Contrast-enhanced mammography for surveillance in women with a personal history of breast cancer.

PURPOSE: Women with a personal history of breast cancer have an increased risk of subsequent breast malignancy and may benefit from more sensitive surveillance than conventional mammography (MG). We previously reported outcomes for first surveillance episode using contrast-enhanced mammography (CEM), demonstrating higher sensitivity and comparable specificity to MG. We now report CEM performance for subsequent surveillance. METHODS: A retrospective study of 1,190 women in an Australian hospital setting undergoing annual surveillance following initial surveillance CEM between June 2016 and December 2022. Outcome measures were recall rate, cancer detection rate, contribution of contrast to recalls, false positive rate, interval cancer rate and characteristics of surveillance detected and interval cancers. RESULTS: 2,592 incident surveillance episodes were analysed, of which 93% involved contrast-based imaging. Of 116 (4.5%) recall episodes, 40/116 (34%) recalls were malignant (27 invasive; 13 ductal carcinoma in situ), totalling 15.4 cancers per 1000 surveillance episodes. 55/116 (47%) recalls were contrast-directed including 17/40 (43%) true positive recalls. Tumour features were similar for contrast-directed recalls and other diagnoses. 8/9 (89%) of contrast-directed invasive recalls were Grade 2-3, and 5/9 (56%) were triple negative breast cancers. There were two symptomatic interval cancers (0.8 per 1000 surveillance episodes, program sensitivity 96%). CONCLUSION: Routine use of CEM in surveillance of women with PHBC led to an increase in the detection of clinically significant malignant lesions, with a low interval cancer rate compared to previous published series. Compared to mammographic surveillance, contrast-enhanced mammography increases the sensitivity of surveillance programs for women with PHBC.

Postoperative radiotherapy omission in selected patients with early breast cancer following preoperative breast MRI (PROSPECT): primary results of a prospective two-arm study.

BACKGROUND: Adjuvant breast radiotherapy as a standard component of breast-conserving treatment for early cancer can overtreat many women. Breast MRI is the most sensitive modality to assess local tumour burden. The aim of this study was to determine whether a combination of MRI and pathology findings can identify women with truly localised breast cancer who can safely avoid radiotherapy. METHODS: PROSPECT is a prospective, multicentre, two-arm, non-randomised trial of radiotherapy omission in patients selected using preoperative MRI and postoperative tumour pathology. It is being conducted at four academic hospitals in Australia. Women aged 50 years or older with cT1N0 non-triple-negative breast cancer were eligible. Those with apparently unifocal cancer had breast-conserving surgery (BCS) and, if pT1N0 or N1mi, had radiotherapy omitted (group 1). Standard treatment including excision of MRI-detected additional cancers was offered to the others (group 2). All were recommended systemic therapy. The primary outcome was ipsilateral invasive recurrence rate (IIRR) at 5 years in group 1. Primary analysis occurred after the 100th group 1 patient reached 5 years follow-up. Quality-adjusted life-years (QALYs) and cost-effectiveness of the PROSPECT pathway were analysed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000810011). FINDINGS: Between May 17, 2011, and May 6, 2019, 443 patients with breast cancer underwent MRI. Median age was 63·0 years. MRI detected 61 malignant occult lesions separate from the index cancer in 48 patients (11%). Of 201 group 1 patients who had BCS without radiotherapy, the IIRR at 5 years was 1·0% (upper 95% CI 5·4%). In group 1, one local recurrence occurred at 4·5 years and a second at 7·5 years. In group 2, nine patients had mastectomy (2% of total cohort), and the 5-year IIRR was 1·7% (upper 95% CI 6·1%). The only distant metastasis in the entire cohort was genetically distinct from the index cancer. The PROSPECT pathway increased QALYs by 0·019 (95% CI 0·008-0·029) and saved AU$1980 (95% CI 1396-2528) or £953 (672-1216) per patient. INTERPRETATION: PROSPECT suggests that women with unifocal breast cancer on MRI and favourable pathology can safely omit radiotherapy. FUNDING: Breast Cancer Trials, National Breast Cancer Foundation, Cancer Council Victoria, the Royal Melbourne Hospital Foundation, and the Breast Cancer Research Foundation.

