Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers.

Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.

First Comparative Evaluation of Short-Chain Fatty Acids and Vitamin-K-Dependent Proteins Levels in Mother-Newborn Pairs at Birth.

BACKGROUND: The interplay between vitamin K (vitK) (as carboxylation cofactor, partially produced by the gut microbiota) and short-chain fatty acids (SCFAs), the end-product of fiber fermentation in the gut, has never been assessed in mother-newborn pairs, although newborns are considered vitK deficient and with sterile gut. METHODS: We collected venous blood from 45 healthy mothers with uncomplicated term pregnancies and umbilical cord blood from their newborns at birth. The concentrations of total SCFAs and hepatic/extra-hepatic vitK-dependent proteins (VKDPs), as proxies of vitK status were assayed: undercarboxylated and total matrix Gla protein (ucMGP and tMGP), undercarboxylated osteocalcin (ucOC), undercarboxylated Gla-rich protein (ucGRP), and protein induced by vitK absence II (PIVKA-II). RESULTS: We found significantly higher ucOC (18.6-fold), ucMGP (9.2-fold), and PIVKA-II (5.6-fold) levels in newborns, while tMGP (5.1-fold) and SCFAs (2.4-fold) were higher in mothers, and ucGRP was insignificantly modified. In mother-newborn pairs, only ucGRP (r = 0.746, p < 0.01) and SCFAs (r = 0.428, p = 0.01) levels were correlated. Conclusions: We report for the first time the presence of SCFAs in humans at birth, probably transferred through the placenta to the fetus. The increased circulating undercarboxylated VKDPSs in newborns revealed a higher vitamin K deficiency at the extrahepatic level compared to liver VKDPs.

Damage Detection on a Beam with Multiple Cracks: A Simplified Method Based on Relative Frequency Shifts.

Identifying cracks in the incipient state is essential to prevent the failure of engineering structures. Detection methods relying on the analysis of the changes in modal parameters are widely used because of the advantages they present. In our previous research, we found that eigenfrequencies were capable of indicating the position and depth of damage when sufficient vibration modes were considered. The damage indicator we developed was based on the relative frequency shifts (RFS). To calculate the RFSs for various positions and depths of a crack, we established a mathematical relation that involved the squared modal curvatures in the healthy state and the deflection of the healthy and damaged beam under dead mass, respectively. In this study, we propose to calculate the RFS for beams with several cracks by applying the superposition principle. We demonstrate that this is possible if the cracks are far enough from each other. In fact, if the cracks are close to each other, the superposition method does not work and we distinguish two cases: (i) when the cracks affect the same beam face, the frequency drop is less than the sum of the individual frequency drops, and (ii) on the contrary, cracks on opposite sides cause a decrease in frequency, which is greater than the sum of the frequency drop due to individual damage. When the RFS curves are known, crack assessment becomes an optimization problem, the cost function being the distance between the measured RFSs and all possible RFSs for several vibration modes. Thus, the RFS constitutes a benchmark that characterizes damage using only the eigenfrequencies. We can accurately locate multiple cracks and estimate their severity through experiments and thus prove the reliability of the proposed method.

Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors.

Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.

Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription.

The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppresses tumor growth in vivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc.

DBC1 Regulates p53 Stability via Inhibition of CBP-Dependent p53 Polyubiquitination.

The control of p53 protein stability is critical to its tumor suppressor functions. The CREB binding protein (CBP) transcriptional co-activator co-operates with MDM2 to maintain normally low physiological p53 levels in cells via exclusively cytoplasmic E4 polyubiquitination activity. Using mass spectrometry to identify nuclear and cytoplasmic CBP-interacting proteins that regulate compartmentalized CBP E4 activity, we identified deleted in breast cancer 1 (DBC1) as a stoichiometric CBP-interacting protein that negatively regulates CBP-dependent p53 polyubiquitination, stabilizes p53, and augments p53-dependent apoptosis. TCGA analysis demonstrated that solid tumors often retain wild-type p53 alleles in conjunction with DBC1 loss, supporting the hypothesis that DBC1 is selected for disruption during carcinogenesis as a surrogate for p53 functional loss. Because DBC1 maintains p53 stability in the nucleus, where p53 exerts its tumor-suppressive transcriptional function, replacement of DBC1 functionality in DBC1-deleted tumors might enhance p53 function and chemosensitivity for therapeutic benefit.

Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis.

Chromosomal rearrangements resulting in the fusion of TMPRSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers. However, the mechanism by which ERG promotes oncogenic gene expression and proliferation remains incompletely understood. Here, we identify a binding interaction between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which is conserved among other oncogenic ETS factors, including ETV1, ETV4, and ETV5. We find that ERG drives genome-wide retargeting of BAF complexes in a manner dependent on binding of ERG to the ETS DNA motif. Moreover, ERG requires intact BAF complexes for chromatin occupancy and BAF complex ATPase activity for target gene regulation. In a prostate organoid model, BAF complexes are required for ERG-mediated basal-to-luminal transition, a hallmark of ERG activity in prostate cancer. These observations suggest a fundamental interdependence between ETS transcription factors and BAF chromatin remodeling complexes in cancer.

Predictive factors of maternal hypothermia during Cesarean delivery: a prospective cohort study.

PURPOSE: Although perioperative hypothermia may increase maternal morbidity, active warming is infrequently performed to maintain normothermia during Cesarean delivery (CD). The aim of this prospective observational study was to determine the factors associated with maternal hypothermia in this setting. METHODS: Women scheduled for elective or emergency CD were consecutively included in this study from November 2014 to October 2015. Maternal temperature was measured using an infrared tympanic thermometer on the patient's arrival in the operating room, at skin incision, and at the end of skin suture. Maternal hypothermia was defined by tympanic temperature < 36°C at the end of skin suture. Univariate analysis was performed, followed by multivariate logistic regression analysis, in order to determine the factors associated with maternal hypothermia at the end of the surgery. RESULTS: Three hundred fifty-nine women were included and analyzed during this study. The incidence of hypothermia was 23% (95% confidence interval, 18 to 27) among the total population included. According to multivariate analysis, obesity, oxytocin augmentation of labour, and use of active forced-air warming were associated with a decreased risk of maternal hypothermia, while maternal temperature < 37.1°C on arrival in the operating room, maternal temperature < 36.6°C at skin incision, and an infused volume of fluids > 650 mL were significantly associated with maternal hypothermia. Both goodness of fit and predictive value of multivariate analysis were high. CONCLUSION: Several predictive factors for maternal hypothermia during CD were identified. These factors should be taken into account to help prevent maternal hypothermia during CD.

Determination of a cut-off value of antral area measured in the supine position for the fast diagnosis of an empty stomach in the parturient: A prospective cohort study.

BACKGROUND: Ultrasound measurement of the antral cross-sectional area of the stomach, performed in the supine position, has been described for preoperative assessment of gastric content in the adult, but, to date, no study has determined the cut-off value of the antral area for the diagnosis of an empty stomach in the parturient. Nevertheless, previous studies in parturients have reported that the use of a simple qualitative grading scale (0 to 2) was reliable for the estimation of the gastric fluid volume. However, this qualitative grading score requires turning the parturient into the right lateral decubitus position for the ultrasound examination, something which may not be easily feasible, particularly in the case of an obstetric emergency. OBJECTIVE: To calculate the cut-off value of the antral area, measured in the supine position during established labour, for the diagnosis of 'empty' stomach. DESIGN: A prospective cohort study. SETTING: Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Lyon, France. PATIENTS: Seventy-three women in established labour. INTERVENTIONS: For each parturient, ultrasound assessment of gastric contents was performed in the supine and right lateral decubitus position and scored 0 to 3 on a qualitative grading scale. This assessment was followed by ultrasound measurement of the antral cross-sectional area in both the supine and right lateral positions. MAIN OUTCOME MEASURES: To assess the performance of the antral area measured in the supine position for the diagnosis of an 'empty' stomach (gastric antrum grade 0), a receiver operating characteristic curve was plotted, and the area under the receiver operating characteristic curve was calculated. RESULTS: Data from 73 women were analysed. For the diagnosis of grade 0, the cut-off value for the antral area measured in the supine position was 381 mm (sensitivity, 81%; specificity, 76% and negative predictive value, 80%). CONCLUSION: With a parturient lying in the supine position, a single assessment of the antral cross-sectional area may be used for the fast diagnosis of an empty stomach. This tool could be useful in assessing the risk of aspiration for parturients who require emergency anaesthesia during labour.

Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile.

Unbiased binding assays involving small-molecule microarrays were used to identify compounds that display unique patterns of selectivity among members of the zinc-dependent histone deacetylase family of enzymes. A novel, hydroxyquinoline-containing compound, BRD4354, was shown to preferentially inhibit activity of HDAC5 and HDAC9 in vitro. Inhibition of deacetylase activity appears to be time-dependent and reversible. Mechanistic studies suggest that the compound undergoes zinc-catalyzed decomposition to an ortho-quinone methide, which covalently modifies nucleophilic cysteines within the proteins. The covalent nature of the compound-enzyme interaction has been demonstrated in experiments with biotinylated probe compound and with electrospray ionization-mass spectrometry.

Advances in discovering small molecules to probe protein function in a systems context.

High throughput screening (HTS) has historically been used for drug discovery almost exclusively by the pharmaceutical industry. Due to a significant decrease in costs associated with establishing a high throughput facility and an exponential interest in discovering probes of development and disease associated biomolecules, HTS core facilities have become an integral part of most academic and non-profit research institutions over the past decade. This major shift has led to the development of new HTS methodologies extending beyond the capabilities and target classes used in classical drug discovery approaches such as traditional enzymatic activity-based screens. In this brief review we describe some of the most interesting developments in HTS technologies and methods for chemical probe discovery.

PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients.

PURPOSE: EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis. EXPERIMENTAL DESIGN: This randomized phase II trial enrolled 78 FIGO stage IB2-IIIB cervical cancer patients to either cisplatin-based radiochemotherapy alone (arm B, n = 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n = 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients. RESULTS: Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P = 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P = 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P = 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18). CONCLUSIONS: Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups.

Probing small-molecule microarrays with tagged proteins in cell lysates.

The technique of small-molecule microarray (SMM) screening is based on the ability of small molecules to bind to various soluble proteins. This type of interaction is easily detected by the presence of a fluorescence signal produced by labeled antibodies that specifically recognize a unique sequence (tag) present on the target protein. The fluorescent signal intensity values are determined based on signal-to-noise ratios (SNRs). SMM screening is a high-throughput, unbiased method that can rapidly identify novel direct ligands for various protein targets. This binding-based assay format is generally applicable to most proteins, but it is especially useful for protein targets that do not possess an enzymatic activity. SMMs enable screening a protein in a purified form or in the context of a cellular lysate, likely providing a more physiologically relevant screening environment.

Prostate cancer. Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer.

Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.

Cerebral oximetry assessed by near-infrared spectrometry during preeclampsia: an observational study: impact of magnesium sulfate administration.

OBJECTIVES: To determine the regional cerebral oxygen saturation of hemoglobin (rcSO2) in severe preeclamptic parturients exhibiting neurologic symptoms compared with healthy pregnant women (control) and to describe the effects of MgSO4 infusion on rcSO2 and cerebral and systemic hemodynamic variables. DESIGN: Prospective, observational study. SETTING: Obstetric critical care unit in a university-affiliated hospital. PATIENTS: Twenty severe preeclamptic parturients presenting with neurologic signs before any administration of MgSO4, and 20 control parturients. INTERVENTION: Infusion of MgSO4 in severe preeclamptic patients. MEASUREMENTS AND MAIN RESULTS: We measured rcSO2 using near-infrared spectroscopy, blood flow velocities of the middle cerebral artery, and cardiac output at baseline, 5 minutes, 1 hour, and 6 hours after the MgSO4 bolus (4 g), followed by continuous MgSO4 infusion (1 g/h). These measurements were also obtained in 20 control parturients at baseline and 6 hours. Baseline rcSO2 was significantly lower in the severe preeclamptic group: 61% (56-69) vs 66% (63-71) (p = 0.037). At inclusion, blood pressures were significantly higher in the severe preeclamptic group compared with the control group, whereas cardiac output and transcranial Doppler readings were similar. Five minutes after the MgSO4 bolus infusion, a median increase of 8.6% (3.2-18.1) in rcSO2 was observed (p = 0.007), reaching values of the control group that were maintained up to 6 hours. Blood pressures and systolic velocities of the middle cerebral artery significantly decreased (p < 0.01) after the MgSO4 bolus, whereas cardiac output did not change. The percentage increase in rcSO2 was negatively correlated to the mean blood pressure (r = 0.60, p < 0.0001). CONCLUSION: Cerebral oxygenation impairment can be detected by near-infrared spectroscopy monitoring in severe preeclamptic parturients. These results suggested the presence of disorders in cerebral microcirculation and/or changes in cerebral oxygenation. MgSO4 infusion in patients with severe preeclampsia restored rcSO2 to control levels with no systemic side effects. Further studies are needed to confirm the usefulness of near-infrared spectroscopy monitoring in patients with preeclampsia and to assess the action of other antihypertensive therapies on rcSO2.

