Receptor Discordance in Metastatic Breast Cancer; a review of clinical and genetic subtype alterations from primary to metastatic disease.

PURPOSE: Receptor and subtype discordance between primary breast tumours and metastases is a frequently reported phenomenon. The aim of this article is to review the current evidence on receptor discordance in metastatic breast cancer and to explore the benefit of performing a repeat biopsy in this context. METHODS: Searches were undertaken on PubMed and Clinicaltrials.gov for relevant publications and trials. CONCLUSION: The current guidelines recommend offering to perform a biopsy of a metastatic lesion to evaluate receptor status. The choice of systemic therapy in metastatic disease is often based on the receptor status of the primary lesion. As therapeutic decision making is guided by subtype, biopsy of the metastatic lesion to determine receptor status may alter treatment. This article discusses discordance rates, the mechanisms of receptor discordance, the effect of discordance on treatment and survival outcomes, as well as highlighting some ongoing clinical trials in patients with metastatic breast cancer.

Monopolar diathermy versus a vessel-sealing device for reducing postoperative drain output after simple mastectomy: randomized clinical trial.

BACKGROUND: Electrosurgical devices are commonly used during mastectomy for simultaneous dissection and haemostasis, and can provide potential benefits regarding vessel and lymphatic ligation. The aim of this prospective RCT was to assess whether using a vessel-sealing device (LigaSure™) improves perioperative outcomes compared with monopolar diathermy when performing simple mastectomy. METHODS: Patients were recruited prospectively and randomized in a 1 : 1 manner to undergo simple mastectomy using either LigaSure™ or conventional monopolar diathermy at a single centre. The primary outcome was the number of days the drain remained in situ after surgery. Secondary outcomes of interest included operating time and complications. RESULTS: A total of 86 patients were recruited (42 were randomized to the monopolar diathermy group and 44 were randomized to the LigaSure™ group). There was no significant difference in the mean number of days the drain remained in situ between the monopolar diathermy group and the LigaSure™ group (7.75 days versus 8.23 days; P = 0.613) and there was no significant difference in the mean total drain output between the monopolar diathermy group and the LigaSure™ group (523.50 ml versus 572.80 ml; P = 0.694). In addition, there was no significant difference in the mean operating time between the groups, for simple mastectomy alone (88.25 min for the monopolar diathermy group versus 107.20 min for the LigaSure™ group; P = 0.078) and simple mastectomy with sentinel lymph node biopsy (107.20 min for the monopolar diathermy group versus 114.40 min for the LigaSure™ group; P = 0.440). CONCLUSION: In this double-blinded single-centre RCT, there was no difference in the total drain output or the number of days the drain remained in situ between the monopolar diathermy group and the LigaSure™ group. REGISTRATION NUMBER: EudraCT 2018-003191-13 BEAUMONT HOSPITAL REC 18/66.

Assessing Mode of Recurrence in Breast Cancer to Identify an Optimised Follow-Up Pathway: 10-Year Institutional Review.

BACKGROUND: Breast cancer surveillance programmes ensure early identification of recurrence which maximises overall survival. Programmes include annual clinical examination and radiological assessment. There remains debate around the value of annual clinical exam in diagnosing recurrent disease/second primaries. The aim was to assess diagnostic modalities for recurrent breast cancer with a focus on evaluating the role of annual clinical examination. PATIENTS AND METHODS: A prospectively maintained database from a symptomatic breast cancer service between 2010-2020 was reviewed. Patients with biopsy-proven recurrence/second breast primary were included. The primary outcome was the diagnostic modality by which recurrences/secondary breast cancers were observed. Diagnostic modalities included (i) self-detection by the patient, (ii) clinical examination by a breast surgeon or (iii) radiological assessment. RESULTS: A total of 233 patients were identified and, following application of exclusion criteria, a total of 140 patients were included. A total of 65/140 (46%) patients were diagnosed clinically, either by self-detection or clinical examination, while 75/140 (54%) were diagnosed radiologically. A total of 59/65 (91%) of patients clinically diagnosed with recurrence presented to the breast clinic after self-detection of an abnormality. Four (6%) patients had cognitive impairment and recurrence was diagnosed by a carer. Two (3%) patients were diagnosed with recurrence by a breast surgeon at clinical examination. The median time to recurrence in all patients was 48 months (range 2-263 months). CONCLUSION: Clinical examination provides little value in diagnosing recurrence (< 5%) and surveillance programmes may benefit from reduced focus on such a modality. Regular radiological assessment and ensuring patients have urgent/easy access to a breast clinic if they develop new symptoms/signs should be the focus of surveillance programmes.

