Breast Neoplasms: Heys SD

Reid DM, Doughty J, Eastell R, Heys SD, Howell A, McCloskey EV, Powles T, Selby P, Coleman RE. · Department of Rheumatology, University of Aberdeen, United Kingdom. · Cancer Treat Rev. · Pubmed #18515009 No free full text.

Abstract: In postmenopausal women, the use of aromatase inhibitors increases bone turnover and induces bone loss at sites rich in trabecular bone at an average rate of 1-3% per year leading to an increase in fracture incidence compared to that seen during tamoxifen use. The bone loss is much more marked in young women with treatment-induced ovarian suppression followed by aromatase inhibitor therapy (average 7-8% per annum). Pre-treatment with tamoxifen for 2-5 years may reduce the clinical significance of the adverse bone effects associated with aromatase inhibitors, particularly if this leads to a shortening in the duration of exposure to an aromatase inhibitor. However, skeletal status should still be assessed at the commencement of aromatase inhibitor therapy. The rate of bone loss in women who experience a premature menopause before the age of 45 or are receiving ovarian suppression therapy is accelerated by the concomitant use of aromatase inhibitors. These patients are considered to be at high risk of clinically important bone loss and should have a baseline dual energy X-ray absorptiometry (DXA) assessment of bone mineral density (BMD). Randomised clinical trials in postmenopausal women indicate that bisphosphonates prevent the bone loss and accelerated bone turnover associated with aromatase inhibitor therapy and are a promising strategy for the prevention and treatment of osteoporosis in this setting. Treatment initiation recommendations are based on a combination of risk factors for osteoporotic fracture and BMD levels. Bisphosphonates, along with a healthy lifestyle and adequate intake of calcium and vitamin D are the treatments of choice to prevent bone loss. Due to the rate of bone loss associated with breast cancer treatments, and uncertainties about the interaction between aromatase inhibitor use and BMD for fracture risk, the threshold for intervention has been set at a higher level than that generally recommended for postmenopausal osteoporosis. Management recommendations have been summarised in two algorithms, one for women experiencing a premature menopause and the other for postmenopausal women requiring adjuvant aromatase inhibitor therapy.

Heys SD, Sarkar T, Hutcheon AW. · Department of Surgery, University of Aberdeen, Aberdeen, UK. · Breast Cancer Res Treat. · Pubmed #15803364 No free full text.

Abstract: Primary chemotherapy achieves high clinical response rates and facilitates breast conservation in many patients with large and locally advanced breast cancer. It may also serve to indicate responsiveness to chemotherapeutic agents. A pathological complete response to primary chemotherapy is a primary predictor and surrogate marker of long-term outcome, but occurs in only approximately 15% of patients. Docetaxel is of particular interest in this setting. Primary docetaxel chemotherapy has single-agent activity in both dose-dense and traditional schedules, with acceptable tolerability. Furthermore, concomitant docetaxel-anthracycline schedules have shown promise in Phase II trials, achieving clinical overall response rates (ORRs) of 77-96%, pathological complete responses of up to 24%, and breast conservation in up to 89% of patients.Two Phase III studies have shown that pathological complete response is significantly improved with the addition of docetaxel to anthracycline-based therapy versus the latter alone: the Aberdeen study achieved a rate of 34% versus 16%, respectively (p = 0.04), and the NSABP-B27 study a rate of 26% versus 14%, respectively (p < 0.001). The Aberdeen study has suggested that the addition of docetaxel may yield a survival benefit at 5 years (p = 0.04). The Phase II GEPAR-DUO study hints at a benefit for sequential over concomitant docetaxel-based therapy, with improvements in both clinical response (ORR 87% versus 77%, respectively) and pathological complete response (23% versus 12%, respectively). Non-anthracycline docetaxel-based primary regimens have shown early promise. As we continue to define the optimal regimen, a growing body of evidence supports the use of docetaxel in primary chemotherapeutic regimens for breast cancer.

Heys SD, Sarkar T, Hutcheon AW. · Department of Surgery, Medical Oncology University Medical Buildings, Foresterhill, Aberdeen, AB9 2ZD, UK. · Expert Opin Pharmacother. · Pubmed #15461550 No free full text.

