Search

Background: Axillary surgery is an established part of the management of primary breast cancer. It provides staging information to guide adjuvant therapy and potentially local control of axillary disease. Several alternative approaches to axillary surgery are available, most of which aim to spare a proportion of women the morbidity of complete axillary dissection., Objectives: To assess the benefits and harms of alternative approaches to axillary surgery (including omitting such surgery altogether) in terms of overall survival; local, regional and distant recurrences; and adverse events., Search Methods: We searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE, Pre-MEDLINE, Embase, CENTRAL, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov on 12 March 2015 without language restrictions. We also contacted study authors and checked reference lists., Selection Criteria: Randomised controlled trials (RCTs) including women with clinically defined operable primary breast cancer conducted to compare axillary lymph node dissection (ALND) with no axillary surgery, axillary sampling or sentinel lymph node biopsy (SLNB); RCTs comparing axillary sampling with SLNB or no axillary surgery; RCTs comparing SLNB with no axillary surgery; and RCTs comparing ALND with or without radiotherapy (RT) versus RT alone., Data Collection and Analysis: Two review authors independently assessed each potentially relevant trial for inclusion. We independently extracted outcome data, risk of bias information and study characteristics from all included trials. We pooled data according to trial interventions, and we used hazard ratios (HRs) for time-to-event outcomes and odds ratios (OR) for binary outcomes., Main Results: We included 26 RCTs in this review. Studies were at low or unclear risk of selection bias. Blinding was not done, but this was only considered a source of bias for outcomes with potential for subjectivity in measurements. We found no RCTs of axillary sampling versus SLNB, axillary sampling versus no axillary surgery or SLNB versus no axillary surgery. No axillary surgery versus ALND Ten trials involving 3849 participants compared no axillary surgery versus ALND. Moderate quality evidence showed no important differences between overall survival of women in the two groups (HR 1.06, 95% confidence interval (CI) 0.96 to 1.17; 3849 participants; 10 studies) although no axillary surgery increased the risk of locoregional recurrence (HR ranging from 1.10 to 3.06; 20,863 person-years of follow-up; four studies). It was uncertain whether no surgery increased the risk of distant metastasis compared with ALND (HR 1.06, 95% CI 0.87 to 1.30; 946 participants; two studies). Low-quality evidence indicated no axillary surgery decreased the risk of lymphoedema compared with ALND (OR 0.31, 95% CI 0.23 to 0.43; 1714 participants; four studies). Axillary sampling versus ALND Six trials involving 1559 participants compared axillary sampling versus ALND. Low-quality evidence indicated similar effectiveness of axillary sampling compared with ALND in terms of overall survival (HR 0.94, 95% CI 0.73 to 1.21; 967 participants; three studies) but it was unclear whether axillary sampling led to increased risk of local recurrence compared with ALND (HR 1.41, 95% CI 0.94 to 2.12; 1404 participants; three studies). The relative effectiveness of axillary sampling and ALND for locoregional recurrence (HR 0.74, 95% CI 0.46 to 1.20; 406 participants; one study) and distant metastasis was uncertain (HR 1.05, 95% CI 0.74 to 1.49; 406 participants; one study). Lymphoedema was less likely after axillary sampling than after ALND (OR 0.32, 95% CI 0.13 to 0.81; 80 participants; one study). SLNB versus ALND Seven trials involving 9426 participants compared SLNB with ALND. Moderate-quality evidence showed similar overall survival following SLNB compared with ALND (HR 1.05, 95% CI 0.89 to 1.25; 6352 participants; three studies; moderate-quality evidence). Differences in local recurrence (HR 0.94, 95% CI 0.24 to 3.77; 516 participants; one study), locoregional recurrence (HR 0.96, 95% CI 0.74 to 1.24; 5611 participants; one study) and distant