Incidence of unilateral arm lymphoedema after breast cancer : a systematic review and meta-analysis

Background The body of evidence related to breast-cancer-related lymphoedema incidence and risk factors has substantially grown and improved in quality over the past decade. We assessed the incidence of unilateral arm lymphoedema after breast cancer and explored the evidence available for lymphoedema risk factors. Methods We searched Academic Search Elite, Cumulative Index to Nursing and Allied Health, Cochrane Central Register of Controlled Trials (clinical trials), and Medline for research articles that assessed the incidence or prevalence of, or risk factors for, arm lymphoedema after breast cancer, published between January 1, 2000, and June 30, 2012. We extracted incidence data and calculated corresponding exact binomial 95% CIs. We used random effects models to calculate a pooled overall estimate of lymphoedema incidence, with subgroup analyses to assess the effect of different study designs, countries of study origin, diagnostic methods, time since diagnosis, and extent of axillary surgery. We assessed risk factors and collated them into four levels of evidence, depending on consistency of findings and quality and quantity of studies contributing to findings. Findings 72 studies met the inclusion criteria for the assessment of lymphoedema incidence, giving a pooled estimate of 16·6% (95% CI 13·6–20·2). Our estimate was 21·4% (14·9–29·8) when restricted to data from prospective cohort studies (30 studies). The incidence of arm lymphoedema seemed to increase up to 2 years after diagnosis or surgery of breast cancer (24 studies with time since diagnosis or surgery of 12 to <24 months; 18·9%, 14·2–24·7), was highest when assessed by more than one diagnostic method (nine studies; 28·2%, 11·8–53·5), and was about four times higher in women who had an axillary-lymph-node dissection (18 studies; 19·9%, 13·5–28·2) than it was in those who had sentinel-node biopsy (18 studies; 5·6%, 6·1–7·9). 29 studies met the inclusion criteria for the assessment of risk factors. Risk factors that had a strong level of evidence were extensive surgery (ie, axillary-lymph-node dissection, greater number of lymph nodes dissected, mastectomy) and being overweight or obese. Interpretation Our findings suggest that more than one in five women who survive breast cancer will develop arm lymphoedema. A clear need exists for improved understanding of contributing risk factors, as well as of prevention and management strategies to reduce the individual and public health burden of this disabling and distressing disorder.

Dynamic changes in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers during various murine peripartum states and over time

Mammographic density (MD) is a strong heritable risk factor for breast cancer, and may decrease with increasing parity. However, the biomolecular basis for MD-associated breast cancer remains unclear, and systemic hormonal effects on MD-associated risk is poorly understood. This study assessed the effect of murine peripartum states on high and low MD tissue maintained in a xenograft model of human MD. Method High and low MD human breast tissues were precisely sampled under radiographic guidance from prophylactic mastectomy specimens of women. The high and low MD tissues were maintained in separate vascularised biochambers in nulliparous or pregnant SCID mice for 4 weeks, or mice undergoing postpartum involution or lactation for three additional weeks. High and low MD biochamber material was harvested for histologic and radiographic comparisons during various murine peripartum states. High and low MD biochamber tissues in nulliparous mice were harvested at different timepoints for histologic and radiographic comparisons. Results High MD biochamber tissues had decreased stromal (p = 0.0027), increased adipose (p = 0.0003) and a trend to increased glandular tissue areas (p = 0.076) after murine postpartum involution. Stromal areas decreased (p = 0.042), while glandular (p = 0.001) and adipose areas (p = 0.009) increased in high MD biochamber tissues during lactation. A difference in radiographic density was observed in high (p = 0.0021) or low MD biochamber tissues (p = 0.004) between nulliparous, pregnant and involution groups. No differences in tissue composition were observed in high or low MD biochamber tissues maintained for different durations, although radiographic density increased over time. Conclusion High MD biochamber tissues had measurable histologic changes after postpartum involution or lactation. Alterations in radiographic density occurred in biochamber tissues between different peripartum states and over time. These findings demonstrate the dynamic nature of the human MD xenograft model, providing a platform for studying the biomolecular basis of MD-associated cancer risk. © 2013 Springer Science+Business Media New York.

