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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.

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes. Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Women previously treated for primary operable breast cancer are at increased risk of developing cancer in the contralateral breast, but the clinical significance of this development is unclear. The purpose of this study was to assess the impact of synchronous bilateral breast cancer or the development of a metachronous contralateral breast primary on the prognosis. In a series of 3210 women age ≤70 years treated between 1975 and 1995 for primary operable breast cancer, 106 were identified to have bilateral breast cancer. Of these women, 26 were noted to have synchronous bilateral breast primaries (0.8%), and 80 developed a contralateral breast cancer after treatment for an initial primary breast cancer. Using life‐tables analysis, there was a significant difference in survival between women with unilateral breast cancer, those with synchronous bilateral breast cancers, and those with metachronous contralateral breast with survivals at 16 years of 53.8%, 42.4%, and 60.1%, respectively (p<0.0001), from the date of the diagnosis of the first primary tumor. There was no difference in survival seen between the three groups when survival was calculated from the date of diagnosis of the second primary in cases of metachronous contralateral breast cancer (p=0.31). When contralateral breast cancer was incorporated as a time‐dependent covariate in a Cox multivariate model together with the three factors used to determine the Nottingham Prognostic Index (invasive tumor size, grade, and lymph node stage), contralateral breast cancer continued to be a significant prognostic determinant (p=0.02). The survival of women with synchronous bilateral breast cancer or metachronous breast cancers diagnosed within 2 years of the original primary was worse than those with unilateral disease. However, the time duration to metachronous contralateral breast cancer did not have prognostic significance in a multivariate model compared with the prognostic features of the original primary. Résumé Toute femme traitée pour cancer du sein a un risque accru de développer un cancer du sein opposé. Néanmoins, la signification clinique du développement d’un cancer du sein controlatérale n’est pas claire. Le but de cette étude a été d’évaluer le retentissement d’un cancer du sein bilatéral synchrone ou le développement métachrone d’un cancer controlatéral sur le pronostic. Dans cette série de 3210 femmes âgées aux alentours de 70 ans, toutes traitées pour cancer du sein opérable entre 1975 et 1994, on a identifié 106 femmes ayant un cancer du sein bilatéral. On a noté 26 cas de cancer bilatéral synchrones (0.8%) alors que 80 femmes ont vu se développer un cancer du sein controlatéral (métachrones). Grâce à l’analyse des courbes de survie, on a not une différence significative en ce qui concerne la survie entre les femmes ayant un cancer du sein unilatéral, celles qui avaient un cancer du sein bilatéral synchrones et celles qui avaient un cancer du sein bilatéral métachrone. Les taux de survie à 16 ans, à partir de la date de découverte de la tumeur primitive, ont été, respectivement, de 53.8%, 42.4% et de 60.1% (p <0.0001). If n’y avait aucune différence significative entre les trois groupes lorsqu’on a calculé la survie à partir de la date du diagnostic du deuxiéme cancer en cas de cancer controlatéral métachrone (p=0.31). Lorsqu’on a incorporé le cancer du sein controlatéral comme une co‐variable temps‐dépendante dans un modéle de Cox, ensemble avec les trois variables utilisés pour déterminer le Nottingham Prognostic Index (taille de la tumeur invasive, son grade et son stade N), le cancer controlatéral a continué d’être un facteur pronostique significatif (p=0.02). La survie des femmes ayant un cancer du sein bilatéral synchrone ou métachrone diagnostiqué à moins de deux ans de leur tumeur primitive n’est pas aussi bonne que celle des femmes ayant un cancer du sein unilatéral. Le temps entre le cancer primitif et la survenue du deuxiéme cancer métachrone n’était pas un facteur pronostique significatif dans le modéle multivarié comparé aux facteurs pronostiques du cancer initial. Resumen Es frecuente, que mujeres previamente tratadas de un cáncer primario y resecable de mama, desarrollen un cáncer en la mama contralateral. No obstante, sigue sin conocerse el pronóstico clinico de la aparición de un cáncer en la mama contralateral. El objetivo de este trabajo fue averiguar el pronóstico del cáncer sincrónico bilateral de mama o del cáncer primario contralateral metacrónico. En una serie de 3,210 mujeres, cuya edad oscilaba alrededor de los 70 años y que habian sido intervenidas, entre 1975 y 1994 por un cáncer primario resecable de mama, se constataron 106 cánceres bilaterales de mama. En 26 casos (0.8%) se trataba de cánceres primarios sincrónicos bilaterales de mama. 80 pacientes desarrollaron un cáncer contralateral tras haber sido intervenidas de un cáncer inicialmente primario de mama. Utilizando un análisis actuarial se constató una diferencia significativa entre la supervivencia de las mujeres con cáncer bilateral de mama, las que desarrollaron un cáncer sincrónico bilateral y aquellas con cáncer metacrónico contralateral de mama. En efecto, a los 16 años a partir de la fecha de diagnóstico del tumor primario, las supervivencias fueron del 53.8%, 42.4% y 60.1% respectivamente (p<0.0001). No se constató diferencia alguna, entre los 3 grupos cuando la supervivencia se calculó a partir del diagnóstico del segundo cáncer primario, en los casos de cáncer metacrónico contralateral de mama (p=0.31). Cuando el cáncer contralateral de mama se incorpora como covariante dependiente del tiempo a un modelo multivariante de Cox, el cáncer contralateral de mama junto con los 3 factores utilizados para determinar el índice pronóstico de Nottingham (grado de invasión tumoral, grado y estadificación de la afectación ganglionar linfática), constituye un factor pronóstico determinante (p=0.02). En mujeres con un cáncer sincrónico bilateral de mama o un cáncer metacrónico, diagnosticado en los dos primeros años tras el cáncer primario, la supervivencia es menor que la de aquellas con un cáncer bilateral de mama. Sin embargo, el tiempo que tarda en producirse un cáncer metacrónico contralateral no tiene significación pronóstica en un análisis multivariante, si se compara con el indice pronóstico del cáncer primario.

