Interleukin-3 production by basal-like breast cancer cells is associated with poor prognosis.

Breast cancer represents a collection of pathologies with different molecular subtypes, histopathology, risk factors, clinical behavior, and responses to treatment. "Basal-like" breast cancers predominantly lack the receptors for estrogen and progesterone (ER/PR), lack amplification of human epidermal growth factor receptor 2 (HER2) but account for 10-15% of all breast cancers, are largely insensitive to targeted treatment and represent a disproportionate number of metastatic cases and deaths. Analysis of interleukin (IL)-3 and the IL-3 receptor subunits (IL-3RA + CSF2RB) reveals elevated expression in predominantly the basal-like group. Further analysis suggests that IL-3 itself, but not the IL-3 receptor subunits, associates with poor patient outcome. Histology on patient-derived xenografts supports the notion that breast cancer cells are a significant source of IL-3 that may promote disease progression. Taken together, these observations suggest that IL-3 may be a useful marker in solid tumors, particularly triple negative breast cancer, and warrants further investigation into its contribution to disease pathogenesis.

Development and Validation of a HER2-Low Focused Immunohistochemical Scoring System With High-Interobserver Concordance: The Australian HER2-Low Breast Cancer Concordance Study.

The DESTINY Breast-04 trial revealed survival advantages of trastuzumab deruxtecan for women with metastatic HER2-low breast cancer (1+ or 2+ immunohistochemistry [IHC], without amplification). Although this trial applied the 2018 Americal Society of Clinial Oncology (ASCO)/College of American Pathologists (CAP) HER2 IHC scoring criteria, the subjectivity and imprecision in IHC scoring have raised concerns that patients' treatment may be misaligned. Our group of 9 experienced breast pathologists collated a deidentified set of 60 breast cancer core biopsies from 3 laboratories, evaluated with the Ventana 4B5 HER2 assay and mostly scored locally as HER2 0 or 1+. Based on ASCO/CAP 2018 criteria and our extensive experience of reporting HER2 IHC, we specified scoring conventions for cancers with low levels of HER2 protein expression, articulating specific scoring pitfalls. Each pathologist then reviewed digitized whole slide images of the IHC slides and scored the HER2 expression for each case. At a subsequent consensus workshop, we reviewed the cases jointly to establish consensus scores for each case and determine the percentage of HER2 expressing tumor cells. Consensus was reached on all cases, with 40 classified as 1+ and 3 as 2+ (not amplified), totaling 43 (71.7%) HER2-low cancers. The remaining cases were HER2 0. In 93.3% of cases (56/60), the consensus score matched with the majority opinion of pathologists' independent scores. Seven (41.2%) of the 17 cases reported locally as HER2 0 were classified as HER2 low. Conversely, among 32 cases with local scores of 1+, 7 (21.8%) were reclassified as ultralow or null. Individual pathologists' accuracy in matching the consensus scores ranged from 73.3% to 91.67% (mean, 80.74%). Among HER2-low cancers those in which <20% of the tumor cells expressed HER2 had the lowest concordance levels. Observers Cohen's κ coefficients for concordance were excellent for 4, good in 1, and moderate in the 4 observers. This reference set of cases with expert consensus HER2 scores will be invaluable for peer training and development of our national external quality assurance program for HER2-low cancers. For assessing breast cancers at the low end of HER2 protein expression, our targeted scoring criteria and explicit instruction on pitfalls improved pathologists' accuracy and concordance.

Investigating the breast cancer screening-treatment-mortality pathway of women diagnosed with invasive breast cancer: Results from linked health data.