High and low mammographic density human breast tissues maintain histological differential in murine tissue engineering chambers

Mammographic density (MD) is the area of breast tissue that appears radiologically white on mammography. Although high MD is a strong risk factor for breast cancer, independent of BRCA1/2 mutation status, the molecular basis of high MD and its associated breast cancer risk is poorly understood. MD studies will benefit from an animal model, where hormonal, gene and drug perturbations on MD can be measured in a preclinical context. High and low MD tissues were selectively sampled by stereotactic biopsy from operative specimens of high-risk women undergoing prophylactic mastectomy. The high and low MD tissues were transferred into separate vascularised biochambers in the groins of SCID mice. Chamber material was harvested after 6 weeks for histological analyses and immunohistochemistry for cytokeratins, vimentin and a human-specific mitochondrial antigen. Within-individual analysis was performed in replicate mice, eliminating confounding by age, body mass index and process-related factors, and comparisons were made to the parental human tissue. Maintenance of differential MD post-propagation was assessed radiographically. Immunohistochemical staining confirmed the preservation of human glandular and stromal components in the murine biochambers, with maintenance of radiographic MD differential. Propagated high MD regions had higher stromal (p = 0.0002) and lower adipose (p = 0.0006) composition, reflecting the findings in the original human breast tissue, although glands appeared small and non-complex in both high and low MD groups. No significant differences were observed in glandular area (p = 0.4) or count (p = 0.4) between high and low MD biochamber tissues. Human mammary glandular and stromal tissues were viably maintained in murine biochambers, with preservation of differential radiographic density and histological features. Our study provides a murine model for future studies into the biomolecular basis of MD as a risk factor for breast cancer.

Image-guided sampling reveals increased stroma and lower glandular complexity in mammographically dense breast tissue

Mammographic density (MD) adjusted for age and body mass index (BMI) is a strong heritable breast cancer risk factor; however, its biological basis remains elusive. Previous studies assessed MD-associated histology using random sampling approaches, despite evidence that high and low MD areas exist within a breast and are negatively correlated with respect to one another. We have used an image-guided approach to sample high and low MD tissues from within individual breasts to examine the relationship between histology and degree of MD. Image-guided sampling was performed using two different methodologies on mastectomy tissues (n = 12): (1) sampling of high and low MD regions within a slice guided by bright (high MD) and dark (low MD) areas in a slice X-ray film; (2) sampling of high and low MD regions within a whole breast using a stereotactically guided vacuum-assisted core biopsy technique. Pairwise analysis accounting for potential confounders (i.e. age, BMI, menopausal status, etc.) provides appropriate power for analysis despite the small sample size. High MD tissues had higher stromal (P = 0.002) and lower fat (P = 0.002) compositions, but no evidence of difference in glandular areas (P = 0.084) compared to low MD tissues from the same breast. High MD regions had higher relative gland counts (P = 0.023), and a preponderance of Type I lobules in high MD compared to low MD regions was observed in 58% of subjects (n = 7), but did not achieve significance. These findings clarify the histologic nature of high MD tissue and support hypotheses regarding the biophysical impact of dense connective tissue on mammary malignancy. They also provide important terms of reference for ongoing analyses of the underlying genetics of MD.

Photon beam dose distributions for patients with implanted temporary tissue expanders

This study examines the effects of temporary tissue expanders (TTEs) on the dose distributions of photon beams in breast cancer radiotherapy treatments. EBT2 radiochromic film and ion chamber measurements were taken to quantify the attenuation and backscatter effects of the inhomogeneity. Results illustrate that the internal magnetic port present in a tissue expander causes a dose reduction of approximately 25% in photon tangent fields immediately downstream of the implant. It was also shown that the silicone elastomer shell of the tissue expander reduced the dose to the target volume by as much as 8%. This work demonstrates the importance for an accurately modelled high-density implant in the treatment planning system for post-mastectomy breast cancer patients.

