Detailed DNA methylation characterisation of phyllodes tumours identifies a signature of malignancy and distinguishes phyllodes from metaplastic breast carcinoma.

Phyllodes tumours (PTs) are rare fibroepithelial lesions of the breast that are classified as benign, borderline, or malignant. As little is known about the molecular underpinnings of PTs, current diagnosis relies on histological examination. However, accurate classification is often difficult, particularly for distinguishing borderline from malignant PTs. Furthermore, PTs can be misdiagnosed as other tumour types with shared histological features, such as fibroadenoma and metaplastic breast cancers. As DNA methylation is a recognised hallmark of many cancers, we hypothesised that DNA methylation could provide novel biomarkers for diagnosis and tumour stratification in PTs, whilst also allowing insight into the molecular aetiology of this otherwise understudied tumour. We generated whole-genome methylation data using the Illumina EPIC microarray in a novel PT cohort (n = 33) and curated methylation microarray data from published datasets including PTs and other potentially histopathologically similar tumours (total n = 817 samples). Analyses revealed that PTs have a unique methylome compared to normal breast tissue and to potentially histopathologically similar tumours (metaplastic breast cancer, fibroadenoma and sarcomas), with PT-specific methylation changes enriched in gene sets involved in KRAS signalling and epithelial-mesenchymal transition. Next, we identified 53 differentially methylated regions (DMRs) (false discovery rate < 0.05) that specifically delineated malignant from non-malignant PTs. The top DMR in both discovery and validation cohorts was hypermethylation at the HSD17B8 CpG island promoter. Matched PT single-cell expression data showed that HSD17B8 had minimal expression in fibroblast (putative tumour) cells. Finally, we created a methylation classifier to distinguish PTs from metaplastic breast cancer samples, where we revealed a likely misdiagnosis for two TCGA metaplastic breast cancer samples. In conclusion, DNA methylation alterations are associated with PT histopathology and hold the potential to improve our understanding of PT molecular aetiology, diagnostics, and risk stratification. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Stromal cell diversity associated with immune evasion in human triple-negative breast cancer.

The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple-negative breast cancers (TNBCs) remains poorly understood, limiting the development of stromal-targeted therapies. Single-cell RNA sequencing of five TNBCs revealed two cancer-associated fibroblast (CAF) and two perivascular-like (PVL) subpopulations. CAFs clustered into two states: the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell signalling predictions, we provide evidence that stromal-immune crosstalk acts via a diverse array of immunoregulatory molecules. Importantly, the investigation of gene signatures from inflammatory-CAFs and differentiated-PVL cells in independent TNBC patient cohorts revealed strong associations with cytotoxic T-cell dysfunction and exclusion, respectively. Such insights present promising candidates to further investigate for new therapeutic strategies in the treatment of TNBCs.

Cost-Effectiveness of Radar Localisation Versus Wire Localisation for Wide Local Excision of Non-palpable Breast Cancer.

BACKGROUND: Wire localisation (WL) is the "gold standard" localisation technique for wide local excision (WLE) of non-palpable breast lesions but has disadvantages that have led to the development of wireless techniques. This study compared the cost-effectiveness of radar localisation (RL) to WL. METHODS: This was a single-institution study of 110 prospective patients with early-stage breast cancer undergoing WLE using RL with the SCOUT® Surgical Guidance System (2021-2023) compared with a cohort of 110 patients using WL. Margin status, re-excision rates, and surgery delays associated with preoperative localisation were compared. Costs from a third-party payer perspective in Australian dollars (AUD$) calculated by using microcosting, break-even point, and cost-utility analyses. RESULTS: A total of 110 WLEs using RL cost a total of AUD$402,281, in addition to the device cost of AUD$77,150. The average additional cost of a surgery delay was AUD$2318. Use of RL reduced the surgery delay rate by 10% (p = 0.029), preventing 11 delays with cost savings of AUD$25,496. No differences were identified in positive margin rates (RL: 11.8% vs. WL: 17.3%, p = 0.25) or re-excision rates (RL: 14.5% vs. WL: 21.8%, p = 0.221). In total, 290 RL cases are needed to break even. The cost of WLE using RL was greater than WL by AUD$567. There was a greater clinical benefit of 1.15 quality-adjusted life-years (QALYs) and an incremental cost-utility ratio of AUD$493 per QALY favouring RL. CONCLUSIONS: Routine use of RL was a more cost-effective intervention than WL. Close to 300 RL cases are likely needed to be performed to recover costs of the medical device. CLINICAL TRIAL REGISTRATION: ACTRN12624000068561.