Impact of a risk based breast screening decision aid on understanding, acceptance and decision making.

Internationally, population breast cancer screening is moving towards a risk-stratified approach and requires engagement and acceptance from current and future screening clients. A decision aid ( www.defineau.org ) was developed based on women's views, values, and knowledge regarding risk-stratified breast cancer screening. This study aims to evaluate the impact of the decision aid on women's knowledge, risk perception, acceptance of risk assessment and change of screening frequency, and decision-making. Here we report the results of a pre and post-survey in which women who are clients of BreastScreen Victoria were invited to complete an online questionnaire before and after viewing the decision aid. 3200 potential participants were invited, 242 responded with 127 participants completing both surveys. After reviewing the decision aid there was a significant change in knowledge, acceptance of risk-stratified breast cancer screening and of decreased frequency screening for lower risk. High levels of acceptance of risk stratification, genetic testing and broad support for tailored screening persisted pre and post review. The DEFINE decision aid has a positive impact on acceptance of lower frequency screening, a major barrier to the success of a risk-stratified program and may contribute to facilitating change to the population breast screening program in Australia.

Contrast enhanced mammography in breast cancer surveillance.

PURPOSE: Mammography (MG) is the standard imaging in surveillance of women with a personal history of breast cancer or DCIS (PHBC), supplemented with ultrasound. Contrast Enhanced Mammography (CEM) has higher sensitivity than MG and US. We report the performance of CEM compared with MG ± US. METHODS: A retrospective study of patients undergoing their first surveillance CEM in an Australian hospital setting between June 2006 and October 2020. Cases where a patient was recalled for assessment were identified, recording radiology, pathology and treatment details. Blinded re-reading of recalled cases was performed to determine the contribution of contrast. Use of surveillance US across the board was assessed for the period. RESULTS: 73/1191 (6.1%) patients were recalled. 35 (48%) were true positives (TP), with 26 invasive cancers and 9 cases of DCIS, while 38 (52%) were false positive (FP) with a positive predictive value (PPV) 47.9%. 32/73 were recalled due to MG findings, while 41/73 were only recalled due to Contrast. 14/73 had 'minimal signs' with a lesion identifiable on MG with knowledge of the contrast finding, while 27/73 were visible only with contrast. 41% (17/41) recalled due to contrast were TP. Contrast-only TPs were found with low and high mammographic density (MD). Screening breast US reduced by 55% in the year after CEM was implemented. CONCLUSION: Compared to MG, CEM as a single surveillance modality for those with PHBC has higher sensitivity and comparable specificity, identifying additional malignant lesions that are clinically significant. Investigation of interval cancer and subsequent round outcomes is warranted.

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).

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.

Outcomes of women at high familial risk for breast cancer: An 8-year single-center experience.

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.

Prospective validation of the NCI Breast Cancer Risk Assessment Tool (Gail Model) on 40,000 Australian women.

