Adjuvant taxanes and the development of breast cancer-related arm lymphoedema.

BACKGROUND: Despite affecting approximately one-quarter of all patients undergoing axillary lymph node dissection, the pathophysiology of breast cancer-related lymphoedema (BCRL) remains poorly understood. More extensive locoregional treatment and higher body mass index have long been identified as major risk factors. This study aimed to identify risk factors for BCRL with a specific focus on the potential impact of chemotherapy on the risk of BCRL. METHODS: This was a retrospective analysis of a cohort of consecutive patients with breast cancer treated at a major London regional teaching hospital between 1 January 2010 and 31 December 2012. All patients had node-positive disease and underwent axillary lymph node dissection. Data regarding tumour-, patient- and treatment-related characteristics were collected prospectively. The diagnosis of BCRL was based on both subjective and objective criteria. Multivariable Cox proportional hazards regression was used to assess the association between treatment and risk of BCRL. RESULTS: Some 27.1 per cent of all patients (74 of 273) developed BCRL over the study period. Administration of taxanes showed a strong association with the development of BCRL, as 52 (33.5 per cent) of 155 patients who received taxanes developed BCRL. Multivariable Cox regression analysis demonstrated that patients who received taxanes were nearly three times more likely to develop BCRL than patients who had no chemotherapy (hazard ratio 2.82, 95 per cent c.i. 1.31 to 6.06). No such increase was observed when taxanes were administered in the neoadjuvant setting. CONCLUSION: The present findings suggest that adjuvant taxanes play a key role in the development of BCRL after surgery. This may support the use of taxanes in a neoadjuvant rather than adjuvant setting.

Global abnormalities in lymphatic function following systemic therapy in patients with breast cancer.

BACKGROUND: Breast cancer-related lymphoedema (BCRL) is a result of interaction between several pathophysiological processes, and is not simply a 'stopcock' effect resulting from removal of axillary lymph nodes. The aim of this study was to test the hypothesis that there is a constitutional 'global' lymphatic dysfunction in patients who develop BCRL. METHODS: Lower-limb lymphoscintigraphy was performed in 30 women who had undergone axillary lymph node dissection at least 3 years previously, of whom 15 had BCRL and 15 did not. No patient had any clinical abnormality of the lower limb. The control group comprised 24 women with no history of cancer or lower-limb lymphoedema. (99m) Tc-Nanocoll was injected subcutaneously into the first webspace of each foot, followed by whole-body imaging. Scans were reported as abnormal if there was delay in lymph transport or rerouting through skin or deep system. Quantification was expressed as the percentage injected activity accumulating in ilioinguinal nodes. RESULTS: Mean(s.d.) ilioinguinal nodal accumulation at 150 min was significantly lower in women with BCRL than in those without (2·7(2·5) versus 5·9(4·8) per cent respectively; P = 0·006). Abnormal findings on lower-limb lymphoscintigraphy were observed in 17 of the 30 patients: ten of the 15 women who had BCRL and seven of the 15 who did not. None of the 24 control subjects had abnormal scan findings. CONCLUSION: Women with BCRL had reduced lower-limb lymph drainage, supporting the hypothesis of a predisposition to BCRL. A surprisingly high proportion of patients with breast cancer also demonstrated lymphatic dysfunction, despite clinically normal lower limbs. Possible explanations could be a systemic effect of breast cancer or its treatment, or an unidentified association between breast cancer and lymphatic dysfunction. REGISTRATION NUMBER: ISRCTN84866416 ( http://www.isrctn.com).

