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Breast cancer in older patients presents an increasing health care challenge. Hypofractionated dose schedules of 15/16 daily fractions of postoperative radiotherapy over 3/3.5 weeks have been established in clinical trials with long term follow up as safe and effective and become the standard of care after breast conserving therapy for most older patients. Emerging clinical trial data are pushing the limits of hypofractionation to even shorter schedules over a week. In this mini-review the applicability of this new data to older patients is discussed and the development of guidelines for hypofractionated dose fractionation schedules adapted to the COVID19 pandemic for this age group.

Breast cancer is increasingly prevalent in older adults and is a substantial part of routine oncology practice. However, management of breast cancer in this population is challenging because the disease is highly heterogeneous and there is insufficient evidence specific to older adults. Decision making should not be driven by age alone but should involve geriatric assessments plus careful consideration of life expectancy, competing risks of mortality, and patient preferences. A multidisciplinary taskforce, including members of the European Society of Breast Cancer Specialists and International Society of Geriatric Oncology, gathered to expand and update the previous 2012 evidence-based recommendations for the management of breast cancer in older individuals with the endorsement of the European Cancer Organisation. These guidelines were expanded to include chemotherapy toxicity prediction calculators, cultural and social considerations, surveillance imaging, genetic screening, gene expression profiles, neoadjuvant systemic treatment options, bone-modifying drugs, targeted therapies, and supportive care. Recommendations on geriatric assessment, ductal carcinoma in situ, screening, primary endocrine therapy, surgery, radiotherapy, adjuvant systemic therapy, and secondary breast cancer were updated.

Real-time monitoring of tumor microenvironment parameters using an implanted biosensor could provide valuable information on the dynamic nature of a tumor’s biology and its response to treatment. However, following implantation biosensors may lose functionality due to biofouling caused by the foreign body response (FBR). This study developed a novel tumor xenograft model to evaluate the potential of 6 biomaterials (silicon dioxide, silicon nitride, Parylene-C, Nafion, biocompatable EPOTEK epoxy resin and platinum) to trigger a FBR when implanted into a solid tumor. Biomaterials were chosen based on their use in the construction of a novel biosensor, designed to measure spatial and temporal changes in intra-tumoral O2 and pH. None of the biomaterials had any detrimental effect on tumor growth or body weight of the murine host. Immunohistochemistry showed no significant changes in tumor necrosis, hypoxic cell number, proliferation, apoptosis, immune cell infiltration or collagen deposition. The absence of biofouling supports the use of these materials in biosensors; future investigations in preclinical cancer models are required, with a view to eventual applications in humans. To our knowledge this is the first documented investigation of the effects of modern biomaterials, used in the production of implantable sensors, on tumor tissue after implantation.

Real-time monitoring of tumor microenvironment parameters using an implanted biosensor could provide valuable information on the dynamic nature of a tumor's biology and its response to treatment. However, following implantation biosensors may lose functionality due to biofouling caused by the foreign body response (FBR). This study developed a novel tumor xenograft model to evaluate the potential of six biomaterials (silicon dioxide, silicon nitride, Parylene-C, Nafion, biocompatible EPOTEK epoxy resin, and platinum) to trigger a FBR when implanted into a solid tumor. Biomaterials were chosen based on their use in the construction of a novel biosensor, designed to measure spatial and temporal changes in intra-tumoral O2 , and pH. None of the biomaterials had any detrimental effect on tumor growth or body weight of the murine host. Immunohistochemistry showed no significant changes in tumor necrosis, hypoxic cell number, proliferation, apoptosis, immune cell infiltration, or collagen deposition. The absence of biofouling supports the use of these materials in biosensors; future investigations in preclinical cancer models are required, with a view to eventual applications in humans. To our knowledge this is the first documented investigation of the effects of modern biomaterials, used in the production of implantable sensors, on tumor tissue after implantation. © 2018 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals, Inc. J Biomed Mater Res Part B, 2018.