OBJECTIVE: To examine the screening-treatment-mortality pathway among women with invasive breast cancer in 2006-2014 using linked data. METHODS: BreastScreen histories of South Australian women diagnosed with breast cancer (n = 8453) were investigated. Treatments recorded within 12 months from diagnosis were obtained from linked registry and administrative data. Associations of screening history with treatment were investigated using logistic regression and with cancer mortality outcomes using competing risk analyses, adjusting for socio-demographic, cancer and comorbidity characteristics. RESULTS AND CONCLUSION: For screening ages of 50-69 years, 70% had participated in BreastScreen SA ≤ 5 years and 53% ≤ 2 years of diagnosis. Five-year disease-specific survival post-diagnosis was 90%. Compared with those not screened ≤5 years, women screened ≤2 years had higher odds, adjusted for socio-demographic, cancer and comorbidity characteristics, and diagnostic period, of breast-conserving surgery (aOR 2.5, 95% CI 1.9-3.2) and radiotherapy (aOR 1.2, 95% CI 1.1-1.3). These women had a lower unadjusted risk of post-diagnostic cancer mortality (SHR 0.33, 95% CI 0.27-0.41), partly mediated by stage (aSHR 0.65, 95% CI 0.51-0.81), and less breast surgery (aSHR 0.78, 95% CI 0.62-0.99). Screening ≤2 years and conserving surgery appeared to have a greater than additive association with lower post-diagnostic mortality (interaction term SHR 0.42, 95% CI 0.23-0.78). The screening-treatment-mortality pathway was investigated using linked data.

Three cases of BRAF-mutant melanoma with divergent differentiation masquerading as sarcoma.

Melanoma is an important cause of skin cancer related death throughout the world, particularly in Europe, the United States, and Australia. Rarely melanoma undergoes divergent differentiation to simulate the full morphologic and immunohistochemical features of other malignancies, notably sarcoma. However, such cases retain the molecular signatures of melanoma, including BRAF gene mutations. Gene mutation analysis of tumour DNA, now standard practice for all melanomas of stage III or above, may establish the diagnosis of melanoma in some advanced malignancies of unknown lineage. A prior history of melanoma or risk factors for melanoma may be the first clue that an advanced malignancy represents metastatic melanoma. Recognition of this presentation of melanoma can allow a patient to access well-tolerated life-prolonging therapies such as targeted therapy, inhibiting the BRAF/MEK pathway, and immune checkpoint inhibitor therapy.

Interobserver concordance in visual assessment of Ki67 immunohistochemistry in surgical excision specimens from patients with lymph node-negative breast cancer.

PURPOSE: This study aimed to determine the interobserver concordance of two methods for proliferation assessment in breast cancer using Ki67 immunohistochemistry. METHODS: Ki67 was independently assessed in randomly selected tumour samples from patients with lymph node-negative breast cancer using two different methods: either cell counting or visual estimation of hot spot areas. For hot spot cell counting, positive and negative cell numbers were recorded for total cell counts of 300-500, 500-800 and 800-1000 cells. Visual estimation involved allocation of a score from 1 to 5 using a visual scale to estimate percentage positivity. Interobserver agreement for hot spot counting was calculated using a two-way fixed effects intraclass correlation model, and by using Cohen's kappa measure for visual assessment. Prognostic concordance between the two methods was also calculated using Cohen's kappa. RESULTS: Samples from 96 patients were included in this analysis. Interobserver agreement for hot spot cell counting was excellent (> 0.75) across all three cell count ranges, with correlation coefficients of 0.88 (95% CI 0.84-0.92), 0.87 (95% CI 0.82-0.91) and 0.89 (95% CI 0.85-0.92), respectively. Interobserver agreement with visual estimation was greatest for hot spots compared with areas of intermediate or low proliferation, with kappa scores of 0.49, 0.42 and 0.40, respectively. Both assessment methods demonstrated excellent prognostic agreement. CONCLUSIONS: Interobserver and prognostic concordance in Ki67 immunohistochemistry assessments was high using either hot spot cell counting or visual estimation, further supporting the utility and reproducibility of these cost-efficient methods to assess proliferation.

Female breast cancer treatment and survival in South Australia: Results from linked health data.

OBJECTIVE: We investigated treatment and survival by clinical and sociodemographic characteristics for service evaluation using linked data. METHOD: Data on invasive female breast cancers (n = 13,494) from the South Australian Cancer Registry (2000-2014 diagnoses) were linked to hospital inpatient, radiotherapy and universal health insurance data. Treatments ≤12 months from diagnosis and survival were analysed, using adjusted odds ratios (aORs) from logistic regression, and adjusted sub-hazard ratios (aSHRs) from competing risk regression. RESULTS AND CONCLUSION: Five-year disease-specific survival increased to 91% for 2010-2014. Most women had breast surgery (90%), systemic therapy (72%) and radiotherapy (60%). Less treatment applied for ages 80+ vs <50 years (aOR 0.10, 95% CI 0.05-0.20) and TNM stage IV vs stage I (aOR 0.13, 95% CI 0.08-0.22). Surgical treatment increased during the study period and strongly predicted higher survival. Compared with no surgery, aSHRs were 0.31 (95% CI 0.26-0.36) for women having breast-conserving surgery, 0.49 (95% CI 0.41-0.57) for mastectomy and 0.42 (95% CI 0.33-0.52) when both surgery types were received. Patients aged 80+ years had lower survival and less treatment. More trial evidence is needed to optimise trade-offs between benefits and harms in these older women. Survival differences were not found by residential remoteness and were marginal by socioeconomic status.