Meta-analysis of superficial versus deep injection of radioactive tracer and blue dye for lymphatic mapping and detection of sentinel lymph nodes in breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in early breast cancer. Currently, no consensus exists on the optimal site of injection of the radioactive tracer or blue dye. METHODS: A systematic review and meta-analysis of studies comparing superficial and deep injections of radioactive tracer or blue dye for lymphatic mapping and SLNB was performed. The axillary and extra-axillary sentinel lymph node (SLN) identification rates obtained by lymphoscintigraphy and intraoperative SLNB were evaluated. Pooled odds ratios (ORs) and 95 per cent c.i. were estimated using fixed-effect analyses, or random-effects analyses if there was statistically significant heterogeneity (P < 0·050). RESULTS: Thirteen studies were included in the meta-analysis. There was no significant difference between superficial and deep injections of radioactive tracer for axillary SLN identification on lymphoscintigraphy (OR 1·59, 95 per cent c.i. 0·79 to 3·17), during surgery (OR 1·27, 0·60 to 2·68) and for SLN identification using blue dye (OR 1·40, 0·83 to 2·35). The rate of extra-axillary SLN identification was significantly greater when deep rather than superficial injection was used (OR 3·00, 1·92 to 4·67). The discordance rate between superficial and deep injections ranged from 4 to 73 per cent for axillary and from 0 to 61 per cent for internal mammary node mapping. CONCLUSION: Both superficial and deep injections of radioactive tracer and blue dye are effective for axillary SLN identification. Clinical consequences of discordance rates between the two injection techniques are unclear. Deep injections are associated with significantly greater extra-axillary SLN identification; however, this may not have a significant impact on clinical management.

A constitutional predisposition to breast cancer-related lymphoedema and effect of axillary lymph node surgery on forearm muscle lymph flow.

AIM: The aims of this prospective study were (a) to examine the relationship between pre-operative muscle lymph flow and the predisposition to BCRL in women treated by axillary nodal surgery for breast cancer; and (b) to test the 'stopcock' hypothesis that axillary lymph node surgery impairs forearm lymph flow in the short term. METHODS: (99m)Tc-nanocoll was injected intramuscularly into both forearms of women undergoing surgery for breast cancer. Lymphatic clearance rate constant, k, representing lymph flow per unit interstitial fluid volume, was measured as the fractional disappearance rate of radioactivity from the depot site by gamma camera imaging. Axillary lymph node activity was calculated as percentage injected activity. BCRL was assessed by clinical examination and upper limb perometry. RESULTS: Of 38 pre-operative women, 33 attended at 8 ± 6 weeks post-operatively and 31 at 58 ± 9 weeks post-operatively. Seven patients (18%) developed BCRL. Prior to surgery the BCRL-destined patients had a higher mean k (0.0962 ± 0.034%/min) than non-BCRL patients (0.0830 ± 0.019%/min) (p = 0.10, unpaired t test). Post-operative k values were not significantly different from pre-operative, in either the ipsilateral (operated) or contralateral limb. Also, post-operative k values did not differ significantly between both upper limbs. Furthermore, there was no significant difference between pre- and post-operative axillary activity. CONCLUSION: Patients who develop BCRL have high lymph flow pre-surgery, which may predispose them to lymphatic overload and failure. Axillary lymph node surgery has no early, measurable effect on forearm muscle lymph flow despite surgical disruption of routes of lymph drainage.

An investigation of lymphovenous communications in the upper limbs of breast cancer patients.

BACKGROUND: Approximately 25% of breast cancer patients who undergo treatment to the axilla develop breast cancer-related lymphoedema (BCRL). The aim of this study was to test the hypothesis that lymphovenous communications (LVCs) open and act as a protective mechanism against the development of BCRL. METHODS: Five patients (Group 1) received intradermal injections of (99m)Technetium-labelled autologous erythrocytes into the 2nd ipsilateral hand webspace before and 6-12 weeks following axillary node clearance surgery (ANC). Ten patients at least three years after ANC were also recruited (Group 2); seven had developed BCRL and three had not. Blood was sampled from ipsilateral and contralateral antecubital veins 5, 15, 30, 60, 120 and 180 min post-injection to assess pre-nodal shunting from lymph to blood (LVCs), since nodes block erythrocyte transit. The proportion of activity remaining in the depot was used to calculate the degree of shunting in those with evidence of LVCs. RESULTS: Significant erythrocyte-bound activity, increasing over time, was detected contralaterally in 3 of the 5 patients from Group 1 (none of whom developed BCRL) and 3 of 7 patients with BCRL from Group 2, which indicated the presence of LVCs. The degree of shunting was more marked in those patients who did not develop BCRL compared with those who did. CONCLUSIONS: The time-course of erythrocyte-bound contralateral activity indicates transit through lymphovenous communications rather than needle-induced trauma. Lymphovenous communications large enough to transmit erythrocytes are probably constitutional rather than induced. A larger study is warranted to assess any resulting protection against BCRL.