BACKGROUND: Postmastectomy radiotherapy in patients with four or more positive axillary nodes reduces breast cancer mortality, but its role in patients with one to three involved nodes is controversial. We assessed the effects of postmastectomy radiotherapy on quality of life (QOL) in women with intermediate-risk breast cancer. METHODS: SUPREMO is an open-label, international, parallel-group, randomised, controlled trial. Women aged 18 years or older with intermediate-risk breast cancer (defined as pT1-2N1; pT3N0; or pT2N0 if also grade III or with lymphovascular invasion) who had undergone mastectomy and, if node positive, axillary surgery, were randomly assigned (1:1) to receive chest wall radiotherapy (50 Gy in 25 fractions or a radiobiologically equivalent dose of 45 Gy in 20 fractions or 40 Gy in 15 fractions) or no radiotherapy. Randomisation was done with permuted blocks of varying block length, and stratified by centre, without masking of patients or investigators. The primary endpoint is 10-year overall survival. Here, we present 2-year results of QOL (a prespecified secondary endpoint). The QOL substudy, open to all UK patients, consists of questionnaires (European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23, Body Image Scale, Hospital Anxiety and Depression Scale [HADS], and EQ-5D-3L) completed before randomisation, and at 1, 2, 5, and 10 years. The prespecified primary outcomes within this QOL substudy were global QOL, fatigue, physical function, chest wall symptoms, shoulder and arm symptoms, body image, and anxiety and depression. Data were analysed by intention to treat, using repeated mixed-effects methods. This trial is registered with the ISRCTN registry, number ISRCTN61145589. FINDINGS: Between Aug 4, 2006, and April 29, 2013, 1688 patients were enrolled internationally and randomly assigned to receive chest wall radiotherapy (n=853) or not (n=835). 989 (79%) of 1258 patients from 111 UK centres consented to participate in the QOL substudy (487 in the radiotherapy group and 502 in the no radiotherapy group), of whom 947 (96%) returned the baseline questionnaires and were included in the analysis (radiotherapy, n=471; no radiotherapy, n=476). At up to 2 years, chest wall symptoms were worse in the radiotherapy group than in the no radiotherapy group (mean score 14·1 [SD 15·8] in the radiotherapy group vs 11·6 [14·6] in the no radiotherapy group; effect estimate 2·17, 95% CI 0·40-3·94; p=0·016); however, there was an improvement in both groups between years 1 and 2 (visit effect -1·34, 95% CI -2·36 to -0·31; p=0·010). No differences were seen between treatment groups in arm and shoulder symptoms, body image, fatigue, overall QOL, physical function, or anxiety or depression scores. INTERPRETATION: Postmastectomy radiotherapy led to more local (chest wall) symptoms up to 2 years postrandomisation compared with no radiotherapy, but the difference between groups was small. These data will inform shared decision making while we await survival (trial primary endpoint) results. FUNDING: Medical Research Council, European Organisation for Research and Treatment of Cancer, Cancer Australia, Dutch Cancer Society, Trustees of Hong Kong and Shanghai Banking Corporation.

The Nottingham Prognostic Index Plus (NPI+) is a clinical decision making tool in breast cancer (BC) that aims to provide improved patient outcome stratification superior to the traditional NPI. This study aimed to validate the NPI+ in an independent series of BC. Eight hundred and eighty five primary early stage BC cases from Edinburgh were semi‐quantitatively assessed for 10 biomarkers [Estrogen Receptor (ER), Progesterone Receptor (PgR), cytokeratin (CK) 5/6, CK7/8, epidermal growth factor receptor (EGFR), HER2, HER3, HER4, p53, and Mucin 1] using immunohistochemistry and classified into biological classes by fuzzy logic‐derived algorithms previously developed in the Nottingham series. Subsequently, NPI+ Prognostic Groups (PGs) were assigned for each class using bespoke NPI‐like formulae, previously developed in each NPI+ biological class of the Nottingham series, utilising clinicopathological parameters: number of positive nodes, pathological tumour size, stage, tubule formation, nuclear pleomorphism and mitotic counts. Biological classes and PGs were compared between the Edinburgh and Nottingham series using Cramer's V and their role in patient outcome prediction using Kaplan–Meier curves and tested using Log Rank. The NPI+ biomarker panel classified the Edinburgh series into seven biological classes similar to the Nottingham series (p > 0.01). The biological classes were significantly associated with patient outcome (p 0.01). The good PGs were similarly validated in Luminal B, Basal p53 normal, HER2+/ER− tumours and the poor PG in the Luminal N class (p > 0.01). Due to small patient numbers assigned to the remaining PGs, Luminal N, Luminal B, Basal p53 normal and HER2+/ER− classes could not be validated. This study demonstrates the reproducibility of NPI+ and confirmed its prognostic value in an independent cohort of primary BC. Further validation in large randomised controlled trial material is warranted.

