A phase 1 trial of human telomerase reverse transcriptase (hTERT) vaccination combined with therapeutic strategies to control immune-suppressor mechanisms.

The presence of inhibitory immune cells and difficulty in generating activated effector T cells remain obstacles to development of effective cancer vaccines. We designed a vaccine regimen combining human telomerase reverse transcriptase (hTERT) peptides with concomitant therapies targeting regulatory T cells (Tregs) and cyclooxygenase-2 (COX2)-mediated immunosuppression. This Phase 1 trial combined an hTERT-derived 7-peptide library, selected to ensure presentation by both HLA class-I and class-II in 90% of patients, with oral low-dose cyclophosphamide (to modulate Tregs) and the COX2 inhibitor celecoxib. Adjuvants were Montanide and topical TLR-7 agonist, to optimise antigen presentation. The primary objective was determination of the safety and tolerability of this combination therapy, with anti-cancer activity, immune response and detection of antigen-specific T cells as additional endpoints. Twenty-nine patients with advanced solid tumours were treated. All were multiply-pretreated, and the majority had either colorectal or prostate cancer. The most common adverse events were injection-site reactions, fatigue and nausea. Median progression-free survival was 9 weeks, with no complete or partial responses, but 24% remained progression-free for ≥6 months. Immunophenotyping showed post-vaccination expansion of CD4+ and CD8+ T cells with effector phenotypes. The in vitro re-challenge of T cells with hTERT peptides, TCR sequencing, and TCR similarity index analysis demonstrated the expansion following vaccination of oligoclonal T cells with specificity for hTERT. However, a population of exhausted PD-1+ cytotoxic T cells was also expanded in vaccinated patients. This vaccine combination regimen was safe and associated with antigen-specific immunological responses. Clinical activity could be improved in future by combination with anti-PD1 checkpoint inhibition to address the emergence of an exhausted T cell population.

Tumour-draining axillary lymph nodes in patients with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC): the crucial contribution of immune cells (effector, regulatory) and cytokines (Th1, Th2) to immune-mediated tumour cell death induced by NAC.

BACKGROUND: The tumour microenvironment consists of malignant cells, stroma and immune cells. In women with large and locally advanced breast cancers (LLABCs) undergoing neoadjuvant chemotherapy (NAC), tumour-infiltrating lymphocytes (TILs), various subsets (effector, regulatory) and cytokines in the primary tumour play a key role in the induction of tumour cell death and a pathological complete response (pCR) with NAC. Their contribution to a pCR in nodal metastases, however, is poorly studied and was investigated. METHODS: Axillary lymph nodes (ALNs) (24 with and 9 without metastases) from women with LLABCs undergoing NAC were immunohistochemically assessed for TILs, T effector and regulatory cell subsets, NK cells and cytokine expression using labelled antibodies, employing established semi-quantitative methods. IBM SPSS statistical package (21v) was used. Non-parametric (paired and unpaired) statistical analyses were performed. Univariate and multivariate regression analyses were carried out to establish the prediction of a pCR and Spearman's Correlation Coefficient was used to determine the correlation of immune cell infiltrates in ALN metastatic and primary breast tumours. RESULTS: In ALN metastases high levels of TILs, CD4+ and CD8+ T and CD56+ NK cells were significantly associated with pCRs.. Significantly higher levels of Tregs (FOXP3+, CTLA-4+) and CD56+ NK cells were documented in ALN metastases than in the corresponding primary breast tumours. CD8+ T and CD56+ NK cells showed a positive correlation between metastatic and primary tumours. A high % CD8+ and low % FOXP3+ T cells and high CD8+: FOXP3+ ratio in metastatic ALNs (tumour-free para-cortex) were associated with pCRs. Metastatic ALNs expressed high IL-10, low IL-2 and IFN-ϒ. CONCLUSIONS: Our study has provided new data characterising the possible contribution of T effector and regulatory cells and NK cells and T helper1 and 2 cytokines to tumour cell death associated with NAC in ALNs. TRIAL REGISTRATION: The Trial was retrospectively registered. Study Registration Number is ISRCTN00407556 .

The Differential Contribution of the Innate Immune System to a Good Pathological Response in the Breast and Axillary Lymph Nodes Induced by Neoadjuvant Chemotherapy in Women with Large and Locally Advanced Breast Cancers.

