Androgen receptor function and targeted therapeutics across breast cancer subtypes.

Despite significant progress in breast cancer (BC) therapy, it is globally the most commonly diagnosed cancer and leads to the death of over 650,000 women annually. Androgen receptor (AR) is emerging as a potential new therapeutic target in BC. While the role of AR is well established in prostate cancer (PCa), its function in BC remains incompletely understood. Emerging data show that AR's role in BC is dependent on several factors including, but not limited to, disease subtype, tumour microenvironment, and levels of circulating oestrogens and androgens. While targeting AR in PCa is becoming increasingly effective, these advances have yet to make any significant impact on the care of BC patients. However, this approach is increasingly being evaluated in BC and it is clear that improvements in our understanding of AR's role in BC will increase the likelihood of success for AR-targeted therapies. This review summarizes our current understanding of the function of AR across BC subtypes. We highlight limitations in our current knowledge and demonstrate the importance of categorizing BC subtypes effectively, in relation to determining AR activity. Further, we describe the current state of the art regarding AR-targeted approaches for BC as monotherapy or in combination with radiotherapy.

Versatile magnetic microdiscs for the radio enhancement and mechanical disruption of glioblastoma cancer cells.

This study describes the use of highly versatile, lithographically defined magnetic microdiscs. Gold covered magnetic microdiscs are used in both radiosensitizing cancer cells, acting as intracellular emitters of secondary electrons during radiotherapy, and as well as inducing mechanical damage by exerting a mechanical torque when exposed to a rotating magnetic field. This study reveals that lithographically defined microdiscs with a uniform size of 2 microns in diameter highly increase the DNA damage and reduce the glioblastoma colony formation potential compared to conventional radiation therapy. Furthermore, the addition of mechanical disruption mediated by the magnetic component of the discs increased the efficiency of brain cancer cell killing.

Cancer Treatment in the Genomic Era.

The complexity of human cancer underlies its devastating clinical consequences. Drugs designed to target the genetic alterations that drive cancer have improved the outcome for many patients, but not the majority of them. Here, we review the genomic landscape of cancer, how genomic data can provide much more than a sum of its parts, and the approaches developed to identify and validate genomic alterations with potential therapeutic value. We highlight notable successes and pitfalls in predicting the value of potential therapeutic targets and discuss the use of multi-omic data to better understand cancer dependencies and drug sensitivity. We discuss how integrated approaches to collecting, curating, and sharing these large data sets might improve the identification and prioritization of cancer vulnerabilities as well as patient stratification within clinical trials. Finally, we outline how future approaches might improve the efficiency and speed of translating genomic data into clinically effective therapies and how the use of unbiased genome-wide information can identify novel predictive biomarkers that can be either simple or complex.

Clinical Development of Novel Drug-Radiotherapy Combinations.

Radiotherapy is a fundamental component of treatment for the majority of patients with cancer. In recent decades, technological advances have enabled patients to receive more targeted doses of radiation to the tumor, with sparing of adjacent normal tissues. There had been hope that the era of precision medicine would enhance the combination of radiotherapy with targeted anticancer drugs; however, this ambition remains to be realized. In view of this lack of progress, the FDA-AACR-ASTRO Clinical Development of Drug-Radiotherapy Combinations Workshop was held in February 2018 to bring together stakeholders and opinion leaders from academia, clinical radiation oncology, industry, patient advocacy groups, and the FDA to discuss challenges to introducing new drug-radiotherapy combinations to the clinic. This Perspectives in Regulatory Science and Policy article summarizes the themes and action points that were discussed. Intelligent trial design is required to increase the number of studies that efficiently meet their primary outcomes; endpoints to be considered include local control, organ preservation, and patient-reported outcomes. Novel approaches including immune-oncology or DNA-repair inhibitor agents combined with radiotherapy should be prioritized. In this article, we focus on how the regulatory challenges associated with defining a new drug-radiotherapy combination can be overcome to improve clinical outcomes for patients with cancer.

Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients.

Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.

The role of high-throughput technologies in clinical cancer genomics.

Cancer is a genetic disease driven by both heritable and somatic alterations in DNA, which underpin not only oncogenesis but also progression and eventual metastasis. The major impetus for elucidating the nature and function of somatic mutations in cancer genomes is the potential for the development of effective targeted anticancer therapies. Over the last decade, high-throughput technologies have allowed us unprecedented access to a host of cancer genomes, leading to an influx of new information about their pathobiology. The challenge now is to integrate such emerging information into clinical practice to achieve tangible benefits for cancer patients. This review examines the roles array-based comparative genomic hybridization and next-generation sequencing are playing in furthering our understanding of both hematological and solid-organ tumors. Furthermore, the authors discuss the current challenges in translating the role of these technologies from bench to bedside.

Cholangiocarcinoma presenting as hemobilia and recurrent iron-deficiency anemia: a case report.

INTRODUCTION: Iron-deficiency anemia is a relatively common presenting feature of several gastrointestinal malignancies. However, cholangiocarcinoma has rarely been reported as an underlying cause. The association of cholangiocarcinoma with the rare clinical finding of hemobilia is also highly unusual. To our knowledge, this is the first case report of cholangiocarcinoma presenting with acute hemobilia and chronic iron-deficiency anemia. CASE PRESENTATION: We report the case of a Caucasian, 84-year-old woman presenting with recurrent, severe iron-deficiency anemia who was eventually diagnosed with intra-hepatic cholangiocarcinoma, following an acute episode of hemobilia. A right hepatectomy was subsequently performed with curative intent, and our patient has now fully recovered. CONCLUSION: This is a rare example of hemobilia and chronic iron-deficiency anemia in association with cholangiocarcinoma. We suggest that a diagnosis of cholangiocarcinoma should be considered in patients who present with iron-deficiency anemia of unknown cause, particularly in the presence of abnormal liver function.