Novel Dual Tracer Indocyanine Green and Radioisotope Versus Gold Standard Sentinel Lymph Node Biopsy in Breast Cancer: The GREENORBLUE Trial.

BACKGROUND: The methods for sentinel lymph node (SLN) biopsy in breast cancer have been variable in type and number of tracers. Some units have abandoned the use of blue dye (BD) due to adverse reactions. Fluorescence-guided biopsy with indocyanine green (ICG) is a relatively novel technique. This study compared the clinical efficacy and costs between novel dual tracer ICG and radioisotope (ICG-RI) with "gold standard" BD and radioisotope (BD-RI). METHODS: Single-surgeon study of 150 prospective patients with early breast cancer undergoing SLN biopsy (2021-2022) using ICG-RI compared with a retrospective cohort of 150 consecutive previous patients using BD-RI. Number of SLNs identified, rate of failed mapping, identification of metastatic SLNs, and adverse reactions were compared between techniques. Cost-minimisation analysis performed by using Medicare item numbers and micro-costing analysis. RESULTS: Total number of SLNs identified with ICG-RI and BD-RI was 351 and 315, respectively. Mean number of SLNs identified with ICG-RI and BD-RI was 2.3 (standard deviation [SD] 1.4) and 2.1 (SD 1.1), respectively (p = 0.156). There were no cases of failed mapping with either dual technique. Metastatic SLNs were identified in 38 (25.3%) ICG-RI patients compared with 30 (20%) BD-RI patients (p = 0.641). There were no adverse reactions to ICG, whereas four cases of skin tattooing and anaphylaxis were associated with BD (p = 0.131). ICG-RI cost an additional AU$197.38 per case in addition to the initial cost for the imaging system. CLINICAL TRIAL REGISTRATION:  ACTRN12621001033831. CONCLUSIONS: Novel tracer combination, ICG-RI, provided an effective and safe alternative to "gold standard" dual tracer. The caveat was the significantly greater costs associated with ICG.

Diagnosis and management of phyllodes tumours for the surgeon: An algorithm.

A Phyllodes Tumour (PT) is an uncommon fibroepithelial lesion, with three histological grades - benign, borderline and malignant. PTs cause significant challenges in diagnosis, management and prognostication. Recent publications have clarified the definitions and prognostication of PTs. Contemporary data currently challenge international guidelines on PT management. We performed an in-depth literature review to develop a best-practice management algorithm for PTs. Diagnostic recommendations are that neither current imaging techniques, nor fine-needle biopsies, can reliably diagnose a PT. Core needle biopsy is the optimal diagnostic technique. Indeterminate or suspicious lesions are recommended to undergo an excisional biopsy due to the inherently heterogeneous nature of PTs. Management guidelines are that benign PTs should be completely excised, although an involved margin is acceptable in select situations. Borderline PTs should have a clear margin on excision due to their higher risk of recurrence, as well as the potential for a recurrence to progress to a malignant PT. In malignant PTs, a margin of 3 mm is acceptable as there is no reduction in recurrence risk if margins are >3 mm. Routine axillary surgery is not indicated in PTs, with axillary surgery only indicated in a histologically-confirmed positive axilla. Adjuvant treatment recommendations are that borderline and malignant PTs should be discussed at MDT, with radiotherapy considered in both. Chemotherapy should be discussed in malignant PT patients. In summary, we have developed an up-to-date simple algorithm to guide the surgeon's management of patients diagnosed with PTs and reduce excessive surgery.

Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome.

AIMS: Triple-negative breast cancer (TNBC) patients generally have a poor outcome; there is a pressing need to identify more effective therapeutic strategies. Clinical trials targeting programmed death 1/programmed death ligand 1 (PD1/PDL1) in melanoma and non-small-cell lung cancer have reported high response rates, and tumoral PDL1 expression has been suggested as a potential biomarker to enrich for patient response to these treatments. There are only very limited data to date reporting the expression of PDL1 in TNBC. METHODS AND RESULTS: PDL1 immunohistochemistry was performed on 161 primary TNBCs and assessed in the tumour as well as immune cells in the stromal compartment. PDL1 expression was very common in TNBC, expressed in the tumour cell membrane (64%), cytoplasm (80%) and stromal (93%) cellular compartments. Cytoplasmic tumoral expression of PDL1 was associated with a lower risk of breast cancer-specific death [hazard ratio (HR) 0.45, P = 0.035] while stromal PDL1 expression was associated with a lower rate of deaths from all causes (HR 0.305, P = 0.0042). Membranous expression of PDL1 was not associated with outcome. While both PDL1 expression and tumour-infiltrating lymphocytes were associated with a better outcome, only lymphovascular invasion and high tumour-infiltrating lymphocytes were independently prognostic for breast cancer-specific death. CONCLUSION: While PDL1 expression is frequent in TNBC, it was not independently prognostic. There were differences in outcome depending on the cellular compartment of PDL1 expression. These data provide further impetus for investigating the utility of immune checkpoint therapies in TNBC, given the clinical significance of tumour-infiltrating lymphocytes (TILs) and PDL1 expression in this cohort.

Workplace Bullying in Surgery.

OBJECTIVE: The aim of this study was to determine the extent and nature of workplace bullying among General Surgery trainees and consultants in Australia. DESIGN, SETTING AND PARTICIPANTS: An online questionnaire survey of General Surgery trainees and consultant surgeons in Australia was conducted between March and May 2012. Prevalence of bullying was measured using both a definition of workplace bullying and the revised Negative Acts Questionnaire (NAQ-R). Sources of bullying were also examined, as well as the barriers and outcomes of formal reporting of bullying. RESULTS: The response rate was 34 % (370/1084) with 41 % (n = 152) of respondents being trainees. Overall, 47 % (n = 173) of respondents reported having been bullied to some degree and 68 % (n = 250) reported having witnessed bullying of surgical colleagues in the last 12 months. The prevalence of bullying was significantly higher in trainees and females, with 64 % of trainees and 57 % of females experiencing some degree of bullying. The majority of respondents (83 %) had experienced at least one negative behavior in the last 12 months, but 38 % experienced at least one negative behavior on a weekly or daily basis. The persistent negative behaviors that represent work-related bullying most commonly experienced were 'having opinions ignored' and 'being exposed to an unmanageable workload.' Consultant surgeons were the most common source of bullying for both trainees and consultants, with administration the next common source. Of those who reported being bullied, only 18 % (n = 32) made a formal complaint. CONCLUSIONS: Despite increased awareness and interventions, workplace bullying remains a significant problem within General Surgery in Australia. The findings in this study serve as a baseline for future questionnaires to monitor the effectiveness of implemented anti-bullying interventions.

Evolution of Indocyanine Green Fluorescence in Breast and Axilla Surgery: An Australasian Experience.

The evolution of indocyanine green (ICG) fluorescence in breast and axilla surgery from an Australasian perspective is discussed in this narrative review with a focus on breast cancer and reconstruction surgery. The authors have nearly a decade of experience with ICG in a high-volume institution, which has resulted in publications and ongoing future research evaluating its use for predicting mastectomy skin flap perfusion for reconstruction, lymphatic mapping for sentinel lymph node (SLN) biopsy, and axillary reverse mapping (ARM) for prevention of lymphoedema. In the authors' experience, routine use of ICG angiography during breast reconstruction postmastectomy was demonstrated to be cost-effective for the reduction of ischemic complications in the Australian setting. A novel tracer combination, ICG-technetium-99m offered a safe and effective substitute to the "gold standard" dual tracer for SLN biopsy, although greater costs were associated with ICG. An ongoing trial will evaluate ARM node identification using ICG fluorescence during axillary lymph node dissection and potential predictive factors of ARM node involvement. These data add to the growing literature on ICG and allow future research to build on this to improve understanding of the potential benefits of fluorescence-guided surgery in breast cancer and reconstruction surgery.

