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The phase III MAX clinical trial randomised patients with metastatic colorectal cancer (mCRC) to receive first-line capecitabine chemotherapy alone or in combination with the anti-VEGF-A antibody bevacizumab (± mitomycin C). We utilised this cohort to examine whether single nucleotide polymorphisms (SNPs) in VEGF-A , VEGFR1 , and VEGFR2 are predictive of efficacy outcomes with bevacizumab or the development of hypertension. Genomic DNA extracted from archival FFPE tissue for 325 patients (69% of the MAX trial population) was used to genotype 16 candidate SNPs in VEGF-A , VEGFR1 , and VEGFR2, which were analysed for associations with efficacy outcomes and hypertension. The VEGF-A rs25648 ‘CC’ genotype was prognostic for improved PFS (HR 0.65, 95% CI 0.49 to 0.85; P  = 0.002) and OS (HR 0.70, 95% CI 0.52 to 0.94; P  = 0.019). The VEGF-A rs699947 ‘AA’ genotype was prognostic for shorter PFS (HR 1.32, 95% CI 1.002 to 1.74; P  = 0.048). None of the analysed SNPs were predictive of bevacizumab efficacy outcomes. VEGFR2 rs11133360 ‘TT’ was associated with a lower risk of grade ≥ 3 hypertension ( P  = 0.028). SNPs in VEGF-A, VEGFR1 and VEGFR2 did not predict bevacizumab benefit. However, VEGF-A rs25648 and rs699947 were identified as novel prognostic biomarkers and VEGFR2 rs11133360 was associated with less grade ≥ 3 hypertension.

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with -mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with -mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).

In a randomized trial involving patients with non–small-cell lung cancer with mutant EGFR (T790M) in whom a tyrosine kinase inhibitor had failed, osimertinib was associated with significantly longer progression-free survival than platinum therapy plus pemetrexed. Among patients with advanced non–small-cell lung cancer with a mutant epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors (TKIs) are the standard first-line therapy. 1 – 4 Despite high tumor response rates with first-line EGFR-TKIs, disease progresses in a majority of patients after 9 to 13 months of treatment. 5 – 12 At the time of progression, approximately 60% of patients (regardless of race or ethnic background) are found to have a p.Thr790Met point mutation (T790M) in the gene encoding EGFR. 13 – 16 The presence of the T790M variant reduces binding of first-generation or second-generation EGFR-TKIs to the ATP-binding pocket of EGFR, thereby reducing . . .

PurposeCardiac function assessment is important for detecting and managing trastuzumab-associated cardiotoxicity. Our study estimates rates and predictors of cardiac assessment among patients receiving trastuzumab for HER2-positive early breast cancer (HER2+EBC) in Australia.MethodsWe conducted a retrospective cohort study of Australians initiating (neo)adjuvant trastuzumab for HER2+EBC between 1 January 2015 and 15 April 2019. We used administrative claims to determine the number of patients receiving guideline-recommended assessment, i.e. evidence of baseline cardiac assessment (between 120 days before and 30 days after trastuzumab initiation) and regular on-treatment cardiac assessments (at least every 120 days). We examined factors associated with baseline and regular on-treatment cardiac assessment.ResultsOur study includes 5621 patients (median age 56 years), of whom 4984 (88.7%) had a baseline cardiac function test. Among 4280 patients with at least 12 months of follow-up, 2702 (63.1%) had guideline-recommended cardiac assessment. Rates of guideline-recommended assessment increased with later year of diagnosis (60.9% in 2015 vs 68.3% in 2018, OR 1.34, 95% CI 1.06–1.69). Patients with higher baseline comorbidities and greater socioeconomic disadvantage were less likely to have guideline-recommended cardiac assessment. Cardiac assessment practices varied by State/Territory. There was no association between baseline cardiac risk or anthracycline use and the likelihood of receiving guideline-recommended cardiac assessment.ConclusionThe majority of patients receiving (neo)adjuvant trastuzumab had guideline-recommended baseline and on-treatment cardiac assessment. Variations in cardiac assessment predominantly related to system-level factors, such as year of diagnosis and geography, rather than individual patient factors.