When is a completion axillary lymph node dissection necessary in the presence of a positive sentinel lymph node?

BACKGROUND: The management of the axilla in the presence of positive sentinel lymph node (SLN) remains controversial. Many centres forgo completion axillary lymph node dissection (cALND) in the presence of micrometastatic disease. The American College of Surgeons Oncology Group (ACOSOG) Z0011 trialists argue for extending this to macrometastasis. The aim of this study was to correlate tumour burden in SLNs with that in the residual lymph node basin to determine the likelihood of residual disease in patients with micro- and macrometastasis in the SLN. METHODS: Patients who underwent cALND following a positive SLN were analysed for histopathological features of the primary tumour and burden of axillary disease. RESULTS: Of 155 patients, 115 (74%) had macrometastases and 40 (26%) micrometastases in the SLNs. Residual axillary disease was detected in 55/155 (35%) patients with macrometastases and 4/40 (10%) with micrometastases. Generally, with increasing size of metastasis in the SLN there was an increasing risk of further disease in residual lymph nodes. Logistic regression analysis showed increased odds ratios for further disease for all groups when compared with the <2mm (micrometastasis) SLN group. CONCLUSION: Patients may be advised to forgo cALND where the SLN contains isolated tumour cells or micrometastasis. Recommendations for proceeding to cALND can be based on the size of metastasis in the SLN, which relates to the risk of further disease in the residual axillary lymph nodes and subsequent regional recurrence.

Patterns of metastatic spread in early breast cancer.

AIMS: The aim of this study was to prospectively investigate metastatic pathways of spread to lymph node versus bone marrow and identify biological characteristics that determine these patterns in early invasive breast cancer. PATIENTS AND METHODS: In all, 177 patients with early invasive breast cancer underwent surgical extirpation of the primary tumour with sentinel lymph node biopsy (SLNB). Bone marrow (BM) aspiration was performed to screen for cytokeratin-positive cells by immunocytochemistry. Lymphatic spread was assessed by histopathological examination of lymph nodes (LN). A representative subset of 87 tumours was analysed by tissue microarray (TMA) to evaluate expression of markers that potentially influence haematogenous vs. lymphatic spread. Patients were followed up for a median of 54.7 months. RESULTS: Of the 177 patients, 114 (64%) were BM-/LN-, 38 (22%) BM-/LN+, 19 (11%) BM+/LN- and 6 (3%) BM+/LN+. Multivariate analysis of histopathological characteristics revealed that increasing tumour size was significantly associated with both LN positivity (p = 0.003) and BM positivity (p = 0.01), the presence of lymphovascular invasion significantly correlated with LN+ (p = 0.01), whereas lower histological grade was significantly associated with BM+ (p = 0.03). LN+ and BM+ were non-significantly negatively related to each other. Univariate analysis of the TMA data showed differential expression patterns for several factors; significant differences between effects on the two metastatic pathways (lymphatic vs. haematogenous) were found for expression of CD54 (p = 0.03), osteopontin (p = 0.04), bone sialoprotein (p = 0.04) and CXCR4 (p = 0.009). High expression of CD54, osteopontin and bone sialoprotein (BSP) was positively associated with BM + but was either not associated, or negatively associated, with LN+. High CXCR4 expression was positively associated with LN+ and negatively with BM+. High VEGF-C expression was associated with both LN+ and BM+, although this did not attain statistical significance. Due to the small number of clinical events during clinical follow-up, no associations were identified between metastatic spread patterns, recurrence and/or death. CONCLUSION: These findings suggest that distinct lymphatic and haematogenous metastatic pathways exist in early breast cancer and that these pathways are governed by specific biological markers.