The impact of 2018 ASCO-CAP HER2 testing guidelines on breast cancer HER2 results. An audit of 2132 consecutive cases evaluated by immunohistochemistry and in situ hybridization.

The 2018 iteration of the ASCO-CAP HER2 testing guidelines proposes significant changes with an emphasis on the integration of concurrent immunohistochemistry (IHC) and in situ hybridization (ISH). We wished to evaluate the impact of these changes on clinical practice. Between Jan 2012 to Feb 2017, 2132 consecutive invasive breast carcinomas were evaluated with IHC and ISH for HER2. The sample tested was the breast primary or axillary nodes in all but 57 (2.7%) distant metastases. For 1824 cases with both dual-probe ISH and IHC results, the ISH subgroup was 1: 299 (16.4%), 2: 19 (1.0%), 1.0%, 3: 6 (0.3%), 4: 48 (2.6%) and 5: 1452 (79.6%). Ultimately 21% of group 2 and 4 cases and 80% of group 4 cases were positive. The change in HER2 status between the 2018 vs 2013 was: amplified in 323 (15.2%) vs 15.5%; not amplified in 1804 (84.6%) vs 82.2%; equivocal in 0 vs 2.3% previously. In 22 of 2127 cases (1.03%) the 2013 and 2018 results were discordant, all in groups 2-4. The discrepant cases included 15 of 331 (4.5%) of 2013 amplified cancers, now negative (all in groups 2 or 3) and 7 of 1796 (0.4%) 2013 nonamplified cases, now positive (all in group 4). Because of routine testing with both IHC and ISH, we found 6 of 1147 (0.52%) IHC negative (0 or 1+) cases were amplified by ISH. Further, 19 of 289 (6.6%) of IHC 3+ cases were nonamplified by ISH, circumstances not covered by these guidelines. In summary at the population level, the 2018 ASCO-CAP guidelines have a 99% agreement with the 2013 results. A major advantage is the abolishment of the clinically problematic equivocal category. Routine performance of both IHC and ISH uncovers a small proportion of cancers whose HER2 status is not addressed by these guidelines.

Meta-analysis of upgrade rates in 3163 radial scars excised after needle core biopsy diagnosis.

BACKGROUND: Since concurrent malignancy may be associated with radial scars (RS) in up to 45% of RS diagnosed on core biopsy, surgical excision is usually advised. Recent very low upgrade rates have caused a re-evaluation of the need for routine surgery. We aimed to find subsets of RS at such low risk of upgrade, as to render imaging surveillance a plausible alternative to surgery. DESIGN: We performed a systematic review of the Pubmed, Cochrane and Embase databases, focusing on the following eligibility criteria: full papers, published after 1998, in English, included at least 5 RS, provided information on needle biopsy gauge and upgrade rates based on the excised lesion. For the meta-analysis, studies were grouped by the presence of histologic atypia and the core needle gauge. Study-specific and pooled upgrade rates were calculated for each subgroup. RESULTS: 49 studies that included 3163 RS with surgical outcomes are included. There were 217 upgrades to malignancies, 71 (32.7%) invasive and 144 (66.4%) DCIS. The random-effects pooled estimate was 7% (95% CI 5, 9%). Among the pre-planned subgroups, in RS assessed by 14G NCB the upgrade rates were: without atypia - 5% (95% CI 3, 8%), mixed or presence of atypia not specified - 15% (95% CI 10, 20%), with atypia - 29% (95% CI 20, 38%). For RS assessed by a mix of 8-16G cores the respective upgrade rates were 2% (95% CI 1, 4%), 12% (95% CI 6, 18%) and 11% (95% CI 3, 23%) and for RS assessed by 8-11 vacuum assisted biopsies 1% (95% CI 0, 4%), 5% (95% CI 0, 11%) and 18% for the one study of RS with atypia assessed by VAB. Surgery after VAB excision showed no upgrades. The difference across all subgroups was statistically significant. CONCLUSION: When stratified by atypia and biopsy gauge, upgrade rates in RS are consistent and predictable. RS assessed by VABs and lacking atypia have a 1% (95% CI 0, 4%) upgrade rate to DCIS. Other groups have upgrade rates of 2-28%. This risk may be reduced by VAB excision. The results of this meta-analysis provide a decision aid and evidence-based selection criteria for surgery after a needle biopsy diagnosis of RS.