Long-term survival in patients with node-positive breast cancer who undergo sentinel lymph node biopsy alone after neoadjuvant chemotherapy: meta-analysis.

BACKGROUND: Sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NACT) in patients with breast cancer who are initially node-positive but convert to clinically/radiologically node-negative remains controversial. The primary aim was to assess pooled 5-year disease-free (DFS) and overall (OS) survival for patients who are initially node-positive but have a negative SLNB after NACT, and do not proceed to axillary lymph node dissection (ALND). METHODS: The study was performed using PRISMA guidelines. A systematic literature search of relevant databases was conducted. The Der Simonian-Laird and Cochran-Mantel-Haenszel methods were used to calculate weighted pooled estimates for OS and DFS for this group compared with patients who had NACT and proceeded to ALND after a negative or positive SLNB. RESULTS: Seven studies involving 915 patients who had a negative SLNB after NACT were included. Pooled estimates of 5-year DFS and OS in patients with a negative SLNB after NACT were 86 (95 per cent c.i. 82.1 to 90.3) and 93.1 (87.8 to 97.0) per cent respectively. Patients with a positive SLNB who underwent ALND had reduced 5-year DFS (OR 0.49, 95 per cent c.i. 0.35 to 0.69; P < 0.001) and OS (OR 0.41, 0.16 to 1.02; P = 0.06) compared with those who had a negative SLNB after NACT. There were no differences in DFS for patients who had a negative SLNB only compared with those undergoing ALND with a pCR (OR 1.65, 0.71 to 3.79; P = 0.24). CONCLUSION: Patients who are initially node-positive and who achieve a complete clinical/radiological axillary response after NACT with a subsequent negative SLNB have high rates of DFS and OS after 5 years. Patients with residual disease have significantly reduced DFS and further axillary treatment may still be warranted.

Poor patient awareness of peripheral arterial disease, it is time to optimize the clinical visit.

INTRODUCTION: Peripheral arterial disease (PAD) is a growing public health burden. The development and progression of PAD is influenced by vascular risk factor management and lifestyle changes. However, public awareness of PAD is low compared with other conditions such as heart disease and stroke, which have been the subject of widespread public health campaigns. This study aimed to determine current levels of PAD awareness among hospital patients. METHODS: This cross-sectional, tertiary hospital-based, descriptive study was conducted over 6 months in 2019. Two investigators administered the survey in face-to-face interviews to patients attending 3 different hospital-based settings including vascular clinics (VC), cardiology clinics (CVC), and Emergency Department (ED). RESULTS: A total of 150 patients were interviewed. Participants demonstrated low overall awareness of vascular disease (32% PAD and 21% AAA) compared to cardiovascular disease including stroke (71%) and myocardial infarction (63%). Awareness of PAD was higher in vascular patients (51%) compared to CVC and ED patients (p=<0.01). Of the total population, 77% and 71% identified the contributory role of smoking and limited exercise to the development of PAD respectively. VC patients were more informed of intermittent claudication (78%) and amputation (80%) (p < 0.01) compared to CVC and ED patients. CONCLUSION: In the global drive to reduce vascular morbidity, this study highlights the poor knowledge of PAD among the public. In addition, there is poor awareness about the incidence, risk factors and complications of PAD. These results highlight the need for accessible and easily understood information regarding PAD in both the clinic setting and public health campaigns.

Breast cancer patients with a negative axillary ultrasound may have clinically significant nodal metastasis.