The tumour microenvironment consists of malignant cells, stroma, and immune cells. The role of adaptive immunity in inducing a pathological complete response (pCR) in breast cancer with neoadjuvant chemotherapy (NAC) is well studied. The contribution of innate immunity, however, is poorly documented. Breast tumours and axillary lymph nodes (ALNs) from 33 women with large and locally advanced breast cancers (LLABCs) undergoing NAC were immunohistochemically assessed for tumour-infiltrating macrophages (TIMs: M1 and M2), neutrophils (TINs), and dendritic cells (TIDCs) using labelled antibodies and semiquantitative methods. Patients' blood neutrophils (n = 108), DCs (mDC1 and pDC), and their costimulatory molecules (n = 30) were also studied. Pathological results were classified as pCR, good (GPR) or poor (PRR). In breast and metastatic ALNs, high levels of CD163+ TIMs were significantly associated with a pCR. In blood, high levels of neutrophils were significantly associated with pCR in metastatic ALNs, whilst the % of mDC1 and pDC and expression of HLA-DR, mDC1 CD40, and CD83 were significantly reduced. NAC significantly reduced tumour DCs but increased blood DCs. PPRs to NAC had significantly reduced HLA-DR, CD40, and CD86 expression. Our study demonstrated novel findings documenting the differential but important contributions of innate immunity to pCRs in patients with LLABCs undergoing NAC.

Crucial Contributions by T Lymphocytes (Effector, Regulatory, and Checkpoint Inhibitor) and Cytokines (TH1, TH2, and TH17) to a Pathological Complete Response Induced by Neoadjuvant Chemotherapy in Women with Breast Cancer.

The tumour microenvironment consists of malignant cells, stroma, and immune cells. Prominent tumour-infiltrating lymphocytes (TILs) in breast cancer are associated with a good prognosis and are predictors of a pathological complete response (pCR) with neoadjuvant chemotherapy (NAC). The contribution of different T effector/regulatory cells and cytokines to tumour cell death with NAC requires further characterisation and was investigated in this study. Breast tumours from 33 women with large and locally advanced breast cancers undergoing NAC were immunohistochemically (intratumoural, stromal) assessed for T cell subsets and cytokine expression using labelled antibodies, employing established semiquantitative methods. Prominent levels of TILs and CD4+, CD8+, and CTLA-4+ (stromal) T cells and CD8+ : FOXP3+ ratios were associated with a significant pCR; no association was seen with FOXP3+, CTLA-4+ (intratumoural), and PD-1+ T cells. NAC significantly reduced CD4+, FOXP3+, CTLA-4+ (stromal) (concurrently blood FOXP3+, CTLA-4+ Tregs), and PD-1+ T cells; no reduction was seen with CD8+ and CTLA-4+ (intratumoural) T cells. High post-NAC tumour levels of FOXP3+ T cells, IL-10, and IL-17 were associated with a failed pCR. Our study has characterised further the contribution of T effector/regulatory cells and cytokines to tumour cell death with NAC.

Natural killer (NK) cell profiles in blood and tumour in women with large and locally advanced breast cancer (LLABC) and their contribution to a pathological complete response (PCR) in the tumour following neoadjuvant chemotherapy (NAC): differential restoration of blood profiles by NAC and surgery.