Disparities in breast screening, stage at diagnosis, cancer treatment and the subsequent risk of cancer death: a retrospective, matched cohort of aboriginal and non-aboriginal women with breast cancer.

BACKGROUND: Australia's Aboriginal and Torres Strait Islander women have poorer survival and twice the disease burden from breast cancer compared to other Australian women. These disparities are influenced, but not fully explained, by more diagnoses at later stages. Incorporating breast screening, hospital and out of hospital treatment and cancer registry records into a person-linked data system can improve our understanding of breast cancer outcomes. We focussed one such system on a population-based cohort of Aboriginal women in South Australia diagnosed with breast cancer and a matched cohort of non-Aboriginal women with breast cancer. We quantify Aboriginal and non-Aboriginal women's contact with publicly funded screening mammograms; quantify exposure to a selection of cancer treatment modalities; then assess the relationship between screening, treatment and the subsequent risk of breast cancer death. METHODS: Breast cancers registered among Aboriginal women in South Australia in 1990-2010 (N = 77) were matched with a random selection of non-Aboriginal women by birth and diagnostic year, then linked to screening records, and treatment 2 months before and 13 months after diagnosis. Competing risk regression summarised associations of Aboriginality, breast screening, cancer stage and treatment with risk of breast cancer death. RESULTS: Aboriginal women were less likely to have breast screening (OR = 0.37, 95%CIs 0.19-0.73); systemic therapies (OR = 0.49, 95%CIs 0.24-0.97); and, surgical intervention (OR = 0.35, 95%CIs 0.15-0.83). Where surgery occurred, mastectomy was more common among Aboriginal women (OR = 2.58, 1.22-5.46). Each of these factors influenced the risk of cancer death, reported as sub-hazard ratios (SHR). Regional spread disease (SHR = 34.23 95%CIs 6.76-13.40) and distant spread (SHR = 49.67 95%CIs 6.79-363.51) carried more risk than localised disease (Reference SHR = 1). Breast screening reduced the risk (SHR = 0.07 95%CIs 0.01-0.83). So too did receipt of systemic therapy (SHR = 0.06 95%CIs 0.01-0.41) and surgical treatments (SHR = 0.17 95%CIs 0.04-0.74). In the presence of adjustment for these factors, Aboriginality did not further explain the risk of breast cancer death. CONCLUSION: Under-exposure to screening and treatment of Aboriginal women with breast cancers in South Australia contributed to excess cancer deaths. Improved access, utilisation and quality of effective treatments is needed to improve survival after breast cancer diagnosis.

Molecular subtypes of screen-detected breast cancer.

BACKGROUND: Detection of breast cancers by mammographic screening confers a survival advantage of 20-50% compared to symptomatic presentations. The improved prognosis is only partly explained by stage migration. The distribution of the molecular subtypes of screen-detected breast cancer (SDBC) or their HER2 status has not been studied extensively. We wished to address these issues through the study of a large series of SDBC, with other presentations serving as controls. DESIGN: Deidentified cases of female invasive cancer, diagnosed in Australia and New Zealand during 2005-2015, were retrieved from the BreastSurgANZ Quality Audit (BQA). Method of detection and selected patient, tumour and treatment data were assessed. Immunohistochemical surrogates for molecular subtypes were defined as Luminal A (ER+ and/or PR+, HER2-), Luminal B (ER+ and/or PR+, HER2+), HER2-enriched (ER-, PR- and HER2+) and basal-like (triple negative). Results were compared with the findings of controls and previous studies. RESULT: 100983 invasive cancers were diagnosed, including 32493 (32.7%) SDBC and 66907 (67.3%) with other presentations. The biomarker profile for SDBC versus other presentations in the same population was ER 89.3 versus 80.3%, PR 78.8 versus 69.8% and for HER2 11 versus 15.6%. The distribution of molecular subtypes was Luminal A 81.9 versus 70.74%, Luminal B 7.39 versus 9.52%, HER2-enriched 3.63 versus 6.06% and Basal-like 7.08 versus 13.68%. These differences were significant (p < 0.0001). CONCLUSION: Molecular profiles of SDBC are significantly different from those of symptomatic cancers, with over-representation of the Luminal A and proportionately lower rates of all other subtypes. We have shown, for the first time, significantly lower rates of HER2 positivity in SDBC. These differences may contribute to the better survival of SDBC and have implications for prognostication, targeted therapy decisions and for laboratory quality assurance programs in setting target ranges for proportions of ER-positive and HER2 results in heavily screened populations.