An in vivo biosensor is a technology in development that will assess the biological activity of cancers to individualise external beam radiotherapy. Inserting such technology into the human body creates cybernetic organisms; a cyborg that is a human–machine hybrid. There is a gap in knowledge relating to patient willingness to allow automated technology to be embedded and to become cyborg. There is little agreement around what makes a cyborg and less understanding of the variation in the cyborgisation process. Understanding the viewpoint of possible beneficiaries addresses such gaps. There are currently three versions of ‘cyborg’ in the literature (i) a critical feminist STS concept to destabilise power inherent in dualisms, (ii) an extreme version of the human/machine in science-fiction that emphasises the ‘man’ in human and (iii) a prediction of internal physiological adaptation required for future space exploration. Interview study findings with 12 men in remission from prostate cancer show a fourth version can be used to describe current and future sub-groups of the population; ‘everyday cyborgs'. For the everyday cyborg the masculine cyborg status found in the fictionalised human–machine related to issues of control of the cancer. This was preferred to the felt stigmatisation of being a ‘leaker and bleeder’. The willingness to become cyborg was matched with a having to get used to the everyday cyborg's technological adaptations and risks. It is crucial to explore the everyday cyborg's sometimes ambivalent viewpoint. The everyday cyborg thus adds the dimension of participant voice currently missing in existing cyborg literatures and imaginations.

This report covers an important component of the EPSRC-funded IMPACT project that is developing implantable biosensors to monitor the tumour micro-environment so as to target X-ray dosage to hypoxic areas, thereby maximising the effectiveness of the treatment (www.eng.ed.ac.uk/impact).This qualitative study explored the views of breast cancer patients about implanted biosensors through a series of semi-structured interviews with 32 women who had successfully completed a course of treatment. The aim was both to consider detailed aspects of patients’ willingness to benefit from a possible technological enhancement of treatment and also to understand their views on the challenges of living with what that treatment might mean.

FK506-binding protein-like (FKBPL) has established roles as an anti-tumor protein, with a therapeutic peptide based on this protein, ALM201, shortly entering phase I/II clinical trials. Here, we evaluated FKBPL’s prognostic ability in primary breast cancer tissue, represented on tissue microarrays (TMA) from 3277 women recruited into five independent retrospective studies, using immunohistochemistry (IHC). In a meta-analysis, FKBPL levels were a significant predictor of BCSS; low FKBPL levels indicated poorer breast cancer specific survival (BCSS) (hazard ratio (HR) = 1.30, 95% confidence interval (CI) 1.14–1.49, p < 0.001). The prognostic impact of FKBPL remained significant after adjusting for other known prognostic factors (HR = 1.25, 95% CI 1.07–1.45, p = 0.004). For the sub-groups of 2365 estrogen receptor (ER) positive patients and 1649 tamoxifen treated patients, FKBPL was significantly associated with BCSS (HR = 1.34, 95% CI 1.13–1.58, p < 0.001, and HR = 1.25, 95% CI 1.04–1.49, p = 0.02, respectively). A univariate analysis revealed that FKBPL was also a significant predictor of relapse free interval (RFI) within the ER positive patient group, but it was only borderline significant within the smaller tamoxifen treated patient group (HR = 1.32 95% CI 1.05–1.65, p = 0.02 and HR = 1.23 95% CI 0.99–1.54, p = 0.06, respectively). The data suggests a role for FKBPL as a prognostic factor for BCSS, with the potential to be routinely evaluated within the clinic.

International audience; PURPOSE: Epidemiologic information on rare cancers is scarce. The project Surveillance of Rare Cancers in Europe (RARECARE) provides estimates of the incidence, prevalence and survival of rare cancers in Europe based on a new and comprehensive list of these diseases. MATERIALS AND METHODS: RARECARE analysed population-based cancer registry (CR) data on European patients diagnosed from 1988 to 2002, with vital status information available up to 31st December 2003 (latest date for which most CRs had verified data). The mean population covered was about 162,000,000. Cancer incidence and survival rates for 1995-2002 and prevalence at 1st January 2003 were estimated. RESULTS: Based on the RARECARE definition (incidence