Radar localization of breast and axillary lesions with SCOUT: a prospective single institution pilot study.

BACKGROUND: Wire-guided localization has been the mainstay of localization techniques for non-palpable breast and axillary lesions prior to excision. Evidence is still growing for relatively newer localization technologies. This study evaluated the efficacy of the wireless localization technology, SCOUT®, for both breast and axillary surgery. METHODS: Data were extracted from a prospective database (2021-2023) of consecutive patients undergoing wide local excision, excisional biopsy, targeted axillary dissection, or axillary lymph node dissection with SCOUT at a high-volume tertiary centre. Rates of successful reflector placement, intraoperative lesion localization, and reflector retrieval were evaluated. A survey of surgeon-reported ease of lesion localization and reflector retrieval was also evaluated. CLINICAL TRIAL REGISTRATION: ACTRN386751. RESULTS: One-hundred-ninety-five reflectors were deployed in 172 patients. Median interval between deployment and surgery was 3 days (range 1-20) and mean distance from reflector to lesion was 3.2 mm (standard deviation, SD 3.1). Rate of successful localization and reflector retrieval was 100% for both breast and axillary procedures. Mean operating time was 65.8 min (SD 33). None of the reflectors migrated. No reflector deployment or localization-related complications occurred. Ninety-eight percent of surgeons were satisfied with ease of localization for the first half of cases. CONCLUSION: SCOUT is an accurate and reliable method to localize and excise both breast and axillary lesions, and it may overcome some of the limitations of wire-guided localization.

Breast conservation versus mastectomy for metaplastic breast cancer: A systematic review and meta-analysis.

Metaplastic breast cancer is a rare aggressive subtype of breast cancer for which there are no clear treatment guidelines regarding the optimal surgical approach. This systematic review and meta-analysis aimed to evaluate survival outcomes of patients with metaplastic breast cancer undergoing breast conservation compared with mastectomy. We identified studies from MEDLINE, Pubmed, EMBASE, Google Scholar, the Cochrane Library Register of Controlled Trials and the EBM Reviews Register. Studies were deemed suitable for inclusion where they compared breast-conserving surgery to mastectomy with the primary outcome of overall survival. Survival data were pooled using a random-effects model. From the 456 citations screened by our search, three studies were assessed as eligible for inclusion. There were a total of 2995 patients who underwent mastectomy and 1909 who underwent breast conservation. The median follow-up time was 43 months. Meta-analysis demonstrated no significant difference between breast conservation and mastectomy (pooled HR 0.89, 95% CI, 0.56-1.42, p = 0.631). Wide local excision, in conjunction with adjuvant radiation and judicious use of chemotherapy, may be a reasonable alternative to mastectomy as surgical management of metaplastic breast cancer as part of an individualized, multidisciplinary approach.

Avoiding unnecessary sentinel lymph node biopsy with the use of superparamagnetic iron oxide mapping agents (Magtrace®) in breast surgery.

