Clinical utility of axillary nodal markers in breast cancer.

BACKGROUND: De-escalation of axillary surgery for lymph node (LN) positive breast cancer is facilitated by marking involved nodes which, when removed with sentinel nodes constitute risk-adapted targeted axillary dissection (TAD). Whether after chemotherapy or for primary surgery, selected patients with biopsy-proven involvement of nodes may be eligible for axillary conservation. Likewise, impalpable recurrence or stage 4 patients with localised axillary disease may benefit. In these contexts, several devices are used to mark biopsied nodes to facilitate their accurate surgical removal. We report our experience using the paramagnetic MAGSEED (Endomag®, Cambridge, UK). METHODS: Local approval (BR2021_149) was obtained to interrogate a prospective database of all axillary markers. The primary endpoint was successful removal of the marked LN. RESULTS: Of 241 markers (in 221 patients) inserted between October 2018 and July 2022, all were retrieved. Of 74 patients who had Magseeds® inserted after completion of NACT (involved nodes initially marked using an UltraCor™Twirl™ marker), the Magseeds® were found outside the node in neighbouring axillary tissue in 18 (24.3%) patients. When Magseeds® were placed at commencement of NACT in 54 patients, in only 1 (1.8%) was the marker found outside the node - a statistically significantly lower rate (Chi2 10.7581 p = 0.001038). For 'primary TAD' patients and those localised for recurrent or stage IV disease, all 93 had the Magseed® found within the biopsied node. CONCLUSION: This series supports our axillary nodal marking technique as safe and reliable. For TAD following NACT, placement at the start of treatment led to a significantly higher localisation rate.

A Comparative Study of Secondary Procedures after Subpectoral and Prepectoral Single-Stage Implant-Based Breast Reconstruction.

BACKGROUND: Implant-based breast reconstruction (IBR) is the most commonly used procedure to reconstruct the breast after mastectomy. The advantages and disadvantages of subpectoral versus prepectoral implant placement remain a matter of debate. This study compares the need for secondary aesthetic procedures between prepectoral and subpectoral IBR. METHODS: This is a retrospective cohort study of consecutive patients who underwent subpectoral or prepectoral IBR between 2015 and 2018 under a single surgeon at a tertiary breast unit. The primary endpoint was the number of secondary procedures performed to improve the aesthetic outcome. Secondary endpoints included the number of secondary procedures during the first year. RESULTS: A total of 271 one-stage IBRs were performed (subpectoral, n = 128 in 74 patients; prepectoral, n = 143 in 84 patients). Overall, more patients required secondary procedures in the subpectoral group (36.5% versus 19%; P = 0.014), although through longer follow-up. The most common procedures were pocket revision and implant exchange [11.7% versus 3.5% ( P = 0.010); 11.7% versus 4.2% ( P = 0.021)], whereas fat grafting was similar between the two groups (46% versus 40.5%; P = 0.777). When adjusted for follow-up time, there was no significant difference in the number of secondary procedures undertaken in the subpectoral versus the prepectoral group (21% versus 16%, respectively; P = 0.288) at 1 year. CONCLUSIONS: The requirement for secondary procedures at 1 year was not different between groups. The need for fat grafting was not increased following prepectoral IBR. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Satisfaction with Long-Term Aesthetic and 10 Years Oncologic Outcome following Risk-Reducing Mastectomy and Implant-Based Breast Reconstruction with or without Nipple Preservation.