International audience; BACKGROUND: Traditional cancer-survival analyses provide data on cancer management at the beginning of a study period, and are often not relevant to current practice because they refer to survival of patients treated with older regimens that might no longer be used. Therefore, shortening the delay in providing survival estimates is desirable. Period analysis can estimate cancer survival by the use of recent data. We aimed to apply the period-analysis method to data that were collected by European cancer registries to estimate recent survival by country and cancer site, and to assess survival changes in Europe. We also compared our findings with data on cancer survival in the USA from the US SEER (Surveillance, Epidemiology, and End Results) programme. METHODS: We analysed survival data for patients diagnosed with cancer in 2000-02, collected from 47 of the European cancer registries participating in the EUROCARE-4 study. 5-year period relative survival for patients diagnosed in 2000-02 was estimated as the product of interval-specific relative survival values of cohorts with different lengths of follow-up. 5-year survival profiles for patients diagnosed in 2000-02 were estimated for the European mean and for five European regions, and findings were compared with US SEER registry data for patients diagnosed in 2000-02. A 5-year survival profile for patients diagnosed in 1991-2002 and a 10-year survival profile for patients diagnosed in 1997-2002 were also estimated by the period method for all malignancies, by geographical area, and by cancer site. FINDINGS: For all cancers, age-adjusted 5-year period survival improved for patients diagnosed in 2000-02, especially for patients with colorectal, breast, prostate, and thyroid cancer, Hodgkin's disease, and non-Hodgkin lymphoma. The European mean age-adjusted 5-year survival calculated by the period method for 2000-02 was high for testicular cancer (97.3% [95% CI 96.4-98.2]), melanoma (86.1% [84.3-88.0]), thyroid cancer (83.2% [80.9-85.6]), Hodgkin's disease (81.4% [78.9-84.1]), female breast cancer (79.0% [78.1-80.0]), corpus uteri (78.0% [76.2-79.9]), and prostate cancer (77.5% [76.5-78.6]); and low for stomach cancer (24.9% [23.7-26.2]), chronic myeloid leukaemia (32.2% [29.0-35.7]), acute myeloid leukaemia (14.8% [13.4-16.4]), and lung cancer (10.9% [10.5-11.4]). Survival for patients diagnosed in 2000-02 was generally highest for those in northern European countries and lowest for those in eastern European countries, although, patients in eastern European had the highest improvement in survival for major cancer sites during 1991-2002 (colorectal cancer from 30.3% [28.3-32.5] to 44.7% [42.8-46.7]; breast cancer from 60% [57.2-63.0] to 73.9% [71.7-76.2]; for prostate cancer from 39.5% [35.0-44.6] to 68.0% [64.2-72.1]). For all solid tumours, with the exception of stomach, testicular, and soft-tissue cancers, survival for patients diagnosed in 2000-02 was higher in the US SEER registries than for the European mean. For haematological malignancies, data from US SEER registries and the European mean were comparable in 2000-02, except for non-Hodgkin lymphoma. INTERPRETATION: Cancer-service infrastructure, prevention and screening programmes, access to diagnostic and treatment facilities, tumour-site-specific protocols, multidisciplinary management, application of evidence-based clinical guidelines, and recruitment to clinical trials probably account for most of the differences that we noted in outcomes.

