Comparing long-term local recurrence rates of surgical and non-surgical management of close anterior margins in breast conserving surgery.

PURPOSE: While it is known that histologically involved margins lead to a higher local recurrence rate, re-excision of anterior margins is less common than that of radial margins. However, there are minimal long-term data on the oncological safety of non-surgical management of anterior margins. PATIENTS AND METHODS: A retrospective study was performed of all patients who underwent breast conserving surgery for breast cancer between 2000 and 2008 at two tertiary referral centres. A close margin was defined as disease within two mm of the resection margin (including disease at the margin). RESULTS: 6922 patients underwent surgery for invasive or in situ breast cancer of whom 277 patients had a close anterior margin alone after breast conserving surgery. Two hundred and twenty patients had non-surgical management of their margins, while 57 had re-excision surgery. Overall, there were 4/57 local recurrences in the surgical management group and 12/220 in the non-surgical management group. The local recurrence-free survival rate at 5 years was 98.2% (1 recurrence, 95% CI 87.8-99.7) in the surgical management group and 97.2% (6 recurrences, 95% CI 93.8-98.7) in the non-surgical management group. At 10 years, the rates were 92.2% (4 recurrences, 95% CI 80.3-97.0) in the surgical management group and 93.9% (12 recurrences, 95% CI 89.4-96.5) in the non-surgical management group. There was no significant difference found in the local recurrence rate between management groups (HR 1.24, 95% CI 0.40, 3.85; p = 0.71). CONCLUSIONS: Local recurrence rates are acceptable and similar in both the surgically and non-surgically managed groups. Non-surgical management of close anterior margins appears oncologically safe when combined with appropriate adjuvant therapy.

Safety and feasibility of breast lesion localization using magnetic seeds (Magseed): a multi-centre, open-label cohort study.

PURPOSE: Wire localization has several disadvantages, notably wire migration and difficulty scheduling the procedure close to surgery. Radioactive seed localization overcomes these disadvantages, but implementation is limited due to radiation safety requirements. Magnetic seeds potentially offer the logistical benefits and transcutaneous detection equivalence of a radioactive seed, with easier implementation. This study was designed to evaluate the feasibility and safety of using magnetic seeds for breast lesion localization. METHODS: A two-centre open-label cohort study to assess the feasibility and safety of magnetic seed (Magseed) localization of breast lesions. Magseeds were placed under radiological guidance into women having total mastectomy surgery. The primary outcome measure was seed migration distance. Secondary outcome measures included accuracy of placement, ease of transcutaneous detection, seed integrity and safety. RESULTS: Twenty-nine Magseeds were placed into the breasts of 28 patients under ultrasound guidance. There was no migration of the seeds between placement and surgery. Twenty-seven seeds were placed directly in the target lesion with the other seeds being 2 and 3 mm away. All seeds were detectable transcutaneously in all breast sizes and at all depths. There were no complications or safety issues. CONCLUSIONS: Magnetic seeds are a feasible and safe method of breast lesion localization. They can be accurately placed, demonstrate no migration in this feasibility study and are detectable in all sizes and depths of breast tissue. Now that safety and feasibility have been demonstrated, further clinical studies are required to evaluate the seed's effectiveness in wide local excision surgery.

Breast cancer research gaps: a questionnaire-based study to determine overall priorities and compare the priorities of patients, the public, clinicians and scientists.

OBJECTIVE: This study aims to prioritise the themes identified from the three gap analyses performed by a combination of scientists, clinicians, patients and members of the public to determine areas in breast cancer care where research is lacking. We also aimed to compare the priorities of areas of agreed research need between patients, the public, clinicians and scientists. DESIGN: A cross-section of patients, public, clinicians and scientists completed a prioritisation exercise to rank the identified themes where research is lacking in breast cancer care. PARTICIPANTS: Patients, clinicians and scientists who have experienced, managed or worked in the field of breast cancer and members of the public. METHODS: The research areas identified in the Breast Cancer Campaign, Association of Breast Surgery and North West Breast Research Collaborative gap analyses were outlined as 22 themes in lay terminology. Patients, members of the public, clinicians and scientists were invited to complete the prioritisation exercise, on paper or electronically, ranking the themes from 1 to 22. Comparisons were made with arithmetic mean ranking. RESULTS: Of the 510 prioritisation exercises completed, 179 (35%) participants were patients, 162 (32%) public, 43 (8%) scientists and 122 (24%) clinicians. The theme ranked of highest priority overall was 'better prevention' (arithmetic mean rank 6.4 (SE 0.23)). 'Better prevention' was ranked top or second by patients, public and clinicians (7 (0.39), 4.7 (0.34) and 6.8 (0.5), respectively), however, scientists ranked this as their sixth most important factor (7.7 (0.92)). The public and clinicians had good agreement with patients (r=0.84 and r=0.75, respectively), whereas scientists had moderate agreement with patients (r=0.65). Certain themes were ranked significantly differently by participant groups. Compared with clinicians, patients prioritised research into 'alternative to mammograms', 'diagnostic (cancer) blood test' and 'rare cancers' (OR 2.1 (95% CI 1.3 to 3.5), p=0.002, OR 2.1 (95% CI 1.3 to 3.5), p=0.004 and OR 1.7 (95% CI 1.1 to 2.8), p=0.03). Compared with scientists, patients deprioritised 'better laboratory models' (OR 0.4 (95% CI 0.2 to 0.8), p=0.01). CONCLUSION: This study demonstrates that patients, public, clinicians and scientists have different research priorities, with scientists being a particular outlier. This highlights the need to ensure the engagement of patients and public in research funding prioritisation decisions.

