AZD9291 is an oral, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI), which specifically targets both sensitizing and resistant T790M ...mutations. This compound has shown outstanding activity, in a phase I/II (AURA) trial. However, despite impressive tumor responses in T790M-positive patients, acquired resistance to this drug limits the benefit of this compound. Mutations at the EGFR C797 codon, located within the kinase-binding site, were very recently reported to be a potential mechanism of resistance to AZD9291 in T790M-positive patients.
To identify potential mechanisms of resistance to AZD9291, we report here on two patients with resistant biopsy specimens that had been treated with AZD9291.
We identified in two distinct cases, HER2 and MET amplification by FISH and CGH as a potential mechanism of acquired resistance to third-generation EGFR-TKI. Interestingly, this event occurred with complete loss of the T790M mutation. In one case, we observed a different molecular status at two biopsy sites (the T790M mutation at the primary site and wild-type T790M at the metastatic site with different pathways of acquired resistance to AZD9291).
Our observations suggest that T790M-positive and wild-type T790M clones may coexist at baseline. AZD9291 efficiently suppresses the growth of T790M-positive cells, but a population of wild-type T790M cells at baseline will mediate the development of resistance, here via a by-pass pathway activating either HER2 or MET.
The objective of the rare-earth free permanent magnets (REFREEPM) project is to develop a new generation of high-performance permanent magnets (PMs) without rare earths. Our approach is based on ...modeling using a combinatorial approach together with micromagnetic modeling and the realization of the modeled systems (I) by using a novel production of high-aspect-ratio (>5) nanostructrures (nanowires, nanorods, and nanoflakes) by exploiting the magnetic shape anisotropy of the constituents that can be produced via chemical nanosynthesis polyol process or electrodeposition, which can be consolidated with novel processes for a new generation of rare-earth free PMs with energy product in the range of 60 kJ/m
3
< (BH)max < 160 kJ/m
3
at room temperature, and (II) by using a high-throughput thin-film synthesis and high-throughput characterization approach to identify promising candidate materials that can be stabilized in a tetragonal or hexagonal structure by epitaxial growth on selected substrates, under various conditions of pressure, stoichiometry, and temperature. In this article, we report the progress so far in selected phases.
We report on the magnetic hyperthermia properties of chemically synthesized ferromagnetic 11 and 16
nm Fe(0) nanoparticles of cubic shape displaying the saturation magnetization of bulk iron. The ...specific absorption rate measured on 16
nm nanocubes is 1690±160
W/g at 300
kHz and 66
mT. This corresponds to specific losses-per-cycle of 5.6
mJ/g, largely exceeding the ones reported in other systems. A way to quantify the degree of optimization of any system with respect to hyperthermia applications is proposed. Applied here, this method shows that our nanoparticles are not fully optimized, probably due to the strong influence of magnetic interactions on their magnetic response. Once protected from oxidation and further optimized, such nano-objects could constitute efficient magnetic cores for biomedical applications requiring very large heating power.
While deregulation of the cyclin D1-CDK4/6-retinoblastoma pathway is common in hormone receptor positive (HR+) breast cancer, Rb is usually intact in HR+breast cancer, and targeted CDK 4/6 inhibitors ...that act upstream of Rb, are routinely being utilized in clinical practice. However, factors that can lead to clinical resistance to CDK 4/6 inhibitors are not known.
We identified patients who had pre- and post-genotyping in tissue and peripheral blood samples after receiving CDK 4/6 inhibitors. Genotyping was carried out in tumor tissue or blood collected before start of CDK 4/6 inhibitor and after disease progression on CDK 4/6 inhibitor, covering more than 90% of the coding region in RB1.
We identified detectable acquired RB1 mutations in circulating tumor DNA (ctDNA) after exposure to CDK4/6 inhibitor (palbociclib, palbociclib, ribociclib) for 5, 8, and 13months, respectively, in three patients. The RB1 mutations included substitution in donor splicing site of exon 8 of the RB1 gene in patient #1; substitution in donor splicing site of exon 22 of RB1 gene, exon 19 deletion, exon 3 insertion in patient #2; and RB1 exon 16 H483Y mutation in patient #3. None of these RB1 mutations were present in the pre-CDK 4/6 specimen highlighting these molecular alterations, which lead to functional loss of Rb1, likely emerged under selective pressure from the CDK4/6 inhibitor potentially confering therapeutic resistance.
This is the first clinical report to describe the emergence of somatic RB1 mutations after exposure to palbociclib or ribociclib, in patients with metastatic breast cancer. Further research is needed to validate these findings, identify how these mutations temporally emerge under selective pressure of CDK 4/6 inhibitor, and develop rational therapeutic strategies.
There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations.
EGFR exon 18 and/or exon 20 mutations were ...collected from 10 117 non-small-cell lung cancer (NSCLC) samples analysed at 15 French National Cancer Institute (INCa)-platforms of the ERMETIC-IFCT network.