Incidence of bilateral risk-reducing mastectomies (RRMs) is increasing. The aim of this study was to compare satisfaction, aesthetic and oncological outcomes in women undergoing RRM with implant-based reconstruction comparing nipple-sparing mastectomy (NSM) with skin-sparing mastectomy (SSM) (sacrificing the nipple +/− nipple reconstruction). Women who had undergone bilateral RRM between 1997 and 2016 were invited. Aesthetic outcome and nipple symmetry were evaluated using standardized anthropometric measurements. The oncological outcome was assessed at last documented follow up. Ninety-three women (186 breasts) participated, 60 (64.5%) had NSM, 33 (35.5%) SSM. Median time between surgery and participation was 98.4 months (IQR: 61.7−133.9). Of the women, 23/33 (69.7%) who had SSM underwent nipple reconstruction. Nipple projection was shorter in the reconstructed SSM group than the maintained NSM group (p < 0.001). There was no significant difference in overall symmetry (p = 0.670), satisfaction regarding nipple preservation (p = 0.257) or overall nipple satisfaction (p = 0.074). There were no diagnoses of breast cancer at a median follow up of 129 months (IQR: 65−160.6). Women who undergo nipple-sparing RRM maintain long-term nipple symmetry. Nipple projection was less maintained after nipple reconstruction. Although satisfaction with the nipples was higher in the NSM group, this did not reach statistical significance. No breast cancers developed after RRM with long-term follow up.

Physical Characteristics of SurgiMend Meshed Biological ADM in Immediate Prepectoral Implant Breast Reconstruction.

With increasing acceptance of prepectoral implant breast reconstruction, there has been a requirement for biological acellular dermal matrices with conformational properties, high tensile strength, and rapid integration. SurgiMendPRS Meshed is a biological acellular dermal matrix derived from fetal calf with these specific characteristics for prepectoral implant breast reconstruction. The aim of this study was to test the performance of this mesh by recreating its surgical use ex-vivo using a variety of implants in an effort to define its physical properties. The mesh is usually attached with a number of interrupted sutures to the implant periphery, the variable being at the inferior border, where it can be attached as a snug fit at the level of the inframammary crease ("tent" technique) or sewn behind the implant, cradling the lower pole ("hammock" technique). The results show mesh elasticity to stretch with increasing implant weight. When used as a "hammock," greater stretch was demonstrated compared with the "tent" technique, allowing greater degrees of ptosis to be achieved. The suture points demonstrated lines of tension that progress evenly over the anterior implant surface. The mesh performed better when used at maximum stretch, but should not be forcibly stretched over an implant as the lines of stress show uneven distribution of lines of tension. These data provide a structural basis on optimum clinical use of this acellular dermal matrix in prepectoral implant breast reconstruction.

Pre-pectoral one-stage breast reconstruction with anterior biological acellular dermal matrix coverage.

BACKGROUND: Pre-pectoral implant breast reconstruction (IBR) is gaining popularity. Several techniques using different types of meshes and methods of placement have been described, but no method is currently considered standard. The aim of this study was to evaluate the outcomes of pre-pectoral IBR using acellular dermal matrix (ADM) for anterior implant cover. METHODS: Retrospective cohort study of consecutive patients who underwent pre-pectoral IBR between November 2016 to August 2018. Data on demographics, adjuvant therapies and operative technique was collected. Postoperative complications, length of hospital stay and secondary cosmetic procedures were recorded. Statistical analysis was performed using descriptive statistics, non-parametric tests and logistic regression. RESULTS: One hundred and eleven pre-pectoral IBR were performed in 65 patients. Median age was 41 [interquartile range (IQR), 35-51.5] years, and BMI 22 (IQR, 20.4-24.4) kg/m2. Therapeutic mastectomy was performed in 33 procedures with nipples preservation in 78 cases. The median mastectomy weight and implant volume was 360 (IQR, 220-533) gr, and 445 (IQR, 400-475) cc respectively. At a median follow-up of 18 (IQR, 12-22.5) months, 37 mastectomies had at least 1 complication, but only 12 required surgery. The implant loss rate was 4.5% (5 cases). Lipofilling as secondary procedure was performed in 10.8% of cases. Factors associated with post-operative complications on univariate analysis were nipple preservation (P=0.028), BMI (P=0.01) and implant volume (P=0.027) but these did not remain significant on multivariate analysis. CONCLUSIONS: Pre-pectoral IBR using ADM for anterior implant cover is associated with low complication and reconstructive failure rate. Patient selection and meticulous surgical technique are important for successful outcome.

The INTEND 1 randomized controlled trial of duct endoscopy as an indicator of margin excision in breast conservation surgery.