Active surveillance of women diagnosed with atypical ductal hyperplasia on core needle biopsy may spare many women potentially unnecessary surgery, but at the risk of undertreatment for a minority: 10-year surgical outcomes of 114 consecutive cases from a single center.

A needle core biopsy diagnosis of atypical ductal hyperplasia is an indication for open biopsy. The launch of randomized clinical trials of active surveillance for low-risk ductal carcinoma in situ leads to the paradoxical situation of women with low-grade ductal carcinoma in situ being observed, whereas those with atypical ductal hyperplasia have surgery. If the malignancies diagnosed after surgery for atypical ductal hyperplasia are dominated by low-risk ductal carcinoma in situ, women with atypical ductal hyperplasia may also be considered for surveillance. This 10-year prospective observational study includes women diagnosed with atypical ductal hyperplasia on core biopsy after screening mammography. We retrieved their clinical, imaging and histologic data and carried out a blind review of core biopsy histology, sub-classifying the atypical ductal hyperplasia along a spectrum from hyperplasia to ductal carcinoma in situ. Using the final surgical pathology data, we calculated: (1) The proportion and grades of ductal carcinoma in situ and invasive cancers diagnosed at open biopsy. (2) The histologic extent of the malignancy at surgery. (3) The biomarker profile and nodal status of any invasive cancers. (4) Ascertained any independent predictors of (i) any malignancy, (ii) high-risk malignancy, defined in this study as invasive cancer, or high-grade ductal carcinoma in situ, or intermediate grade ductal carcinoma in situ with any necrosis. (5) Extrapolated the above to simulate active surveillance for women with screen-detected atypical ductal hyperplasia. Between January 2005 and December 2014, 114 women, mean age 59 years (range 40-79 years) were included. Surgical pathology, available in 110 (97%), confirmed malignancy in 46 (40%). All 46 malignant cases had ductal carcinoma in situ, accompanied by invasive carcinoma in 9 (8%) women. Together, 21 (19%) women had either invasive cancer (9%), high-grade ductal carcinoma in situ (6%), or necrotizing, intermediate grade ductal carcinoma in situ (6%). Only one of nine invasive breast cancers was grade 1, 3 were multifocal, all were ≤8 mm, node negative, and ER positive but two were HER2 amplified. The mean extent of the ductal carcinoma in situ in any one specimen was 19.8 mm, median 13 mm, range 2-110 mm. Overall 32 women, 29% of the whole cohort and 70% of those 46 with malignancy, required further surgery, including mastectomy in 12 (11%). A multivariable model for predicting the likelihood of any malignancy showed a statistically significant association only with the post review subtype of atypical ductal hyperplasia, adjusting for lesion size. Independent predictors of high-risk malignancy (invasive cancer or non-low-grade ductal carcinoma in situ) were not identified. If active surveillance is adopted for screen-detected atypical ductal hyperplasia diagnosed on core biopsy, 60% of women will avoid unnecessary surgery and a further 24% would meet eligibility criteria for ductal carcinoma in situ surveillance trials. However, 18% of women will have undiagnosed invasive breast cancer or non-low-risk ductal carcinoma in situ. These women with high-risk lesions are not reliably identified pre-operatively.

Contemporary indications for diagnostic open biopsy in women assessed for screen-detected breast lesions: A ten-year, single institution series of 814 consecutive cases.