Establishing the impact of temporary tissue expanders on electron and photon beam dose distributions

Purpose: This study investigates the effects of temporary tissue expanders (TTEs) on the dose distributions in breast cancer radiotherapy treatments under a variety of conditions. Methods: Using EBT2 radiochromic film, both electron and photon beam dose distribution measurements were made for different phantoms, and beam geometries. This was done to establish a more comprehensive understanding of the implant’s perturbation effects under a wider variety of conditions. Results: The magnetic disk present in a tissue expander causes a dose reduction of approximately 20% in a photon tangent treatment and 56% in electron boost fields immediately downstream of the implant. The effects of the silicon elastomer are also much more apparent in an electron beam than a photon beam. Conclusions: Evidently, each component of the TTE attenuates the radiation beam to different degrees. This study has demonstrated that the accuracy of photon and electron treatments of post-mastectomy patients is influenced by the presence of a tissue expander for various beam orientations. The impact of TTEs on dose distributions establishes the importance of an accurately modelled high-density implant in the treatment planning system for post-mastectomy patients.

Additive tissue manufacturing for breast reconstruction: Combining CAD/CAM with adipose tissue engineering

The primary aim of this multidisciplinary project was to develop a new generation of breast implants. Disrupting the currently prevailing paradigm of silicone implants which permanently introduce a foreign body into mastectomy patients, highly porous implants developed as part of this PhD project are biodegradable by the body and augment the growth of natural tissue. Our technology platform leverages computer-assisted-design which allows us to manufacture fully patient-specific implants based on a personalised medicine approach. Multiple animal studies conducted in this project have shown that the polymeric implant slowly degrades within the body harmlessly while the body's own tissue forms concurrently.

Effects of Tamoxifen and oestrogen on histology and radiographic density in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers

Mammographic density (MD) is a strong risk factor for breast cancer. It is altered by exogenous endocrine treatments, including hormone replacement therapy and Tamoxifen. Such agents also modify breast cancer (BC) risk. However, the biomolecular basis of how systemic endocrine therapy modifies MD and MD-associated BC risk is poorly understood. This study aims to determine whether our xenograft biochamber model can be used to study the effectiveness of therapies aimed at modulating MD, by examine the effects of Tamoxifen and oestrogen on histologic and radiographic changes in high and low MD tissues maintained within the biochamber model. High and low MD human tissues were precisely sampled under radiographic guidance from prophylactic mastectomy fresh specimens of high-risk women, then inserted into separate vascularized murine biochambers. The murine hosts were concurrently implanted with Tamoxifen, oestrogen or placebo pellets, and the high and low MD biochamber tissues maintained in the murine host environment for 3 months, before the high and low MD biochamber tissues were harvested for histologic and radiographic analyses. The radiographic density of high MD tissue maintained in murine biochambers was decreased in Tamoxifen-treated mice compared to oestrogen-treated mice (p = 0.02). Tamoxifen treatment of high MD tissue in SCID mice led to a decrease in stromal (p = 0.009), and an increase in adipose (p = 0.023) percent areas, compared to placebo-treated mice. No histologic or radiographic differences were observed in low MD biochamber tissue with any treatment. High MD biochamber tissues maintained in mice implanted with Tamoxifen, oestrogen or placebo pellets had dynamic and measurable histologic compositional and radiographic changes. This further validates the dynamic nature of the MD xenograft model, and suggests the biochamber model may be useful for assessing the underlying molecular pathways of Tamoxifen-reduced MD, and in testing of other pharmacologic interventions in a preclinical model of high MD.

