Surgery (RMH) - Research Publications

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    Universal genetic testing for women with newly diagnosed breast cancer in the context of multidisciplinary team care
    De Silva, DL ; Stafford, L ; Skandarajah, AR ; Sinclair, M ; Devereux, L ; Hogg, K ; Kentwell, M ; Park, A ; Lal, L ; Zethoven, M ; Jayawardana, MW ; Chan, F ; Butow, PN ; James, PA ; Mann, GB ; Campbell, IG ; Lindeman, GJ (WILEY, 2023-05-01)
    OBJECTIVE: To determine the feasibility of universal genetic testing of women with newly diagnosed breast cancer, to estimate the incidence of pathogenic gene variants and their impact on patient management, and to evaluate patient and clinician acceptance of universal testing. DESIGN, SETTING, PARTICIPANTS: Prospective study of women with invasive or high grade in situ breast cancer and unknown germline status discussed at the Parkville Breast Service (Melbourne) multidisciplinary team meeting. Women were recruited to the pilot (12 June 2020 - 22 March 2021) and expansion phases (17 October 2021 - 8 November 2022) of the Mutational Assessment of newly diagnosed breast cancer using Germline and tumour genomICs (MAGIC) study. MAIN OUTCOME MEASURES: Germline testing by DNA sequencing, filtered for nineteen hereditary breast and ovarian cancer genes that could be classified as actionable; only pathogenic variants were reported. Surveys before and after genetic testing assessed pilot phase participants' perceptions of genetic testing, and psychological distress and cancer-specific worry. A separate survey assessed clinicians' views on universal testing. RESULTS: Pathogenic germline variants were identified in 31 of 474 expanded study phase participants (6.5%), including 28 of 429 women with invasive breast cancer (6.5%). Eighteen of the 31 did not meet current genetic testing eligibility guidelines (probability of a germline pathogenic variant ≥ 10%, based on CanRisk, or Manchester score ≥ 15). Clinical management was changed for 24 of 31 women after identification of a pathogenic variant. Including 68 further women who underwent genetic testing outside the study, 44 of 542 women carried pathogenic variants (8.1%). Acceptance of universal testing was high among both patients (90 of 103, 87%) and clinicians; no decision regret or adverse impact on psychological distress or cancer-specific worry were reported. CONCLUSION: Universal genetic testing following the diagnosis of breast cancer detects clinically significant germline pathogenic variants that might otherwise be missed because of testing guidelines. Routine testing and reporting of pathogenic variants is feasible and acceptable for both patients and clinicians.
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    A Novel Biosignature Identifies Patients With DCIS With High Risk of Local Recurrence After Breast Conserving Surgery and Radiation Therapy
    Vicini, FA ; Mann, GB ; Shah, C ; Weinmann, S ; Leo, MC ; Whitworth, P ; Rabinovitch, R ; Torres, MA ; Margenthaler, JA ; Dabbs, D ; Savala, J ; Shivers, SC ; Mittal, K ; Warnberg, F ; Bremer, T (ELSEVIER SCIENCE INC, 2023-01-01)
    PURPOSE: There is an unmet need to identify women diagnosed with ductal carcinoma in situ (DCIS) with a low risk of in-breast recurrence (IBR) after breast conserving surgery (BCS), which could omit radiation therapy (RT), and also to identify those with elevated IBR risk remaining after BCS plus RT. We evaluated a novel biosignature for a residual risk subtype (RRt) to help identify patients with elevated IBR risk after BCS plus RT. METHODS AND MATERIALS: Women with DCIS treated with BCS with or without RT at centers in the US, Australia, and Sweden (n = 926) were evaluated. Patients were classified into 3 biosignature risk groups using the decision score (DS) and the RRt category: (1) Low Risk (DS ≤2.8 without RRt), (2) Elevated Risk (DS >2.8 without RRt), and (3) Residual Risk (DS >2.8 with RRt). Total and invasive IBR rates were assessed by risk group and treatment. RESULTS: In patients at low risk, there was no significant difference in IBR rates with or without RT (total, P = .8; invasive IBR, P = .7), and there were low overall 10-year rates (total, 5.1%; invasive, 2.7%). In patients with elevated risk, IBR rates were decreased with RT (total: hazard ratio [HR], 0.25; P < .001; invasive: HR, 0.28; P = .005); 10-year rates were 20.6% versus 4.9% (total) and 10.9% versus 3.1% (invasive). In patients with residual risk, although IBR rates decreased with RT after BCS (total: HR, 0.21; P < .001; invasive: HR, 0.29; P = .028), IBR rates remained significantly higher after RT compared with patients with elevated risk (HR, 2.5; 95% CI, 1.2-5.4; P = .018), with 10-year rates of 42.1% versus 14.7% (total) and 18.3% versus 6.5% (invasive). CONCLUSIONS: The novel biosignature identified patients with 3 distinct risk profiles: Low Risk patients with a low recurrence risk with or without adjuvant RT, Elevated Risk patients with excellent outcomes after BCS plus RT, and Residual Risk patients with an elevated recurrence risk remaining after BCS plus RT, warranting potential intensified or alternative treatment approaches.