PURPOSE: In contemporary practice, 5% of women with non-malignant needle biopsies of screen-detected lesions still require diagnostic open biopsy (OBx). Our aims are to (i) capture a snapshot of the contemporary indications for OBx in screen-detected lesions; (ii) determine upgrade rates to malignancy (DCIS or invasive cancer); (iii) identify indications with sufficiently low upgrades to justify avoidance of OBx and (iv) propose plausible non-surgical alternatives. METHODS: Between Jan 2005 and Dec 2014, women assessed for a screen-detected lesion and recommended for OBx are included. We retrieved patient, imaging, biopsy and final pathology or follow-up data. RESULTS: 814 lesions, mean diameter 16.7 mm, microcalcifications in 353 (43.4%) cases, lesions other than calcifications in 461 (56.6%), mean patient age 58.4 yrs, are included. Surgery was performed in 98.2% cases. Imaging follow-up (1-6.5 yrs) is available in 13 of 15 remaining cases. 27 indications for OBx were identified, with a prevalence of 0.3-13.9%. Borderline lesions (BL) comprised 64% of OBx indications, amongst which atypical ductal hyperplasia was the most prevalent at 13.9%, followed by papillary lesions, radial scars, flat epithelial atypia and lobular neoplasia. Imaging factors contributed 26.3% of OBx. In 9.8% of cases, NCB was not performed due to client, technical or cytologic factors. Overall, 261(32.1%) lesions were malignant at OBx. Upgrade rates varied from 0 to 100%, depending on the specific indication for OBx. CONCLUSIONS: Surgical biopsy remains a valuable method of last resort for breast cancer diagnosis but strategies to limit benign breast surgery merit attention as a public health issue.

Phyllodes tumours of the breast: a consensus review.

Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours.

A novel case-control design to estimate the extent of over-diagnosis of breast cancer due to organised population-based mammography screening.

Debate about the extent of breast cancer over-diagnosis due to mammography screening has continued for over a decade, without consensus. Estimates range from 0 to 54%, but many studies have been criticized for having flawed methodology. In this study we used a novel study design to estimate over-diagnosis due to organised mammography screening in South Australia (SA). To estimate breast cancer incidence at and following screening we used a population-based, age-matched case-control design involving 4,931 breast cancer cases and 22,914 controls to obtain OR for yearly time intervals since women's last screening mammogram. The level of over-diagnosis was estimated by comparing the cumulative breast cancer incidence with and without screening. The former was derived by applying ORs for each time window to incidence rates in the absence of screening, and the latter, by projecting pre-screening incidence rates. Sensitivity analyses were undertaken to assess potential biases. Over-diagnosis was estimated to be 8% (95%CI 2-14%) and 14% (95%CI 8-19%) among SA women aged 45 to 85 years from 2006-2010, for invasive breast cancer and all breast cancer respectively. These estimates were robust when applying various sensitivity analyses, except for adjustment for potential confounding assuming higher risk among screened than non-screened women, which reduced levels of over-diagnosis to 1% (95%CI 5-7%) and 8% (95%CI 2-14%) respectively when incidence rates for screening participants were adjusted by 10%. Our results indicate that the level of over-diagnosis due to mammography screening is modest and considerably lower than many previous estimates, including others for Australia.

The clinical utility of assessment of the axilla in women with suspicious screen detected breast lesions in the post Z0011 era.

Axillary ultrasound (AUS) and biopsy are now part of the preoperative assessment of breast cancer based on the assumption that any nodal disease is an indication for axillary clearance (AC). The Z0011 trial erodes this assumption. We applied Z0011 eligibility criteria to patients with screen detected cancers and positive axillary assessment to determine the relevance of AUS to contemporary practice. Women screened between 1/1/2012 and 30/6/2013 and assessed for lesions with highly suspicious imaging features are included. We analysed demographic and assessment data and ascertained the final histopathology with particular reference to axillary nodal status. Among 449 lesions, AUS was recorded in 303 lesions (67.5 %). 290 (96 %) were carcinomas, 30.3 % with nodal disease. AUS was abnormal in 46 (15.9 %). AUS had a sensitivity of 39.8 %, specificity 94.6 %, positive predictive value (PPV) 79.2 % and negative predictive value (NPV) 78.1 %. Axillary FNAB was positive in 27 women, suspicious in two, benign in 16 and not performed in one. In one FNA positive case, the lesion was a nodular breast primary in the axillary tail in a multifocal breast cancer. Combining AUS and FNAB, the sensitivity was 76.5 %, specificity 90.9 %, PPV 96.3 % and NPV 55.6 %. Applying the Z0011 inclusion criteria, 24 of the 27 (88.9 %) women with abnormal AUS and positive FNA were ineligible for Z0011-based management. Of three women eligible for Z0011, one proceeded to AC after SN biopsy, leaving only two women (7.4 %) who might have been considered for SN only management had it not been for the results of the axillary assessment. Among women with negative AUS, nodal metastasis was demonstrated in 21.7 %, 86.8 % of these women having only 1-2 positive nodes. Abnormal AUS and FNA preferentially identify candidates for AC. Negative AUS predicts negative or low nodal burden. Axillary assessment streamlines care.

