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PURPOSE: Current policy in the United Kingdom (UK) recommends that people with breast cancer (PWBC) are managed in follow-up pathways that suit their needs. With an increasing trend towards patient-initiated follow-up (PIFU) pathways for PWBC, this study conducted qualitative research exploring PWBC's experiences of a nurse-led PIFU service (termed 'Supported Early Discharge') to inform how PIFU pathways could be optimised. METHOD: PWBC on a PIFU pathway were recruited from two UK hospitals (one large cancer centre, one district general hospital) as part of a wider mixed-methods study (N = 118). Following completion of a series of surveys, a purposive subsample of 20 women were interviewed in-depth about their experiences. Thematic analysis was conducted. RESULTS: The majority of participants described positive views towards being on PIFU; however a significant minority struggled with uncertainties and difficulties related to: accessing ongoing care and support; performing breast self-examination (BSE); managing ongoing treatment side-effects; and fear of recurrence. Themes included: self-efficacy to manage own health; barriers and facilitators to help-seeking on a PIFU pathway; effective information sharing about side effects; preferences for personalised care; emotional wellbeing on PIFU- influences on fear of recurrence. A novel conceptual model is presented that highlights influences on self-management during PIFU. CONCLUSIONS: Findings highlight ways in which PIFU pathways could be further optimised through greater and more effective education on BSE and recognising signs of recurrence, information on when and how to seek further help with any problems, targeted provision of psychological support, and clearer signposting to support for ongoing side-effects.

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IMPORTANCE: Randomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad activity in preclinical breast cancer models, showing superior activity to everolimus. OBJECTIVE: To evaluate the safety and efficacy of vistusertib in combination with fulvestrant compared with fulvestrant alone or fulvestrant plus everolimus in postmenopausal women with estrogen receptor-positive advanced or metastatic breast cancer. DESIGN, SETTING, AND PARTICIPANTS: The MANTA trial is an open-label, phase 2 randomized clinical trial in which 333 patients with estrogen receptor-positive breast cancer progressing after prior aromatase inhibitor treatment underwent randomization (2:3:3:2) between April 1, 2014, and October 24, 2016, at 88 sites in 9 countries: 67 patients were assigned to receive fulvestrant, 103 fulvestrant plus vistusertib daily, 98 fulvestrant plus vistusertib intermittently, and 65 fulvestrant plus everolimus. Treatment was continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. Analysis was performed on an intention-to-treat basis. INTERVENTIONS: Fulvestrant alone or in combination with vistusertib (continuous or intermittent dosing schedules) or everolimus. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS). RESULTS: Among the 333 women in the study (median age, 63 years [range, 56-70 years]), median PFS was 5.4 months (95% CI, 3.5-9.2 months) with fulvestrant, 7.6 months (95% CI, 5.9-9.4 months) with fulvestrant plus daily vistusertib, 8.0 months (95% CI, 5.6-9.9 months) with fulvestrant plus intermittent vistusertib, and 12.3 months (95% CI, 7.7-15.7 months) with fulvestrant plus everolimus. There was no significant difference in PFS between those receiving fulvestrant plus daily or intermittent vistusertib and fulvestrant alone (hazard ratio, 0.88 [95% CI, 0.63-1.24]; P = .46; and hazard ratio, 0.79 [95% CI, 0.55-1.12]; P = .16). CONCLUSIONS AND RELEVANCE: The combination of fulvestrant plus everolimus demonstrated significantly longer PFS compared with fulvestrant plus vistusertib or fulvestrant alone. The trial failed to demonstrate a benefit of adding the dual mTORC1 and mTORC2 inhibitor vistusertib to fulvestrant. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02216786 and EudraCT number: 2013-002403-34.

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Mammalian hibernation is a complex phenotype involving metabolic rate reduction, bradycardia, profound hypothermia, and a reliance on stored fat that allows the animal to survive for months without food in a state of suspended animation. To determine the genes responsible for this phenotype in the thirteen-lined ground squirrel (Ictidomys tridecemlineatus) we used the Roche 454 platform to sequence mRNA isolated at six points throughout the year from three key tissues: heart, skeletal muscle, and white adipose tissue (WAT). Deep sequencing generated approximately 3.7 million cDNA reads from 18 samples (6 time points ×3 tissues) with a mean read length of 335 bases. Of these, 3,125,337 reads were assembled into 140,703 contigs. Approximately 90% of all sequences were matched to proteins in the human UniProt database. The total number of distinct human proteins matched by ground squirrel transcripts was 13,637 for heart, 12,496 for skeletal muscle, and 14,351 for WAT. Extensive mitochondrial RNA sequences enabled a novel approach of using the transcriptome to construct the complete mitochondrial genome for I. tridecemlineatus. Seasonal and activity-specific changes in mRNA levels that met our stringent false discovery rate cutoff (1.0 × 10(-11)) were used to identify patterns of gene expression involving various aspects of the hibernation phenotype. Among these patterns are differentially expressed genes encoding heart proteins AT1A1, NAC1 and RYR2 controlling ion transport required for contraction and relaxation at low body temperatures. Abundant RNAs in skeletal muscle coding ubiquitin pathway proteins ASB2, UBC and DDB1 peak in October, suggesting an increase in muscle proteolysis. Finally, genes in WAT that encode proteins involved in lipogenesis (ACOD, FABP4) are highly expressed in August, but gradually decline in expression during the seasonal transition to lipolysis.