PURPOSE: With early detection, breast conservation surgery with adequate surgical margins is the standard of care. The aim of this study was to evaluate the use of pre-operative duct endoscopy (DE) to target surgical resection, improve adequate margins and reduce re-excision operations. METHODS: Women with DCIS, stage I and II breast cancer suitable for breast conservation were randomized to DE-assisted wide local excision versus standard wide local excision (without DE). The primary endpoint was margin re-excision rates between the two groups. Secondary end points were: (i) volume differences of the surgical specimen; (ii) whether an extensive in situ component (EIC) influenced successful DE-guided resection. RESULTS: 78 women were randomized: 44 patients to no-DE and 34 patients to the DE group. The median age was 59 (49-65) and 56 (48-64) years in the two groups respectively with mean follow-up of 9.1 (4.2-11.1) years. There were 23 positive findings in 17 women in 30 successful DE procedures (17/30 = 56.7%). The surgical specimen volume, no-DE (17 [IQR 10-29] cm3) and DE 20 [IQR 12-28] cm3), did not differ, p = 0.377. The overall re-excision rate was 20/78 (26%), 9 (20%) and 11 (32% in the no-DE and DE groups, respectively, p = 0.233. CONCLUSIONS: This randomized clinical trial was limited by incomplete accrual. DE did not contribute to improved margin excision rates whether a target lesion was visualized or not. The presence of EIC did not improve efficacy of DE.

Direct to implant breast reconstruction with biological acellular dermal matrices.

Breast cancer is the most commonly diagnosed female cancer in the UK, with one in eight women receiving a cancer diagnosis during their lifetime. Forty per cent of women diagnosed with breast cancer undergo mastectomy as their primary therapeutic procedure. While a full range of choices is offered, breast reconstruction using implants is the patient-preferred method of reconstruction following mastectomy. This review discusses the evolution of implant-based reconstruction, focusing on the recent trend towards prepectoral breast reconstruction. Key quality indicators in the current literature are considered, including oncological outcomes, aesthetics and patient-related outcome measures, as are the health-care economics of this emerging surgical technique.

Contralateral Prophylactic Mastectomy in Women with Unilateral Breast Cancer Who Are Genetic Carriers, Have a Strong Family History or Are just Young at Presentation.

The uptake of contralateral prophylactic mastectomy is rising with increasing trends that are possibly highest in the USA. Whilst its role is generally accepted in carriers of recognized high-risk predisposition genes such as BRCA1 and BRCA2 when the affected individual is premenopausal, controversy surrounds the benefit in less understood risk-profile clinical scenarios. This comprehensive review explores the current evidence underpinning the role of contralateral prophylactic mastectomy and its impact on contralateral breast cancer risk and survival in three distinct at-risk groups affected by unilateral breast cancer: known genetic carriers, those with strong familial risk but no demonstrable genetic mutation and women who are of young age at presentation. The review supports the role of contralateral prophylactic mastectomy in "high risk" groups where the evidence suggests a reduction in contralateral breast cancer risk. However, this benefit is less evident in women who are just young at presentation or those who have strong family history but no demonstrable genetic mutation. A multidisciplinary and personalized approach to support individuals in a shared-decision making process is recommended.

Acellular dermal matrices as an adjunct to implant breast reconstruction: Analysis of outcomes and complications.

PURPOSE: Acellular dermal matrices (ADM) are increasingly used in implant-based breast reconstruction (IBR). Uncertainty remains with regard to their efficacy and complications. The aim of this study was to evaluate the outcomes and complication rates associated with the use of ADMs in IBR. METHODS: Retrospective cohort study of patients undergoing ADM-assisted IBR between 2008 and 2013. Cases were identified from a prospectively collected database. Simple descriptive statistics and logistic regression analysis were performed. RESULTS: A total of 110 patients (175 mastectomies) were included in the analysis. The median age was 46 (19-75) years and the median BMI was 22.2 (16.2-41.5). Seventy nine mastectomies were performed for therapeutic purposes. The median mastectomy weight was 244 (185-335) gr. The majority of reconstructions were performed with fixed volume (n = 115, 66%) or permanent expandable implants (n = 53, 30%) as one-stage procedures. Forty mastectomies were associated with at least one complication. The infection rate was 2.3% (n = 4). Post-operative haematoma developed in 5 cases (2.9%), but only 2 required surgical interventions. Three mastectomies were complicated by nipple necrosis (3.6%), 3 with skin necrosis (1.7%) and 9 with wound dehiscence (5.1%). The capsule formation rate was 2.3% (n = 4). Reconstruction failure with implant loss occurred in 3 cases (1.7%). CONCLUSIONS: The complication rates following ADM-assisted IBR can be very low with appropriate patient selection and meticulous surgical technique. This supports the safety of using ADM in carefully selected patients. Further research is warranted to assess the health economics of ADM use in IBR.