Immediate Breast Reconstructions in the Treatment of Breast Cancer

Breast cancer is the most common form of potentially fatal cancer in women in the Western world. Better understanding of the breast cancer disease process together with developments in treatments have led to improved survival and reduced risk of recurrence, significantly influencing the acceptance of breast reconstructions as part of breast cancer treatment. Skin-sparing mastectomy followed by immediate breast reconstruction has proved superior to other forms of breast reconstruction in terms of aesthetic outcome. However, due to the relatively recent introduction of skin-sparing mastectomy concerns on the surgical and oncological safety of the operation persist. The aim of the present study is to evaluate the surgical and oncological safety of skin-sparing mastectomy and immediate breast reconstruction in a consecutive patient series with ensuing follow-up. Subsequent aims of the study are to examine possibilities of reducing surgical complications of the operation and to assess the feasibility of sentinel node biopsy together with immediate breast reconstruction. The study population comprises a consecutive series of patients having undergone skin-sparing mastectomy followed by immediate breast reconstruction at the Helsinki University Central Hospital between 1992 and 2006. In Study I, the hospital records of 207 patients, operated between 1992 and 2001, were analyzed for surgical complications and recurrences of breast cancer during follow-up. In Study II, 60 consecutive patients were randomized into either conventional diathermy or radiofrequency coagulation groups to examine possibilities of reducing skin-flap complications. Study III consists of 62 consecutive breast cancer patients evaluated for the feasibility of sentinel node biopsy simultaneously with immediate breast reconstruction. In Study IV, hospital records were analyzed to examine local recurrence of breast cancer in a consecutive series of 146 patients with Stage I or II disease. Post-operative complications in Study I included native skin-flap necrosis (10.1%), hematoma (10.1%), anastomose thrombosis (5.3%), infection (3.4%), hernia (2.6%) and loss of one microvascular flap (0.7%). The Stage I and II patients in Study IV had a local recurrence rate of 2.7%, an isolated regional lymph node recurrence rate of 2.1% and a systemic recurrence rate of 2.7%, during a mean follow-up time of 51 months. The Stage III patients in study I had a locoregional recurrence rate of 31.3% during follow-up. Radiofrequency coagulation in Study II did not decrease skin-flap complications when compared with conventional diathermy. An increased skin-flap complication rate in Study II was associated with smoking and the type of skin incision used. In Study III, eleven patients had tumor positive sentinel nodes, nine of which were detected intraoperatively. Skin-sparing mastectomy followed by immediate breast reconstruction is a safe procedure both surgically and oncologically, especially for early stage breast cancer. Tennis racket type incision is associated with an increased skin-flap complication rate. Sentinel node biopsy with intraoperative assessment of sentinel node metastases is feasible in patients undergoing immediate breast reconstruction.

Sentinel lymph node biopsy as a diagnostic tool in the treatment of breast cancer

The purpose of this study was to evaluate the use of sentinel node biopsy (SNB) in the axillary nodal staging in breast cancer. A special interest was in sentinel node (SN) visualization, intraoperative detection of SN metastases, the feasibility of SNB in patients with pure tubular carcinoma (PTC) and in those with ductal carcinoma in situ (DCIS) in core needle biopsy (CNB) and additionally in the detection of axillary recurrences after tumour negative SNB. Patients and methods. 1580 clinically stage T1-T2 node-negative breast cancer patients, who underwent lymphoscintigraphy (LS), SNB and breast surgery between June 2000 - 2004 at the Breast Surgery Unit. The CNB samples were obtained from women, who participated the biennial, population based mammography screening at the Mammography Screening Centre of Helsinki 2001 - 2004.In the follow- up, a cohort of 205 patients who avoided AC due to negative SNB findings were evaluated using ultrasonography one and three years after breast surgery. Results. The visualization rate of axillary SNs was not enhanced by adjusting radioisotope doses according to BMI. The sensitivity of the intraoperative diagnosis of SN metastases of invasive lobular carcinoma (ILC) was higher, 87%, with rapid, intraoperative immunohistochemistry (IHC) group compared to 66% without it. The prevalence of tumour positive SN findings was 27% in the 33 patients with breast tumours diagnosed as PTC. The median histological tumour size was similar in patients with or without axillary metastases. After the histopathological review, six out of 27 patients with true PTC had axillary metastases, with no significant change in the risk factors for axillary metastases. Of the 67 patients with DCIS in the preoperative percutaneous biopsy specimen , 30% had invasion in the surgical specimen. The strongest predictive factor for invasion was the visibility of the lesion in ultrasound. In the three year follow-up, axillary recurrence was found in only two (0.5%) of the total of 383 ultrasound examinations performed during the study, and only one of the 369 examinations revealed cancer. None of the ultrasound examinations were false positive, and no study participant was subjected to unnecessary surgery due to ultrasound monitoring. Conclusions. Adjusting the dose of the radioactive tracer according to patient BMI does not increase the visualization rate of SNs. The intraoperative diagnosis of SN metastases is enhanced by rapid IHC particularly in patients with ILC. SNB seems to be a feasible method for axillary staging of pure tubular carcinoma in patients with a low prevalence of axillary metatastases. SNB also appears to be a sensible method in patients undergoing mastectomy due to DCIS in CNB. It also seems useful in patients with lesions visible in breast US. During follow-up, routine monitoring of the ipsilateral axilla using US is not worthwhile among breast cancer patients who avoided AC due to negative SN findings.