INTRODUCTION: The non-invasive nature of the preoperative axillary ultrasound (AUS) fits the current trend of increasingly conservative axillary management. Recent publications suggest that early disease patients with clinically and radiologically negative axillae do not require sentinel lymph node biopsy (SLNB). This study aims to determine the true extent of axillary node disease in negative preoperative AUS patients. METHODS: A 10-year breast cancer registry was reviewed to identify women with pathologically confirmed T1-2 invasive breast cancer and a negative preoperative AUS. Patients who received neoadjuvant chemotherapy were excluded. Combined positive lymph node count of SLNB ± ALND was used to determine total nodal burden (TNB). Axillae were classified into low nodal burden (LNB) defined as 1-2 positive nodes and high nodal burden (HNB) defined as ≥ 3 positive nodes. RESULTS: 762 patients with negative AUS were included. There were 46.9% and 53.0% T1 and T2 tumours, respectively. 76.9% were node negative (0 LN +), 18.9% had LNB (1-2 LN +) and 4.2% had HNB (≥ 3LN +). Specifically, HNB disease was seen in 2% of T1 tumours and 6.2 % of T2 tumours with a negative AUS. In multivariate analysis, T2 strongly associated with ≥ 3 positive ALNs (OR 2.66 CI 1.09-6.51 p = 0.03) as did lymphovascular invasion (OR 3.56 CI 1.52-8.30 p = < 0.01). CONCLUSION: This study shows that AUS in its current form cannot exclude HNB axillary metastasis to the extent of eliminating the need for surgical staging of the axilla. This may impact axillary local-regional recurrence and disease-free survival. We caution that a negative AUS has a rate of 4.2% of HNB. Therefore, in cases of negative AUS with a T2 tumour, we advocate continued use of SLNB.

Arteriovenous Fistula for dialysis - Let's Google it. Readability and quality of online information.

BACKGROUND: This study evaluated the readability and quality of information regarding arteriovenous (AV) fistula for dialysis on the Internet in the English language. STUDY DESIGN: Using Google© search, the keywords "AV Fistula for dialysis" were searched. The top 75 ranking sites were analyzed. One website was excluded due to repetition. Each landing page was assessed independently by two authors (RB, LR) for readability using the Flesch Reading Ease Score (FRES) and Gunning Fog Index (GFI). Web site quality was assessed using the DISCERN instrument. The individual position of the top 15 websites in the search engine ranking order list was noted. The country of origin, organization type and issuance of Health on the Net (HoN) Certification was recorded. Statistical analyses were performed using unpaired t-tests and ANOVA variance. RESULTS: The mean GFI score was 9.2 and the mean FRES score was 50.6, indicating poor readability. The mean DISCERN score was 48.4, indicating weak quality of websites. Website quality was influenced by the academic/healthcare organization type (p = 0.012). Organization type was not found to impact GFI and FRES scores. Presence of a HoN Certification was not found to impact the quality of information. The majority of sites originated from the United States (61%). CONCLUSION: Our study demonstrates that internet information pertaining to AV fistula for dialysis is of poor quality necessitating improvements to readability and overall website quality to improve the patient experience. Further research into how to improve healthcare web information is needed.

ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis.

BACKGROUND: Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood-brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets. METHODS: Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target's natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis. RESULTS: Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis. CONCLUSION: ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease.

Diagnostic accuracy of intraoperative methods for margin assessment in breast cancer surgery: A systematic review & meta-analysis.

PURPOSE: There are a wide variety of intraoperative techniques available in breast surgery to achieve low rates for positive margins of excision. The objective of this systematic review was to determine the pooled diagnostic accuracy of intraoperative breast margin assessment techniques that have been evaluated in clinical practice. METHODS: This study was performed in accordance with PRISMA guidelines. A systematic search of the literature was conducted to identify studies assessing the diagnostic accuracy of intraoperative margin assessment techniques. Only clinical studies with raw diagnostic accuracy data as compared with final permanent section histopathology were included in the meta-analysis. A bivariate model for diagnostic meta-analysis was used to determine overall pooled sensitivity and specificity. RESULTS: Sixty-one studies were eligible for inclusion in this systematic review and meta-analysis. Cytology demonstrated the best diagnostic accuracy, with pooled sensitivity of 0.92 (95 % CI 0.77-0.98) and a pooled specificity of 0.95 (95 % CI 0.90-0.97). The findings also indicate good diagnostic accuracy for optical spectroscopy, with a pooled sensitivity of 0.86 (95 % CI 0.76-0.93) and a pooled specificity of 0.92 (95 % CI 0.82-0.97). CONCLUSION: Pooled data indicate that optical spectroscopy, cytology and frozen section have the greatest diagnostic accuracy of currently available intraoperative margin assessment techniques. However, long turnaround time for results and their resource intensive nature has prevented widespread adoption of these methods. The aim of emerging technologies is to compete with the diagnostic accuracy of these established techniques, while improving speed and usability.