The Use of Hydrodissection in Nipple- and Skin-sparing Mastectomy: A Retrospective Cohort Study.

Hydrodissection (HD) is a method to create a subcutaneous and prepectoral plane during mastectomy using a mixture of crystalloid solution with local anesthetic and epinephrine. The aim of this study was to evaluate postoperative complications and surgical outcomes of this technique compared with standard mastectomy. METHODS: This is a retrospective cohort study of patients who underwent bilateral risk-reducing, nipple-sparing mastectomy and immediate implant-based reconstruction through an inframammary crease incision either with standard electrocautery (control group) or HD (HD group) between January 2013 and January 2017. Patient demographics, procedural details, surgical outcomes, and complications were compared using nonparametric statistical tests and logistic regression analysis. RESULTS: Forty-one patients (82 nipple-sparing mastectomies) were analyzed (23 patients in the HD group and 18 in the control group). Patients' demographics were similar for both groups. Surgical time was shorter with HD compared with standard mastectomy (median 168 versus 207.5 minutes, P = 0.016) with shorter median hospital stay (2 versus 2.5 days, P = 0.033). Complication rates were similar in both groups, and fewer patients in the HD group required Coleman fat transfer to improve cosmesis (12 versus 3, P = 0.003). CONCLUSIONS: HD mastectomy is a safe alternative to standard technique in selected patients. Further surgical research to explore the role of HD in a wider clinical setting is warranted.

Use of acellular dermal matrix (ADM) in nipple reconstruction: the 'central-pillar technique'.

Nipple reconstructions are prone to a variable and unpredictable degree of flattening, which in some cases lead to secondary reconstruction. The use of an acellular dermal matrix (ADM) augmentation may be appropriate in cases with very thin dermis that are particularly prone to flattening or in revision cases where the first procedure has already failed. The authors present a series of 13 nipple reconstructions in ten cases. Average projection at 12 months was 51% in primary cases and 46% in secondary revision cases. This represents a better than expected long term result in a difficult cohort of patients.

Central round block repair of large breast resection defects: oncologic and aesthetic outcomes.

BACKGROUND: The central round block repair is a volume displacement technique to reconstruct large wide local excision (WLE) defects in breasts with moderate ptosis or hypertrophy. There are limited published data on the outcomes of this technique. METHODS: Data were collected prospectively for 57 consecutive patients and follow up information obtained from patient records. The volume of breast resection was estimated geometrically from mammography. Aesthetic outcomes were assessed from clinical measurements and panel review of patient photographs. RESULTS: The median age was 51 [22-86] years and follow-up 5 (1.9-8.4) years. The median specimen resection weight was 50 [25-361] g and tumour size 25 [10-75] mm. Estimated volume of breast excised was 17.8% (6-31%). In total, 12/57 patients had incomplete margins: five patients had re-excision to achieve clear margins and seven required mastectomy. Two patients had local recurrence during the follow-up period, five developed distant metastases. Aesthetic data were completed for 35/50 patients. Twelve (34%) had no measurable asymmetry and 31 (89%) had a nipple position within 2 cm of the original height. Only two patients requested symmetrising surgery. CONCLUSIONS: Central round block reconstruction of large defects after WLE is a safe technique with good aesthetic outcomes. Contralateral symmetrising surgery is not usually required.

Trends in Immediate Postmastectomy Breast Reconstruction in the United Kingdom.