Breast cancer following augmentation mammoplasty - a review of its impact on prognosis and management

The incidence of breast cancer in women with implants is increasing and will continue to do so for the foreseeable future due to the marked increase in breast implant insertion in recent years. Undoubtedly many of these women will wish to know whether the presence of implants worsens the prognosis of their breast cancer. Furthermore, the clinical management of such patients may be difficult, as aesthetic results are likely to be a major concern for women who have already undergone cosmetic surgery to the breast. There is no consensus on surgical approach to this scenario. This article reviews the literature on the prognosis of breast cancer patients with a history of augmentation mammoplasty and examines the available data regarding their surgical treatment. (c) 2007 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.

Local recurrence in patients with large and locally advanced breast cancer treated with primary chemotherapy

Background: Primary chemotherapy is being given in the treatment of large and locally advanced breast cancers, but a major concern is local relapse after therapy. This paper has examined patients treated with primary chemotherapy and surgery (either breast-conserving surgery or mastectomy) and has examined the role of factors which may indicate those patients who are subsequently more likely to experience local recurrence of,disease.

Methods: A consecutive series of 173 women, with data available for 166 of these, presenting with large and locally advanced breast cancer (T2 >4 cm, T3, T4, or N2) were treated with primary chemotherapy comprising cyclophosphamide, vincristine, doxorubicin, and prednisolone and then surgery (either conservation or mastectomy with axillary surgery) followed by radiotherapy were examined.

Results: The clinical response rate of these patients was 75% (21% complete and 54% partial), with a complete pathological response rate of 15%. A total of 10 patients (6%) experienced local disease relapse, and the median time to relapse was 14 months (ranging from 3 to 40). The median survival in this group was 27 months (ranging from 13 to 78). In patients having breast conservation surgery, local recurrence occurred in 2%, and in those undergoing mastectomy 7% experience local relapse of disease. Factors predicting patients most likely to experience local recurrence were poor clinical response and residual axillary nodal disease after chemotherapy.

Conclusions: Excellent local control of disease can be achieved in patients with large and locally advanced breast cancers using a combination of primary chemotherapy, surgery and radiotherapy. However, the presence of residual tumor in the axillary lymph nodes after chemotherapy is a predictor of local recurrence and patients with a better clinical response were also less likely to experience local disease recurrence. The size and degree of pathological response did not predict patients most likely to experience recurrence of disease. (C) 2003 Excerpta Medica, Inc. All rights reserved.

Lymphatic mapping and sentinel node biopsy in breast cancer

Background Sentinel lymph node biopsy is a recently developed, minimally invasive technique for staging the axilla in patients with breast cancer. It has been suggested that this technique will avoid the morbidity associated with more extensive axillary dissection. A wide range of different methods and materials has been employed for lymphatic mapping, but there has been little consensus on the most reliable and reproducible technique.

Methods This is a comprehensive review of all published literature on sentinel node biopsy in breast cancer, using the Medline and Embase databases and cross-referencing of major articles on the subject.