Cancer risk and prevention in a globalised world: solving the public policy mismatch.

The world faces an unprecedented growth in cancer incidence over the next fifty years, the majority of the burden falling on low-middle income countries. At the same time as the changing demographic profiles, including global population ageing we are also seeing the rapid globalisation of pro-cancer behaviours and commodities such as tobacco. The human and economic impact will continue to be severe unless radical changes occur to current public policy mismatches in cancer prevention. At the same time high level political actions through bodies such as the UN suggest that supra-national approaches are needed to solve these issues. However, we argue that only local nation-state approaches can fundamentally address cancer risk and enhance prevention in a globalised world.

Integrated Cancer System: a perspective on developing an integrated system for cancer services in London.

This article explores the potential for integrated cancer systems to improve the quality of care and deliver cost efficiencies and improve outcomes for cancer patients. Currently, patients in the UK still have poorer survival rates than comparable countries such as Canada, Sweden, Norway and Australia. Improving the quality of cancer services is a key policy objective and cancer is a priority outcome measure in both the NHS and Public Health Outcomes Framework. Evidence suggests that better integrated delivery has the potential to improve the quality and reduce the cost of healthcare, and ultimately improve health outcomes. One of the key themes from the Model of Care for Cancer Services (1) was that cancer services should be commissioned along pathways and that provider networks should be established to deliver care. London has two integrated cancer systems; one covering north central and east London (London Cancer) and the other covering west and south London (London Cancer Alliance). There a number of areas in cancer care that the current model of service provision has failed to adequately address and which have the potential to improve significantly though implementation of integrated services. These include improving early diagnosis, reducing inequalities in access to treatment and outcomes and maximising research and training across the system. Important drivers for the integration of cancer services are strong clinical leadership, shared informatics systems, focusing on quality of services and improving patient experience. Emerging needs of integrated cancer in London are around strengthening the involvement of primary care, public health and the third sector; working to develop sufficient capacity and expertise in primary care and collaborating more closely with commissioners to develop integrated systems.

Monitoring the response to primary medical therapy for breast cancer using three- dimensional time-resolved optical mammography.

Primary medical therapy is used to reduce tumour size prior to surgery in women with locally advanced breast cancer. Optical tomography is a functional imaging technique using near- infrared light to produce three-dimensional breast images of tissue oxygen saturation and haemoglobin concentration. Its advantages include the ability to display quantitative physiological information, and to allow repeated scans without the hazards associated with exposure to ionising radiation. There is a need for a non-invasive functional imaging tool to evaluate response to treatment, so that non-responders can be given the opportunity to change their treatment regimen. Here, we evaluate the use of optical tomography for this purpose. Four women with newly diagnosed breast cancer who were about to undergo primary medical therapy gave informed and voluntary consent to take part in the study. Changes in physiological and optical properties within the tumour were evaluated during the course of neoadjuvant chemotherapy. Optical imaging was performed prior to treatment, after the first cycle of chemotherapy, halfway through, and on completion of chemotherapy. Images of light absorption and scatter at two wavelengths were produced, from which images of total haemoglobin concentration and oxygen saturation were derived. All patients that showed a good or complete response to treatment on MRI showed a corresponding recovery in the haemoglobin concentration images. Changes in mean tumour total haemoglobin concentration could be seen four weeks into treatment. The tumour oxygen saturation was low compared to background in three out of four patients, and also showed a return to baseline over treatment. Optical imaging of the breast is feasible during primary medical therapy and can be used to assess response to treatment over six months.

Avoiding the zero sum game in global cancer policy: beyond 2011 UN high level summit.

In September 2011 a unique high level summit on non-communicable diseases will be held in New York. For cancer as for many of the other chronic diseases this marks their first high level recognition. However, the reality of cancer control in middle and low income countries is and will be very different from the trajectory experienced by developed countries. This perspective seeks to critically examine the approach being taken, mapping pitfalls and presenting alternative solutions for an international cancer control policy.

An analysis of research activity in major UK cancer centres.