Abstract: Developments in the role of adjuvant and neoadjuvant chemotherapy for the treatment of patients with breast cancer have focused on the taxes, in particular, docetaxel. This paper discusses the rationale for the introduction of docetaxel into the management of patients following surgery and also its role in those patients with locally-advanced disease, focussing on key clinical trials. The addition of docetaxel to standard adjuvant chemotherapeutic regimens does seem to result in an increased survival in some patients with early-stage disease. In the neoadjuvant setting, the addition of docetaxel to standard regimens does increase pathological response rates, which is a surrogate marker of eventual outcome.

Hutcheon AW, Heys SD, Sarkar TK, Anonymous00402. · University of Aberdeen Hospital, Aberdeen, Scotland · Breast Cancer Res Treat. · Pubmed #12868802 No free full text.

Abstract: Neoadjuvant chemotherapy produces substantial increases in clinical response rates and rates of breast conserving therapy. Pathologic response rate, though generally low, is an important outcome as it is presumably associated with eradication of micrometastatic disease and may likely result in improved outcomes. Anthracyclines have long been considered the most efficacious chemotherapy agents for neoadjuvant therapy of early breast cancer. Unfortunately, not all patients respond to neoadjuvant anthracycline-based chemotherapy. In an effort to improve primary tumor response, docetaxel, an active agent in breast cancer, has been evaluated in the neoadjuvant setting. Several randomized trials, including the NSABP B-27, GEPAR-duo, and the Aberdeen trial, evaluating docetaxel in sequence with a doxorubicin-based neoadjuvant regimen have been reported, with encouraging findings. We designed the Aberdeen trial with two primary aims: (1) to evaluate primary docetaxel in patients that initially fail a neoadjuvant anthracycline-based polychemotherapy regimen, and (2) to compare a docetaxel-based neoadjuvant regimen with a standard anthracycline-based regimen in patients who do respond to the first four cycles of the anthracycline-based regimen. Eligible patients (n = 162) had previously untreated large (> or = 3 cm) or locally advanced (T3, T4, T x N2) breast cancer. All received four cycles of CVAP, after which clinical response was assessed. Responding patients were then randomized to four additional cycles of CVAP or to docetaxel 100 mg/m2 every 3 weeks for four cycles. Patients failing to respond to CVAP received the docetaxel regimen. After the first four cycles of CVAP, the overall response rate (ORR) was 67%. Ultimately, responses were higher in the group randomized to docetaxel compared with those continuing CVAP (cCR: 94% vs. 66%; p = 0.001; pCR 34% vs. 16%; p = 0.04). The addition of docetaxel improved overall survival and disease-free survival for patients responding to four cycles of CVAP as compared with those receiving eight cycles of CVAP. Relative dose intensity was higher and the incidence of severe leukopenia was lower in the group randomized to docetaxel. These data and data from the NSABP B-27 and GEPAR-duo trials strongly support a combined anthracycline/docetaxel regimen in the neoadjuvant setting.

Wahle KW, Heys SD. · Rowett Research Institut, Bucksburn, Aberdeen, Scotland, UK. · Prostaglandins Leukot Essent Fatty Acids. · Pubmed #12324239 No free full text.

Abstract: Fats have been adversely implicated in the aetiology of many forms of cancer yet evidence is accumulating that certain types of fatty acids have anticancer properties. This is well documented for fish-oil fatty acids of the n-3 family. Recently, fatty acids found to occur naturally in ruminant-derived food products were found to have anticancer properties. These fatty acids were identified as conjugated linoleic acids (CLAs) derived from the parent linoleic acid by its partial hydrogenation by rumen bacteria. Studies with tumour-bearing animals have shown that consumption of CLAs particularly with regard to breast and prostate cancer is beneficial. Studies with cancer cells have also shown that these fatty acids can inhibit cell proliferation and induce cell death. However, little is known regarding the mechanisms of action of these CLAs. In particular, which cellular signal mechanisms are regulated by CLAs which can explain their anticancer properties. We have shown that CLAs specifically up-regulate cell signal systems at the level of gene expression (mRNA, protein) in human breast and prostate cancer cells which are responsible for the induction of apoptosis or programmed cell death. These findings support the anticancer effects of CLA found in animal models and indicate similar effects could occur in man.

Heys SD. · Section of Surgical Oncology, Department of Surgery, and the Aberdeen Breast Unit, University Medical Buildings, University of Aberdeen, Foresterhill, Aberdeen AB9 2ZD, Scotland, UK. · Breast Cancer. · Pubmed #11791128 No free full text.