BACKGROUND: The study aimed to evaluate local and national trends in immediate breast reconstruction (IBR) using the national English administrative records, Hospital Episode Statistics. Our prediction was an increase in implant-only and free flap procedures and a decline in latissimus flap reconstructions. METHODS: Data from an oncoplastic center were interrogated to derive numbers of implant-only, autologous latissimus dorsi (LD), LD-assisted, and autologous pedicled or free flap IBR procedures performed between 2004 and 2013. Similarly, Hospital Episode Statistics data were used to quantify national trends in these procedures from 1996 to 2012 using a curve fitting analysis. RESULTS: National data suggest an increase in LD procedures between 1996 (n = 250) and 2002 (n = 958), a gradual rise until 2008 (n = 1398) followed by a decline until 2012 (n = 1090). As a percentage of total IBR, trends in LD flap reconstruction better fit a quadratic (R(2) = 0.97) than a linear function (R(2) = 0.63), confirming a proportional recent decline in LD flap procedures. Conversely, autologous (non-LD) flap reconstructions have increased (1996 = 0.44%; 2012 = 2.76%), whereas implant-only reconstructions have declined (1996 = 95.42%; 2012 = 84.92%). Locally, 70 implant-assisted LD procedures were performed in 2003 -2004, but only 2 were performed in 2012 to 2013. CONCLUSIONS: Implants are the most common IBR technique; autologous free flap procedures have increased, and pedicled LD flap procedures are in decline.

A case-control study of treatment choices made by doctors diagnosed with early breast cancer.

INTRODUCTION: Doctors who are diagnosed with breast cancer form a small subset of women with unique insight into their disease. The aim of this study was to compare key treatment decisions in medically-qualified doctors with equivalent degree-educated, matched controls diagnosed with early breast cancer. METHODS: Patients diagnosed with breast cancer between 01/01/2006 and 31/12/2011 were included and screened for occupation by 2 independent investigators. Allied health professionals with a medical background (e.g. nurses, physiotherapists) were excluded. Patient controls were matched by age, nodal status and grade. If there were more than 5 possible matches then those patients with the closest tumour size were selected. RESULTS: 5259 of 8623 patients had signed the generic research consent form. 619 of these were either doctors, or had received tertiary level education and could form appropriate controls. After exclusions, 46 medically-qualified doctors and 230 matched control patients were included in the analysis. No statistical differences in age or tumour characteristics were identified between doctors with breast cancer and matched controls. No differences were identified between the two groups in the uptake of mastectomy, chemotherapy, immediate breast reconstruction or post-mastectomy radiotherapy. CONCLUSION: Medically-qualified patients diagnosed with early breast cancer are no more likely to opt for mastectomy, chemotherapy, immediate breast reconstruction or post-mastectomy radiotherapy than non-medically-qualified controls. The level of information generally provided to patients with breast cancer is adequate for a similar decision to be made by control patients with equivalent levels of education, independent of any knowledge of pathology or understanding of the medical system that medically-qualified patients may possess.

Optimum duration of neoadjuvant letrozole to permit breast conserving surgery.

The aim of this multicenter, prospective, longitudinal phase IV study was to establish the optimal duration of neoadjuvant letrozole that would allow breast conservation surgery (BCS) in patients with early breast cancer who were initially unsuitable. Primary, invasive, estrogen-receptor- and/or progesterone-receptor-positive breast cancer patients, with large tumors (≥T2 i.e., >20 mm) not initially suitable for BCS, received 2.5 mg letrozole p.o. daily. Patients continued treatment until they became eligible for BCS, progressed, failed to meet criteria for BCS and withdrew for scheduled mastectomy, withdrew for other reasons, or completed 12 months of letrozole treatment without a BCS decision being made. A total of 146 patients were enrolled; seven patients who did not have a valid postbaseline tumor assessment were excluded from the final efficacy analysis. At study closure, 69 % of patients (96 of 139) were eligible for BCS. The median time to achieve a tumor response sufficient to allow BCS with neoadjuvant letrozole was 7.5 months (95 % CI 6.3-8.5 months). Letrozole was well tolerated, and most adverse events were mild-to-moderate (grade 1-2). The results from this trial suggest that extended letrozole therapy in the neoadjuvant setting (7.5 months), as opposed to conventional treatment of 4 months, is optimal to achieve maximum reduction in tumor volume sufficient for BCS.

