Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition.

Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.

The phantom chorus: birdsong boosts human well-being in protected areas.

Spending time in nature is known to benefit human health and well-being, but evidence is mixed as to whether biodiversity or perceptions of biodiversity contribute to these benefits. Perhaps more importantly, little is known about the sensory modalities by which humans perceive biodiversity and obtain benefits from their interactions with nature. Here, we used a 'phantom birdsong chorus' consisting of hidden speakers to experimentally increase audible birdsong biodiversity during 'on' and 'off' (i.e. ambient conditions) blocks on two trails to study the role of audition in biodiversity perception and self-reported well-being among hikers. Hikers exposed to the phantom chorus reported higher levels of restorative effects compared to those that experienced ambient conditions on both trails; however, increased restorative effects were directly linked to the phantom chorus on one trail and indirectly linked to the phantom chorus on the other trail through perceptions of avian biodiversity. Our findings add to a growing body of evidence linking mental health to nature experiences and suggest that audition is an important modality by which natural environments confer restorative effects. Finally, our results suggest that maintaining or improving natural soundscapes within protected areas may be an important component to maximizing human experiences.

Effects of Experimental Anthropogenic Noise Exposure on the Reproductive Success of Secondary Cavity Nesting Birds.

Artificial nest boxes are critical nesting sites for secondary cavity-nesting birds; however, they are often placed near roadways and in urban areas that experience noise pollution and other human-caused stressors. Recent correlative studies document both negative and positive influences of noise pollution on reproductive success. Additionally, observational studies have not determined which stage of the breeding process is most vulnerable to noise pollution-settlement, incubation, and/or provisioning. Here, we controlled for possible effects from non-random settlement and eliminated potential effects of roadways, such as collisions and chemical and light pollution, by experimentally introducing traffic noise into nest boxes after clutch initiation in two secondary-cavity nesting bird species. We found no evidence for an influence of noise on clutch size, brood size, number of fledglings, or overall nest success in western bluebirds (Sialia mexicana). In contrast, we found that ash-throated flycatcher (Myiarchus cinerascens) nests exposed to noise had lower reproductive success than quiet nests due to higher rates of abandonment at the incubation stage. Our results match recent research demonstrating that ash-throated flycatchers avoid energy-sector noise in their nest placement and, when they do nest in noise, experience stress hormone dysregulation and fitness costs. The lack of a response among western bluebirds differs from reported declines in reproductive success due to exposure to energy-sector noise; however, the absence of a response matches the response seen in other species using an in-box noise playback experiment. These results suggest that in-box noise exposure experiments may be appropriate for assessing noise impacts at the nest, and through some pathways (e.g., direct effects of noise on nestlings), but do not capture other ways in which noise can negatively affect birds during the breeding season that may ultimately cause declines in fitness. Additionally, although manipulative experiments that examine the influence of a single anthropogenic stressor on a single life stage can help reveal causal pathways, urban and other human-dominated environments are characterized by many stressors and future studies should seek to understand how noise interacts with other stressors to impact birds and other wildlife. Finally, in light of mounting evidence demonstrating declines in reproductive success due to noise, our results suggest that nest box placement near roads may be counterproductive to efforts to bolster population densities of some species.

Discussing and prescribing expensive unfunded anticancer drugs in Australia.