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    Prognostic Risk Assessment and Prediction of Radiotherapy Benefit for Women with Ductal Carcinoma In Situ (DCIS) of the Breast, in a Randomized Clinical Trial (SweDCIS)
    Waernberg, F ; Karlsson, P ; Holmberg, E ; Sandelin, K ; Whitworth, PW ; Savala, J ; Barry, T ; Leesman, G ; Linke, SP ; Shivers, SC ; Vicini, F ; Shah, C ; Weinmann, S ; Mann, GB ; Bremer, T (MDPI, 2021-12)
    Prediction of radiotherapy (RT) benefit after breast-conserving surgery (BCS) for DCIS is crucial. The aim was to validate a biosignature, DCISionRT®, in the SweDCIS randomized trial. Women were randomly assigned to RT or not after BCS, between 1987 and 2000. Tumor blocks were collected, and slides were sent to PreludeDxTM for testing. In 504 women with complete data and negative margins, DCISionRT divided 52% women into Elevated (DS > 3) and 48% in Low (DS ≤ 3) Risk groups. In the Elevated Risk group, RT significantly decreased relative 10-year ipsilateral total recurrence (TotBE) and 10-year ipsilateral invasive recurrence (InvBE) rates, HR 0.32 and HR 0.24, with absolute decreases of 15.5% and 9.3%. In the Low Risk group, there were no significant risk differences observed with radiotherapy. Using a cutoff of DS > 3.0, the test was not predictive for RT benefit (p = 0.093); however, above DS > 2.8 RT benefit was greater for InvBE (interaction p = 0.038). Recurrences at 10 years without radiotherapy increased significantly per 5 DS units (TotBE HR:1.5 and InvBE HR:1.5). Continuous DS was prognostic for TotBE risk although categorical DS did not reach significance. Absolute 10-year TotBE and InvBE risks appear sufficiently different to indicate that DCISionRT can aid physicians in selecting individualized adjuvant DCIS treatment strategies. Further analyses are planned in combined cohorts to increase statistical power.
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    Factors involved in treatment decision making for women diagnosed with ductal carcinoma in situ: A qualitative study
    Hatton, A ; Heriot, N ; Zalcberg, J ; Ayton, D ; Evans, J ; Roder, D ; Chua, BH ; Hersch, J ; Lippey, J ; Fox, J ; Saunders, C ; Mann, GB ; Synnot, J ; Bell, RJ (CHURCHILL LIVINGSTONE, 2021-12)
    Whilst some of the diversity in management of women with ductal carcinoma in situ (DCIS) may be explained by tumour characteristics, the role of patient preference and the factors underlying those preferences have been less frequently examined. We have used a descriptive qualitative study to explore treatment decisions for a group of Australian women diagnosed with DCIS through mammographic screening. Semi-structured telephone interviews were performed with 16 women diagnosed with DCIS between January 2012 and December 2018, recruited through the LifePool dataset (a subset of BreastScreen participants who have agreed to participate in research). Content analysis using deductive coding identified three themes: participants did not have a clear understanding of their diagnosis or prognosis; reported involvement in decision making about management varied; specific factors including the psychosexual impact of mastectomy and perceptions of radiotherapy, could act as barriers or facilitators to specific decisions about treatment. The treatment the women received was not simply determined by the characteristics of their disease. Interaction with the managing clinician was pivotal, however many other factors played a part in individual decisions. Recognising that decisions are not purely a function of disease characteristics is important for both women with DCIS and the clinicians who care for them.