Breast Reconstruction Outcomes with and without Strattice: Long-Term Outcomes of a Multicenter Study Comparing Strattice Immediate Implant Breast Reconstruction with Submuscular Implant Reconstruction.

BACKGROUND: Over half of immediate implant-based breast reconstructions (IBBR) are performed with an acellular dermal matrix, despite limited long-term outcome data. METHODS: The Breast Reconstruction Outcomes with and without Strattice, or BROWSE, study was a retrospective multicenter cohort study comparing consecutive patients who had undergone immediate Strattice IBBR with those who had undergone immediate IBBR with a submuscular technique between January of 2009 and December of 2015. RESULTS: This study compared 553 Strattice reconstructions with 242 submuscular reconstructions, with a median follow-up of 4.3 years (range, 2 to 9.3 years) and 5.7 years (range, 2 to 8.1 years), respectively, demonstrating an equivalent total complication rate [Strattice, n = 204 (36.9%); submuscular, n = 77 (31.8%); P = 0.17] and implant loss rate (8.5% versus 5.4%, respectively; P = 0.12). Infection rates and wound dehiscence rates were higher in the Strattice cohort [ n = 114 (20.6%) versus n = 31 (12.8%), P = 0.009; and n = 90 (16.3%) versus n = 25 (10.4%), P = 0.03, respectively]. Overall revision rates were comparable [ n = 226 (46.7%) versus n = 79 (41.1%); P = 0.2], but significantly fewer Strattice reconstructions required revision surgery for capsular contracture (5.3% versus 15.6%; P < 0.001). CONCLUSION: Although the risk of complications associated with Strattice reconstruction is numerically higher than that for submuscular coverage, the difference is small and not statistically significant, and likely outweighed by the clear reduced rate of revision surgery because of capsular contracture when Strattice is used. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

BROWSE: A multicentre comparison of nine year outcomes in acellular dermal matrix based and complete submuscular implant-based immediate breast reconstruction-aesthetics, capsular contracture and patient reported outcomes.

Approximately 60% of implant-based breast reconstructions (IBBR) are performed with an acellular dermal matrix (ADM), for which, reliable, good quality long-term outcome data is limited. In a retrospective multicentre cohort study, we aimed to determine long-term aesthetic and quality of life outcomes of IBBR with ADM (Strattice™) compared to a submuscular technique. METHODS: Capsular contracture (Baker III/IV capsule) was determined by clinical examination by an independent researcher. Quality of life was assessed using BREAST-Q and aesthetic outcome by photographic assessment from a breast surgeon, breast care nurse and lay person, blinded to reconstruction type. RESULTS: We recruited 117 (51 bilateral) patients with ADM reconstructions, median follow-up 62 months (range 29-113) and 49 patients (16 bilateral) with submuscular reconstructions, median follow-up 76 months (range 38-111). 17 (10.1%) ADM reconstructions were Baker 3/4 compared to six (9.2%) submuscular (p = 0.85). Of the Baker 1/2 reconstructions six (3.6%) ADM and eight (13.6%) submuscular had previously undergone revision surgery to correct capsular contracture (p = 0.01). Combining both findings gave an estimated rate of capsular contracture of 13.6% in the ADM group and 21.2% in the submuscular (p = 0.14). A higher mean score for satisfaction with breasts was demonstrated when comparing ADM to submuscular (62 and 55, respectively; p = 0.01) but no significant difference in other BREAST-Q domains. The mean 'general satisfaction' score was higher in the ADM group for all three photograph assessors. CONCLUSION: This study provides evidence of improved aesthetic outcome and reduction in capsular contracture with ADM reconstruction when compared to submuscular, consistent over long-term follow-up.