Efficacy and Safety of Trastuzumab Deruxtecan in Breast Cancer: A Systematic Review and Meta-Analysis.

Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug-conjugate (ADC), primarily used in the treatment of HER2-positive breast cancer. This study aimed to conduct a systematic review to evaluate the efficacy and safety of T-DXd in treating breast cancer, based on clinical trials. A systematic search of the literature was conducted to identify clinical trials investigating the efficacy and safety of T-DXd in breast cancer. Clinical trials of any phase were included. Outcome measures were any adverse events and survival. Meta-analysis was conducted where possible. Pooled prevalence for each adverse event of any grade and grade 3 or greater were estimated. Progression-free survival (PFS), overall survival (OS) and objective response rates (ORRs) were also reported to evaluate the efficacy of T-DXd in breast cancer. A total of 1593 patients from 6 clinical trials were included. Common adverse events of any grade were nausea, anemia, neutropenia, vomiting, fatigue, constipation and diarrhea, occurring in greater than 30% of cases. In terms of adverse events of grade 3 or more, only anemia and neutropenia occurred at a relatively high rate. Median PFS ranged from 11.1 to 22.1 months. There was evidence of a benefit of T-DXd compared to controls in terms of both PFS (OR: 0.38; 95% CI: 0.32, 0.45) and OS (OR: 0.61; 95% CI: 0.48, 0.78). ORRs ranged from 37% to 79.9%. The present systematic review shows evidence that T-DXd is a safe and effective agent in the treatment of breast cancer based on currently available data. The most common adverse events affected the blood, lymphatic and gastrointestinal systems. Interstitial lung disease (ILD) is a notable and potentially serious adverse event.

Review of the status of neoadjuvant therapy in HER2-positive breast cancer.

Purpose: The development of human epidermal growth factor receptor 2 (HER2)-directed therapies has revolutionized the treatment of HER2-positive breast cancer. The aim of this article is to review the continually evolving treatment strategies in the neoadjuvant setting of HER2-positive breast cancer, as well as the current challenges and future perspectives. Methods: Searches were undertaken on PubMed and Clinicaltrials.gov for relevant publications and trials. Findings: The current standard of care in high-risk HER2-positive breast cancer is to combine chemotherapy with dual anti-HER2 therapy, for a synergistic anti-tumor effect. We discuss the pivotal trials which led to the adoption of this approach, as well as the benefit of these neoadjuvant strategies for guiding appropriate adjuvant therapy. De-escalation strategies are currently being investigated to avoid over treatment, and aim to safely reduce chemotherapy, while optimizing HER2-targeted therapies. The development and validation of a reliable biomarker is essential to enable these de-escalation strategies and personalization of treatment. In addition, promising novel therapies are currently being explored to further improve outcomes in HER2-positive breast cancer.

The Impact of Chemotherapy Prescription on Long-Term Survival Outcomes in Early-Stage Invasive Lobular Carcinoma - A Systematic Review and Meta-Analysis.

