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Background: Radiotherapy reduces in-breast recurrence risk in early breast cancer (EBC) in older women. This benefit may be small and should be balanced against treatment effect and holistic patient assessment. This study described treatment patterns according to fitness and impact on health-related quality-of-life (HRQoL)., Methods: A multicentre, observational study of EBC patients aged ≥ 70 years, undergoing breast-conserving surgery (BCS) or mastectomy, was undertaken. Associations between radiotherapy use, surgery, clinico-pathological parameters, fitness based on geriatric parameters and treatment centre were determined. HRQoL was measured using the European Organisation for the Research and Treatment of Cancer (EORTC) questionnaires., Results: In 2013-2018 2811 women in 56 UK study centres underwent surgery with a median follow-up of 52 months. On multivariable analysis, age and tumour risk predicted radiotherapy use. Among healthier patients (based on geriatric assessments) with high-risk tumours, 534/613 (87.1%) having BCS and 185/341 (54.2%) having mastectomy received radiotherapy. In less fit individuals with low-risk tumours undergoing BCS, 149/207 (72.0%) received radiotherapy. Radiotherapy effects on HRQoL domains, including breast symptoms and fatigue were seen, resolving by 18 months., Conclusion: Radiotherapy use in EBC patients ≥ 70 years is affected by age and recurrence risk, whereas geriatric parameters have limited impact regardless of type of surgery. There was geographical variation in treatment, with some fit older women with high-risk tumours not receiving radiotherapy, and some older, low-risk, EBC patients receiving radiotherapy after BCS despite evidence of limited benefit. The impact on HRQoL is transient., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy., Methods: A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage., Results: Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19-0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20-0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08-0.49];BCSS: HR 0.12 [95% CI 0.03-0.44]).Transient negative quality-of-life impacts were observed., Conclusions: Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient., Trial Registration: ISRCTN 46099296., (© 2021. The Author(s).)

Delays in cancer diagnosis and treatment due to the COVID-19 pandemic is a widespread source of concern, but the scale of the challenge for different tumour sites is not known. Routinely collected NHS England Cancer Waiting Time data were analysed to compare activity for breast cancer in the first 6 months of 2020 compared to the same time period in 2019. The number of referrals for suspected breast cancer was 28% lower (N = 231,765 versus N = 322,994), and the number of patients who received their first treatment for a breast cancer diagnosis was 16% lower (N = 19,965 versus N = 23,881). These data suggest that the number of breast cancers diagnosed during the first half of 2020 is not as low as initially feared, and a substantial proportion of the shortfall can be explained by the suspension of routine screening in March 2020. Further work is needed to examine in detail the impact of measures to manage the COVID-19 pandemic on breast cancer outcomes.

Background: Surgery and chemotherapy use were studied among older women with early stage triple negative breast cancer (TNBC) in a population-based cohort., Methods: Women aged ≥50 years with unilateral early (stage 1-3a) TNBC diagnosed in 2014-2017 were identified from English cancer registration data. Information on surgery and chemotherapy was from linked Hospital Episode Statistics and Systemic Anti-Cancer Therapy datasets, respectively. Logistic regression was used to investigate the influences of patient age, comorbidity and frailty on uptake of surgery and chemotherapy., Results: There were 7094 women with early stage TNBC. Overall rate of surgery was 94%, which only decreased among women aged ≥85 years (74%) and among the most frail. Among the 6681 women receiving surgery, 16% had neoadjuvant and 42% had adjuvant chemotherapy; the use of both decreased with age. More comorbidities and greater frailty were associated with lower rates of chemotherapy. There were differences in the uptake of chemotherapy across geographical regions and in the neoadjuvant and adjuvant chemotherapy regimens between age groups., Conclusion: Majority of older women with early TNBC had surgery, although some physically fit older women did not. Chemotherapy use varied by age and fitness., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

