vs. WT (
< 0.001)/(
< 0.002).
TP53 co-mutations are frequent in EGFR mt+ NSCLC and have a strong negative impact on all clinical endpoints of TKI therapy.
The PACIFIC study showed that after radio-chemotherapy, patients with NSCLC derived a benefit in PFS and OS when treated with durvalumab. This effect was limited to patients with a PD-L1 expression ...of >1%, partly because the outcome in the observational control arm was surprisingly favorable. Thus, it could be speculated that a lack of PD-L1 expression confers a favorable outcome for patients with stage III NSCLC.
Clinical data, PD-L1 expression, predictive blood markers, and the outcomes of 99 homogeneously treated patients with stage III NSCLC were retrospectively captured. Statistical analyses using the log rank test were performed.
The median OS of patients with an expression of PD-L1 < 1% was 20 months (CI 10.5-29.5) and the median OS of patients with an expression of PD-L1 ≥ 1% was 28 months (CI 16.5-39.2) (
= 0.734). The median PFS of patients with an expression of PD-L1 < 1% was 9 months (CI 6.3-11.6) and the median PFS of patients with an expression of PD-L1 ≥ 1% was 12 months (CI 9.8-14.2) (
= 0.112).
The assumption that the lack of PD-L1 expression represents a favorable prognostic factor after radio-chemotherapy vs. PD-L1 expression > 1% was not confirmed.
Since 2009, several first, second, and third generation EGFR tyrosine kinase inhibitors (TKI) have been approved for targeted treatment of EGFR mutated metastatic non-small lung cancer (NSCLC). A ...vast majority of patients is improving quickly on treatment; however, resistance is inevitable and typically occurs after one year for TKI of the first and second generation. Osimertinib, a third generation TKI, has recently been approved for first line treatment in the palliative setting and is expected to become approved for the adjuvant setting as well. Progression-free survival (PFS) under osimertinib is superior to its predecessors but its spectrum of resistance alterations appears significantly more diverse compared to first and second generation EGFR TKI. As resistance mechanisms to osimertinib are therapeutically targetable in some cases, it is important to comprehensively test for molecular alterations in the relapse scenario. Liquid biopsy may be advantageous over tissue analysis as it has the potential to represent tumor heterogeneity and clonal diversification. We have previously shown high concordance of hybrid capture (HC) based next generation sequencing (NGS) in liquid biopsy versus solid tumor biopsies. In this study, we now present real-word data from 56 patients with metastatic NSCLC that were tested by liquid biopsy at the time of disease progression on mostly second line treated osimertinib treatment. We present examples of single and multiple TKI resistance mechanisms, including mutations in multiple pathways, copy number changes and rare fusions of RET, ALK, FGFR3 and BRAF. In addition, we present the added value of HC based NGS to reveal polyclonal resistance development at the DNA level encoding multiple EGFR C797S and PIK3CA mutations.
The worldwide approval of the combination maintenance therapy of olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are ...sufficiently robust for the routine detection of driver mutations in homologous recombination repair (HRR) genes and genomic instability (GI), employing formalin-fixed (FFPE) paraffin-embedded tumor samples without matched normal tissue. We therefore established a DNA-based hybrid capture NGS assay and an associated bioinformatic pipeline that fulfils our institution's specific needs. The assay´s target regions cover the full exonic territory of relevant cancer-related genes and HRR genes and more than 20,000 evenly distributed single nucleotide polymorphism (SNP) loci to allow for the detection of genome-wide allele specific copy number alterations (CNA). To determine GI status, we implemented an %CNA score that is robust across a broad range of tumor cell content (25-85%) often found in routine FFPE samples. The assay was established using high-grade serous ovarian cancer samples for which
and
mutation status as well as Myriad MyChoice homologous repair deficiency (HRD) status was known. The NOGGO (Northeastern German Society for Gynecologic Oncology) GIS (GI-Score) v1 assay was clinically validated on more than 400 samples of the ENGOT PAOLA-1 clinical trial as part of the European Network for Gynaecological Oncological Trial groups (ENGOT) HRD European Initiative. The "NOGGO GIS v1 assay" performed using highly robust hazard ratios for progression-free survival (PFS) and overall survival (OS), as well a significantly lower dropout rate than the Myriad MyChoice clinical trial assay supporting the clinical utility of the assay. We also provide proof of a modular and scalable routine diagnostic method, that can be flexibly adapted and adjusted to meet future clinical needs, emerging biomarkers, and further tumor entities.