BACKGROUND: There is a growing interest in delivering more personalised, risk-based breast cancer screening protocols. This requires population-level validation of practical models that can stratify women into breast cancer risk groups. Few studies have evaluated the Gail model (NCI Breast Cancer Risk Assessment Tool) in a population screening setting; we validated this tool in a large, screened population. METHODS: We used data from 40,158 women aged 50-69 years (via the lifepool cohort) participating in Australia's BreastScreen programme. We investigated the association between Gail scores and future invasive breast cancer, comparing observed and expected outcomes by Gail score ranked groups. We also used machine learning to rank Gail model input variables by importance and then assessed the incremental benefit in risk prediction obtained by adding variables in order of diminishing importance. RESULTS: Over a median of 4.3 years, the Gail model predicted 612 invasive breast cancers compared with 564 observed cancers (expected/observed (E/O) = 1.09, 95% confidence interval (CI) 1.00-1.18). There was good agreement across decile groups of Gail scores (χ2 = 7.1, p = 0.6) although there was some overestimation of cancer risk in the top decile of our study group (E/O = 1.65, 95% CI 1.33-2.07). Women in the highest quintile (Q5) of Gail scores had a 2.28-fold increased risk of breast cancer (95% CI 1.73-3.02, p < 0.0001) compared with the lowest quintile (Q1). Compared with the median quintile, women in Q5 had a 34% increased risk (95% CI 1.06-1.70, p = 0.014) and those in Q1 had a 41% reduced risk (95% CI 0.44-0.79, p < 0.0001). Similar patterns were observed separately for women aged 50-59 and 60-69 years. The model's overall discrimination was modest (area under the curve (AUC) 0.59, 95% CI 0.56-0.61). A reduced Gail model excluding information on ethnicity and hyperplasia was comparable to the full Gail model in terms of correctly stratifying women into risk groups. CONCLUSIONS: This study confirms that the Gail model (or a reduced model excluding information on hyperplasia and ethnicity) can effectively stratify a screened population aged 50-69 years according to the risk of future invasive breast cancer. This information has the potential to enable more personalised, risk-based screening strategies that aim to improve the balance of the benefits and harms of screening.

Management of Early Node-Positive Breast Cancer in Australia: A Multicentre Study.

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.

Sentinel node biopsy in breast cancer revisited.

The axilla has long been a focus of clinicians' attention in the management of breast cancer. The approach to the axilla has undergone dramatic changes over the last century, from radical and extended radical excisions, through the introduction of sentinel node biopsy for node negative patients to the current situation where selective management of those with nodal involvement is being introduced. The introduction of lymphatic mapping and sentinel node biopsy in the 1990's has been key to the major changes that have occurred. In less than 20 years it has moved from a hypothesis to a situation where it is the default approach to almost all clinically node negative patients and is being considered in other situations where axillary clearance was previously considered standard. This article reviews the development and introduction of sentinel node biopsy, its current uncertainties and limitations, and possible future developments.

Comparison of outcomes after laparoscopic versus posterior retroperitoneoscopic adrenalectomy: a pilot study.

BACKGROUND: Posterior retroperitoneoscopic adrenalectomy (PRA) was popularized by Walz and colleagues as an alternative approach to minimally invasive adrenalectomy, offering less postoperative pain and faster return to normal activity compared with laparoscopic transperitoneal adrenalectomy (LA). The authors have recently changed from LA to PRA in suitable patients and audited their outcomes. METHODS: Data were prospectively collected for 10 patients who underwent PRA, and a chart review and telephone interviews were conducted with 13 consecutive patients who underwent LA by the same surgeon. Patient demographics, tumor characteristics, analgesia use, operative and anesthetic time, length of stay, and complications were recorded. RESULTS: Data were collected for 13 LAs and 10 PRAs. Patients' baseline characteristics, including age, BMI, and tumor size, were similar between the 2 groups. There were no conversions to open surgery, transfusions, or deaths. Operative time was similar between the 2 groups. PRA patients required less, inpatient postoperative opioid analgesia compared with LA patients (median 1.25 vs. 23 mg of intravenous morphine equivalent, P=0.003), and had a shorter length of stay (median 1 vs. 2 d, P<0.001). The median total days on opioids were lower for PRA patients compared with LA patients (0.5 vs. 9 d, P<0.001). CONCLUSION: Our initial results supports previously published findings that PRA is a safe procedure, with a relatively short learning curve, resulting in reduced postoperative analgesia use, and reduced length of hospital stay when compared with the laparoscopic transperitoneal approach.

A new bioinformatics paradigm for the theory, research, and practice of therapeutic hypnosis.

