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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Acute and chronic shortages of various pharmaceuticals and particularly of sterile injectable products are being reported on a global scale, prompting evaluation of more effective strategies to manage current shortages and development of new, high-quality pharmaceutical products to mitigate the risk of potential future shortages. Oncology drugs such as liposomal doxorubicin and 5-fluorouracil represent examples of first-choice drugs critically affected by shortages. Survey results indicate that the majority of hospitals and practicing oncologists have experienced drug shortages, which may have compromised patient safety and clinical outcomes, and increased health care costs, due to delays or changes in treatment regimens. Clinical trials evaluating novel agents in combination with standard-of-care drugs are also being affected by drug shortages. Clinical and ethical considerations on treatment objectives, drug indication, and availability of alternative options may help in prioritizing cancer patients involved in active drug shortages. The United States Food and Drug Administration and the European Medicines Agency have identified manufacturing problems, delays in supply, and lack of available active ingredients as the most frequent causes of recent or ongoing drug shortages, and have released specific guidance to monitor, manage, and reduce the risk of shortages. The upcoming loss of exclusivity for a number of anticancer biologics, together with the introduction of an abbreviated approval pathway for biosimilars, raises the question of whether these products will be vulnerable to shortages. Future supply by reliable manufacturers of well characterized biosimilar monoclonal antibodies, developed in compliance with regulatory and manufacturing guidelines and with substantial investments, may contribute to prevent future biologics shortages and ensure access to effective and safe treatment options for patients with cancer. Preclinical and clinical characterization is ongoing for potential biosimilars of trastuzumab, rituximab, and bevacizumab, with promising results.

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Diet affects the risk and progression of prostate cancer (PCa), but the interplay between diet and genetic alterations in this disease is not understood. Here we present genetic evidence in the mouse showing that PCa progression driven by loss of the tumor suppressor Pten is mainly unresponsive to a high fat diet (HFD), but that coordinate loss of the protein tyrosine phosphatase Ptpn1 (PTP1B in human) enables a highly invasive disease. PCa in Pten-/-Ptpn1-/- mice was characterized by increased cell proliferation and Akt activation, interpreted to reflect a heightened sensitivity to IGF-1 stimulation upon HFD feeding. Prostate-specific overexpression of PTP1B was not sufficient to initiate PCa, arguing that it acted as a diet-dependent modifier of prostate cancer development in Pten-/- mice. Our findings offer a preclinical rationale to investigate the anticancer effects of PTP1B inhibitors currently being studied clinically for diabetes treatment as a new modality for management of prostate cancer.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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