Epidermal growth factor receptor (EGFR) mt+ nonsmall cell lung cancer (NSCLC) were the first molecularly described NSCLC with an established 'targeted' therapy inhibiting mutated EGFR EGFR tyrosine ...kinase inhibitor (TKI). EGFR TKI of first and second generation have led to an unprecedented improvement in objective response rate, progression-free survival (PFS) and overall survival (OS) compared with chemotherapy with a significantly reduced toxicity and improved quality of life. Fast elucidation of the most frequent resistance mechanism against first and second-generation TKI, T790M, led to the approval of the third-generation TKI osimertinib in second line.
Recently, the FLAURA study showed an impressive PFS benefit and immature OS data for osimertinib against solely first-generation TKI's. Also, the ARCHER study comparing dacomitinib against first-generation TKI showed a PFS and also OS benefit. Two studies combining EGFR TKI and antiangiogenesis showed PFS but no OS benefit. Lately, the combination of TKI and chemotherapy has seen a revival with the NEJ009 study, resulting in an impressive median OS of 55 months.
Therefore, potentially four different therapeutic options are available in first-line therapy of EGFR mt+ NSCLC, first, second, third generation, TKI + antiangiogenic agent and TKI + chemotherapy. The purpose of the review is to help to guide physicians to decide in their treatment choice and discuss potential directions of research.
IntroductionIn connection with a hospital stay, patients have to make important health-related decisions. They need to find, understand, assess and apply health-related information, and therefore, ...require health literacy. Adequately responding to the needs of patients requires promoting the communication skills of healthcare professionals within healthcare organisations. Health-literate healthcare organisations can provide an environment strengthening professionals’ and patients’ health literacy. When developing health-literate healthcare organisations, it has to be considered that implementing organisational change is typically challenging. In this study, a communication concept based on previously evaluated communication training is codesigned, implemented and evaluated in four clinical departments of a university hospital.Method and analysisIn a codesign phase, focus group interviews among employees and patients as well as a workshop series with employees and hospital management are used to tailor the communication concept to the clinical departments and to patients’ needs. Also, representatives responsible for the topic of health literacy are established among employees. The communication concept is implemented over a 12-month period; outcomes studied are health literacy on the organisational and patient levels. Longitudinal survey data acquired from a control cohort prior to the implementation phase are compared with data of an intervention cohort after the implementation phase. Moreover, survey data from healthcare professionals before and after the implementation are compared. For formative evaluation, healthcare professionals are interviewed in focus groups.Ethics and disseminationThe study protocol was approved by the Ethics Committee of the Medical Faculty of the University of Oldenburg and is in accordance with the Declaration of Helsinki. Study participants are asked to provide written informed consent. The results are disseminated via direct communication within the hospital, publications and conference presentations. If the intervention turns out to be successful, the intervention and implementation strategies will be made available to other hospitals.Trial registration numberDRKS00019830.
This paper challenges the orientations and assumptions underpinning policies for disadvantaged young people (DYP) in Australia. We argue that policy interventions for young people generally exhibit a ...binary divide, some policies fostering leadership and creative endeavours targeted on 'high-functioning' young people, especially within educational and arts milieus, while other policies, focusing on DYP, take a remedial orientation. The basis for this binary divide is, we argue, flawed social constructions of young people, constructions that pathologise or privilege behaviours, attitudes and lifestyles. The consequences for DYP are that remedial policies, designed to get and keep young people 'on track', are often ignoring deeper developmental needs. Using recent research findings from arts programmes for young people, the paper argues for a broader policy orientation, including developmental needs, to strengthen remedial policies and programmes and open the potential for pathways to resilience.
The development of global social networking sites using Web 2.0 technologies (MySpace, Facebook, YouTube, Wikipedia, Flickr, etc.) is signalling a shift in media usage towards an environment in which ...the distinction between producer and consumer is less clearly defined. While audiences still demand and enjoy a quality professional product, their active personal experience of media production means that they are no longer content to remain outside the production process. This paper outlines the first part of a multi-stage research project that is monitoring responses on both sides of the divide. Through analysis of media coverage, policy reports, submissions to government and interviews with a number of senior executives in leading Australian screen agencies and industry organisations, we have identified four distinct categories of Australian film industry response to technological change and shifts in media consumption, provisionally referred to as ‘Denial’, ‘Panic’, ‘Embrace’ and ‘Co-create’. In this paper, we offer a critical examination of these responses.
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