In a 2008 pilot study we used DNA microarrays to explore the historical ideo-plastic faculty of therapeutic hypnosis. We documented how to measure changes in activity or experience-dependent gene expression over relatively brief time periods (1 hour and 24 hours) following a single intervention of therapeutic hypnosis (about 1 hour). In the present paper we utilize bioinformatic software to explore the possible meaning and significance of this ideo-plastic faculty of therapeutic hypnosis. Indications suggest that the ideo-plastic process of therapeutic hypnosis may be associated with (1) the heightening of a molecular-genomic signature for the up-regulation (heightened activity) of genes characteristic of stem cell growth, (2) a reduction in cellular oxidative stress, and (3) a reduction in chronic inflammation. We identify these three empirical associations as an initial beta version of the molecular-genomic signature of the ideo-plastic process of therapeutic hypnosis, which can serve as a theoretical and practical guide for clinical excellence by beginners as well as senior professionals. We propose this molecular-genomic level of discourse as a supplement to the traditional cognitive-behavioral description of therapeutic suggestion, hypnosis, and psychotherapy that is consistent with "translational research" currently funded by the National Institute of Mental Health (NIMH).

Benign papilloma on core biopsy requires surgical excision.

BACKGROUND: When a papillary lesion is identified on core biopsy of an impalpable breast lesion, standard practice involves excisional biopsy. Recent literature has questioned the need for surgical excision in patients with benign core biopsy and radiological concordance. Our aim was to assess whether surgical excision is required by targeting this concordant group in a large screen-detected population. METHODS: A retrospective review of a prospectively collected database of all benign papillary core biopsies between February 1995 and September 2007 at North Western Breast Screen and Monash Breast Screen in Melbourne, Australia was performed. All patients had surgical excision, enabling correlation between core and final excisional biopsy results on all lesions. All histology reports were reviewed and the radiology was reassessed. RESULTS: During a 14-year period, 5783 core biopsies were performed from 633,163 screening mammograms. Eighty patients (0.01%) had benign papilloma on core biopsy, no patients had atypia on core biopsy, and all patients had benign radiological features. Of the 80 patients, 15 patients were found to have ductal carcinoma in situ (8) or invasive ductal carcinoma (7) on final pathology, yielding a 19% malignant rate. CONCLUSION: Core biopsy showing benign papillary lesion, even where radiology is also suggestive of a benign process, cannot exclude malignancy, and therefore surgical excision is required.

RFHVMn ORF73 is structurally related to the KSHV ORF73 latency-associated nuclear antigen (LANA) and is expressed in retroperitoneal fibromatosis (RF) tumor cells.

Retroperitoneal fibromatosis herpesvirus (RFHV), the macaque homolog of the human rhadinovirus, Kaposi's sarcoma-associated herpesvirus (KSHV), was first identified in retroperitoneal fibromatosis (RF) tumor lesions of macaques with simian AIDS. We cloned and sequenced the ORF73 latency-associated nuclear antigen (LANA) of RFHVMn from the pig-tailed macaque. RFHVMn LANA is structurally analogous to KSHV ORF73 LANA and contains an N-terminal serine-proline-rich region, a large internal glutamic acidic-rich repeat region and a conserved C-terminal domain. RFHVMn LANA reacts with monoclonal antibodies specific for a glutamic acid-proline dipeptide motif and a glutamic acid-glutamine-rich motif in the KSHV LANA repeat region. Immunohistochemical and immunofluorescence analysis revealed that RFHVMn LANA is a nuclear antigen which is highly expressed in RF spindloid tumor cells. These data suggest that RFHV LANA is an ortholog of KSHV LANA and will function similarly to maintain viral latency and play a role in tumorigenicity in macaques.

Antigenic specificity of the Mycobacterium leprae homologue of ESAT-6.

The sequence of the Mycobacterium leprae homologue of ESAT-6 shows only 36% amino acid correspondence to that from Mycobacterium tuberculosis. Anti-M. leprae ESAT-6 polyclonal and monoclonal antibodies and T-cell hybridomas reacted only with the homologous protein and allowed identification of the B- and T-cell epitopes. The protein is expressed in M. leprae and appears in the cell wall fraction. Thus, M. leprae ESAT-6 shows promise as a specific diagnostic agent for leprosy.