metastasis (HR 0.80, 95% CI 0.42 to 1.53; 516 participants; one study) were uncertain. However, studies showed little absolute difference in the aforementioned outcomes. Lymphoedema was less likely after SLNB than ALND (OR ranged from 0.04 to 0.60; three studies; 1965 participants; low-quality evidence). Three studies including 1755 participants reported quality of life: Investigators in two studies found quality of life better after SLNB than ALND, and in the other study observed no difference. RT versus ALND Four trials involving 2585 participants compared RT alone with ALND (with or without RT). High-quality evidence indicated that overall survival was reduced among women treated with radiotherapy alone compared with those treated with ALND (HR 1.10, 95% CI 1.00 to 1.21; 2469 participants; four studies), and local recurrence was less likely in women treated with radiotherapy than in those treated with ALND (HR 0.80, 95% CI 0.64 to 0.99; 22,256 person-years of follow-up; four studies). Risk of distant metastasis was similar for radiotherapy alone as for ALND (HR 1.07, 95% CI 0.93 to 1.25; 1313 participants; one study), and whether lymphoedema was less likely after RT alone than ALND remained uncertain (OR 0.47, 95% CI 0.16 to 1.44; 200 participants; one study). Less surgery versus ALND When combining results from all trials, treatment involving less surgery was associated with reduced overall survival compared with ALND (HR 1.08, 95% CI 1.01 to 1.17; 6478 participants; 18 studies). Whether local recurrence was reduced with less axillary surgery when compared with ALND was uncertain (HR 0.90, 95% CI 0.75 to 1.09; 24,176 participant-years of follow up; eight studies). Locoregional recurrence was more likely with less surgery than with ALND (HR 1.53, 95% CI 1.31 to 1.78; 26,880 participant-years of follow-up; seven studies). Whether risk of distant metastasis was increased after less axillary surgery compared with ALND was uncertain (HR 1.07, 95% CI 0.95 to 1.20; 2665 participants; five studies). Lymphoedema was less likely after less axillary surgery than with ALND (OR 0.37, 95% CI 0.29 to 0.46; 3964 participants; nine studies).No studies reported on disease control in the axilla., Authors' Conclusions: This review confirms the benefit of SLNB and axillary sampling as alternatives to ALND for axillary staging, supporting the view that ALND of the clinically and radiologically uninvolved axilla is no longer acceptable practice in people with breast cancer.

Objective: Primary endocrine therapy (PET) is an alternative to surgery for oestrogen receptor positive operable breast cancer in some older women. However the decision to offer PET involves complex trade-offs and is influenced by both patient choice and healthcare professional (HCP) preference. This study aimed to compare the views of patients and HCPs about this decision and explore decision-making (DM) preferences and whether these are taken into account during consultations., Methods: This multicentre, UK, mixed methods study had three components: (a) questionnaires to older women undergoing counseling about breast cancer treatment options which assessed their DM preferences and realities; (b) qualitative interviews with older women with operable breast cancer offered a choice of either surgery or PET and (c) qualitative interviews with HCPs (both of which focused on DM preferences in this setting)., Results: Thirty-three patients and 34 HCPs were interviewed. A range of opinions about patient involvement in DM were identified. Patients indicated varying preferences for DM involvement which were variably taken into account by HCPs. These qualitative findings were broadly supported by the questionnaire results. Most patients (536/729; 73.5%) achieved their preferred DM style; however, the remainder felt that their DM preferences had not been taken into consideration., Conclusions: These results suggest that whilst many older women achieve their desired level of DM engagement, some do not, raising the possibility that they may be making choices which are not concordant with their treatment preferences., (Copyright © 2015 John Wiley & Sons, Ltd.)