DNA promoter hypermethylation profiles in breast duct fluid.

DNA methylation of tumor-suppressor genes occurs early in the molecular transformation of precursor events to breast cancer and is therefore of interest to screening in high-risk women. The aim of this study was to use tumor-suppressor genes that have previously been shown to be cancer predictive in tissue to evaluate the potential of DNA methylation assays in cells from duct lavage (DL) fluid. The frequency of target gene DNA methylation in tissue and DL of cancer and healthy control patients was assessed, and an association of DNA methylation between different duct systems in the same breast was explored. The cancer and control groups were identified in the outpatient clinic when surgical treatment was finalized. Tumor, adjacent tissue and bilateral DL samples for comparative DNA methylation studies were obtained during surgery from women with cancer. In the healthy control group, samples of tissue and DL were collected. Reverse transcriptase methylation-specific PCR was conducted on modified DNA purified from 42 cancer biopsies, 41 benign excision cavity biopsies (internal control), 29 benign biopsies (external control), and 119 DL specimens. A validated panel of cancer predictive genes was analyzed in the study bank of tissue and DL samples from cancer and healthy patients. The sensitivity of DNA methylation in DL samples compared with matched cancer tissue was highest for SCGB3A1 (90 %), CDH13 (91 %), and RARB (83 %). The genetic algorithm selected RASSF1A, RARB, and IGFBP7 as the optimum predictor set for detecting DNA methylation in cancer tissue. The optimum area under the ROC curve for DNA methylation in cancer compared with internal control healthy tissue from excision margins was 0.84. The area under the ROC curve for DNA methylation in cancer DL compared with contralateral benign DL was 0.76. DL cytology was not a helpful predictor of breast cancer. This study shows that relative patterns of tumor-suppressor gene hypermethylation in breast cancer tissue are significantly reflected in the DL from the cancer affected breast. Using DL, nonconcordant patterns of DNA methylation between different duct systems confer independent oncologic potential for distinct breast lobes. The approach of DNA methylation in DL may be substantiated by a larger trial of breast cancer biomarkers.

The feasibility of nipple aspiration and duct lavage to evaluate the breast duct epithelium of women with increased breast cancer risk.

AIM: Nipple aspiration (NA) and duct lavage (DL) are modalities for obtaining breast duct fluid for biomarker analyses. The aim of this study was to assess the feasibility of obtaining serial NA and DL samples at consecutive patient visits for cytology assessment and the creation of a biobank. METHODS: Seventy eligible subjects were enroled at a single institution in the United Kingdom as part of an international multicentre study. Entry criteria were based on a 5-year Gail model risk of ≥2% or Claus score lifetime risk of ≥26%. Women underwent NA and DL in an outpatient clinic under local anaesthesia. RESULTS: The mean patient age was 48 (range 41-69)years. Sixty seven out of 70 women (96%) attended three consecutive 6 monthly visits and follow-up for 2 years. Three women withdrew due to intolerance of the DL procedure. 56/67 (83%) women produced NA fluid from at least one duct. 204/264 (77%) of ducts declared by NA were cannulated for DL. 170/204 (83%) produced DL samples with adequate cellularity. By the final visit 52/67 (78%) women produced DL, 28/52 (54%) of whom were premenopausal and 24/52 (46%) were postmenopausal. 50/52 women (96%) underwent repeated DL of 81 ducts on 3 consecutive visits. CONCLUSION: NA and DL are well tolerated for repeated assessment to obtain material for cytology and to create a biobank for future biomarker studies in women at high breast cancer risk.

Biomarkers in the diagnosis of primary and recurrent breast cancer.

Despite the widespread use of mammography for breast cancer screening, breast cancer remains the most common cause of cancer-related mortality among women worldwide. The identification of biomarkers that identify cancers when they are small, localized and most treatable is an important aim of current breast cancer research. Biomarkers need to be sensitive, specific, reproducible and easily collected from patients from readily accessible tissue or body fluids. While conventional biomarker research has focused on soluble proteins, cell markers, proteomics and DNA methylation, much progress has also been made in the field of immunobiomarkers and multiparameter gene arrays. Currently, no one biomarker has demonstrated sufficient sensitivity and reproducibility for independent clinical and commercial use. This review summarizes the current state of breast cancer biomarker research and anticipated future directions.