BACKGROUND: Superparamagnetic iron oxide (SPIO) (Magtrace®) is a non-radioactive liquid tracer that can stay in the sentinel lymph nodes for 30 days. Injection of SPIO at time of primary breast surgery where upfront sentinel lymph node biopsy (SLNB) is not immediately indicated allows for a return to theatre if pathology then identifies invasive disease. SLNB is associated with paraesthesia, pain, seroma formation and lymphoedema risk. Hence, our study aims to assess the use of SPIO to avoid upfront SLNB in breast surgery for ductal carcinoma in situ (DCIS) and prophylaxis. METHODS: Retrospective single-centre study of consecutive patients who underwent injection of SPIO tracer at time of primary breast surgery to avoid upfront SLNB at Chris O'Brien Lifehouse, Sydney, NSW, Australia over a 10-month period. RESULTS: SPIO was injected 38 times, with 34 at time of mastectomy and four cases at time of wide local excision. The indication for surgery was DCIS in 18 cases, risk reduction in 17 cases and other indications in three patients. Six cases (15.8%) required delayed SLNB (D-SLNB) due to the finding of invasive disease on post-operative histopathology. All patients who underwent D-SLNB had nodes successfully localized with SPIO. CONCLUSION: In our cohort, 84.2% of cases were able to avoid upfront SLNB, and hence avoid the associated complications of SLNB. SPIO injection was successful in localizing the SLN in all cases at time of surgery for D-SLNB. This technique was safe with few associated complications.

Feasibility study of a multimodal prehabilitation programme in women receiving neoadjuvant therapy for breast cancer in a major cancer hospital: a protocol.

INTRODUCTION: Neoadjuvant therapy has become a standard treatment for patients with stage II/III HER2 positive and triple negative breast cancer, and in well-selected patients with locally advanced and borderline resectable high risk, luminal B breast cancer. Side effects of neoadjuvant therapy, such as fatigue, cardiotoxicity, neurotoxicity, anxiety, insomnia, vasomotor symptoms, gastrointestinal disturbance as well as a raft of immune-related adverse events, may impact treatment tolerance, long-term outcomes, and quality of life. Providing early supportive care prior to surgery (typically termed 'prehabilitation') may mitigate these side effects and improve quality of life.During our codesign of the intervention, consumers and healthcare professionals expressed desire for a programme that 'packaged' care, was easy to access, and was embedded in their care pathway. We hypothesise that a multimodal supportive care programme including exercise and complementary therapies, underpinned by behavioural change theory will improve self-efficacy, quality of life, readiness for surgery and any additional treatment for women with breast cancer. We seek to explore cardiometabolic, residual cancer burden and surgical outcomes, along with chemotherapy completion (relative dose intensity). This article describes the protocol for a feasibility study of a multimodal prehabilitation programme. METHODS AND ANALYSIS: This is a prospective, mixed-method, feasibility study of a multi-modal programme in a hospital setting for 20-30 women with breast cancer receiving neoadjuvant therapy. Primary outcomes are recruitment rate, retention rate, adherence and acceptability. Secondary outcomes include patient reported outcome measures (PROMs), surgical outcomes, length of stay, satisfaction with surgery, chemotherapy completion rates, changes in metabolic markers and adverse events. Interviews and focus groups to understand the experience with prehabilitation and different factors that may affect feasibility of the intervention . The output of this study will be a codesigned, evidence-informed intervention assessed for feasibility and acceptability by women with breast cancer and the healthcare professionals that care for them. ETHICS AND DISSEMINATION: The study received ethics approval from the St Vincents Hospital HREC (HREC/2021/ETH12198). Trial results will be communicated to participants, healthcare professionals, and the public via publication and conferences. TRIAL REGISTRATION NUMBER: ACTRN12622000584730.

Trends and variations in post-mastectomy breast reconstruction rates in Australia over 10 years.

BACKGROUND: Offering breast reconstruction (BR) at the time of mastectomy is standard of care in Australia with proven quality-of-life benefits. Previously BR rates in Australia have been low compared to similar countries. Accurate up-to-date information is needed to promote equity in access to BR and inform future planning of services. This study analysed recent trends and variations of BR uptake in Australia. METHOD: Data from the BreastSurgANZ Quality Audit (BQA) were used to identify patients who underwent mastectomy with or without reconstruction for invasive or in situ breast carcinoma from 2010 to 2019. The association between BR uptake and the variables of jurisdiction (state or territory), age, hospital type and remoteness, and remoteness of patients' home addresses were analysed. RESULTS: A total 41 880 women underwent mastectomy between 2010 to 2019. The national BR rate steadily increased from 12.8% in 2010 to 29% in 2019, with a 10-year national average of 21.3%. Statistically significant differences in BR uptake (P < 0.001) were found between states with higher rates in New South Wales and Victoria, with BR more likely in private hospitals and in younger women (P < 0.001), and less likely in remote areas (P < 0.001). CONCLUSION: The Australian BR rate has increased over the 10-year period, but significant variation still exists between states. BR is lower in older women and those living in regional and remote areas. While the steady increase in BR uptake is encouraging, barriers that exist to equitable provision of reconstructive surgical services for all women living with breast cancer still need to be corrected.