Objective: Primary Endocrine Therapy (PET) is a good alternative to surgery for breast cancer in older frailer women. Overall survival rates are equivalent although rates of local control are inferior. There is little research regarding the decision support needs of older patients faced with this choice. This qualitative study aimed to explore these among older breast cancer patients offered a choice of treatment, as the basis to develop an appropriate decision support tool., Methods: Semi-structured interviews were undertaken with older women (>75 years) with breast cancer who had been offered a choice of PET or surgery at diagnosis. Women's involvement in their treatment decision and support for the process were explored and analysed using framework analysis., Results: Thirty-three interviews were undertaken (median age 82, range 75-95 years, 22 PET, 11 surgery). Most women, regardless of treatment choice, wanted tailored information about the different treatment options, their impact on independence, the practicalities of treatment and the risk of recurrence and spread. Surgery was the treatment of choice in women wanting optimal disease control; those choosing PET felt that they were 'too old' for surgery and wanted minimal disruption., Conclusions: Older women described making active treatment decisions. However, some knowledge was inaccurate. Women wanted information and decision support from their clinicians along with a specific tailored information booklet to support this process., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Several studies have evaluated the clinical effectiveness of endocrine therapy alone in women aged 70 years or over with operable breast cancer and who are fit for surgery., Objectives: To systematically review the evidence for the clinical effectiveness of surgery (with or without adjuvant endocrine therapy) in comparison to primary endocrine therapy in the treatment of operable breast cancer in women aged 70 years and over, both in terms of local progression and mortality., Search Methods: We conducted an updated search of the Cochrane Breast Cancer Group's Specialised Register (27th March 2013) and new searches of the Cochrane Central Register of Controlled Trials (CENTRAL, 2013, Issue 3), MEDLINE, EMBASE, the World Health Organization's International Clinical Trials Registry Platform (apps.who.int/trialsearch/) and www., Clinicaltrials: gov, using the search terms 'early breast cancer', 'endocrine therapy', 'psychosocial' or 'surgery'., Selection Criteria: Randomised trials comparing surgery, with or without adjuvant endocrine therapy, to primary endocrine therapy in the management of women aged 70 years or over with early breast cancer and who were fit for surgery., Data Collection and Analysis: We assessed studies for eligibility and quality, and two review authors independently extracted data from published trials. We derived hazard ratios for time-to-event outcomes, where possible, and used a fixed-effect model for meta-analysis. We extracted toxicity and quality-of-life data, where present. Where outcome data were not available, we contacted trialists and requested unpublished data., Main Results: We identified seven eligible trials, of which six had published time-to-event data and one was published only in abstract form with no usable data. The quality of the allocation concealment was adequate in three studies and unclear in the remainder. In each case the endocrine therapy used was tamoxifen. Data, based on an estimated 1081 deaths in 1571 women, did not show a statistically significant difference in favour of either surgery or primary endocrine therapy in respect of overall survival. However, there was a statistically significant difference in terms of progression-free survival, which favoured surgery with (474 participants) or without endocrine therapy (164 participants). The hazard ratios (HRs) for overall survival were: HR 0.98 (95% confidence interval (CI) 0.81 to 1.20, P = 0.85; 3 trials, 495 participants) for surgery alone versus primary endocrine therapy; HR 0.86 (95% CI 0.73 to 1.00, P = 0.06; 3 trials, 1076 participants) for surgery plus endocrine therapy versus primary endocrine therapy. The HRs for progression-free survival were: HR 0.55 (95% CI 0.39 to 0.77, P = 0.0006) for surgery alone versus primary endocrine therapy; HR 0.65 (95% CI 0.53 to 0.81, P = 0.0001) for surgery plus endocrine therapy versus primary endocrine therapy (each comparison based on only one trial). Tamoxifen-related adverse effects included hot flushes, skin rash, vaginal discharge, indigestion, breast pain, sleepiness, headache, vertigo, itching, hair loss, cystitis, acute thrombophlebitis, nausea, and indigestion. Surgery-related adverse effects included paraesthesia on the ipsilateral arm and lateral thoracic wall in those who had axillary clearance. One study suggested that those undergoing surgery suffered more psychosocial morbidity at three months post-surgery, although this difference had disappeared by two years., Authors' Conclusions: Primary endocrine therapy should only be offered