3D radiation therapy boost improves the outcome of whole brain radiation therapy treated RPA II patients with one or two brain metastases.

PURPOSE: to evaluate the role of whole brain radiotherapy (WBRT) and radiation boost (RB) for 208 patients recursive partitioning analysis (RPA) II with 1 or 2 brain metastases (BM) at a single institution. METHODS AND MATERIALS: the dose of WBRT was 30 Gy (10 fractions of 3 Gy). One hundred thirty-two patients (63.5%) benefited from RB of 9 Gy in 3 fractions of 3 Gy at the metastatic site. Patients had 1 or 2 BM in 122 (58.7%) and 86 cases (41.3%), respectively. RESULTS: patients with one or two metastases had similar survival (4.6 and 5.1 months, respectively) (p = 0.4). Median overall survival (OS) for patients treated with WBRT and RB, and with WBRT alone was 5.9 and 3.7 months, respectively (p = 0.03). The 6-, 12- and 24-month OS rates after WBRT and RB were 48.5%, 25% and 10.6%, respectively, while WBRT alone resulted in OS rates of 34%, 22.4% and 3.2%, respectively (p = 0.03). After WBRT and RB, the 6-, 12- and 24-month local control rates were 92%, 82% and 67%, respectively, while they were 81.2%, 75% and 37.5%, respectively, after WBRT alone (p = 0.03). The 6-, 12- and 24-month brain control rates after WBRT and RB were 88.7%, 75.8% and 62%, respectively, and after WBRT alone they were 78.5%, 59% and 37.7%, respectively (p = 0.03). CONCLUSION: additional boost delivered with 3D conformal radiotherapy improves local and brain control rates significantly as well as overall survival for RPA II patients with 1 or 2 unresectable BM.

A small molecule that binds and inhibits the ETV1 transcription factor oncoprotein.

Members of the ETS transcription factor family have been implicated in several cancers, where they are often dysregulated by genomic derangement. ETS variant 1 (ETV1) is an ETS factor gene that undergoes chromosomal translocation in prostate cancers and Ewing sarcomas, amplification in melanomas, and lineage dysregulation in gastrointestinal stromal tumors. Pharmacologic perturbation of ETV1 would be appealing in these cancers; however, oncogenic transcription factors are often deemed "undruggable" by conventional methods. Here, we used small-molecule microarray screens to identify and characterize drug-like compounds that modulate the biologic function of ETV1. We identified the 1,3,5-triazine small molecule BRD32048 as a top candidate ETV1 perturbagen. BRD32048 binds ETV1 directly, modulating both ETV1-mediated transcriptional activity and invasion of ETV1-driven cancer cells. Moreover, BRD32048 inhibits p300-dependent acetylation of ETV1, thereby promoting its degradation. These results point to a new avenue for pharmacologic ETV1 inhibition and may inform a general means to discover small molecule perturbagens of transcription factor oncoproteins.

Institutional, retrospective analysis of 777 patients with brain metastases: treatment outcomes and diagnosis-specific prognostic factors.

