BMC Med

BACKGROUND: Overall survival (OS) is the gold standard endpoint to assess treatment efficacy in cancer clinical trials. In metastatic breast cancer (mBC), progression-free survival (PFS) is commonly used as an intermediate endpoint. Evidence remains scarce regarding the degree of association between PFS and OS. Our study aimed to describe the individual-level association between real-world PFS (rwPFS) and OS according to first-line treatment in female patients with mBC managed in real-world setting for each BC subtype (defined by status for both hormone-receptor [HR] expression and HER2 protein expression/gene amplification). METHODS: We extracted data from the ESME mBC database (NCT03275311) which gathers deidentified data from consecutive patients managed in 18 French Comprehensive Cancer Centers. Adult women diagnosed with mBC between 2008 and 2017 were included. Endpoints (PFS, OS) were described using the Kaplan-Meier method. Individual-level associations between rwPFS and OS were estimated using the Spearman's correlation coefficient. Analyses were conducted by tumor subtype. RESULTS: 20,033 women were eligible. Median age was 60.0 years. Median follow-up duration was 62.3 months. Median rwPFS ranged from 6.0 months (95% CI 5.8-6.2) for HR-/HER2 - subtype to 13.3 months (36% CI 12.7-14.3) for HR + /HER2 + subtype. Correlation coefficients were highly variable across subtypes and first-line (L1) treatments. Among patients with HR - /HER2 - mBC, correlation coefficients ranged from 0.73 to 0.81, suggesting a strong rwPFS/OS association. For HR + /HER2 + mBC patients, the individual-level associations were weak to strong with coefficients ranging from 0.33 to 0.43 for monotherapy and from 0.67 to 0.78 for combined therapies. CONCLUSIONS: Our study provides comprehensive information on individual-level association between rwPFS and OS for L1 treatments in mBC women managed in real-life practice. Our results could be used as a basis for future research dedicated to surrogate endpoint candidates

Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations

International audienceINTRODUCTION: Breast carcinoma is the main malignant tumor occurring in patients with Cowden disease, a cancer-prone syndrome caused by germline mutation of the tumor suppressor gene PTEN characterized by the occurrence throughout life of hyperplastic, hamartomatous and malignant growths affecting various organs. The absence of known histological features for breast cancer arising in a PTEN-mutant background prompted us to explore them for potential new markers. METHODS: We first performed a microarray study of three tumors from patients with Cowden disease in the context of a transcriptomic study of 74 familial breast cancers. A subsequent histological and immunohistochemical study including 12 additional cases of Cowden disease breast carcinomas was performed to confirm the microarray data. RESULTS: Unsupervised clustering of the 74 familial tumors followed the intrinsic gene classification of breast cancer except for a group of five tumors that included the three Cowden tumors. The gene expression profile of the Cowden tumors shows considerable overlap with that of a breast cancer subgroup known as molecular apocrine breast carcinoma, which is suspected to have increased androgenic signaling and shows frequent ERBB2 amplification in sporadic tumors. The histological and immunohistochemical study showed that several cases had apocrine histological features and expressed GGT1, which is a potential new marker for apocrine breast carcinoma. CONCLUSIONS: These data suggest that activation of the ERBB2-PI3K-AKT pathway by loss of PTEN at early stages of tumorigenesis promotes the formation of breast tumors with apocrine features