Background Randomised clinical trials (RCTs) demonstrate that trastuzumab improves survival in patients with human epidermal growth factor 2-positive early breast cancer (HER2 + EBC), but real-world patients and clinical practice often differ from RCTs. We examine real-world treatment patterns and outcomes associated with trastuzumab for HER2 + EBC. Methods We identified all Australians dispensed trastuzumab for HER2 + EBC between 1/1/2007 and 30/6/2016. We estimated the proportion of patients completing 12 months of treatment (defined as ≥350 days of exposure within 540 days of initiation). We estimated overall survival (OS) and recurrence-free survival (RFS) by using trastuzumab dispensing for metastatic breast cancer as a surrogate for recurrence. Results Our study included 14,644 patients. Among patients with ≥540 days of follow-up ( n  = 11,903), 67.4% completed 12 months of trastuzumab. OS rates at 5 and 9 years were 92.7 and 87.9%, and RFS rates at 5 and 9 years were 86.8 and 81.4%, respectively. Patients who completed 12 months of trastuzumab had a 9-year OS rate of 90.2% compared with 86.2% among patients receiving <12 months of therapy (adjusted HR 0.71, 95% CI 0.62–0.81). Conclusions Real-world HER2 + EBC patients are less likely to complete 12 months of trastuzumab than some clinical trial counterparts but have survival outcomes comparable to those reported in landmark RCTs.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background Chemo-immunotherapy is standard of care for women with recurrent or advanced mismatch repair deficient endometrial carcinoma. However, it is uncertain whether patients with mismatch repair deficient advanced or recurrent endometrial carcinoma derive less benefit from chemotherapy than those with mismatch repair proficient endometrial carcinoma. Methods We performed a meta-analysis of randomized controlled trials (RCTs) in advanced or recurrent endometrial carcinoma to determine the difference in the benefit of chemotherapy in mismatch repair deficient vs mismatch repair proficient endometrial carcinoma. Data on chemotherapy outcomes including objective response rate, progression-free survival (PFS), and overall survival were retrieved. We pooled these data using the inverse variance method and examined subgroup difference by mismatch repair status. We also compared differences in PFS and overall survival outcomes by creating individual patient data from the Kaplan–Meier curves of trial publications for sensitivity analyses. Results A total of 5 RCTs with 1137 participants (mismatch repair deficient, 26%; mismatch repair proficient, 74%) were included. All participants were treated with carboplatin-based chemotherapy. There was no difference between the mismatch repair deficient and mismatch repair proficient subgroups for objective response rate (66.5% vs 64.0%; P = .20 for subgroup difference), PFS (hazard ratio [HR] = 0.93, 95% confidence interval [CI] = 0.77 to 1.12; P = .44; median PFS = 7.6 vs 9.5 months) or overall survival (HR = 1.03, 95% CI = 0.73 to 1.44; P = .88; median overall survival = not reached vs 28.6 months). Conclusions Objective response rate, PFS, and overall survival were similar among those with mismatch repair deficient vs mismatch repair proficient endometrial cancer treated with front-line, platinum-doublet chemotherapy in RCTs. These findings reinforce the importance of combining chemotherapy together with immune checkpoint inhibitors until the results of trials comparing immune checkpoint therapy alone with combination therapy are available.

We investigate if PD-L1 expression and other clinical characteristics predict chemoimmunotherapy (CIT) benefits versus chemotherapy in advanced non-small-cell lung cancer. We performed a meta-analysis of randomized controlled trials of CIT versus chemotherapy identified through electronic searches. In seven randomized controlled trials (n = 4170), CIT prolonged progression-free survival over chemotherapy (hazard ratio [HR]: 0.62; 95% CI: 0.58–0.67; p < 0.00001). The treatment benefits differed between PD-L1-high (HR: 0.41; 95% CI: 0.34–0.49) and PD-L1 low (HR: 0.63; 95% CI: 0.55–0.72; interaction-p = 0.00002) and PD-L1-high and PD-L1-negative (HR: 0.72; 95% CI: 0.65–0.80; interaction-p < 0.00001). Similar benefits were observed regardless of gender, status and histological subtype. PD-L1 status is predictive of CIT benefit and may assist patient selection and design of future trials.

Loss of phosphatase and tensin homologue (PTEN) expression may be prognostic in colorectal cancer (CRC) and may have a correlation with vascular endothelial growth factor (VEGF) expression via hypoxia‐inducible factor 1 (HIF‐1) alpha, and the PI3K/mTOR pathways. We therefore have explored the prognostic association of PTEN loss and the potential that PTEN loss may be predictive of outcome with bevacizumab. Patients enrolled in the AGITG MAX trial, a randomized Phase III trial of capecitabine (C) +/− bevacizumab (B) (+/− mitomycin C [M]) with available tissues were analyzed for PTEN expression (loss vs. no loss) as assessed using a Taqman® copy number assay (CNA). Of the original 471 patients enrolled, tissues from 302 (64.1%) patients were analyzed. PTEN loss was observed in 38.7% of patients. There was no relationship between PTEN loss and KRAS or BRAF mutation. PTEN status was not prognostic for progression‐free survival (PFS) or overall survival (OS) in multivariate analyses adjusting for other baseline factors; loss versus no loss PFS hazard ratio (HR) 0.9 (0.7–1.16), OS HR 1.04 (0.79–1.38). PTEN was not prognostic when assessed by KRAS and BRAF status. By using the comparison of C versus CB+CBM, PTEN status was not significantly predictive of the effectiveness of B for PFS or OS. PTEN status was not prognostic for survival in advanced colorectal cancer, irrespective of KRAS or BRAF status. PTEN status did not significantly predict different benefit with bevacizumb therapy. Phosphatase and tensin homologue (PTEN) remains controversial as a predictive and prognostic marker. There also remains uncertainty as to the best method to assess PTEN status. Here, we use PTEN copy number and assess the association of outcome and PTEN loss, as defined by copy number variation.

The future of microelectronic and nanoelectronics devices could lie in one-dimensional nanomaterials including boron nitride nanotubes (BNNTs). In such applications, however, the flow of electrical current may induce structural failure resulting in reduction of component Service life. Here, we utilized scanning tunneling microscopy inside a transmission electron microscope to study the thermal failure of individual multi-walled BNNTs via Joule heating. At elevated temperatures, the nanotube failed by the formation of amorphous nanoclusters and progression of structural defects. These Clusters have various sizes and initially form on the outermost shell layers of BNNTs.