PURPOSE: To retrospectively evaluate the prognostic factors and survival of a series of 777 patients with brain metastases (BM) from a single institution. METHODS AND MATERIALS: Patients were treated with surgery followed by whole-brain radiation therapy (WBRT) or with WBRT alone in 16.3% and 83.7% of the cases, respectively. The patients were RPA (recursive partitioning analysis) class I, II, and III in 11.2%, 69.6%, and 18.4% of the cases, respectively; RPA class II-a, II-b, and II-c in 8.3%, 24.8%, and 66.9% of the cases, respectively; and with GPA (graded prognostic assessment) scores of 0-1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 in 35%, 27.5%, 18.2%, and 8.6% of the cases, respectively. RESULTS: The median overall survival (OS) times according to RPA class I, II, and III were 20.1, 5.1, and 1.3 months, respectively (P<.0001); according to RPA class II-a, II-b, II-c: 9.1, 8.9, and 4.0 months, respectively (P<.0001); and according to GPA score 0-1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0: 2.5, 4.4, 9.0, and 19.1 months, respectively (P<.0001). By multivariate analysis, the favorable independent prognostic factors for survival were as follows: for gastrointestinal tumor, a high Karnofsky performance status (KPS) (P=.0003) and an absence of extracranial metastases (ECM) (P=.003); for kidney cancer, few BM (P=.002); for melanoma, few BM (P=.01), an absence of ECM (P=.002), and few ECM (P=.0002); for lung cancer, age (P=.007), a high KPS (P<.0001), an absence of ECM (P<.0001), few ECM and BM (P<.0001 and P=.0006, respectively), and control of the primary tumor (P=.004); and for breast cancer, age (P=.001), a high KPS (P=.007), control of the primary tumor (P=.05), and few ECM and BM (P=.01 and P=.0002, respectively). The triple-negative subtype was a significant unfavorable factor (P=.007). CONCLUSION: Prognostic factors varied by pathology. Our analysis confirms the strength of prognostic factors used to determine the GPA score, including the genetic subtype for breast cancer.

Early evaluation predicts pain relief of irradiated bone metastases: a single-center prospective study.

BACKGROUND: Radiation therapy is a well-recognized, effective modality used for palliative care. Most studies completed to date have endpoints of one month or greater after treatment completion. This study analyzed the response rates at different time points during the first month after treatment. METHODS: From May 2010 to November 2011, 61 patients treated for 74 metastases were included in the study. The end points were defined as the completion of treatment (CT) and d8, d15 and d30 after the completion of treatment. The response rate was measured by the worst pain in the last 24 hours and the administered opioid dose. Patient assessment was performed during consultations and phone appointments. RESULTS: The overall response rate significantly improved from the CT (38%) to d8 (53.8%), d15 (53.8%) and d30 (57.1%) (respectively p < 0.001; p < 0.001 and p = 0.001). The improvement peaked at d8. Patients responding to the treatment at d8 had a significative longer pain relapse free survival (PRFS) compared to patients not responding (3.38 weeks vs 0.3 weeks; p < 0.001). From the beginning of treatment to the CT and at d8 , d15 and d30, oral morphine equivalent dose (OMED) did not significantly differ. However, the pain decrease did not result in a performance status improvement, which declined over time (p < 0.001). CONCLUSION: Radiation therapy is an efficient treatment method for providing pain relief. This relief peaked at d8 after treatment, and the response at d8 is predictive of the response at 4 weeks. Pain management alone is not enough to improve performance status; further studies are needed to evaluate a more global supportive care approach.

An institutional retrospective analysis of 93 patients with brain metastases from breast cancer: treatment outcomes, diagnosis-specific prognostic factors.

To evaluate the prognostic factors and indexes of a series of 93 patients with breast cancer and brain metastases (BM) in a single institution. Treatment outcomes were evaluated according to the major prognostic indexes (RPA, BSBM, GPA scores) and breast cancer subtypes. Independent prognostic factors for overall survival (OS) were identified. The median OS values according to GPA 0-1, 1.5-2, 2.5-3 and 3.5-4, were 4.5, 9.5, 14.2 and 19.1 months, respectively (p < 0.0001) and according to genetic subtypes, they were 5, 14.2, 16.5 and 17.1 months for basal-like, luminal A and B and HER, respectively (p = 0.04). Using multivariate analysis, we established a new grading system using the six factors that were identified as indicators of longer survival: age under 60 (p = 0.001), high KPS (p = 0.007), primary tumor control (p = 0.05), low number of extracranial metastases and BM (p = 0.01 and 0.0002, respectively) and triple negative subtype (p = 0.002). Three groups with significantly different median survival times were identified: 4.1, 9.5 and 26.3 months, respectively (p < 0.0001). Our new grading system shows that prognostic indexes could be improved by using more levels of classification and confirms the strength of biological prognostic factors.