BACKGROUND: NK cells contribute to tumour surveillance, inhibition of growth and dissemination by cytotoxicity, secretion of cytokines and interaction with immune cells. Their precise role in human breast cancer is unclear and the effect of therapy poorly studied. The purpose of our study was to characterise NK cells in women with large (≥3 cm) and locally advanced (T3-4, N1-2, M0) breast cancers (LLABCs) undergoing neoadjuvant chemotherapy (NAC) and surgery, and to ascertain their possible contribution to a pathological complete response (pCR). METHODS: Women with LLABCs (n = 25) and healthy female donors [HFDs (n = 10)] were studied. Pathological responses in the breast were assessed using established criteria. Blood samples were collected pre and post NAC and surgery. Flow cytometry and labelled monoclonal antibodies established absolute numbers (AbNs) and percentages (%) of NK cells, and expressing granzyme B/perforin and NKG2D. In vitro NK cytotoxicity was assessed and NK cells and cytokines (IL-2, INF-γ, TGF-ß) documented in tumours using immunohistochemical techniques. Data was analysed by SPSS. RESULTS: Women with LLABCs had significantly reduced AbNs (160.00 ± 40.00 cells/µl) but not % of NK cells, compared with HFDs (NK: 266.78 ± 55.00 cells/µl; p = 0.020). NAC enhanced the AbN (p = 0.001) and % (p = 0.006) of NK cells in patients with good pathological responses. Granzyme B(+)/perforin(+) cells were significantly reduced (43.41 ± 4.00%), compared with HFDs (60.26 ± 7.00%; p = 0.003). NAC increased the % in good (p = 0.006) and poor (p = 0.005) pathological responders. Pretreatment NK cytotoxicity was significantly reduced in good (37.80 ± 8.05%) and poor (22.80 ± 7.97%) responders (p = 0.001) but remained unchanged following NAC. NK-NKG2D(+) cells were unaltered and unaffected by NAC; NKG2D expression was increased in patients with a pCR (p = 0.001). Surgery following NAC was not beneficial, except in those with a pCR. Tumour-infiltrating NK cells were infrequent but increased peritumourally (p = 0.005) showing a significant correlation (p = 0.004) between CD56(+) cells and grade of response. Tumour cytokines had no effect. CONCLUSION: Women with LLABCs have inhibited blood innate immunity, variably reversed by NAC (especially with tumour pCRs), which returned to pretreatment levels following surgery. These and in situ tumour findings suggest a role for NK cells in NAC-induced breast pCR.

Women with large (≥3 cm) and locally advanced breast cancers (T3, 4, N1, 2, M0) receiving neoadjuvant chemotherapy (NAC: cyclophosphamide, doxorubicin, docetaxel): addition of capecitabine improves 4-year disease-free survival.

PURPOSE: To determine whether capecitabine (X), combined with docetaxel (T) following doxorubicin (A) and cyclophosphamide (C), enhanced the pathological complete response (pCR) in the breast and axillary lymph nodes (ALNs) of women with large or locally advanced breast cancers (LLABCs) improving outcome, and the effect on quality of life (QoL). PATIENTS AND METHODS: 117 women were enrolled, 112 randomised to 2 cycles of AC (60 mg/m(2), 600 mg/m(2)) given 3 weekly. Tumour responses were assessed by magnetic resonance mammography. Responders (n = 77) received 2 further cycles of AC and were randomised to 4 cycles of T (100 mg/m(2)) (Group A) or T (75 mg/m(2)) and X (2000 mg/m(2)/day), day one to 14 of each 3 weekly cycle (Group B). Non-responders (n = 35) were randomised to 6 cycles of T (Group C) or T + X (Group D). QoL questionnaires were completed at each chemotherapy visit. Pathological responses were evaluated using established criteria. RESULTS: The groups were comparable in patient and tumour characteristics (79.5% T2, 85.7% ductal, 73.2% ER +ve, 22.3% HER2 +ve, 42% involved ALNs). Overall breast pCR was 27.1%, Groups A + C versus B + D (p = 0.446). ALN +ve pCR was 41.9%, Groups A + C versus B + D (p = 0.231). 4-year disease-free survival (DFS) was significantly improved with X (p = 0.016) but not overall survival (p = 0.056). Triple -ve and HER2 +ve tumours, and persistent ALN disease were risk factors for metastases. X increased severe nail changes (p = 0.0002) and hand-foot syndrome (p = 0.014) without affecting QoL. CONCLUSION: NAC-X did not increase breast and ALN pCR but improved 4-year DFS, without detriment to QoL.

Abnormal T regulatory cells (Tregs: FOXP3+, CTLA-4+), myeloid-derived suppressor cells (MDSCs: monocytic, granulocytic) and polarised T helper cell profiles (Th1, Th2, Th17) in women with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC) and surgery: failure of abolition of abnormal treg profile with treatment and correlation of treg levels with pathological response to NAC.