Purpose: Breast cancer tumour-infiltrating lymphocytes associate with clinico-pathological factors, including survival, although the literature includes many conflicting findings. Our aim was to assess these associations for key lymphocyte subtypes and in different tumour compartments, to determine whether these provide differential correlations and could, therefore, explain published inconsistencies. Uniquely, we also examine whether infiltrating levels merely reflect systemic lymphocyte levels or whether local factors are predominant in recruitment., Methods: Immunohistochemistry was used to detect tumour-infiltrating CD20+ (B), CD4+ (helper T), CD8+ (cytotoxic T) and FoxP3+ (regulatory T) cells in breast cancers from 62 patients, with quantification in tumour stroma, tumour cell nests, and tumour margins. Levels were analysed with respect to clinico-pathological characteristics and matched circulating levels (determined by flow-cytometry)., Results: CD4+ lymphocytes were the most prevalent subtype in tumour stroma and at tumour edge and CD8+ lymphocytes were most prevalent in tumour nests; FoxP3+ lymphocytes were rarest in all compartments. High grade or hormone receptor negative tumours generally had significantly increased lymphocytes, especially in tumour stroma. Only intra-tumoural levels of CD8+ lymphocytes correlated significantly with matched circulating levels (p < 0.03), suggesting that recruitment is mainly unrelated to systemic activity. High levels of stromal CD4+ and CD20+ cells associated with improved survival in hormone receptor negative cases (p < 0.04), while tumour nest CD8+ and FoxP3+ cells associated with poor survival in hormone receptor positives (p < 0.005)., Conclusions: Lymphocyte subtype and location define differential impacts on tumour biology, therefore, roles of tumour-infiltrating lymphocytes will only be unravelled through thorough analyses that take this into account.

Background: Clinical guidance on recommended treatment for older patients with breast cancer is often ambiguous, particularly in the context of comorbidities and poor functional status. Older patients, aged 70 years and over, account for a substantial proportion of women with breast cancer yet are underrepresented in randomized controlled trials. This paper investigates the initiation of adjuvant chemotherapy and trastuzumab in older patients in routine care., Materials and Methods: Women, aged 50 years and over, newly diagnosed with human epidermal growth receptor 2 (HER2)-positive early invasive breast cancer from January 2014 to December 2017 were identified from the England Cancer Registry. Chemotherapy and trastuzumab use was obtained from the Systemic Anti-Cancer Therapy (SACT) dataset. Patient and tumor characteristics influential in treatment decision-making were included in multilevel mixed-effects logistic regression models., Results: 10% of women had HER2-positive tumors. Initiation of adjuvant chemotherapy and trastuzumab decreased with age from ≥70% among women aged 50-64 years to <15% among women aged 80+ years. Initiation varied additionally by tumor characteristics and number of comorbidities. Age remained a factor in treatment decisions despite favorable other factors, with lower use among women aged 70+ years. There was also marked variation across geographical regions., Conclusions: In women with operable HER2-positive early invasive breast cancer, adjuvant chemotherapy plus trastuzumab was started less frequently as age increased, regardless of tumor characteristics or comorbidity burden. There was substantial variation in the proportion of women who started these treatments across the country., Competing Interests: Declaration of Competing Interest None, (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation., Patients and Methods: STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study in patients with newly diagnosed ER + invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3β, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring., Results: After 4.5 days' exposure, capivasertib 480 mg b.i.d. ( n = 17) produced significant decreases from baseline versus placebo ( n = 11) in pGSK3β (H-score absolute change: -55.3, P = 0.006) and pPRAS40 (-83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: -9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (-42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. ( n = 5) and 240 mg b.i.d. ( n = 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident., Conclusions: Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers., (©2019 American Association for Cancer Research.)

Various studies have documented variation in the management of older patients with breast cancer, and some of this variation stems from different approaches to balancing the expected benefit of different treatments, with the ability of patients to tolerate them. Frailty is an emerging concept that can help to make clinical decisions for older patients more consistent, not least by providing a measure of 'biological' ageing. This would reduce reliance on 'chronological' age, which is not a reliable guide for decisions on the appropriate breast cancer care for older patients. This article examines the potential of frailty assessment to inform on breast cancer treatments. Overall, the current evidence highlights various benefits from implementing comprehensive geriatric assessment and screening for frailty in breast cancer patients. This includes a role in supporting the selection of appropriate therapies and improving physical fitness prior to treatment. However, there are challenges in implementing routine frailty assessments in a breast cancer service. Studies have used a diverse array of frailty assessment instruments, which hampers the generalisability of research findings. Consequently, a number of issues need to be addressed to clearly establish the optimal timing of frailty assessment and the role of geriatric medicine specialists in the breast cancer care pathway., (Copyright © 2019. Published by Elsevier Ltd.)