Impact of hormone replacement therapy use on mammographic screening outcomes.

PURPOSE: This study aims to measure the impact of HRT use at the time of screening on rates of screen-detected invasive breast cancer (IBC) and ductal carcinoma in situ (DCIS), interval cancers and investigative procedures, within a well-established population-based mammography screening program. METHODS: Using South Australian BreastScreen data from 1998 to 2009 pertaining to 819,722 screening episodes, Poisson regression models were undertaken to estimate the incidence risk ratios (IRR) for various screening outcomes at both the first and subsequent screening rounds, among women who had been using HRT in the 6 months prior to screening compared with those who had not. RESULTS: Current HRT use was associated with increased risk of recall for assessment, biopsy procedures, and breast cancer diagnosis among BreastScreen participants. Risk of screen-detected breast cancer was increased at subsequent screening rounds (IRR = 1.30, 95% confidence interval 1.18-1.34), but not at women's first screening round (1.05, 0.88-1.25). This increased risk applied to IBC (1.35, 1.27-1.45), but not to DCIS (1.04, 0.89-1.23). Interval cancer risk was elevated among HRT users following both the first screen (1.77, 1.33-2.37) and subsequent screening episodes (1.92, 1.72-2.15). CONCLUSIONS: Increased risks of recall, biopsy rates, screen-detected, and interval cancers among HRT users have important implications for population-based breast cancer screening programs. Our findings support the concept that HRT use may increase the growth of preexisting cancers. Lack of effect on DCIS could imply different etiology or time frames for DCIS and IBC development or increased transition from preinvasive to invasive disease due to HRT use.

Silver In Situ Hybridization for the Rapid Assessment of MDM2 Amplification in Soft Tissue and Bone Tumors. Validation Based on an Audit of 192 Consecutive Cases Evaluated by Silver In Situ Hybridization and Fluorescence In Situ Hybridization.

The discovery of almost invariable mouse double minute 2 (MDM2) amplification among atypical lipomatous tumors (ALT)/well-differentiated liposarcoma and dedifferentiated liposarcoma is incorporated into the contemporary diagnostic workup of fatty lesions. MDM2 amplifications are also found frequently in intimal sarcomas and in low-grade osteogenic sarcoma. At present, fluorescence in situ hybridization (FISH) is the reference test for MDM2 assessment. We are interested in evaluating silver in situ hybridization (SISH) for this purpose. Between October 2016 and May 2020, in 192 consecutive cases requiring MDM2 FISH, SISH was also performed concurrently, including 77 (40.1%) core biopsies and 115 (58.9%) surgical specimens. The mean patient age was 61.0 years. SISH results were available overnight or within 48 hours if repeat testing was required. FISH results were available within 2 to 5 weeks. The cost of SISH was one third of FISH. FISH demonstrated MDM2 amplification in 44 cases (23.6%), was negative in 144 cases (74.4%) and nondiagnostic in 4 decalcified cases (2.0%). SISH showed MDM2 amplification in 33 cases (17.2%), no amplification in 119 cases (62.0%), and indeterminate results because of poor signal in 40 (20.8%) cases. All 33 (100%) SISH-amplified tumors and 113 of 119 (95.0%) nonamplified results were confirmed by FISH. There were no clear differences in the performance of SISH on NCB versus surgical specimens. The overall performance indices of SISH are sensitivity 75%, specificity 78.5%, positive predictive value 100%, and negative predictive value 95.8%. FISH is not required when SISH is clearly amplified. This is clinically useful and improves efficiency. Nonamplified SISH results provide early indications of the likely FISH findings, but there is a 4.2% chance of FISH being positive. At present, the main drawback of SISH is the high rate of nondiagnostic tests. Optimization of SISH signal detection to reduce the proportion of indeterminate results is our current focus.