to women with oestrogen receptor (ER)-positive tumours who are unfit for surgery, at increased risk of serious surgical or anaesthetic complications if subjected to surgery, or who refuse surgery. In a cohort of women with significant co-morbid disease and ER-positive tumours it is possible that primary endocrine therapy may be a superior option to surgery. Trials are needed to evaluate the clinical effectiveness of aromatase inhibitors as primary therapy for an infirm older population with ER-positive tumours., (Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: There is interest in interventions that provide support for patients facing challenging decisions, such as the choice between mastectomy and breast conservation surgery for breast cancer. However, it is difficult to implement these interventions. One potential source of resistance is the attitudes of clinicians., Objective: To examine specialist breast clinicians' opinions about the provision of decision support interventions (DesIs) for patients., Methods: As part of the development of a web-based DesI (BresDex), semi-structured interviews were conducted with specialist clinicians [breast surgeons, breast care nurses (BCNs) and oncologists] from four breast units in a UK region, and speciality national opinion leaders. Interviews were recorded, transcribed and analysed using the Framework approach., Results: A majority of the 24 clinicians interviewed did not have a working knowledge of DesIs and were ambivalent or sceptical. Many expressed conflicting opinions: they noted the potential benefits, but at the same time expressed reservations about information overlap, overload and about content that they considered inappropriate. Many wanted access to DesIs to be always under clinical supervision. In particular, they were uncertain as regards how DeSIs could be tailored to individual patients' needs and also accommodate clinical practice variation. BCNs were particularly concerned that DesIs might induce patient anxiety and replace their role., Conclusions: The concept of providing interventions to support patients in decision-making tasks generated concern, defensiveness and scepticism. These attitudes will be a significant barrier. Implementation efforts will need to recognize and address these issues if these interventions are to become embedded in clinical practice., (© 2010 Blackwell Publishing Ltd.)

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. Formerly GISTs were commonly classified histologically as leiomyosarcomas; however, they are now known to arise from the interstitial cells of Cajal. Majority of GISTs overexpress KIT and have characteristic mutations within the gene, which are the targets of drug treatment with tyrosine kinase inhibitors. Leiomyosarcoma is a malignant tumour of smooth muscle differentiation and falls into a group of sarcomas that show complex karyotypic changes with no consistent recurrent genetic abnormality. We have used comparative genomic hybridization in combination with fluorescence in situ hybridization to determine genetic differences between the tumour types. We found leiomyosarcomas and GISTs share common regions of chromosomal 13q and 11q imbalance, in addition to more specific 1p and 8p losses in leiomyosarcoma and 15q and 22q losses in GISTs. More importantly, we have shown for the first time a deletion in the ataxia telangiectasia mutated (ATM) gene locus with decreased/absent expression of ATM protein, and amplification in the region 13q21-q32 in both tumour types, suggesting both regions may play a role in leiomyosarcoma and GIST biology.

The study of angiogenesis has grown exponentially over the past 40 years with the recognition that angiogenesis is essential for numerous pathologies and, more recently, with the advent of successful drugs to inhibit angiogenesis in tumours. The main problem with angiogenesis research remains the choice of appropriate assays to evaluate the efficacy of potential new drugs and to identify potential targets within the angiogenic process. This selection is made more complex by the recognition that heterogeneity occurs, not only within the endothelial cells themselves, but also within the specific microenvironment to be studied. Thus, it is essential to choose the assay conditions and cell types that most closely resemble the angiogenic disease being studied. This is especially important when aiming to translate data from in vitro to in vivo and from preclinical to the clinic. Here we critically review and highlight recent advances in the principle assays in common use including those for endothelial cell proliferation, migration, differentiation and co-culture with fibroblasts and mural cells in vitro, vessel outgrowth from organ cultures and in vivo assays such as chick chorioallantoic membrane (CAM), zebrafish, sponge implantation, corneal, dorsal air sac, chamber and tumour angiogenesis models. Finally, we briefly discuss the direction likely to be taken in future studies, which include the use of increasingly sophisticated imaging analysis systems for data acquisition.