Introduction: Approximately 55,000 women in the United Kingdom are diagnosed with new breast cancer annually. Since emerging in December 2019, SARS-CoV-2 (coronavirus disease 2019, COVID-19) has become a global pandemic, affecting healthcare delivery worldwide. In response to the pandemic, multiple guidelines were issued to assist with rationalising breast cancer care. The primary aim of the B-MaP-C study is to audit and describe breast cancer management of patients newly diagnosed with breast cancer during the COVID-19 pandemic against pre-COVID-19 management practice in the UK. The implications of changes to management will be determined and the impact of a COVID-19 diagnosis on the patient's breast cancer management will be determined., Methods and Analysis: This is a multi-centre collaborative audit of consecutive breast cancer patients undergoing treatment decisions during the acute and recovery phases of the COVID-19 pandemic. All patients with newly diagnosed primary breast cancer, whose treatment was decided in a multidisciplinary meeting from the 16th March 2020, are eligible for inclusion., Ethics and Dissemination: As this is an audit ethical approval is not required. Each participating centre is required to register the study locally and obtain local governance approvals prior to commencement of data collection. Local audit data will be available to individual participating units for governance purposes. The results of the data analysis will be submitted for publication, as well as disseminated via the ABS newsletter and a webinar. All data will be presented at national and international conferences, circumstances permitting., Registration Details: Each participating centre received local governance audit registration., (© 2020 Published by Elsevier Ltd on behalf of Surgical Associates Ltd.)

Background: There is little clinical evidence to guide treatment decisions for ductal carcinoma in situ (DCIS) in older women. This study evaluated how the management of DCIS in women aged 70 or more compared with women aged 50-69 in England and Wales., Method: The study identified women aged ≥50 years with new unilateral DCIS diagnosed between 2014 and 2016 from linked cancer registration and routine hospital datasets for England and Wales. Rates of surgery and adjuvant radiotherapy were examined by age, deprivation, fitness measures (comorbidity and frailty), method of presentation and tumour grade using multilevel logistic regression., Results: 12,716 women were diagnosed with unilateral DCIS between 2014 and 2016, of whom 2,754 (22%) were aged ≥70 years and 74% were screen detected. High grade DCIS was common, irrespective of age and method of presentation. Fewer women aged ≥70 had surgery compared to women aged 50-69 (81% vs. 94%), which was only partly explained by poor fitness. Use of radiotherapy following breast conserving surgery was strongly associated with grade, and was received by less than 16% of all patients with low grade tumours. Over 70% of women aged 50-69 with high grade DCIS received radiotherapy, but this fell to 35% among women aged ≥80. Use of radiotherapy was not associated with patient fitness., Conclusion: Treatment decisions for women with DCIS varied by age at diagnosis. Lower rates of surgery and adjuvant radiotherapy in older women were only partly explained by patient fitness. Better evidence is needed to aid treatment selection for older women with DCIS., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Biobanks provide a window of opportunity to store and add value to material from rare cases allowing their future use in biomedical research. One such example is the opportunityto obtain good quality tissue from patients undergoing gender re-assignment. Following patient agreement to donate tissue samples to our biobank we catalogued the histological appearance, defined the expression of the hormone receptors ERα, PR, AR and the proliferation marker Ki67, and generated and characterised primary cell cultures in a female to male (FTM) transgender patient referred to our unit for surgery. Immunohistochemistry was performed for ERα, PR and AR and the proliferation marker Ki67. Hormone receptor expression was confined to epithelial cells lining the breast ducts. Ki67 immunoreactivity was sparse indicating little proliferation of luminal epithelium, consistent with normal mammary gland. Cultures of epithelial cells and fibroblasts were derived from surplus tissue. The latter lacked expression of epithelial markers and hormone receptors but exhibited expression of vimentin. Culture of the former on Matrigel saw an outgrowth of more rounded "epithelial-like" cells. Immunofluoresence characterisation showed a mixed phenotype with expression of vimentin and both myoepithelial and luminal epithelial markers. Sporadic weak ERα expression and moderate PR expression was seen. In summary, as well as routinely collecting tissue and blood samples, we have characterised and stored tissue and cells from a FTM transgender patient, adding value to this resource which,available from the Breast Cancer Campaign Tissue Bank for those interested in further studying the biology of FTM transgender tissue.