Rivaroxaban compared to no treatment in ER-negative stage I-III early breast cancer patients (the TIP Trial): study protocol for a phase II preoperative window-of-opportunity study design randomised controlled trial.

BACKGROUND: Breast cancer patients are at a four-fold increased risk of developing a venous thromboembolism (VTE), a major cause of death in this group. Conversely, coagulation factors promote tumour growth and metastasis. This has been evidenced in preclinical models, with an inhibitory effect of anticoagulants on cancer growth through proliferative, angiogenic, apoptotic, cancer stem cell and metastatic processes. The extrinsic clotting pathway is also more upregulated in patients in the relatively poorer prognosis oestrogen receptor (ER)-negative breast cancer subgroup, with increased tumour stromal expression of the coagulation factors Tissue Factor and thrombin. Rivaroxaban (Xarelto®, Bayer AG, Leverkusen, Germany) is a direct oral anticoagulant (DOAC). It is a Factor Xa inhibitor that is routinely prescribed for the prevention of stroke in non-valvular atrial fibrillation and for both VTE prophylaxis and treatment. This trial will assess the anti-proliferative and other anti-cancer progression mechanisms of Rivaroxaban in ER-negative early breast cancer patients. METHODS: This UK-based preoperative window-of-opportunity phase II randomised control trial will randomise 88 treatment-naïve early breast cancer patients to receive 20 mg OD Rivaroxaban treatment for 11 to 17 days or no treatment. Treatment will be stopped 24 h (range 18-36 h) prior to surgery or repeat core biopsy. All patients will be followed up for 2 weeks following surgery or repeat core biopsy. The primary endpoint is change in tumour Ki67. Secondary outcome measures include tumour markers of apoptosis and angiogenesis, extrinsic clotting pathway activation and systemic markers of metastasis, tumour load and coagulation. DISCUSSION: Laboratory evidence supports an anti-cancer role for anticoagulants; however, this has failed to translate into survival benefit when trialled in patients with metastatic disease or poor prognosis cancers, such as lung cancer. Subgroup analysis supported a potential survival benefit in better prognosis advanced disease patients. This is the first study to investigate the anti-cancer effects of anticoagulants in early breast cancer. TRIAL REGISTRATION: UK National Research Ethics Service (NRES) approval 15/NW/0406, MHRA Clinical Trials Authorisation 48380/0003/001-0001. The sponsor is Manchester University NHS Foundation Trust, and the trial is co-ordinated by Cancer Research UK Liverpool Cancer Trials Unit (LCTU). EudraCT 2014-004909-33 , registered 27 July 2015. ISRCTN14785273 .

Inhibition of CXCR4-mediated breast cancer metastasis: a potential role for heparinoids?

PURPOSE: The pattern of breast cancer metastasis may be determined by interactions between CXCR4 on breast cancer cells and CXCL12 within normal tissues. Glycosaminoglycans bind chemokines for presentation to responsive cells. This study was designed to test the hypothesis that soluble heparinoid glycosaminoglycan molecules can disrupt the normal response to CXCL12, thereby reducing the metastasis of CXCR4-expressing cancer cells. EXPERIMENTAL DESIGN: Inhibition of the response of CXCR4-expressing Chinese hamster ovary cells to CXCL12 was assessed by measurement of calcium flux and chemotaxis. Radioligand binding was also assessed to quantify the potential of soluble heparinoids to prevent specific receptor ligation. The human breast cancer cell line MDA-MB-231 and a range of sublines were assessed for their sensitivity to heparinoid-mediated inhibition of chemotaxis. A model of hematogenous breast cancer metastasis was established, and the potential of clinically relevant doses of heparinoids to inhibit CXCL12 presentation and metastatic disease was assessed. RESULTS: Unfractionated heparin and the low-molecular-weight heparin tinzaparin inhibited receptor ligation and the response of CXCR4-expressing Chinese hamster ovary cells and human breast cancer cell lines to CXCL12. Heparin also removed CXCL12 from its normal site of expression on the surface of parenchymal cells in the murine lung. Both heparin and two clinically relevant dose regimens of tinzaparin reduced hematogenous metastatic spread of human breast cancer cells to the lung in a murine model. CONCLUSIONS: Clinically relevant concentrations of tinzaparin inhibit the interaction between CXCL12 and CXCR4 and may be useful to prevent chemokine-driven breast cancer metastasis.

A Prospective Comparison of Short-Term Outcomes of Subpectoral and Prepectoral Strattice-Based Immediate Breast Reconstruction.