Trends in outcomes with adoption of indocyanine green angiography in postmastectomy reconstruction.

BACKGROUND: Indocyanine green angiography (ICGA) aims to reduce ischaemic complications by supplementing intraoperative perfusion assessment of mastectomy flaps. Learning curves for this technology have not been analysed. We evaluated changes in patient outcomes with increasing case volume after ICGA adoption in postmastectomy reconstruction. METHODS: Single-institution retrospective analysis of 320 implant-based reconstructions following mastectomy using ICGA from 2015, when it was introduced, to 2021. Cases chronologically divided into tertiles and complications amongst groups evaluated. Trends in ischaemic complications plotted using weighted moving average. CUSUM analysis determined after how many cases plateau was reached. Number of ischaemic complications prior to plateau calculated with AUC analysis. RESULTS: Ischaemic complications decreased over time (Group 1, 15.1%; Group 2, 11.2%; Group 3, 4.7%, P = 0.034). Cases of delayed reconstruction increased over time (Group 1, 6.6%; Group 2, 28%; Group 3, 22.4%; P < 0.001). Our institution reached plateau of 10% ischaemic complications after 160 cases. Mean incidence of ischaemic complications decreased from 16.9% during the first 160 cases to 3.8% after plateau was reached (P < 0.001). Eleven extra breasts (6.9%) experienced ischaemic complications, that may have been avoided if operated by surgeons after the first 160 cases. CONCLUSIONS: There was increased tendency towards a conservative approach of delaying reconstruction and decreased rates of ischaemic complications with increasing case volume after ICGA implementation. A significant number of cases were needed to reach plateau of minimal ischaemic complications. This data could encourage development of standardized protocols for this technology to shorten learning curves for improved patient outcomes.

Cost-effectiveness of indocyanine green angiography in postmastectomy breast reconstruction.

BACKGROUND: Mastectomy skin flap necrosis is a major complication of skin- or nipple-sparing mastectomy. Indocyanine green angiography (ICGA) is a novel technology that can identify flaps at risk of necrosis, but there is paucity of cost-effectiveness data particularly in the Australian context. We evaluated its cost-effectiveness in breast reconstruction surgery. METHODS: Single-institution retrospective study of 295 implant-based breast reconstructions using ICGA compared with 228 reconstructions without ICGA from 2015 to 2020. Costs were calculated using Medicare item numbers and micro-costing analysis. Break-even point analysis determined the number needed to break-even. Cost-utility analysis compared probabilities of ischaemic complications and utility estimates derived from surveys of surgeons to fit into a decision model. RESULTS: There were 295 breast reconstructions using ICGA with a total cost of AU$164,657. The average cost of treating an ischaemic complication was AU$21,375. Use of ICGA reduced the ischaemic complication rate from 14.9% to 8.8%. Ischaemic complications were prevented in 18 breasts resulting in gross cost savings of AU$384,745 and net savings of AU$220,088. Three hundred eighteen cases using ICGA are needed to break-even. The decision model demonstrated a baseline cost difference of AU$1,179, a quality-adjusted life-years (QALY) difference of 1.77, and an incremental cost-utility ratio (ICUR) of AU$656 per QALY favouring ICGA. CONCLUSIONS: Routine use of ICGA during implant-based breast reconstruction is a cost-effective intervention for the reduction of ischaemic complications in the Australian setting. ICGA use was associated with a gain of 1.77 additional years of perfect health at a cost of AU$656 more per year.