The aim of this study was to validate ImmunoRatio, a web-based automated image analysis application, by comparing the manual and automated analysis scores for oestrogen receptor α (ERα) in breast carcinomas. Tissue microarrays comprising 200 breast cancer cases prestained for ERα were scanned and scored manually using ImageScope viewing software. Corresponding images were then uploaded and assessed according to the web-based ImmunoRatio programme. There was excellent correlation between manual and ImmunoRatio ERα scores (Spearman correlation=0.872; p≥0.001). The manual and ImmunoRatio ERα scores showed only a moderate agreement (κ=0.421; Weighted kappa=0.874 (CI 0.839 to 0.902)), most probably due to lack of specificity of the algorithm to differentiate between cancer and non-cancer nuclei. Further development to enable differentiation of cancer and non-cancer elements should improve the specificity of the application. Our results support the use of ImmunoRatio software for analysing ERα immunohistochemistry in breast cancer tissues for the purposes of research.

Compared with other markers of cell proliferation, geminin is unique being expressed selectively during the proliferative phase of the cell cycle, specifically S, G2 and early mitosis, disappearing completely at the metaphase-anaphase transition. We aimed to compare the prognostic significance of geminin to that of Ki67, a proliferation marker which has been investigated in many breast cancer studies. Breast cancer tissue microarrays containing 368 tumours were stained using anti-geminin and Ki67 antibodies. Labelling index (LI) was calculated for geminin, and the percentage of positive cancer nuclei was determined for Ki67. A receiver operation characteristics analysis was used to determine the optimum cut-off value for geminin (LI ≥ 2), and for Ki67, a score of ≥14 % was considered as positive for survival analysis. Geminin expression correlated positively with Ki67 expression (r = 0.686, p = 0.001). Survival analysis showed only geminin, and not Ki67-positive patients to have poor (breast cancer-specific survival) BCSS [HR 2.85 (1.53-5.32)] and (disease-free survival) DFS [HR 2.63 (1.47-4.71)]. On univariate analysis, along with known clinicopathological variables, both Ki67 and geminin LI were found to be significant predictors of BCSS and DFS. On multivariate analysis, only tumour size, nodal status and adjuvant hormonal therapy were found to be independent predictors for both BCSS and DFS, while geminin positivity (LI ≥ 2 %) was found to be an independent predictor for BCSS [HR 2.27 (1.01-5.06); p = 0.04]. In comparison with Ki67, a more established proliferation marker, geminin expression was a better predictor of adverse outcome in this cohort of breast cancers. Selective expression of geminin during the proliferative phase of the cell cycle and its nuclear specificity increase its potential to be used as an alternative marker of proliferation in breast cancer patients.

Surgery and anaesthesia result in a variety of metabolic and endocrine responses, which result in a generalised state of immunosuppression in the immediate post-operative period. Surgery induced immunosuppression has been implicated in the development of post-operative septic complications and tumour metastasis formation. In addition the effectiveness of many treatments in the adjuvant setting is dependent on a functioning immune system. By understanding the mechanisms contributing to surgery-induced immunosuppression, surgeons may undertake strategies to minimise its effect and reduce potential short-term and long-term consequences to patients., (2010 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Background: Little is known about the influence of culture and beliefs about breast cancer, and its implications on preventive health behaviour among South Asian people in the UK., Methods: Using a qualitative approach, 24 South Asian breast cancer patients and their significant others were interviewed., Results: Most patients were unfamiliar with the subject of cancer; they expressed lack of knowledge of cancer as a disease and its symptoms. They identified a painless lump in the breast as sign of abnormality, but not cancer. They also did not know any non-lump breast symptoms. Over half participated in breast screening after encouragement from daughters or relatives. Most did not practise breast self-examination. Perceptions of cancer and health behaviour were influenced by cultural beliefs. Common themes were cancer is a taboo subject and cancer is a stigma. Patients also expressed misunderstandings about the cause of cancer. Cancer in the family had ramifications on children' s marriage prospects and may cause marital breakdown. Terminology used also caused communication problems with healthcare professionals and within the family: the use of ' chest' to substitute ' breast' changed the meaning of the message conveyed., Conclusions: Cultural beliefs and practices accentuate difficulties in understanding breast cancer, breast screening and breast self-examination, and can prevent South Asian women from adopting preventive health practices.