OBJECTIVE: Australia has a publicly funded universal healthcare system which heavily subsidises the cost of most registered anticancer drugs. The use of anticancer drugs that are unfunded, that is, not subsidised by the government, entails substantial out-of-pocket costs for patients. We sought to determine how frequently Australian medical oncologists discuss and prescribe unfunded anticancer drugs, and their attitudes and beliefs about their use. METHODS: Members of the Medical Oncology Group of Australia (MOGA) completed an online survey about their clinical practices over a recent 3-month period. A negative binomial regression model was used to examine the influence of respondent characteristics on the rate of discussions about, and prescription of, unfunded anticancer drugs. RESULTS: Of the 154 respondents (27% of 575 MOGA members), 92% had discussed and 68% had prescribed at least one unfunded anticancer drug in the last 3 months. Respondents reported discussing unfunded anticancer drugs with an average of 2.5 patients per month (95% CI 2.1 to 2.9), and prescribed them to an average of 0.9 patients per month (95% CI 0.7 to 1.2). The rate of discussing unfunded anticancer drugs was associated with being fully qualified (p=0.01), and being in a metropolitan practice (p=0.009), the rate of prescription was associated only with being in metropolitan practice (p=0.006). The concerns about discussing and prescribing unfunded anticancer drugs rated most important were as follows: 'potential to cause financial hardship' and 'difficulty for patients to evaluate the benefits versus the costs'. CONCLUSIONS: Australian medical oncologists frequently discuss and prescribe unfunded anticancer drugs, and are concerned about their patients having to face difficult decisions and financial hardship. Further research is needed to better understand the factors that affect how oncologists and patients value expensive, unfunded anticancer drugs.

Panitumumab added to docetaxel, cisplatin and fluoropyrimidine in oesophagogastric cancer: ATTAX3 phase II trial.

BACKGROUND: This randomised phase II study evaluated the efficacy and safety of panitumumab added to docetaxel-based chemotherapy in advanced oesophagogastric cancer. METHODS: Patients with metastatic or locally recurrent cancer of the oesophagus, oesophagogastric junction or stomach received docetaxel and a fluoropyrimidine with or without panitumumab for 8 cycles or until progression. The primary end point was response rate (RECIST1.1). We planned to enrol 100 patients, with 50% expected response rate for combination therapy. RESULTS: A total of 77 patients were enrolled. A safety alert from the REAL3 trial prompted a review of data that found no evidence of adverse outcomes associated with panitumumab but questionable efficacy, and new enrolment was ceased. Enrolled patients were treated according to protocol. Response rates were 49% (95% CI 34-64%) in the chemotherapy arm and 58% (95% CI 42-72%) in the combination arm. Common grade 3 and 4 toxicities included infection, anorexia, vomiting, diarrhoea and fatigue. At 23.7 months of median follow-up, median progression-free survival was 6.9 months vs 6.0 months and median overall survival was 11.7 months vs 10.0 months in the chemotherapy arm and the combination arm, respectively. CONCLUSIONS: Adding panitumumab to docetaxel-based chemotherapy for advanced oesophagogastric cancer did not improve efficacy and increased toxicities.

Regorafenib in gastrointestinal stromal tumors: clinical evidence and place in therapy.

Gastrointestinal stromal tumors (GISTs) are rare malignancies, and historically had a poor prognosis, with little benefit from traditional anticancer therapies. The management of GISTs has undergone a paradigm change in recent years with the detection of activating mutations in the majority of these tumors. This knowledge has led to the development of targeted treatments which have dramatically improved benefit rates and survival. The tyrosine kinase inhibitor, imatinib, has become the standard of care for both those with high-risk resected GIST, and as first-line therapy in metastatic GIST. However, some patients demonstrate innate resistance to imatinib or, for many, resistance develops despite an initial response. Other tyrosine kinase inhibitors with a broader spectrum of action, such as sunitinib and sorafenib, have been investigated and show some benefit after the use of imatinib. Regorafenib, an orally available multitargeted tyrosine kinase inhibitor with antiangiogenic activity, has also demonstrated preclinical evidence of activity against a number of solid tumors and further studies have proven it to be effective in GISTs following failure of standard therapy, with manageable toxicity profile. It has now received licensing approval in a number of countries both for the treatment of GISTs and for colorectal cancer, and further research is ongoing. With a number of potential agents now available to treat this disease, clinicians must now consider questions of timing and sequencing to maximize the benefit from these treatments, and the role that new agents such as regorafenib could play in further advancing changes.