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    POSNOC-POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy: a randomised controlled trial of axillary treatment in women with early-stage breast cancer who have metastases in one or two sentinel nodes
    Goyal, A ; Mann, GB ; Fallowfield, L ; Duley, L ; Reed, M ; Dodwell, D ; Coleman, RE ; Fakis, A ; Newcombe, R ; Jenkins, V ; Whitham, D ; Childs, M ; Whynes, D ; Keeley, V ; Ellis, I ; Fairbrother, P ; Sadiq, S ; Monson, K ; Montgomery, A ; Tan, W ; Vale, L ; Homer, T ; Badger, H ; Haines, RH ; Lewis, M ; Megias, D ; Nabi, Z ; Singh, P ; Caraman, A ; Miles, E (BMJ PUBLISHING GROUP, 2021-12)
    INTRODUCTION: ACOSOG-Z0011(Z11) trial showed that axillary node clearance (ANC) may be omitted in women with ≤2 positive nodes undergoing breast conserving surgery (BCS) and whole breast radiotherapy (RT). A confirmatory study is needed to clarify the role of axillary treatment in women with ≤2 macrometastases undergoing BCS and groups that were not included in Z11 for example, mastectomy and those with microscopic extranodal invasion. The primary objective of POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy (POSNOC) is to evaluate whether for women with breast cancer and 1 or 2 macrometastases, adjuvant therapy alone is non-inferior to adjuvant therapy plus axillary treatment, in terms of 5-year axillary recurrence. METHODS AND ANALYSIS: POSNOC is a pragmatic, multicentre, non-inferiority, international trial with participants randomised in a 1:1 ratio. Women are eligible if they have T1/T2, unifocal or multifocal invasive breast cancer, and 1 or 2 macrometastases at sentinel node biopsy, with or without extranodal extension. In the intervention group women receive adjuvant therapy alone, in the standard care group they receive ANC or axillary RT. In both groups women receive adjuvant therapy, according to local guidelines. This includes systemic therapy and, if indicated, RT to breast or chest wall. The UK Radiotherapy Trials Quality Assurance Group manages the in-built radiotherapy quality assurance programme. Primary endpoint is 5-year axillary recurrence. Secondary outcomes are arm morbidity assessed by Lymphoedema and Breast Cancer Questionnaire and QuickDASH questionnaires; quality of life and anxiety as assessed with FACT B+4 and State/Trait Anxiety Inventory questionnaires, respectively; other oncological outcomes; economic evaluation using EQ-5D-5L. Target sample size is 1900. Primary analysis is per protocol. Recruitment started on 1 August 2014 and as of 9 June 2021, 1866 participants have been randomised. ETHICS AND DISSEMINATION: Protocol was approved by the National Research Ethics Service Committee East Midlands-Nottingham 2 (REC reference: 13/EM/0459). Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN54765244; NCT0240168Cite Now.
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    Laparoscopic or open appendicectomy for suspected appendicitis in pregnancy and evaluation of foetal outcome in Australia
    Winter, NN ; Guest, GD ; Bozin, M ; Thomson, BN ; Mann, GB ; Tan, SBM ; Clark, DA ; Daruwalla, J ; Muralidharan, V ; Najan, N ; Pitcher, ME ; Vilhelm, K ; Cox, MR ; Lane, SE ; Watters, DA (WILEY, 2017-05)
    BACKGROUND: Recent data suggest that laparoscopic appendicectomy (LA) in pregnancy is associated with higher rates of foetal loss when compared to open appendicectomy (OA). However, the influence of gestational age and maternal age, both recognized risk factors for foetal loss, was not assessed. METHOD: This was a multicentre retrospective review of all pregnant patients who underwent appendicectomy for suspected appendicitis from 2000 to 2012 across seven hospitals in Australia. Perioperative data and foetal outcome were evaluated. RESULTS: Data on 218 patients from the seven hospitals were included in the analysis. A total of 125 underwent LA and 93 OA. There were seven (5.6%) foetal losses in the LA group, six of which occurred in the first trimester, and none in the OA group. After matching using propensity scores, the estimated risk difference was 5.1% (95% confidence interval (CI): 1.4%, 9.8%). First trimester patients were more likely to undergo LA (84%), while those in the third were more likely to undergo OA (85%). Preterm delivery rates (6.8% LA versus 8.6% OA; CI: -12.6%, 5.3%) and hospital length of stay (3.7 days LA versus 4.5 days OA; CI: -1.3, 0.2 days) were similar. CONCLUSION: This is the largest published dataset investigating the outcome after LA versus OA while adjusting for gestational and maternal age. OA appears to be a safer approach for pregnant patients with suspected appendicitis.