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Targeting the epidermal growth factor receptor (EGFR), an important component in carcinogenesis, is an attractive therapeutic option for selective anticancer therapy. Several EGFR inhibitors, mostly monoclonal antibodies and tyrosine kinase inhibitors are under investigation in the treatment of colorectal cancer. Although there has been some progress in the treatment of colorectal cancer with combination chemotherapy, the repertoire of active agents is still limited. More recently the anti-EGFR drugs cetuximab and panitumumab have made an impact in the treatment of metastatic disease but with variable response rates. Although the appearance of a skin rash confers a higher response rate, immunohistochemical staining of EGFR at baseline does not. Several studies have now focused on identifying predictive biological markers at a molecular level. Exciting data has demonstrated KRAS mutation status to be the first predictive marker of response to anti-EGFR monoclonal antibodies (mAbs) and has led a new era in the development of targeted therapies in colorectal malignant disease. The aim of this review is to evaluate the impact of anti-EGFR therapies in the treatment of metastatic colorectal cancer; and to present the current data on predictive markers including KRAS status, PTEN expression and germinal gene polymorphisms. The relevant patents are discussed.

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Aromatase inhibitors play a key role in the clinical management of hormone receptor-positive breast cancer and have potential utility as chemopreventive agents. Further understanding of the molecular effects of estrogen and its deprivation in normal breast tissue may allow the development of biomarkers of risk of breast cancer and help to predict the value of chemoprevention with aromatase inhibitors. Core biopsies of normal breast tissue were taken before and after letrozole treatment from postmenopausal women in the LITMaS pilot prevention study. RNA was extracted from these samples and used for cDNA microarray analysis. Gene expression changes induced by letrozole treatment were much less extensive than observed in estrogen receptor-positive malignant tissue; however, overall, they correlated to a highly significant degree (rho = 0.511; P < 10(-20)). As well as some classically estrogen-associated genes, many genes associated with extracellular matrix remodeling were affected by estrogen deprivation in the normal breast in vivo. These data indicate for the first time that gene expression of normal breast tissue remains dependent on endogenous estrogens after the menopause. The modest degree of gene change suggests that intermediate markers of chemoprevention may be difficult to identify.

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Sex hormones are intrinsically linked to the development and treatment of the majority of breast cancers. High oestradiol levels are associated with elevated breast cancer risk in the postmenopausal setting and are given increasing importance in determining chemoprevention target groups. This review aims to evaluate the impact of various lifestyle factors including body mass index, diet, smoking, and alcohol on normal physiological sex hormone profiles. The role of genetic polymorphisms is also discussed, and all are placed within the context of designing future epidemiological studies and breast cancer risk algorithms.

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Breast cancer accounts for 1 in 4 of all female cancers worldwide; approaching 13,000 women dying per year in the UK alone. Seventy five per cent of all diagnosed breast cancers are oestrogen receptor (ER) positive. Ovarian synthesis of oestrogens ceases at menopause and as breast cancer is more prevalent in postmenopausal women the non-ovarian sources of oestrogen are important in disease progression. There is now considerable evidence that associates increased breast cancer risk with prolonged exposure to oestrogens hence greater attention is now being given to determining whether the measurement of plasma oestrogen may assist in identifying chemoprevention target groups. Studies suggest that in most postmenopausal patients the intra-tumoural concentrations of oestrogens are up to 20-fold higher than those present in the plasma however, while the extent of biosynthesis of oestrogens within breast tissue is a major determinant of local exposure, plasma levels are a useful indicator of overall metabolism in peripheral tissues. As such it is important to understand factors that influence these measurements. This review summarises the impact of lifestyle such as body mass index, together with the role of genetic polymorphisms placed within the context of designing future epidemiological studies and breast cancer risk algorithms.

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Aromatase inhibitors (AIs) have a proven role in the treatment of early and metastatic breast cancer. The success of tamoxifen in reducing the relative risk of developing hormone-sensitive breast cancer in chemoprevention trials has been hampered by their long-term toxicity profile. AIs have the potential to further reduce rates of breast cancer in high-risk postmenopausal women. This article reviews the evidence to support the potential efficacy of AIs in the chemoprevention setting. It particularly focuses on a discussion of novel concepts of utilising AIs, so that they reduce breast cancer risk while minimising systemic toxicity, and highlights the importance of accurately developing risk prediction algorithms.

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Gestational trophoblastic diseases comprise a rare spectrum of disorders in which the normal regulatory mechanisms controlling the behavior of trophoblastic tissue are lost. They vary from the benign complete and partial hydatidiform moles to the frankly malignant choriocarcinoma and placental site trophoblastic tumors. The majority will be cured by suction curettage, followed by human chorionic gonadotrphin screening but some will go on to need chemotherapy. The majority of patients will be cured even despite the presence of metastatic disease. Patients should have their treatment stratified according to various prognostic factors in order to ensure firstly their disease is eliminated and secondly to reduce the incidence of long-term treatment complications.

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Gestational trophoblastic diseases comprise a rare spectrum of disorders in which the normal regulatory mechanisms controlling the behaviour of trophoblastic tissue are lost. They vary from the benign complete and partial hydatidiform moles to the frankly malignant choriocarcinoma and placental site trophoblastic tumours. The majority will be cured by suction curettage, followed by human chorionic gonadotrophin screening, but some will go on to need chemotherapy. The majority of patients will be cured even despite the presence of metastatic disease. Patients should have their treatment stratified according to various prognostic factors in order to ensure firstly their disease is eliminated and secondly to reduce the incidence of long-term treatment complications.

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