BACKGROUND: Host defences play a key role in tumour growth. Some of the benefits of chemotherapy may occur through modulation of these defences. The aim of this study was to define the status of regulatory cells in women with large and locally advanced breast cancers (LLABCs) undergoing neoadjuvant chemotherapy (NAC) and surgery. METHODS: Bloods were collected from patients (n=56) before, during and following NAC, and surgery. Controls (n=10) were healthy, age-matched females donors (HFDs). Blood mononuclear cells (BMCs) were isolated and T regulatory cells (Tregs) (n=31) determined. Absolute numbers (AbNs) of Tregs and myeloid-derived suppressor cells (MDSCs) were ascertained from whole blood (n=25). Reverse transcriptase polymerase chain reaction analysis determined Treg mRNA (n=16). In vitro production of Th1, Th2 and Th17 cytokines (n=30), was documented. Patients were classified as clinical responders by magnetic resonance mammography after two cycles of NAC and as pathological responders using established criteria, following surgery. RESULTS: Patients with LLABCs had significantly increased circulating Tregs (≥ 6 fold AbN and percentage (%)) and MDSCs (≥ 1.5 fold AbN (p=0.025)). Percentage of FOXP3+ Tregs in blood predicted the response of the LLABCs to subsequent NAC (p=0.04). Post NAC blood Tregs (%) were significantly reduced in patients where tumours showed a good pathological response to NAC (p=0.05). Blood MDSCs (granulocytic, monocytic) were significantly reduced in all patients, irrespective of the pathological tumour response to chemotherapy. NAC followed by surgery failed to restore blood Tregs to normal levels. MDSCs, however, were reduced to or below normal levels by NAC alone. Invitro Th1 profile (IL-1ß, IL-2, INF-γ, TNF-α) was significantly reduced (p ≤ 0.009), whilst Th2 (IL-4, IL-5) was significantly enhanced (P ≤ 0.004). Th1 and Th2 (IL-5) were unaffected by NAC and surgery. IL-17A was significantly increased (p ≤ 0.023) but unaffected by chemotherapy and surgery. CONCLUSION: Women with LLABCs have abnormal blood regulatory cell levels (Tregs and MDSCs) and cytokine profiles (Th1, Th2, Th17). NAC followed by surgery failed to abolish the abnormal Treg and Th profiles. There was a significant correlation between the circulatory levels of Tregs and the pathological response of the breast cancers to NAC.

The stem cell factor antibody enhances the chemotherapeutic effect of adriamycin on chemoresistant breast cancer cells.

BACKGROUND: The outcome of chemotherapy in breast cancer is strongly influenced by multidrug resistance (MDR). Several surrogate markers of chemoresistance have been identified including - CD24 (cluster differentiation 24) expression, stem cell growth factor (SCF), B-cell lymphocyte protein 2 (Bcl-2) and annexin V. The present study aimed to examine the expression of CD24 in the sensitive breast cancer cell line MCF-7 (Michigan Foudation-7) and MCF-7/adriamycin resistant (MCF-7/AdrRes) cells, and, if minimal effective doses of the anthracycline drug adriamycin (0.579 µM and 88.2 µM) would be enhanced by the antibody to SCF (anti-SCF). METHODS: CD24 expression was analysed by flow cytometry. Both Bcl-2 and annexin V protein expression were quantitatively assessed by the enzyme-linked immunosorbent assay (ELISA). RESULTS: In MCF-7/AdrRes cells the expression of CD24 was significantly higher compared to MCF-7 cells, 86.6% and 16.3% (p < 0.001), respectively. Bcl-2 expression was significantly increased in the presence of adriamycin and SCF (p < 0.038) and decreased in the presence of adriamycin and anti-SCF. When adriamycin, anti-SCF and SCF were combined or when adriamycin was used alone the decrease in Bcl-2 expression was insignificantly altered. In the presence of both adriamycin and SCF the expression of annexin V was decreased. However, it was significantly increased in the presence of adriamycin and anti-SCF (p < 0.042), as well as adriamycin, anti-SCF and SCF combined.In MCF-7 cells the effect of adriamycin alone or with either SCF, anti-SCF or anti-SCF or SCF combined, did not significantly alter the expression of Bcl-2. However, in the presence of both adriamycin and SCF the expression of annexin V was decreased, but was significantly increased in the presence of adriamycin and anti-SCF (p < 0.001), adriamycin, anti-SCF and SCF combined and adriamycin alone. Our results demonstrate that anti-SCF with low dose of adriamycin reduces Bcl-2 expression in MCF-7/AdrRes cells and increases annexin V expression in both MCF7/AdrRes and MCF-7 cells. CONCLUSION: Adding anti-SCF to the chemotherapeutic regime of adriamycin may strongly enhance its chemotherapeutic effect in the treatment of patients with breast cancer.