BACKGROUND: Prepectoral acellular dermal matrix-assisted immediate implant-based breast reconstruction is gaining popularity, involving complete implant coverage with acellular dermal matrix. The authors aimed to compare pain, patient-reported outcome measures (including implant rippling), and safety of prepectoral and subpectoral Strattice-assisted implant-based breast reconstruction. METHODS: Consecutive patients were recruited prospectively, having either therapeutic or risk-reducing mastectomy. Patients scored their pain three times per day for the first 7 postoperative days on a Likert scale, and completed the BREAST-Q reconstruction module 3 months postoperatively. Clinical records and the authors' prospective complications database were used to compare the early morbidity of the two procedures. RESULTS: Forty patients were recruited into the study. There was no significant difference in pain scores between the prepectoral group (mean, 1.5) and the subpectoral cohort (mean, 1.5; p = 0.45) during the first 7 days. Thirty-one BREAST-Q questionnaires were returned; mean Q scores were similar for both prepectoral and subpectoral (72 and 71, respectively; p = 0.81) groups. Patients reported significantly more visible implant rippling in the prepectoral group than in the subpectoral group (seven of 13 versus two of 17; p = 0.02). There was no significant difference in length of stay or early morbidity, with implant loss being 4.7 percent in the prepectoral group compared with 0 percent in the subpectoral group. CONCLUSIONS: Early postoperative pain and quality of life at 3 months are equivalent between groups. Early experience of prepectoral implant placement with complete acellular dermal matrix coverage suggests this is safe and provides good quality of life for patients. Further studies are required to compare short- and long-term outcomes with the current standard forms of reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Systematic review of the effectiveness of polyurethane-coated compared with textured silicone implants in breast surgery.

BACKGROUND: Silicone gel implants are used worldwide for breast augmentation and breast reconstruction. Textured silicone implants are the most commonly placed implant, but polyurethane-coated implants are increasingly being used in an attempt to ameliorate the long-term complications associated with implant insertion. METHODS: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Electronic searches of MEDLINE, EMBASE, the Cochrane Library and www.ClinicalTrials.gov were undertaken in March 2014 using keywords. RESULTS: Following data extraction, 18 studies were included in the review, including four core studies of textured silicone implants and five studies reporting outcomes for polyurethane-coated silicone implants. There are no clear data reporting revision rates in patients treated with polyurethane implants. In the primary reconstructive setting, capsular contracture rates with silicone implants are 10-15% at 6 years, whilst studies of polyurethane implants report rates of 1.8-3.4%. In the primary augmentation setting, core studies show a capsular contracture rate of 2-15% at 6 years compared with 0.4-1% in polyurethane-coated implants; however, the polyurethane studies are limited by their design and poor follow-up. CONCLUSIONS: The use of polyurethane implants should be considered a safe alternative to textured silicone implants. It is likely that an implant surface does influence short- and long-term outcomes; however, the extent of any benefit cannot be determined from the available evidence base. Future implant studies should target the short- and long-term benefits of implant surfacing by procedure with defined outcome measures; a head-to-head comparison would help clarify outcomes.

Current attitudes to breast reconstruction surgery for women at risk of post-mastectomy radiotherapy: A survey of UK breast surgeons.

Decision-making for women requiring reconstruction and post-mastectomy radiotherapy (PMRT) includes oncological safety, cosmesis, patient choice, potential delay/interference with adjuvant treatment and surgeon/oncologist preference. This study aimed to quantitatively assess surgeons' attitudes and perceptions about reconstructive options in this setting, and to ascertain if surgical volume influenced advice given. A questionnaire was sent to surgical members of the UK Association of Breast Surgery (ABS) in March-June 2014. The questionnaire elicited information on surgeon volume, reconstructive practice and drivers influencing decision-making. Response rate was 42% (148/355), representing 71% of UK breast units. Delayed breast reconstruction (DBR) was offered more commonly than immediate implant, delayed-immediate or immediate autologous reconstruction (p < 0.05). Cosmesis was thought to be equivalent between IBR and DBR by 15% of surgeons, and 26% believe IBR and DBR offer similar Health-related Quality of Life (HRQoL). Surgeon volume had no effect on reconstruction choice. Common decision-making drivers included negative effects of radiotherapy upon reconstructive and cosmetic outcome. The majority of surgeons (77%) believe the current evidence base is insufficient to guide decision-making. Despite surgeons believing that cosmesis and quality of life are not equivalent between IBR and DBR, DBR remains the commonest approach to this difficult clinical scenario. Surgeons perceive they are using a variety of newer techniques such as Delayed-Immediate Reconstruction and Acellular Dermal Matrices to try to ameliorate the effects of PMRT. This survey demonstrates that there is wide variation in reported surgical practice in this difficult setting. There is widespread acknowledgement of the lack of evidence to guide decision-making.