Results and conclusion Sentinel node biopsy is a valid technique in breast cancer management, providing valuable axillary staging information. The optimal technique of lymphatic mapping utilizes a combination of vital blue dye and radiolabelled colloid. However, there remain controversial issues which require to be resolved before sentinel node biopsy becomes a widely accepted part of breast cancer care.

Accelerated partial breast irradiation (APBI): Are breath-hold and volumetric radiation therapy techniques useful?

Background: In a selective group of patients accelerated partial breast irradiation (APBI) might be applied after conservative breast surgery to reduce the amount of irradiated healthy tissue. The role of volumetric modulated arc therapy (VMAT) and voluntary moderately deep inspiration breath-hold (vmDIBH) techniques in further reducing irradiated healthy – especially heart – tissue is investigated.

Material and methods: For 37 partial breast planning target volumes (PTVs), three-dimensional conformal radiotherapy (3D-CRT) (3 – 5 coplanar or non-coplanar 6 and/or 10 MV beams) and VMAT (two partial 6 MV arcs) plans were made on CTs acquired in free-breathing (FB) and/or in vmDIBH. Dose-volume parameters for the PTV, heart, lungs, and breasts were compared. 

Results: Better dose conformity was achieved with VMAT compared to 3D-CRT (conformity index 1.24 0.09 vs. 1.49 0.20). Non-PTV ipsilateral breast receiving 50% of the prescribed dose was on average reduced by 28% in VMAT plans compared to 3D-CRT plans. Mean heart dose (MHD) reduced from 2.0 (0.1 – 5.1) Gy in 3D-CRT(FB) to 0.6 (0.1 – 1.6) Gy in VMAT(vmDIBH). VMAT is benefi cial for MHD reduction if MHD with 3D-CRT exceeds 0.5Gy. Cardiac dose reduction as a result of VMAT increases with increasing initial MHD, and adding vmDIBH reduces the cardiac dose further. Mean dose to the ipsilateral lung decreased from 3.7 (0.7 – 8.7) to 1.8 (0.5 – 4.0) Gy with VMAT(vmDIBH) compared to 3D-CRT(FB). VMAT resulted in a slight increase in the contralateral breast dose (DMean ) always remaining 1.9 Gy). 

Conclusions: For APBI patients, VMAT improves PTV dose conformity and delivers lower doses to the ipsilateral breast and lung compared to 3D-CRT. This goes at the cost of a slight but acceptable increase of the contralateral breast dose. VMAT reduces cardiac dose if MHD exceeds 0.5 Gy for 3D-CRT. Adding vmDIBH results in a further reduction of heart and ipsilateral lung dose. 

Molecular classification of non-invasive breast lesions for personalised therapy and chemoprevention

Breast cancer screening has led to a dramatic increase in the detection of pre-invasive breast lesions. While mastectomy is almost guaranteed to treat the disease, more conservative approaches could be as effective if patients can be stratified based on risk of co-existing or recurrent invasive disease.Here we use a range of biomarkers to interrogate and classify purely non-invasive lesions (PNL) and those with co-existing invasive breast cancer (CEIN). Apart from Ductal Carcinoma In Situ (DCIS), relative homogeneity is observed. DCIS contained a greater spread of molecular subtypes. Interestingly, high expression of p-mTOR was observed in all PNL with lower expression in DCIS and invasive carcinoma while the opposite expression pattern was observed for TOP2A.Comparing PNL with CEIN, we have identified p53 and Ki67 as predictors of CEIN with a combined PPV and NPV of 90.48% and 43.3% respectively. Furthermore, HER2 expression showed the best concordance between DCIS and its invasive counterpart.We propose that these biomarkers can be used to improve the management of patients with pre-invasive breast lesions following further validation and clinical trials. p53 and Ki67 could be used to stratify patients into low and high-risk groups for co-existing disease. Knowledge of expression of more actionable targets such as HER2 or TOP2A can be used to design chemoprevention or neo-adjuvant strategies. Increased knowledge of the molecular profile of pre-invasive lesions can only serve to enhance our understanding of the disease and, in the era of personalised medicine, bring us closer to improving breast cancer care.