Effects on quality of life, anti-cancer responses, breast conserving surgery and survival with neoadjuvant docetaxel: a randomised study of sequential weekly versus three-weekly docetaxel following neoadjuvant doxorubicin and cyclophosphamide in women with primary breast cancer.

BACKGROUND: Weekly docetaxel has occasionally been used in the neoadjuvant to downstage breast cancer to reduce toxicity and possibly enhance quality of life. However, no studies have compared the standard three weekly regimen to the weekly regimen in terms of quality of life. The primary aim of our study was to compare the effects on QoL of weekly versus 3-weekly sequential neoadjuvant docetaxel. Secondary aims were to determine the clinical and pathological responses, incidence of Breast Conserving Surgery (BCS), Disease Free Survival (DFS) and Overall Survival (OS). METHODS: Eighty-nine patients receiving four cycles of doxorubicin and cyclophosphamide were randomised to receive twelve cycles of weekly docetaxel (33 mg/m2) or four cycles of 3-weekly docetaxel (100 mg/m2). The Functional Assessment of Cancer Therapy-Breast and psychosocial questionnaires were completed. RESULTS: At a median follow-up of 71.5 months, there was no difference in the Trial Outcome Index scores between treatment groups. During weekly docetaxel, patients experienced less constipation, nail problems, neuropathy, tiredness, distress, depressed mood, and unhappiness. There were no differences in overall clinical response (93% vs. 90%), pathological complete response (20% vs. 27%), and breast-conserving surgery (BCS) rates (49% vs. 42%). Disease-free survival and overall survival were similar between treatment groups. CONCLUSIONS: Weekly docetaxel is well-tolerated and has less distressing side-effects, without compromising therapeutic responses, Breast Conserving Surgery (BCS) or survival outcomes in the neoadjuvant setting. TRIAL REGISTRATION: ISRCTN: ISRCTN09184069.

Breast cancer chemoresistance: emerging importance of cancer stem cells.

Cancer stem cells (CSCs) have recently been documented in solid tumours. Evidence has suggested that CSCs are involved in carcinogenesis, tumour invasion and metastases, and resistance to various forms of therapies, including chemotherapy. Breast CSCs are characterised by the expression of CD44 but lack of CD24 (CD44(+)/CD24(-) cells). The mechanisms involved in chemoresistance of breast CSCs are complex and not clearly defined. Overexpression of ABC transporters, detoxification enzymes (aldehyde dehydrogenase), low cell turn over rate and the ability to activate the DNA check point response are possibly all involved. Innovative therapies, based on a better understanding of CSCs, should lead to enhanced and long-term cure rates in breast cancer.

Generation in vivo of peptide-specific cytotoxic T cells and presence of regulatory T cells during vaccination with hTERT (class I and II) peptide-pulsed DCs.

BACKGROUND: Optimal techniques for DC generation for immunotherapy in cancer are yet to be established. Study aims were to evaluate: (i) DC activation/maturation milieu (TNF-alpha +/- IFN-alpha) and its effects on CD8+ hTERT-specific T cell responses to class I epitopes (p540 or p865), (ii) CD8+ hTERT-specific T cell responses elicited by vaccination with class I alone or both class I and II epitope (p766 and p672)-pulsed DCs, prepared without IFN-alpha, (iii) association between circulating T regulatory cells (Tregs) and clinical responses. METHODS: Autologous DCs were generated from 10 patients (HLA-0201) with advanced cancer by culturing CD14+ blood monocytes in the presence of GM-CSF and IL-4 supplemented with TNF-alpha [DCT] or TNF-alpha and IFN-alpha [DCTI]. The capacity of the DCs to induce functional CD8+ T cell responses to hTERT HLA-0201 restricted nonapeptides was assessed by MHC tetramer binding and peptide-specific cytotoxicity. Each DC preparation (DCT or DCTI) was pulsed with only one type of hTERT peptide (p540 or p865) and both preparations were injected into separate lymph node draining regions every 2-3 weeks. This vaccination design enabled comparison of efficacy between DCT and DCTI in generating hTERT peptide specific CD8+ T cells and comparison of class I hTERT peptide (p540 or p865)-loaded DCT with or without class II cognate help (p766 and p672) in 6 patients. T regulatory cells were evaluated in 8 patients. RESULTS: (i) DCTIs and DCTs, pulsed with hTERT peptides, were comparable (p = 0.45, t-test) in inducing peptide-specific CD8+ T cell responses. (ii) Class II cognate help, significantly enhanced (p < 0.05, t-test) peptide-specific CD8+T cell responses, compared with class I pulsed DCs alone. (iii) Clinical responders had significantly lower (p < 0.05, Mann-Whitney U test) T regs, compared with non-responders. 4/16 patients experienced partial but transient clinical responses during vaccination. Vaccination was well tolerated with minimal toxicity. CONCLUSION: Addition of IFN-alpha to ex vivo monocyte-derived DCs, did not significantly enhance peptide-specific T cell responses in vivo, compared with TNF-alpha alone. Class II cognate help significantly augments peptide-specific T cell responses. Clinically favourable responses were seen in patients with low levels of circulating T regs.