Between 2008 and 2011, 1047 (10%) samples were EGFR-mutated, 102 (10%) with rare mutations: 41 (4%) in exon 18, 49 (5%) in exon 20, and 12 (1%) with other EGFR mutations. Exon 20 mutations were related to never-smoker status, when compared with exon 18 mutations (P < 0.001). Median overall survival (OS) of metastatic disease was 21 months 95% confidence interval (CI) 12–24, worse in smokers than in non-smoker patients with exon 20 mutations (12 versus 21 months; hazard ratio HR for death 0.27, 95% CI 0.08–0.87, P = 0.03). Under EGFR-tyrosine kinase inhibitors (TKIs), median OS was 14 months (95% CI 6–21); disease control rate was better for complex mutations (6 of 7, 86%) than for single mutations (16 of 40, 40%) (P = 0.03).
Rare EGFR-mutated NSCLCs are heterogeneous, with resistance of distal exon 20 insertions and better sensitivity of exon 18 or complex mutations to EGFR-TKIs, probably requiring individual assessment.
Flower and easy-axis vortex states are well-known magnetic configurations that can be stabilized in small particles. However, vortex (V ), i.e. a vortex state with its core axis along the hard-axis ...direction, has been recently evidenced as a stable configuration in Fe nanocubes of intermediate sizes in the flower/vortex transition. In this context, we present here extensive micromagnetic simulations to determine the different magnetic ground states in ferromagnetic nanocuboids exhibiting cubic magnetocrystalline anisotropy (MCA). Focusing our study in the single-domain/multidomain size range (10–50nm), we showed that V is only stable in nanocuboids exhibiting peculiar features, such as a specific size, shape and magnetic environment, contrarily to the classical flower and easy-axis vortex states. Thus, to track experimentally these V states, one should focused on (i) nanocuboids exhibiting a nearly perfect cubic shape (size distorsion <12%) made of (ii) a material which combines a zero or positive MCA and a high saturation magnetization, such as Fe or FeCo; and (iii) a low magnetic field environment, V being only observed in virgin or remanent states.
•The vortex is numerically determined in nanocubes of cubic anisotropy.•It constitutes an intermediate state in the single-domain limit.•Such a vortex can only be stabilized in perfect or slightly deformed nanocuboids.•It exists in nanocuboids made of materials with zero or positive cubic anisotropy.•The associated magnetization reversal is described by a rotation of the vortex axis.
α-Selective phosphatidylinositol 3-kinase (PI3K) inhibitors improve outcome in patients with PIK3CA-mutated, hormone receptor-positive (HR+)/Her2− metastatic breast cancer (mBC). Nevertheless, it is ...still unclear how to integrate this new drug family in the treatment landscape.
A total of 649 patients with mBC from the SAFIR02 trial (NCT02299999), with available mutational profiles were selected for outcome analysis. PIK3CA mutations were prospectively determined by next-generation sequencing on metastatic samples. The mutational landscape of PIK3CA-mutated mBC was assessed by whole-exome sequencing (n = 617). Finally, the prognostic value of PIK3CA mutations during chemotherapy was assessed in plasma samples (n = 44) by next-generation sequencing and digital PCR.
Some 28% (104/364) of HR+/Her2− tumors and 10% (27/255) of triple-negative breast cancer (TNBC) presented a PIK3CA mutation (P < 0.001). PIK3CA-mutated HR+/Her2− mBC was less sensitive to chemotherapy adjusted odds ratio: 0.40; 95% confidence interval (0.22–0.71); P = 0.002, and presented a worse overall survival (OS) compared with PIK3CA wild-type adjusted hazard ratio: 1.44; 95% confidence interval (1.02–2.03); P = 0.04. PIK3CA-mutated HR+/Her2− mBC was enriched in MAP3K1 mutations (15% versus 5%, P = 0.0005). In metastatic TNBC (mTNBC), the median OS in patients with PIK3CA mutation was 24 versus 14 months for PIK3CA wild-type (P = 0.03). We further looked at the distribution of PIK3CA mutation in mTNBC according to HR expression on the primary tumor. Some 6% (9/138) of patients without HR expression on the primary and 36% (14/39) of patients with HR+ on the primary presented PIK3CA mutation (P < 0.001). The level of residual PIK3CA mutations in plasma after one to three cycles of chemotherapy was associated with a poor OS continuous variable, hazard ratio: 1.03, 95% confidence interval (1.01–1.05), P = 0.007.
PIK3CA-mutated HR+/Her2− mBC patients present a poor outcome and resistance to chemotherapy. Patients with PIK3CA-mutated TNBC present a better OS. This could be explained by an enrichment of PIK3CA mutations in luminal BC which lost HR expression in the metastatic setting.
SAFIR02 trial: NCT02299999.
•Patients with HR+/Her2- mBC and PIK3CA mutation were less sensitive to chemotherapy and presented worse overall survival.•Patients with TNBC tumors and PIK3CA mutation present a better overall survival as compared with wt.•A subset of patients with PIK3CA-mutated TNBC could be luminal breast cancers that lost hormone receptor expression.•Persistant levels of cell-free circulating PIK3CA mutations on plasma during chemotherapy are indicative of a poor outcome.
Facial expression is widely used as a measure of pain in infants; whether nonhuman animals display such pain expressions has never been systematically assessed. We developed the mouse grimace scale ...(MGS), a standardized behavioral coding system with high accuracy and reliability; assays involving noxious stimuli of moderate duration are accompanied by facial expressions of pain. This measure of spontaneously emitted pain may provide insight into the subjective pain experience of mice.
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