This publication has no abstract.

Smith IC, Hutcheon AW, Heys SD. · Aberdeen Breast Unit, Grampian University Hospitals NHS Trust and the Department of Surgery, Aberdeen, Scotland, UK. · Curr Pharm Des. · Pubmed #10637382 No free full text.

Abstract: A substantial proportion of breast cancers are large (<3 cm) or locally advanced (T3, T4, TXN2) at the time of initial presentation. The therapeutic goals that must be achieved in patients with such cancers are to obtain adequate local disease control so that surgery can be performed and to abolish occult distant metastases therefore improving survival. Over the past three decades conventional adjuvant chemotherapy regimens have been employed pre-operatively (neo-adjuvant or primary chemotherapy) to achieve these goals. Studies have now shown that the survival of patients who receive neo-adjuvant chemotherapy is comparable to that of those who receive the same chemotherapy regimen following surgery. It is also apparent that although clinical tumour response rates to neo-adjuvant chemotherapy may be high there is considerable scope for improvement in the corresponding pathological tumour response. Furthermore, data from major studies that have comprehensively evaluated the use of pre-operative chemotherapy now indicates that the pathological response of breast cancers following treatment is of far greater prognostic importance than the clinical response. Recent interests has focoused, therefore, on the implementation of more prolonged or dose intensive chemotherapy regimens with the aims of improving pathological response to treatment and ultimately overall survival. Newer antineoplastic agents are also becoming available that may be used alone or in combination with conventional therapies in order that tumor response may be improved. This review describes current and potential therapeutic agents that may be used for the induction therapy of breast cancer.

Semple SI, Staff RT, Heys SD, Redpath TW, Welch AE, Ahearn TS, Hutcheon A, Gilbert FJ. · Department of Radiology, University of Aberdeen, Scotland, UK. · Ann Oncol. · Pubmed #16788001 links to  free full text

Abstract: BACKGROUND: The aim of the study was to investigate whether pre-therapy vascular delivery assessment [using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI)] can predict reduction in breast cancer metabolism [detected using 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography ((18)F(-)FDG-PET)] after a single cycle of chemotherapy. Reduction in (18)F-FDG PET metabolism has previously been shown to correlate with histological response to primary chemotherapy. PATIENTS AND METHODS: Seventeen patients with large or locally advanced invasive ductal carcinomas of the breast were imaged using DCE-MRI and (18)F-FDG-PET prior to therapy and 20 days after the first cycle of chemotherapy. MRI data were analysed using a multi-compartment model. PET data were analysed using standardised uptake value (SUV) analysis. RESULTS: A significant association (P <0.05) was observed between pre-therapy DCE-MRI vascular parameters and the reduction in PET metabolism resulting from administration of one cycle of chemotherapy. CONCLUSIONS: A relationship was demonstrated between pre-therapy DCE-MRI vascular parameters and the reduction in PET metabolism after a single cycle of chemotherapy. This suggests that reduction in PET metabolism as a result of chemotherapy may be dependent, at least in part, on pre-therapy vascular delivery. These pre-therapy vascular characteristics may be suitable for use as a surrogate measure for initial chemotherapy delivery, a key factor in chemotherapeutic efficacy.

Ogston KN, Miller ID, Schofield AC, Spyrantis A, Pavlidou E, Sarkar TK, Hutcheon AW, Payne S, Heys SD. · Department of Surgery, University of Aberdeen, UK. · Breast Cancer Res Treat. · Pubmed #15319570 No free full text.