Annexins in human breast cancer: Possible predictors of pathological response to neoadjuvant chemotherapy.

Neoadjuvant chemotherapy is used in women who have large or locally advanced breast cancers. However, up to 70% of women who receive neoadjuvant chemotherapy fail to achieve a complete pathological response in their primary tumour (a surrogate marker of long-term survival). Five proteins, previously identified to be linked with chemoresistance in our in vitro experiments, were identified histochemically in pre-treatment core needle biopsies from 40 women with large or locally advanced breast cancers. Immunohistochemical staining with the five proteins showed no single protein to be a predictor of response to chemotherapy. However, pre-treatment breast cancer specimens that were annexin-A2 positive but annexin-A1 negative correlated with a poor pathological response (p=0.04, Fisher's exact test). The mechanisms by which annexins confer chemoresistance have not been identified, but may be due to inhibition of apoptosis. Annexin-A1 has been shown to enhance apoptosis, whilst annexin-A2, by contrast, inhibits apoptosis.

Predicting response to neoadjuvant chemotherapy in breast cancer: molecular imaging, systemic biomarkers and the cancer metabolome (Review).

The ability to predict the response to neoadjuvant chemotherapy (NAC) prior to or shortly after commencing treatment, in women with large or locally advanced breast cancers, would not only prevent patients from experiencing unnecessary drug morbidity but also reduce the high cost associated with drug usage and utilisation of resources with NAC. Ability to estimate residual cancer volume after NAC is of clinical relevance to subsequent therapeutic surgical options. Various approaches, using conventional histopathological characteristics and imaging modalities to evaluate and predict the response to NAC, have not been able to provide accurate and reliable data. Novel biomolecular imaging, new biomarkers and recent cancer genomic and proteomic profiling, introduced into clinical practice, have produced preliminary promising results. We describe and discuss these molecular characteristics and approaches and their applications to NAC in breast cancer management.

Management of the axilla in women with breast cancer: current clinical practice and a new selective targeted approach.

BACKGROUND: Axillary nodal status is the most important prognostic factor for patients with breast cancer. Clinical assessment and imaging modalities are not always reliable. Surgical removal and histopathological examination of axillary lymph nodes remain essential methods of staging the axilla. However, the optimal management of the axilla remains uncertain. METHODS: We performed Medline searches to identify relevant systematic reviews, meta-analysis, and nonrandomized and randomized controlled trials for the past 5 years (up to December 2007), as well as important historical articles and clinical guidelines relating to management of the axilla in women with breast cancer. RESULTS: Axillary lymph node dissection (ALND) has been the standard surgical approach for many years. It is, however, associated with marked morbidity; survival benefit remains uncertain. Axillary node sampling, widely practiced in the United Kingdom, is a reliable alternative procedure in staging the axilla, with less morbidity. Sentinel lymph node biopsy (SLNB) has become an accurate method for staging the axilla in women with operable, clinically node-negative breast cancer. SLNB alone appears to be a safe and acceptable procedure for patients with uninvolved SLNs. Completion ALND or axillary radiotherapy remains the standard treatment for patients with tumor-involved SLNs. SLNB is associated with less morbidity than ALND. However, long-term follow-up and therapeutic outcomes are being awaited from randomized controlled trials. CONCLUSIONS: Several procedures are available for staging and treating the axilla. A tailored surgical approach, with careful assessment of risk-benefit and patient preference, is guiding the evolving modern management of the axilla for women with breast cancer.

18F-FDG dual-headed gamma camera PET in detection of axillary nodal disease in patients with large or locally advanced breast cancer: possible alternative staging of axilla.