The organisation of cancer research is critical to its overall creativity and productivity. Cancer centres are a major organisational structure for this research, however, little is known about their effect on research or how national policy-making intersects with this complex policy nexus. This study of the evolution of United Kingdom cancer centres (UKCC), part of a wider European and United States programme, uses a bibliometric analysis of research activity prior to the creation of the NCRI and after its formation (1995-2004/5). In terms of critical research mass UKCC are very heterogeneous with a fourfold difference between the top and bottom quintiles. UK centres published just over one eighth of the total UKCC in 1995 but almost a quarter by 2004. This centrification occurred in the absence of any national strategy. Overall these centres conduct more fundamental (laboratory-based) research than that being conducted in the wider network but this hides major heterogeneity. UKCC collaborate with European investigators in 5-28% of all their outputs and with USA the range is between 6% and 21%. We have also derived new measures of research impact on clinical management and the general public as well as the impact of national policy on research assessment for certain types of cancer research.

Darwin, medicine and cancer.

'Nothing in biology makes sense except in the light of evolution'! So said Theodore Dobzhansky. It is extraordinary how little Darwinism and post-Darwinian evolutionary science has penetrated medicine despite the fact that all biology is built upon its foundations. Randy Nesse, one of the fathers of Darwinian medicine, recently observed that doctors 'know the facts but not the origins'. Clearly, then, in this auspicious year-200 years since Charles Darwin's birth and 150 years since the first edition of the Origin of Species-it is time to reconsider Darwin's legacy to medicine and to invite evolution back into the biomedical fold. Here, we consider the legacy of Darwin and the contribution of the other great evolutionists such as Ernst Mayr to cancer and medicine.

Treatment and survival in breast cancer in the Eastern Region of England.

BACKGROUND: The reasons for variation in survival in breast cancer are multifactorial. METHODS: From 1999 to 2003, the vital status of 9051 cases of invasive breast cancer was identified in the Eastern Region of England. Survival analysis was by Cox proportional hazards regression. Data were analysed separately for patients aged <70 years and those older due to differences in treatment policies. RESULTS: Overall 5-year survival was 78%. In patients aged <70 years, significant differences in survival lost their formal significance after adjustment for detection mode and node status, although this remained close to statistical significance with some residual differences between relative hazards. There was significant negative ecological correlation between proportion with nodes positive or not examined and 9-year survival rates. Patients with estrogen receptor (ER) status unknown were at significantly higher risk of dying than ER-positive patients. There was a clear trend of increasing hazard of dying with increasing deprivation. Survival differences in women aged > or =70 years were related to whether surgery was included as part of treatment. CONCLUSION: This variation in treatment and survival may be attributed to lack of information, in particular nodal and ER status, thereby impacting on staging and prescription of adjuvant therapy.

Sympathetic nerve damage as a potential cause of lymphoedema after axillary dissection for breast cancer.

BACKGROUND: The physiological disturbances leading to lymphoedema after breast cancer surgery are poorly understood. Damage to sympathetic nerves during axillary lymph node dissection (ALND), leading to increased capillary fluid filtration, was investigated as a possible contributory factor. METHODS: The integrity of the upper limb sympathetic nervous system was tested in 36 patients before, and 3 and 12 months after ALND. Forearm vascular resistance (FVR), calculated from forearm blood flow and mean systemic arterial pressure, was measured before and after exposure to lower-body negative pressure. Forearm venous compliance was measured using (99m)Tc-labelled autologous erythrocytes and radionuclide plethysmography before and after cold water immersion of the feet. RESULTS: There were clear changes in FVR and venous compliance in response to sympathetic stimulation but no differences attributable to surgery or between the nine patients who developed lymphoedema and the 27 who did not; nor were there differences between the two arms. There was a trend towards lower preoperative FVR in patients who developed lymphoedema. CONCLUSION: Lymphoedema is not the result of sympathetic nerve damage sustained during ALND. Preoperative FVR may help predict who will get lymphoedema following this surgery.

Understanding breast cancer-related lymphoedema.