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    Management of Early Node-Positive Breast Cancer in Australia: A Multicentre Study
    Gannan, E ; Khoo, J ; Nightingale, S ; Suhardja, TS ; Lippey, J ; Keane, H ; Tan, KJ ; Clouston, D ; Gorelik, A ; Mann, GB (WILEY, 2016-07)
    To examine practice patterns for breast cancer patients with limited sentinel node (SN) disease in light of the ACOSOG Z0011 results. Retrospective analysis of patients with T1-2 breast cancer and positive sentinel lymph node biopsy (SLNB) admitted between January 2009 and December 2012. Patient demographics, tumor characteristics, and treatments were recorded. Eight hundred positive SLNBs were identified. A total of 452 (56.5%) proceeded to completion axillary lymph node dissection (cALND). cALND rate decreased from 65.1% to 49.7% from 2009-2010 to 2011-2012. cALND was performed for micrometastasis or isolated tumor cells in 39.3% in 2009-2010 and 22.2% in 2011-2012, whereas for macrometastases the rates were 83.1% and 68.6%, respectively. cALND rates diminished for both Z0011-eligible and -ineligible patients. The ACOSOG Z0011 trial presentation and publication coincided with a reduction in cALND for breast cancer with limited nodal disease. There appears equipoise regarding management of macrometastatic SN disease.
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    Window of opportunity treatment in breast cancer
    Chen, J ; Easwaralingam, N ; Warrier, S ; Ong, A ; Carson, E-K ; Mak, C ; Snook, K ; Middleton, K ; Parker, A ; Palmieri, C ; Spillane, A ; Mann, GB ; Lim, E ; Segara, D (WILEY, 2020-01)
    Window of opportunity therapies, which involve short-term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone-receptor positive breast cancer, a 2-week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision-making regarding treatment options. Changes in short-term biomarker endpoints such as cell proliferation measured by Ki-67 can act as surrogate markers of long-term outcomes. Paired tissues obtained pre- and post-investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space.
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    Outcomes of women at high familial risk for breast cancer: An 8-year single-center experience
    Lammert, J ; Skandarajah, AR ; Shackleton, K ; Calder, P ; Thomas, S ; Lindeman, GJ ; Mann, GB (WILEY, 2020-04)
    OBJECTIVES: The value of a high-risk surveillance program for mutation carriers and women at high familial breast cancer risk has not been extensively studied. A Breast and Ovarian Cancer Risk Management Clinic (BOCRMC) was established at the Royal Melbourne Hospital in 2010 to provide multimodality screening and risk management strategies for this group of women. The aims of this study were to evaluate the program and describe breast cancer diagnoses for BRCA1, BRCA2, and other germline mutation carriers as well as high-risk noncarriers attending the BOCRMC. METHODS: Clinical data from mutation carriers and noncarriers with a ≥25% lifetime risk of developing breast cancer who attended between 2010 and 2018 were extracted from clinic records and compared. The pattern and mode of detection of cancer were determined. RESULTS: A total of 206 mutation carriers and 305 noncarriers attended the BOCRMC and underwent screening on at least one occasion. Median age was 37 years. After a median follow-up of 34 months, 15 (seven invasive) breast cancers were identified in mutation carriers, with seven (six invasive) breast cancers identified in noncarriers. Of these, 20 (90.9%) were detected by annual screening, whereas two (9.1%) were detected as interval cancers (both in BRCA1 mutation carriers). Median size of the invasive breast cancers was 11 mm (range: 1.5-30 mm). The majority (76.9%) were axillary node negative. In women aged 25-49 years, the annualized cancer incidence was 1.6% in BRCA1, 1.4% in BRCA2 mutation carriers, and 0.5% in noncarriers. This compares to 0.06% annualized cancer incidence in the general Australian population. CONCLUSIONS: Screening was effective at detecting early-stage cancers. The incidence of events in young noncarriers was substantially higher than in the general population. This potentially justifies ongoing management through a specialty clinic, although further research to better personalize risk assessment in noncarriers is required.