Positron emission tomography (PET) has been used in staging the axilla. Gamma Camera PET (GCPET) is a cost effective alternative, but poorly studied. The aim of this study was to assess GCPET in demonstrating metastatic deposits in axillary nodes in patients with a high likelihood of nodal disease. Twenty-seven women with large (T2, T3 or T4) or advanced breast cancer (N1, N2 or M1) were recruited. All patients underwent axillary lymph node removal or biopsy (fine needle aspiration cytology (FNAC) or core cut) and whole body GCPET imaging. Images were reported anonymously and compared with the histological findings. Twenty-one patients proceeded to surgery and 10 had tumour-involved axillary nodes; GCPET was positive in 8 of these. The remaining 6 patients underwent core cut or FNAC of the axillary nodes, 2 of which contained a tumour. GCPET was positive in both cases. Thus, the diagnostic values were: sensitivity 83%, specificity 100%, positive predictive value 100%, negative predictive value 88% and accuracy 93%. In conclusion, GCPET is a reliable method and can be performed in a district general hospital and detecting disease in axillary nodes in certain patients, possibly obviating the need for surgery.

Monitoring the response of large (>3 cm) and locally advanced (T3-4, N0-2) breast cancer to neoadjuvant chemotherapy using (99m)Tc-Sestamibi uptake.

BACKGROUND AND AIM: (99m)Tc-Sestamibi (MIBI) scintimammography has an established role in the diagnosis of breast cancer. As a functional imaging technique, it may also be useful in assessing the response to chemotherapy. The aim of this study was to assess the effectiveness of the technique for this purpose. METHODS: Twenty-six patients undergoing neoadjuvant chemotherapy for large or locally advanced breast cancer were monitored using the tumour to background ratio measured on MIBI scintimammograms. Patients were assessed and the size of the tumour was measured by callipers and ultrasonography before and at the end of treatment. Patients were assessed as complete, partial or non-responders. Following chemotherapy, patients proceeded to surgery with pathological evaluation of the operative specimen. RESULTS: Twenty-four of the 26 patients showed a reduction in MIBI uptake on completion of chemotherapy. Residual tumour was demonstrated on the scintimammogram in four patients and all had significant residual disease on histology. In the remaining 22 patients, the final scintimammogram was negative, although three patients were assessed as non-responders and had large residual tumours on histology. CONCLUSION: A positive MIBI scan is highly predictive of the presence of significant residual disease on completion of chemotherapy. However, a negative MIBI scan does not rule out the presence of considerable residual tumour. Whereas ultrasound and clinical assessment may underestimate the response to chemotherapy, MIBI imaging tends to overestimate the response.

A comparison of 18F-FDG gamma camera PET, mammography and ultrasonography in demonstrating primary disease in locally advanced breast cancer.

BACKGROUND: Positron emission tomography (PET) imaging using [18F]fluorodeoxyglucose (18F-FDG) is recognized to have a major role in oncological imaging. Over recent years there has been a steady increase in the use of gamma camera PET (GCPET) systems as these are less expensive than dedicated PET scanners and facilitate the full range of nuclear medicine imaging. However, there is ongoing debate about their application and usefulness in the management of oncological patients. OBJECTIVES: To assess the feasibility of GCPET in a nuclear medicine department in a district general hospital remote from a cyclotron, compared with other imaging modalities in demonstrating disease in patients with large or locally advanced breast cancer. METHODS: 18F-FDG was transported by road from a production unit 100 miles from the imaging department. Twenty-five patients (mean age 68 years) with primary breast tumours measuring > or =20 mm on clinical examination were studied. All patients underwent triple assessment prior to PET imaging with an ADAC Solus camera with molecular coincidence detection capability. Histopathology was obtained in 20 cases following surgery. RESULTS: GCPET detected 24/25 primary breast tumours (sensitivity 96%). This compared with 22/25 (88%) for ultrasound and 15/25 (60%) for mammography. The lesion missed by PET was a grade 1 tumour, 8 mm in size. CONCLUSION: In this pilot study GCPET has been shown to be feasible in a district general hospital, enabling a limited on-site PET imaging service to be provided. In the cases studied it was more sensitive than mammography or ultrasonography. GCPET may provide additional information that could be important in planning the management of some patients with breast cancer.