Abstract: PURPOSE: Primary chemotherapy is commonly used in patients with breast cancer to downstage the primary tumour prior to surgery. There is a need to establish, prior to commencement of chemotherapy, predictors of clinical and pathological response, which may then be surrogate markers for patient survival and thus allow identification of patients who are most likely to benefit from such treatment. PATIENTS AND METHODS: A total of 104 patients with large and locally advanced breast cancers received an anthracycline/docetaxel-based regimen prior to surgery. Immunohistochemistry was carried out on pre-treatment core biopsies of the tumour to detect hormone receptors (oestrogen-ER; progesterone-PR), a proliferation marker (MIB-1), the oncoprotein Bcl-2, an extracellular matrix degradation enzyme (cathepsin D), p53, and an oestrogen associated protein (pS2). Both clinical and pathological response were assessed following completion of chemotherapy. RESULTS: Patients whose tumours did not express oestrogen receptor (p = 0.02) or did not express Bcl-2 (p < 0.01) had a better pathological response in a univariate analysis. However, in a multivariate model, it was only the absence of detectable Bcl-2 protein that predicted a better pathological response (p = 0.001). CONCLUSIONS: This study has identified that patients whose breast cancers are most likely to experience the greatest degree of tumour destruction by primary chemotherapy do not express either oestrogen receptors or Bcl-2. This may have important implications in the selection of patients with breast cancer for primary chemotherapy who are most likely to gain a survival benefit.

Heys SD, Hutcheon AW, Sarkar TK, Ogston KN, Miller ID, Payne S, Smith I, Walker LG, Eremin O, Anonymous00203. · Department of Surgery, University of Aberdeen, Foresterhill, Scotland, UK. · Clin Breast Cancer. · Pubmed #12435290 No free full text.

Abstract: Over the past 30 years there has been an increased use of neoadjuvant (or primary) chemotherapy for treating patients with breast cancer. However, while it is clear that chemotherapy given in the adjuvant setting after surgery does prolong patients' overall and disease-free survival, the evidence that chemotherapy in the neoadjuvant setting also increases survival remains unproven. In the Aberdeen study, 162 patients with large and locally advanced breast cancer underwent 4 cycles of CVAP (cyclophosphamide/vincristine/doxorubicin/prednisone) primary chemotherapy. Patients with a complete or partial response were then randomized to either 4 further cycles of CVAP or 4 cycles of docetaxel (100 mg/m2). It was shown that the addition of sequential docetaxel (100 mg/m2) to CVAP neoadjuvant chemotherapy resulted in a significantly enhanced clinical response rate (94% vs. 64%) and a substantially increased complete histopathological response rate (34% vs. 16%) when compared to patients receiving CVAP alone. Furthermore, patients receiving docetaxel had an increased breast conservation rate (67% vs. 48%) and an increased survival at a median follow-up of 3 years. It is important to note that this was a small study, and the survival results should be interpreted with caution. The results are encouraging, however, and further studies are urgently required.

Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, Ah-See AK, Eremin O, Walker LG, Sarkar TK, Eggleton SP, Ogston KN. · Department of Academic Radiology, University of Aberdeen, Foresterhill, Aberdeen, Scotland, United Kingdom. · J Clin Oncol. · Pubmed #11896092 No free full text.

Abstract: PURPOSE: To compare the efficacy of neoadjuvant (NA) docetaxel (DOC) with anthracycline-based therapy and determine the efficacy of NA DOC in patients with breast cancer initially failing to respond to anthracycline-based NA chemotherapy (CT). PATIENTS AND METHODS: Patients with large or locally advanced breast cancer received four pulses of cyclophosphamide 1,000 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1.5 mg/m(2), and prednisolone 40 mg (4 x CVAP) for 5 days. Clinical tumor response was assessed. Those who responded (complete response [CR] or partial response [PR]) were randomized to receive further 4 x CVAP or 4 x DOC (100 mg/m(2)). All nonresponders received 4 x DOC. RESULTS: One hundred sixty-two patients were enrolled; 145 patients completed eight cycles of NA CT. One hundred two patients (66%) achieved a clinical response (PR or CR) after 4 x CVAP. After randomization, 50 patients received 4 x CVAP and 47 patients received 4 x DOC. In patients who received eight cycles of CT, the clinical CR (cCR) and clinical PR (cPR) (94% v 66%) and pathologic CR (pCR) (34% v 16%) response rates were higher (P =.001 and P =.04) in those who received further DOC. Intention-to-treat analysis demonstrated cCR and cPR (85% v 64%; P =.03) and pCR (31% v 15%; P =.06). Axillary lymph node examination revealed residual tumor in 33% of patients who received 8 x CVAP and 38% of patients who received further DOC. In patients who failed to respond to the initial CVAP, 4 x DOC resulted in a cCR and cPR rate of 55% and a pCR rate of 2%. Forty-four percent of these patients had residual tumor within axillary lymph nodes. CONCLUSION: NA DOC resulted in substantial improvement in responses to DOC.