INTRODUCTION: Invasive lobular carcinoma (ILCs) are typically endocrine responsive breast cancers which respond poorly to chemotherapy. The long-term survival advantage of prescribing chemotherapy in such cases remains unclear. To perform a systematic review and meta-analysis assessing, the impact of prescribing chemotherapy in such patients on long-term disease-free (DFS) and overall (OS) survival outcomes. METHODS: A systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. Ten-year DFS and OS were pooled as odds ratios (ORs) with 95% confidence intervals (CI) using the Mantel-Haenszel method. Time-to-effect modelling was performed using the generic inverse variance method. RESULTS: Overall, 9 studies including 28,218 patients were included. The mean follow-up was 74 months (range: 0-150 months) and mean age was 60 years (range: 22-90 years). Of these, 34.7% received chemotherapy (9,797/28,218) and 66.3% did not receive chemotherapy (18,421/28,218). Chemotherapy prescription failed to improve 10-year DFS (OR: 0.89, 95% CI: 0.65-1.23) and OS (OR: 0.92, 95% CI: 0.72-1.18). When using time-to-effect modelling, chemotherapy prescription failed to improve DFS (hazard ratio (HR): 1.01, 95% CI: 0.78-1.31) and OS (HR: 1.07, 95% CI: 0.89-1.27, I2= 67%). CONCLUSION: This meta-analysis illustrates no long-term survival advantage associated with chemotherapy prescription in the setting of early-stage ILC. In the absence of well-designed, prospective clinical trials evaluating the impact of chemotherapy on long-term outcomes in ILC, these results should be considered by the multidisciplinary team when deciding on the value of systemic chemotherapy prescription in ILC.

Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities.

The molecular events and transcriptional plasticity driving brain metastasis in clinically relevant breast tumor subtypes has not been determined. Here we comprehensively dissect genomic, transcriptomic and clinical data in patient-matched longitudinal tumor samples, and unravel distinct transcriptional programs enriched in brain metastasis. We report on subtype specific hub genes and functional processes, central to disease-affected networks in brain metastasis. Importantly, in luminal brain metastases we identify homologous recombination deficiency operative in transcriptomic and genomic data with recurrent breast mutational signatures A, F and K, associated with mismatch repair defects, TP53 mutations and homologous recombination deficiency (HRD) respectively. Utilizing PARP inhibition in patient-derived brain metastatic tumor explants we functionally validate HRD as a key vulnerability. Here, we demonstrate a functionally relevant HRD evident at genomic and transcriptomic levels pointing to genomic instability in breast cancer brain metastasis which is of potential translational significance.

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism.

Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.

Evolving Trends in Surgical Management of Breast Cancer: An Analysis of 30 Years of Practice Changing Papers.

The management of breast cancer has evolved into a multidisciplinary evidence-based surgical speciality, with emphasis on conservative surgery. A number of landmark trials have established lumpectomy followed by radiation as the standard of care for many patients. The aim of this study is to construct a narrative review of recent developments in the surgical management of breast cancer and how such developments have impacted surgical practice. A comprehensive literature search of Pubmed was conducted. The latest search was performed on October 31st, 2020. Search terms "breast cancer" were used in combinations with specific key words and Boolean operators relating to surgical management. The reference lists of retrieved articles were comprehensively screened for additional eligible publications. Articles were selected and reviewed based on relevance. We selected publications in the past 10 years but did not exclude commonly referenced and highly regarded previous publications. Review articles and book chapters were also cited to provide reference on details not discussed in the academic literature. This article reviews the current evidence in surgical management of early-stage breast cancer, discusses recent trends in surgical practice for therapeutic and prophylactic procedures and provides commentary on implications and factors associated with these trends.

A systematic review and meta-analysis comparing the effectiveness of negative-pressure wound therapy to standard therapy in the prevention of complications after vascular surgery.

INTRODUCTION: Negative pressure wound therapy (NPWT) dressings reduce wound complications in a variety of settings but it is unclear whether they reduce groin wound complications in closed incisions after vascular surgery. Therefore, we performed a systematic review and meta-analysis. METHODS: Randomised controlled trials on the use of negative pressure wound dressings on closed groin incisions following vascular surgery were identified from an electronic search of abstract databases, conference proceedings and article reference lists. The primary outcome was surgical site infection (SSI) and secondary outcomes were seromas, readmissions within 30 days postoperatively, reoperations and length of stay. RESULTS: 7 exploratory trials involving 935 incisions and an unclear number of patients were identified. 4 trials yielded primary outcome results that favoured NPWT. Meta-analysis found that NPWT dressings reduced SSIs (RR 0.47; 95%CI 0.31-0.70; 3 studies, 422 patients). No other meta-analyses could be performed. CONCLUSION: NPWT dressings are a promising intervention that may reduce the incidence of groin wound complications following vascular surgery. However, further large-scale well-designed studies are needed before NPWT dressings can become the standard of care.