Breast cancer-related lymphoedema (BCRL) is a chronic swelling of the upper limb following surgery to axillary lymph nodes. This clinical literature review considers the risk factors that have been identified for the development of BCRL: the extent of surgery to the breast and the axilla, radiotherapy, nodal status, infection and patient characteristics such as BMI and patient age. The management of BCRL is primarily conservative, but the evidence for pharmacological and surgical approaches is also considered.

A pilot study of dual-isotope lymphoscintigraphy for breast sentinel node biopsy comparing intradermal and intraparenchymal injection.

AIMS: Identification of sentinel lymph nodes (SLN) may depend on the tissue plane of tracer injection. To explore this, we developed a dual-isotope technique to compare the lymphatic drainage basins accessed by intradermal and parenchymal injections. METHODS: Fifteen breast cancer patients had simultaneous parenchymal and intradermal injections of (99m)Tc-labelled human immunoglobulin G (HIG) and (111)In-HIG, respectively, 2-4h before axillary lymph node clearance surgery. All 228 freshly dissected nodes were assayed by well counting and examined for metastatic disease by haematoxylin/eosin staining and immuno-histochemistry. RESULTS: Total nodal uptake following intradermal injection was 10 times more than after parenchymal injection. Tracer uptake within the first three draining nodes divided patients into three groups; four (group 1) had identical 1st, 2nd and 3rd echelon nodes, six (group 2) had identical 1st and 2nd echelon nodes and five (group 3) had different 1st echelon nodes. With respect to the first, second and third groups, there was close, moderate and poor correlation (Pearson), respectively, between individual nodal counts accumulated from the two injection sites. Of eight patients with nodal disease, the SLN identified by intradermal and parenchymal injections contained disease in seven and four patients, respectively. CONCLUSIONS: Comparison of nodal tracer distributions from the two injection planes allows a functional model to be developed with two possible routes of drainage from the parenchymal plane, one joining the tract from the areolar plexus and the other passing independently to the axilla which builds upon Sappey's original anatomical model. This may explain the variable uptake, discordance and false negative SLN identification.

Screen-detected vs symptomatic breast cancer: is improved survival due to stage migration alone?

This paper examines whether screen-detected breast cancer confers additional prognostic benefit to the patient, over and above that expected by any shift in stage at presentation. In all, 5604 women (aged 50-70 years) diagnosed with invasive breast cancer between 1998 and 2003 were identified by the Eastern Cancer Registration and Information Centre (ECRIC) and mammographic screening status was determined. Using proportional hazards regression, we estimated the effect of screen detection compared with symptomatic diagnosis on 5-year survival unadjusted, then adjusted for age and Nottingham Prognostic Index (NPI). A total of 72% of the survival benefit associated with screen-detected breast cancer can be accounted for by age and shift in NPI. Survival analysis by continuous NPI showed a small but systematic survival benefit for screen-detected cancers at each NPI value. These data show that although most of the screen-detected survival advantage is due to a shift in NPI, the mode of detection does impact on survival in patients with equivalent NPI scores. This residual survival benefit is small but significant, and is likely to be due to differences in tumour biology. Current prognostication tools may, therefore, overestimate the benefit of systemic treatments in screen-detected cancers and lead to overtreatment of these patients.

Stem cells and breast cancer.

Proliferation in continuously renewing tissues, including the mammary gland, is hierarchically organized with a small number of slowly dividing stem cells and a greater number of more rapidly proliferating 'transit amplifying' cells. Mammary stem cells have been recently identified and purified based on their surface antigen expression. The recognition of mammary epithelial stem cells had led to the hypothesis that these may be at the root of breast cancer. In support of this, a highly tumorigenic subpopulation of cancer cells - cancer stem cells - has recently been identified in primary and metastatic breast cancer samples and in a number of established breast cancer cell lines. The existence of cancer stem cells would explain why only a small minority of cancer cells is capable of extensive proliferation and transferral of the tumour. In this article we aim to review the evidence in support of the existence of both normal mammary stem cells and breast cancer stem cells, and provide further insight into how taking this subpopulation of cells into account may affect the way we treat epithelial cancers in the future.