Proteins and carbohydrates in nipple aspirate fluid predict the presence of atypia and cancer in women requiring diagnostic breast biopsy.

BACKGROUND: Herein we present the results of two related investigations. The first study determined if concentrations in breast nipple discharge (ND) of two proteins (urinary plasminogen activator, uPA and its inhibitor, PAI-1) predicted the presence of breast atypia and cancer in pre- and/or postmenopausal women requiring surgery because of a suspicious breast lesion. The second study assessed if these proteins increased the predictive ability of a carbohydrate (Thomsen Friedenreich, TF) which we previously demonstrated predicted the presence of disease in postmenopausal women requiring surgery. METHODS: In the first study we prospectively enrolled 79 participants from whom we collected ND, measured uPA and PAI-1 and correlated expression with pathologic findings. In the second study we analyzed 35 (uPA and PAI-1 in 24, uPA in an additional 11) ND samples collected from different participants requiring breast surgery, all of whom also had TF results. RESULTS: uPA expression was higher in pre- and PAI-1 in postmenopausal women with 1) cancer (DCIS or invasive) vs. either no cancer (atypia or benign pathology, p = .018 and .025, respectively), or benign pathology (p = .017 and .033, respectively); and 2) abnormal (atypia or cancer) versus benign pathology (p = .018 and .052, respectively). High uPA and PAI-1 concentrations and age were independent predictors of disease in premenopausal women, with an area under the curve (AUC) of 83-87% when comparing diseased vs. benign pathology. uPA, TF, and age correctly classified 35 pre- and postmenopausal women as having disease or not 84-91% of the time, whereas combining uPA+PAI-1+TF correctly classified 24 women 97-100% of the time. CONCLUSIONS: uPA and PAI-1 concentrations in ND were higher in women with atypia and cancer compared to women with benign disease. Combining uPA, PAI-1 and TF in the assessment of women requiring diagnostic breast surgery maximized disease prediction. The assessment of these markers may prove useful in early breast cancer detection.

The anatomy of fluid-yielding ducts in breast cancer.

The concept of an intraductal approach to evaluate the breast microenvironment assumes direct access to the cancer-containing duct. Central duct access to the cancer-affected lobe is essential if cytology or cell markers are to be useful indicators of pre-malignant change. Access to the cancer-bearing lobe would be less important if field change effects of malignant change were predominantly supra-lobar. The aim of this study was to determine how often duct lavage fluid drains the breast cancer-affected segment. 58 patients undergoing mastectomy for breast cancer were recruited among which 47 had at least one fluid-yielding duct. Following duct lavage, fluid-yielding ducts were perfused ex vivo with Polyurethane Elastomer (PU4ii) resin. Specimens were sliced sagittally, and the extent of resin perfusion and anatomical relationship to the cancer-affected segment was recorded. Computed tomography (CT) scanning was performed on selected mastectomies before cut-up for a feasibility study of 3D duct reconstruction. The median number of fluid-yielding ducts cannulated per cancer-affected breast was 2 (range 1-4). 35/47 (74%) mastectomy specimens were successfully cannulated for resin perfusion. 29/35 (83%) showed tracing of the cancer-affected duct system, 6/35 resin perfusions traced duct systems unaffected by cancer and 12/35 perfusions extravasated. The proportion of sagittal breast slices perfused by resin was 13-68% (median 43%). Volume rendering CT showed it is feasible to produce a simulated image of the perfused ducts. Duct access to the cancer-containing segment is feasible in the majority of patients. Fluid-yielding ducts proportionately drain a significant volume of the breast. Large symptomatic cancers may cause obstruction with distal collapse. Further quantitative study of breast perfusion CT scans may be helpful for estimating the volume fraction of breast tissue perfused by fluid-yielding ducts. The intraductal approach is a valid concept for biomarker assessment of cancer-containing breast segments.