Trade and the environment: a survey of the literature

International audienceIntegration of neurotransmitter and neuromodulator signals in the striatum plays a central role in the functions and dysfunctions of the basal ganglia. DARPP-32 is a key actor of this integration in the GABAergic medium-size spiny neurons, in particular in response to dopamine and glutamate. When phosphorylated by cAMP-dependent protein kinase (PKA), DARPP-32 inhibits protein phosphatase-1 (PP1), whereas when phosphorylated by cyclin-dependent kinase 5 (CDK5) it inhibits PKA. DARPP-32 is also regulated by casein kinases and by several protein phosphatases. These complex and intricate regulations make simple predictions of DARPP-32 dynamic behaviour virtually impossible. We used detailed quantitative modelling of the regulation of DARPP-32 phosphorylation to improve our understanding of its function. The models included all the combinations of the three best-characterized phosphorylation sites of DARPP-32, their regulation by kinases and phosphatases, and the regulation of those enzymes by cAMP and Ca(2+) signals. Dynamic simulations allowed us to observe the temporal relationships between cAMP and Ca(2+) signals. We confirmed that the proposed regulation of protein phosphatase-2A (PP2A) by calcium can account for the observed decrease of Threonine 75 phosphorylation upon glutamate receptor activation. DARPP-32 is not simply a switch between PP1-inhibiting and PKA-inhibiting states. Sensitivity analysis showed that CDK5 activity is a major regulator of the response, as previously suggested. Conversely, the strength of the regulation of PP2A by PKA or by calcium had little effect on the PP1-inhibiting function of DARPP-32 in these conditions. The simulations showed that DARPP-32 is not only a robust signal integrator, but that its response also depends on the delay between cAMP and calcium signals affecting the response to the latter. This integration did not depend on the concentration of DARPP-32, while the absolute effect on PP1 varied linearly. In silico mutants showed that Ser137 phosphorylation affects the influence of the delay between dopamine and glutamate, and that constitutive phosphorylation in Ser137 transforms DARPP-32 in a quasi-irreversible switch. This work is a first attempt to better understand the complex interactions between cAMP and Ca(2+) regulation of DARPP-32. Progressive inclusion of additional components should lead to a realistic model of signalling networks underlying the function of striatal neurons

Effects of a Train of Ca²⁺ Spikes on DARPP-32 Phosphorylation

<p>Time-course of DARPP-32 isoforms triggered by a train of Ca²⁺ spikes. Bordeaux line represents the number of calcium ions in the dendritic spine. Colour code of DARPP-32 isoforms is the same as for <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.0020176#pcbi-0020176-g003" target="_blank">Figure 3</a>. In the absence of a cAMP signal, the phosphorylation on Thr34 remains null. (A) model A; (B) model B.</p

Effect of a Pulse of cAMP on DARPP-32 Phosphorylation

<p>Time-course of DARPP-32 isoforms after a pulse of cAMP. Brown line represents the number of cAMP molecules. Orange line represents the total number of PKA catalytic subunits not bound to regulatory subunits. DARPP-32 species are represented in black (unphosphorylated), red (D34*), blue (D75*), and green (D137*).</p

In Silico Site-Directed Mutagenesis of DARPP-32

<p>Same simulation paradigm as the one depicted in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.0020176#pcbi-0020176-g005" target="_blank">Figure 5</a>, but describing the predicted behaviour of mutants by model B. Wild-type DARPP-32 species are represented in green, Ser137Ala in red, and constitutive Ser137P in blue. (A) D34*; (B) D75*.</p

Cross-Sensitivity to the Inhibition of PKA by DARPP-32 and the Activity of CDK5 or the Stimulation of PP2A by PKA

<div><p>Values corresponding to model A are blue, while values corresponding to model B are magenta.</p><p>(A) Cross-sensitivity to the inhibition of PKA by DARPP-32 and the activity of CDK5. Note the inverse relationship between CDK5 activity and Thr34min for strong inhibition of PKA (low kcat) while the relationship is reversed at weak inhibition.</p><p>(B) Cross-sensitivity to the inhibition of PKA by DARPP-32 and the stimulation of PP2A by PKA.</p></div

Sensitivity to the Auto-Phosphorylation Activity of CK1

<div><p>(A) Sensitivity of Thr34min to the autophosphorylation activity of CK1. The maximal values of the <i>x</i>-axis correspond to a very fast auto-inhibition of CK1, with effects identical to a Ser137Ala mutation, see red curve on <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.0020176#pcbi-0020176-g010" target="_blank">Figure 10</a>A.</p><p>(B) Sensitivity of the relaxation time after calcium signal (the “sharpness” of the response) to the autophosphorylation activity of CK1.</p></div

Effect of One Pulse of cAMP Followed by a Train of Ca²⁺ Spikes on DARPP-32 Phosphorylation

<p>Time-course of DARPP-32 isoforms triggered by a pulse of cAMP followed by a train of Ca²⁺ spikes. Colour code of DARPP-32 isoforms is the same as for <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.0020176#pcbi-0020176-g003" target="_blank">Figure 3</a>. Relax and Thr34min show the two readouts used in sensitivity analysis. (A) model A; (B) model B.</p