10-Year axillary recurrence in the RACS SNAC1 randomised trial of sentinel lymph node-based management versus routine axillary lymph node dissection.

BACKGROUND: Sentinel node-based management (SNBM) is the international standard of care for early breast cancer that is clinically node-negative based on randomised trials comparing it with axillary lymph node dissection (ALND) and reporting similar rates of axillary recurrence (AR) without distant disease. We report all ARs, overall survival, and breast cancer-specific survival at 10-years in SNAC1. METHODS: 1.088 women with clinically node-negative, unifocal breast cancers 3 cm or less in diameter were randomly assigned to either SNBM with ALND if the sentinel node (SN) was positive, or to SN biopsy followed by ALND regardless of SN involvement. RESULTS: First ARs were more frequent in those assigned SNBM rather than ALND (11 events, cumulative risk at 10-years 1·85%, 95% CI 0·95-3.27% versus 2 events, 0·37%, 95% CI 0·08-1·26%; HR 5·47, 95% CI 1·21-24·63; p = 0·013). Disease-free survival, breast cancer-specific survival, and overall survival were similar in those assigned SNBM versus ALND. Lymphovascular invasion was an independent predictor of AR (HR 6·6, 95% CI 2·25-19·36, p < 0·001). CONCLUSION: First ARs were more frequent with SNBM than ALND in women with small, unifocal breast cancers when all first axillary events were considered. We recommend that studies of axillary treatment should report all ARs to give an accurate indication of treatment effects. The absolute frequency of AR was low in women meeting our eligibility criteria, and SNBM should remain the treatment of choice in this group. However, for those with higher-risk breast cancers, further study is needed because the estimated risk of AR might alter their choice of axillary surgery.

Looking beyond workforce parity: addressing gender inequity in pathology.

While women pathologists have made up over one-third of pathologists in the Australian workforce for over 15 years and at least 50% since 2019, they are under-represented in senior leadership roles, scientific publications, grant recipients, editorial boards, key presentations, and professional awards. This is not unique to pathology and is seen in the broader medical and academic community. Barriers to gender equity and equality in pathology, medicine and academia include gender stereotypes, gender-based discrimination, structural and organisational barriers as well as broader social and cultural barriers. A diverse leadership reflective of the whole professional body and the broader community is important for optimal health outcomes. It is the responsibility and moral duty of individuals and organisations to address any gender disparities, inequities, and inequalities by monitoring, identifying, and acting on gender biases and systemic barriers that hinder appropriate levels of representation by women.

Assessing HER2 amplification in breast cancer: findings from the Australian In Situ Hybridization Program.

In August 2006, the Australian government approved subsidized trastuzumab therapy for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, and it was mandated that HER2 testing should be performed using in situ hybridization (ISH) rather than immunohistochemistry (IHC). Here we review results of the first regulated, nationwide program to provide HER2 ISH testing for all newly diagnosed breast cancer patients, with a particular emphasis on cases where IHC and ISH results were discordant. Data from all laboratories participating in the program were collated. Cases with an equivocal ISH test result [by chromogenic ISH (CISH) or silver ISH (SISH)] were tested centrally by fluorescence ISH. Most laboratories also performed HER2 IHC, and 200 cases with discordant IHC and ISH results were selected for further analysis in a central laboratory. A total of 26 laboratories were involved and 53,402 tests were reported. Over a 4-year period the HER2 positivity rate decreased for primary cancers from 23.8 to 14.6 %, but remained relatively constant for samples from metastases. Average ISH reporting times were <5 days for all yearly reporting periods. Test-repeat rates decreased for CISH (8.9-3.6 %) and SISH (13.7-8.4 %). Only 12 of 196 cases remained discordant after retesting in a central laboratory. These findings demonstrate the successful implementation of a regulated, national program that continues to collect data on HER2 status. The results also highlight the differences in IHC interpretation between local laboratories and a central, more experienced, laboratory. This model could be used to establish future biomarker-testing programs in other countries.