Background: Several studies have evaluated the clinical effectiveness of endocrine therapy alone in women aged 70 years or over and who are fit for surgery., Objectives: To identify and review the evidence from randomised trials comparing primary endocrine therapy (endocrine therapy alone) to surgery, with or without adjuvant endocrine therapy, in the management of women aged 70 years or over with operable breast cancer., Search Strategy: The Cochrane Breast Cancer Group Specialised Register was searched on 21st August 2003 using the codes for "early breast cancer", "endocrine therapy", "psychosocial" or "surgery". Details of the search strategy applied to create the register and the procedure used to code references are described in the Cochrane Breast Cancer Group module on The Cochrane Library., Selection Criteria: Randomised trials comparing primary endocrine therapy with surgery, with or without adjuvant endocrine therapy, in the management of women aged 70 years or over with early breast cancer and who are fit for surgery., Data Collection and Analysis: Studies were assessed for eligibility and quality, and data from published trials were extracted by two independent reviewers. Hazard ratios were derived for time-to-event outcomes, where possible, and a fixed-effect model was used for meta-analysis. Toxicity and quality-of-life data were extracted, where present. Where outcome data were not available, trialists were contacted and unpublished data requested., Main Results: Seven eligible trials were identified of which six had published time-to-event data and one was published only in abstract form with no usable data. The quality of the allocation concealment was adequate in three studies and unclear in the remainder. In each case the endocrine therapy used was tamoxifen.Data, based on an estimated 869 deaths in 1571 women, were unable to show a statistically significant difference in favour of either surgery or primary endocrine therapy in respect of overall survival. However, there was a statistically significant difference in terms of progression-free survival, which favoured surgery with or without endocrine therapy.The hazard ratios (HR) for overall survival were: 0.98 (95% confidence interval (CI) 0.74 to 1.30, P value 0.9) for surgery alone versus primary endocrine therapy; 0.86 (95% CI 0.73 to 1.00, P value 0.06) for surgery plus endocrine therapy versus primary endocrine therapy. The HRs for progression-free survival were: 0.55 (95% CI 0.39 to 0.77, P value 0.0006) for surgery alone versus primary endocrine therapy; 0.65 (95% CI 0.53 to 0.81, P value 0.0001) for surgery plus endocrine therapy versus primary endocrine therapy (each comparison based on only one trial). Tamoxifen-related adverse effects included hot flushes, skin rash, vaginal discharge, indigestion, breast pain, sleepiness, headache, vertigo, itching, hair loss, cystitis, acute thrombophlebitis, nausea, and indigestion. Surgery-related adverse effects included paresthesia on the ipsilateral arm and lateral thoracic wall in those who had axillary clearance. One study suggested that those undergoing surgery suffered more psychosocial morbidity at three months postsurgery, although this difference had disappeared by two years., Authors' Conclusions: Primary endocrine therapy should only be offered to women with oestrogen receptor (ER) positive tumours who are unfit for or who refuse surgery. In a cohort of women with significant co-morbid disease and ER-positive tumours it is possible that primary endocrine therapy may be a superior option to surgery. Trials are needed to evaluate the clinical effectiveness of aromatase inhibitors as primary therapy for an infirm older population with ER-positive tumours.

A method utilizing electroporation to deliver antisense oligodeoxynucleotides into Paramecium tetraurelia has been developed. For these studies antisense oligonucleotides directed to different regions of the calmodulin mRNA were used. It was found that a pulse delivered at 150-250 V (375-625 V/cm field strength) for 3.9-4.2 ms using a 275 microF capacitor with resistance set at 13 Ohms was sufficient to achieve measurable incorporation of fluorescently-labeled oligodeoxynucleotides in up to 95% of the cells treated. Optimal parameters included using oligodeoxynucleotides of at least 12 bases in length with a 3' blocking group at a dose of around 10 microM. In addition, multiple oligodeoxynucleotides directed to the same target mRNA resulted in at least a 10-fold reduction in the dose of oligodeoxynucleotide required to achieve the desired effects. Taken together, these results indicate that the use of antisense oligodeoxynucleotides can be an easy and useful method for linking genes to specific functions in Paramecium tetraurelia. Finally, this report discusses how different 3' blocking groups and the use of combinations of oligodeoxynucleotides directed to different regions of the same target mRNA can help address concerns about specificity.