BBC Radio 4, 14 February, 8 to 8 30 pm

Radiotherapy (RT) is commonly used for the local control of many cancer types. Unfortunately, not all patients will achieve a therapeutic benefit, and some will develop loco-regional recurrences and/or metastatic disease. The hypoxic nature of the tumour microenvironment and the development of radioresistant cancer cells can contribute to these treatment failures. Understanding the mechanisms involved in acquired radioresistance and the development of techniques to identify and target hypoxic tumour areas has the potential to improve RT response rates. The first aim of this project was to investigate the development of acquired radioresistance and identify radiation-induced secreted biomarkers which could be used as indicators of a radiation response or radiosensitivity. Human radioresistant (RR) breast cancer cell lines were developed from parental MCF-7, ZR-751 and MDA-MB-231 cells. Parental and RR cells underwent genotypic, phenotypic and functional characterisation. RR cells exhibited enhanced migration and invasion, with evidence of epithelial-to-mesenchymal transition. MCF-7 RR and ZR-751 RR cell lines exhibited significant phenotypic changes, including loss of ERα and PgR expression and increased EGFR expression, which were associated with the down-regulation of ER signalling genes and up-regulation of genes associated with PI3K, MAPK and WNT pathway activation. A change in subtype classification from luminal A to HER2-overexpressing (MCF-7 RR) and normal-like (ZR-751 RR) subtypes was also observed, consistent with radiation and endocrine therapy resistance and a more aggressive phenotype. To identify biomarkers secreted in response to radiation, human and canine breast and ovine lung cancer cell lines were radiated. Secretome samples were analysed by liquid chromatography-mass spectrometry. Using results from the MCF- 7 cell line, 33 radiation-induced secreted biomarkers were identified which had higher (up to 12-fold) secretion levels compared to untreated controls. Based on secretion profiles and functional analysis 9 candidate biomarkers were selected (YBX3, TK1, SEC24C, EIF3G, EIF4EBP2, NAP1L4, VPS29, GNPNAT1 and DKK1) of which the first 4 underwent in-lab validation. To identify biomarkers related to radiosensitivity transcriptomic analysis identified higher expression of genes encoding 7 of the candidate biomarkers in the MCF-7 cell line compared to its radioresistant derivative. WB analysis identified increased levels of the 4 biomarkers in the conditioned media of parental cells 24 h post-radiation which was not seen in the RR cell lines. These biomarkers, which had differential gene expression and secretion profiles between parental and RR cell lines, may be useful for both predicting and monitoring a tumour’s response to RT. A further aim was to investigate the biocompatibility and functionality of an implantable electrochemical sensor, developed within the Engineering and Physical Sciences Research Council funded IMPACT project. This sensor was designed to measure tissue O2 tension (ptO2) within a tumour, enabling the identification and monitoring of radioresistant hypoxic tumour areas. This study developed a novel in vivo tumour xenograft model to evaluate the potential of 6 materials (silicon dioxide, silicon nitride, Parylene-C, Nafion, biocompatible EPOTEK epoxy resin and platinum) used in the construction of the sensor, to trigger a foreign body response (FBR) when implanted into a solid tumour. Following implantation none of the materials affected tumour growth and all mice remained healthy. Immunohistochemistry performed on the tumour showed no significant changes in necrosis, hypoxic cell number, proliferation, apoptosis, immune cell infiltration or collagen deposition around the implant site. The absence of a FBR supports their use in the construction of implantable medical devices. In vivo validation of the O2 sensor to provide real-time measurements on intra-tumoural ptO2 was performed using a novel large animal ovine model. To achieve this aim, we developed a novel computed tomography (CT) guided transthoracic percutaneous implantation technique for the delivery of sensors into naturally occurring ovine pulmonary adenocarcinoma (OPA) tumours. This model successfully integrated techniques such as ultrasound, general anaesthesia, CT and surgery into the OPA model, all of which are techniques commonly used in the treatment of human lung cancer patients. This methodology resulted in the accurate implantation of sensors into OPA tumours with minimal complications and demonstrated the sensor’s ability to detect changes in intra-tumoural ptO2 following manipulation of the inspired fractional O2 concentration (FiO2). To investigate other possible clinical applications, sensors were validated for measuring intestinal ptO2 using a novel rat model. These experiments assessed the potential of the sensor to monitor intestinal perfusion following an intestinal resection and anastomosis. The sensor was placed onto the serosal surface of the small intestine of anaesthetised rats that were subsequently exposed to ischaemic, hypoxaemic and haemorrhagic insults. Decreases in intestinal ptO2 were observed following superior mesenteric artery occlusion and reductions in FiO2; these changes were reversible after reinstating blood flow or increasing FiO2. These results provided evidence that the sensors could detect changes in intestinal perfusion which could be utilised in a clinical setting to monitor peri-anastomotic intestinal ptO2. Overall this PhD project has conducted both in vitro and in vivo work aimed at the investigation of mechanisms of radioresistance, identifying secreted biomarkers of radiosensitivity and validating the ability of an implantable sensor to measure real-time intra-tumoural and visceral surface O2 tension. Identification of factors contributing to poor RT responses, such as radioresistance development and hypoxic tumour areas could provide a means by which RT could become personalised. Patients identified as having radioresistant tumours or those not responding to RT based on radiation-induced secreted biomarkers, could be given higher dose of radiation or radiosensitising agents to improve patient outcomes.