Women with breast cancer frequently develop painful bone metastases. This retrospective study was designed to longitudinally characterize patterns of patient-reported symptoms among patients with breast cancer relative to the diagnosis of bone metastases.
Patient records were identified from the Oncology Services Comprehensive Electronic Records (OSCER) database which includes outpatient oncology practices across the USA. Symptom burden was assessed by Patient Care Monitor (PCM) assessments, which are administered as part of routine care in a subset of these practices. Eligible patients were women diagnosed with breast cancer (ICD-9-CM 174.xx) who developed bone metastases (ICD-9-CM 198.5) and had ≥1 PCM assessment between January 2007 and December 2012. The pre-specified endpoint was the occurrence of moderate to severe symptom burden, defined as PCM score ≥4 (0-10 scale).
One thousand one hundred five women (median age, 61) met the eligibility criteria. Worsening of symptoms, particularly fatigue and pain, occurred in the months leading up to the diagnosis of bone metastases. After bone metastases diagnosis, the rate of increase in the proportion of patients experiencing moderate/severe symptoms slowed, but continued to climb during follow-up. Median time to moderate/severe symptoms was 0.9 month for fatigue, 1 month for pain, 2.9 months for trouble sleeping, and 7.7 months for numbness/tingling. Half of the patients received bone-targeted agents after diagnosis of bone metastases.
Symptom burden, especially pain and fatigue, increased both before and after the diagnosis of bone metastases, highlighting the need for proactive monitoring and management of symptoms in breast cancer patients.

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Delamanid (Deltyba; OPC-67683) is the first approved drug in a novel class of nitro-dihydro-imidazooxazoles developed for the treatment of multidrug-resistant tuberculosis. Patients with tuberculosis require treatment with multiple drugs, several of which have known drug-drug interactions. Transporters regulate drug absorption, distribution and excretion; therefore, the inhibition of transport by one agent may alter the pharmacokinetics of another, leading to unexpected adverse events. Therefore, it is important to understand how delamanid affects transport activity. In the present study, the potencies of delamanid and its main metabolites as substrates and inhibitors of various transporters were evaluated in vitro. Delamanid was not transported by the efflux ATP-binding cassette (ABC) transporters P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), solute carrier (SLC) transporters, organic anion transporting polypeptides or organic cation transporter 1. Similarly, metabolite M1 was not a substrate for any of these transporters except P-gp. Delamanid showed no inhibitory effect on ABC transporters MDR1, BCRP and the bile salt export pump (BSEP, ABCB11), SLC transporters or organic anion transporters. Metabolites M1 and M2 inhibited P-gp- and BCRP-mediated transport, but only at IC50values (M1: 4.65 and 5.71 μmol/L; M2: 7.80 and 6.02 μmol/L), well above corresponding Cmaxvalues observed following multiple dosing in clinical trials. Metabolites M3 and M4 did not affect the activities of any transporters tested. These in vitro data suggest that delamanid is unlikely to have clinically relevant interactions with drugs for which absorption and disposition are mediated by this group of transporters.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.

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Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a non-steroidal small molecule inhibitor of ERα which is a potent and selective antagonist and down-regulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumour growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth inhibitory effects compared to monotherapy alone. Tumour regressions were also seen in a long-term estrogen-deprived breast model, where significant down-regulation of ERα protein was observed. AZD9496 bound and down-regulated clinically relevant ESR1 mutants in vitro and inhibited tumour growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacological evidence showed that AZD9496 is an oral, non-steroidal, selective estrogen receptor antagonist and down-regulator in ER-positive breast cells that could provide meaningful benefit to ER-positive breast cancer patients. AZD9496 is currently being evaluated in a Phase 1 clinical trial.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Biosimilar monoclonal antibodies are being developed globally for patients with different types of solid tumors and hematologic malignancies. Applications for proposed biosimilar monoclonal antibodies are being submitted to the regulatory authorities around the world and may increase patient access to key treatment options upon approval. An understanding among stakeholders (e.g., physicians, patients and their caregivers, pharmacists, payers) of the approval criteria, as well as the similarities and differences in regulatory pathways involved in biosimilar approval in different countries, as presented in this review, will facilitate identification of high-quality, safe, monoclonal antibodies that have been developed according to strict, biosimilar regulatory standards. Further guidance and resolution of the ongoing discussions on biosimilar labeling, naming, automatic substitution, and indication extrapolation may ensure, in the future, an effective and appropriate use of biosimilar monoclonal antibodies by oncologists and other stakeholders in daily clinical practice.

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American association for the study of liver diseases (AASLD) and European Association for the Study of the Liver (EASL) guidelines recommend biannual hepatocellular carcinoma (HCC) screening for noncirrhotic patients with chronic hepatitis B infection (HBV), yet there are no data estimating surveillance rates or factors associated with surveillance. We performed a retrospective cohort study of US patients using the Truven Health Analytics databases from 2006 to 2010 and identified patients with noncirrhotic chronic HBV. Surveillance patterns were characterized using categorical and continuous outcomes, with the continuous measure of the proportion of time ‘up to date’ with surveillance (PUTDS), with the 6-month interval following each ultrasound categorized as ‘up to date’. During a median follow-up of 26.0 (IQR: 16.2-40.0) months among 4576 noncirrhotic patients with chronic HBV (median age: 44 years, IQR: 36-52), only 306 (6.7%) had complete surveillance (one ultrasound every 6-month interval), 2727 (59.6%) incomplete (≥1 ultrasound) and 1543 (33.7%) none. The mean PUTDS was 0.34 ± 0.29, and the median was 0.32 (IQR: 0.03-0.52). In multinomial logistic regression models, patients diagnosed by a nongastroenterologist were significantly less likely to have complete surveillance (P < 0.001), as were those coinfected with HBV/HIV (P < 0.001). In linear regression models, nongastroenterologist provider, health insurance subtype, HBV/HIV coinfection, rural status and metabolic syndrome were independently associated with decreased surveillance. Patients with HIV had an absolute decrease in the PUTDS of 0.24, while patients in less populated rural areas had an absolute decrease of 0.10. HCC surveillance rates in noncirrhotic patients with chronic HBV in the United States are poor and lower than reported rates of HCC surveillance in cirrhotic patients.
© 2015 John Wiley & Sons Ltd.

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