Estrogen receptor (ER) action is modulated by posttranslational modifications. Although ERalpha phosphorylation correlates with patient outcome, ERbeta is similarly phosphorylated but its significance in breast cancer has not been addressed. We investigated whether ERbeta that is phosphorylated at serine 105 (S105-ERbeta) is expressed in breast cancer and assessed potential clinical implications of this phosphorylation. Following antibody validation, S105-ERbeta expression was studied in tissue microarrays comprising 108 tamoxifen-resistant and 351 tamoxifen-sensitive cases and analyzed against clinical data. S105-ERbeta regulation in vitro was assessed by Western blot, flow cytometry, and immunofluorescence. Nuclear S105-ERbeta was observed in breast carcinoma and was associated with better survival (Allred score > or =3), even in tamoxifen-resistant cases, and additionally correlated with ERbeta1 and ERbeta2 expression. Distinct S105-ERbeta nuclear speckles were seen in some higher grade tumors. S105-ERbeta levels increased in MCF-7 cells in response to 17beta-estradiol, the ERbeta-specific agonist diarylpropionitrile, and the partial ERbeta-agonist genistein. S105-ERbeta nuclear speckles were also seen in MCF-7 cells and markedly increased in size and number at 24 hours following 17beta-estradiol and, in particular diarylpropionitrile, treatment. These speckles were coexpressed with ERbeta1 and ERbeta2. Presence of S105-ERbeta in breast cancer and association with improved survival, even in endocrine resistant breast tumors suggest S105-ERbeta might be a useful additional prognostic marker in this disease.

Circulating tumour cells (CTCs) have been of considerable interest for many years. The rarity of these cells presents the main challenge associated with their analysis. Current detection methods use antibody and nucleic acid techniques and are sensitive for CTC detection but limited in their utility by the occurrence of false-positive results. Despite this, there are a number of clinical studies which show that the presence of CTCs is an important prognostic indicator, particularly in the metastatic setting. Current efforts to phenotype CTCs may provide a valuable insight into the metastatic process and may also allow the development of specific CTC-targeted treatment strategies in the future.

Hepatocellular carcinoma is the most common primary tumour of the liver. Metastasis is frequent in these aggressive tumours and is commonly to the lungs, regional lymph nodes, or bone. Metastasis as a discrete subcutaneous nodule has not been described before. We report a case of hepatocellular carcinoma with a solitary subcutaneous metastatic deposit identified 18 months after the initial hepatic surgery.

To gain insights into the possible role of oestrogen receptor (ER) beta in breast carcinogenesis, immunohistochemical analysis of ER beta was performed on 512 breast specimens encompassing normal (n = 138), pure ductal carcinoma in situ (n = 16), invasive cancers (n = 319), lymph node metastases (n = 31), and recurrences (n = 8). Real-time polymerase chain reaction (PCR) was used to investigate the methylation status of the ER beta gene in the ER beta negative breast cancer cell lines SkBr3 and MDA-MB-435. A gradual reduction in, but not a complete loss of, ER beta expression was observed during the transition from normal and pre-invasive lesions to invasive cancers, where ER beta was lost in 21% of cases. This was more pronounced in invasive ductal than in lobular carcinomas, a significantly higher proportion of which were ER beta-positive (74% compared with 91%, respectively, p = 0.0004). Examination of paired primary cancers with their axillary lymph node metastases showed that if ER beta was present in the primary tumour, it persisted in the metastasis. Treatment of ER beta-negative cell lines with DNA methyl transferase inhibitors restored ER beta expression, providing experimental evidence that silencing of ER beta in breast carcinomas could be due to promoter hypermethylation. These results suggest that loss of ER beta expression is one of the hallmarks of breast carcinogenesis and that it may be a reversible process involving methylation., (Copyright 2003 John Wiley & Sons, Ltd.)