Objective. Early invasive breast cancer data from the Australian National Breast Cancer Audit were used to compare case fatality by surgeon case load, treatment centre location and health insurance status. Method. Deaths were traced to 31 December 2007, for cancers diagnosed in 1998-2005. Risk of breast cancer death was compared using Cox proportional hazards regression. Results. When adjustment was made for age and clinical risk factors: (i) the relative risk of breast cancer death (95% confidence limit) was lower whensurgeons' annual case loads exceeded 20 cases, at 0.87 (0.76, 0.995) for 21-100 cases and 0.83 (0.72, 0.97) for higher case loads. These relative risks were not statistically significant when also adjusting for treatment centre location (P>=0.15); and (ii) compared with major city centres, inner regional centres had a relative risk of 1.32 (1.18, 1.48), but the risk was not elevated for more remote sites at 0.95 (0.74, 1.22). Risk of death was not related to private insurance status. Conclusion. Higher breast cancer mortality in patients treated in inner regional than major city centres and in those treated by surgeons with lower case loads requires further study.

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.

Background Surgeon performed ultrasound (US) is being increasingly embraced by breast surgeons worldwide as an integral part of patient assessment. The extent of its application within Australia and New Zealand is not well documented. The present study aimed to evaluate its current usage patterns and to determine suitable future training models. Methods An online survey was sent to members of Breast Surgeons of Australia and New Zealand (BreastSurgANZ) between July and September 2010, with emphases on practice demographics, access to US equipment, usage, biopsy patterns, and training. Results Of the 126 surveys sent, 59 were returned. The majority of respondents were metropolitan based (64 %), worked in both public and private sectors (71 %), and practiced endocrine or general surgery (85 %), as well as breast surgery. A preponderance of surgeons had access to equipment (63 %), performed at least 1 US monthly (63 %), but did not perform regular guided biopsies. Rural practice did not affect access or usage patterns. Most respondents underwent structured US training (73 %), which was associated with greater US and biopsy usage, biopsy complexity, intraoperative applications, and cross discipline applications ( p  < 0.03). Most surgeons favored a structured training program for future trainees (83 %). Conclusions The majority of breast surgeons from Australia and New Zealand have adopted office US to varying degrees. Geographic variation did not lead to access inequity and variation in scanning patterns. Formal US training may result in a wider scope of clinical applications by increasing operator confidence and is the preferred model within a specialist breast surgical curriculum.

Background Immediate breast reconstruction has been accepted as safe and practical after mastectomy for breast cancer; factors limiting its use are patient comorbidities and potential complications caused by adjuvant therapies (particularly radiotherapy). The aim of this study was to identify factors considered by surgeons when deciding whether to offer immediate breast reconstruction, to determine the surgeon’s accuracy when predicting postmastectomy radiotherapy, and to assess the impact of premastectomy investigations on decision-making. Methods Four oncoplastic breast surgeons completed a survey for every mastectomy performed over an 11-month period. On the survey form they indicated reason for mastectomy, investigations available premastectomy, if they offered immediate reconstruction, and if not offered, why they did not offer it. Data on adjuvant therapies employed was also collected. Results A total of 157 women underwent mastectomy during the study period. Seventy-six (48.4%) were offered immediate reconstruction and 36 (22.9%) accepted. The most common reason for not offering immediate reconstruction was the predicted need for postmastectomy radiotherapy (56.8%). Of the 76 patients offered immediate reconstruction, 9 went onto be offered postmastectomy radiotherapy (11.8%). Decision-making was no more accurate in those women who had MRI, axillary staging, or excisional pathology available premastectomy. Conclusions The most common reason for not offering immediate breast reconstruction is the need for postmastectomy radiotherapy and surgeons are able to predict this accurately. The addition of invasive and expensive staging investigations premastectomy does not appear to assist this decision-making process. Despite careful patient selection, a high rate of immediate reconstruction may be maintained.

We sought the extent to which arm morbidity could be reduced by using sentinel-lymph-node-based management in women with clinically node-negative early breast cancer. One thousand eighty-eight women were randomly allocated to sentinel-lymph-node biopsy followed by axillary clearance if the sentinel node was positive or not detected (SNBM) or routine axillary clearance (RAC, sentinel-lymph-node biopsy followed immediately by axillary clearance). Sentinel nodes were located using blue dye, alone or with technetium-labeled antimony sulfide colloid. The primary endpoint was increase in arm volume from baseline to the average of measurements at 6 and 12 months. Secondary endpoints were the proportions of women with at least 15% increase in arm volume or early axillary morbidity, and average scores for arm symptoms, dysfunctions, and disabilities assessed at 6 and 12 months by patients with the SNAC Study-Specific Scales and other quality-of-life instruments. Sensitivity, false-negative rates, and negative predictive values for sentinel-lymph-node biopsy were estimated in the RAC group. The average increase in arm volume was 2.8% in the SNBM group and 4.2% in the RAC group ( P  = 0.002). Patients in the SNBM group gave lower ratings for arm swelling ( P  < 0.001), symptoms ( P  < 0.001), and dysfunctions ( P  = 0.02), but not disabilities ( P  = 0.5). Sentinel nodes were found in 95% of the SNBM group (29% positive) and 93% of the RAC group (25% positive). SNB had sensitivity 94.5%, false-negative rate 5.5%, and negative predictive value 98%. SNBM was successfully undertaken in a wide range of surgical centers and caused significantly less morbidity than RAC.

Objective 99m Tc-Evans Blue (EB) is an agent that contains both radioactive and color signals in a single dose. Earlier studies in animal models have suggested that this agent when compared with the dual-injection technique of radiocolloid/blue dye can successfully discriminate the sentinel lymph node. The aim of this study was to investigate the potential of 99m Tc-EB as an agent to map the lymphatic system in an ovine model. Methods Doses of 99m Tc-EB (23 MBq) containing EB dye (4 mg) were administered intradermally to the limbs of four anesthetized sheep, and they were then imaged over 20–30 min using a gamma camera. The study protocol was repeated using 99m Tc-antimony trisulfide colloid (ATC) and Patent Blue V dye. The lymph nodes (popliteal, inguinal, and iliac for hind limbs or prescapular for fore limbs) were identified with a gamma probe during the operative exposure, then dissected and counted in a large volume counter. Results Simple and complex (dual) drainage patterns were visible on the scans, and the sentinel node was more radioactive than higher tier nodes in a chain, for both radiotracers. For 99m Tc-EB, maximum radioactive uptake was achieved at 3–6 min for popliteal lymph nodes, 12–14 min for iliac nodes, and 13–14 min for prescapular nodes. 99m Tc-ATC resulted in maximum radioactive uptake at 4–6 min for popliteal lymph nodes, 13 min for an inguinal node, 13–20 min for iliac nodes, and 18 min for a prescapular node. Following 99m Tc-EB injection, 15/15 lymph nodes harvested were all radioactive and blue. For 99m Tc-radiocolloid/Patent Blue V injection, 8/14 nodes were radioactive and blue, and 6/14 nodes were radioactive only. Conclusions The soluble radiotracer 99m Tc-EB appeared to be a useful lymphoscintigraphic agent in sheep, in which radioactive counts from superficial lymphatic channels and lymph nodes were sufficient for planar imaging. In comparison with 99m Tc-antimony trisulfide colloid, both tracers discriminated the sentinel lymph node up to 50 min after administration; however, 99m Tc-EB had the advantage of providing radioactive (gamma probe) and color signals simultaneously during the operative exposure.