Walker LG, Heys SD, Walker MB, Ogston K, Miller ID, Hutcheon AW, Sarkar TK, Ah-See AK, Eremin O. · Institute of Rehabilitation, University of Hull, U.K. · Eur J Cancer. · Pubmed #10673992 No free full text.

Abstract: This study evaluated the possible value of psychological variables in predicting clinical and pathological response to primary chemotherapy. 96 women with newly diagnosed large, or locally advanced, breast cancer (T2 > 4 cm, T3, T4, N2 and M0) participated in a prospective, randomised trial to evaluate the effects of relaxation training with guided imagery and L-arginine on response to primary chemotherapy. Before the first of six cycles of primary chemotherapy, women were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Eysenck Personality Questionnaire (EPQ). The primary outcomes were clinical response (evaluated using standard International Union Against Cancer (UICC) criteria) and pathological response (graded by means of a previously published 5-point scale) following primary chemotherapy. Stepwise linear regressions were used to estimate the predictive value of age, menopausal status, clinical nodal status, tumour size at diagnosis, oestrogen receptor status, dietary supplementation (L-arginine versus placebo), personality (EPQ-L scores), mood (HADS scores) and a psychological intervention. HADS depression score was a significant independent predictor of pathological response to chemotherapy. HADS anxiety score was a significant independent predictor of clinical response. Because the original tumour size before chemotherapy (also a significant predictor of clinical and pathological responses) was taken into account in the analyses, the results cannot be explained in terms of psychobiological factors related to tumour size. This study supports the importance of psychological factors as independent predictors of response to primary chemotherapy in patients with breast cancer. If they can be replicated, these findings have major implications for the management of women with breast cancer. Psychological factors need to be assessed and evaluated in future trials of chemotherapy.

Khan AL, Larsen F, Heys SD, Eremin O. · Department of Surgery, University of Aberdeen, Aberdeen, Foresterhill, AB9 2ZD, UK. · Eur J Surg Oncol. · Pubmed #10556002 No free full text.

Abstract: AIMS: Acute phase reactants (APRs) are believed to play an important biological role in trauma, sepsis and malignant disease. We have investigated the induction of the APR, C-reactive protein (CRP), by the biological response modifier, polyadenylic-polyuridylic acid (PAPU) during the peri-operative period. METHODS: Twenty post-menopausal women with breast cancer undergoing mastectomy were randomized into a double blind, placebo-controlled, parallel group pilot study. PAPU (150 mg) or placebo was given intravenously the day prior to surgery (D -1), the day of surgery (D 0) and post-operatively on days (D 1, 3, 5, 7 and 14). Blood samples were collected on eight different days (D -2, -1, 0, 1, 2, 4, 6 and 18). CRP was significantly elevated in the PAPU group (P<0.05) on days 2 and 4, when compared with patients receiving placebo. The serum levels of cytokines believed to induce hepatic APRs, were also measured. RESULTS: The serum concentration of IL-6 was elevated on days 1, 2, 4 and 6 (P<0.05), TNF- alpha and IL-1 beta levels were increased on days 1 and 2 (P<0.05), respectively, while the serum level of soluble interleukin-2 receptor (sIL-2R) was elevated above the baseline on days 0, 2, 4, 6 and 18 in the PAPU group, when compared with the baseline. CONCLUSIONS: This modulation of acute phase response may have important implications for patients with cancer undergoing surgery.

Walker LG, Walker MB, Ogston K, Heys SD, Ah-See AK, Miller ID, Hutcheon AW, Sarkar TK, Eremin O. · Behavioural Oncology Unit, University of Aberdeen, Medical School, Foresterhill, UK. · Br J Cancer. · Pubmed #10390006 No free full text.

Abstract: The diagnosis and treatment of breast cancer are stressful, and stress may be associated with a poorer response to chemotherapy. There is a need, therefore, to develop and evaluate interventions that might enhance quality of life and, possibly, improve treatment response. The effects of relaxation combined with guided imagery (visualizing host defences destroying tumour cells) on quality of life and response to primary chemotherapy, to date, have not been adequately evaluated. Ninety-six women with newly diagnosed large or locally advanced breast cancer (T2 > 4 cm, T3, T4, or TxN2 and M0) took part in a prospective, randomized controlled trial. Patients were randomized following diagnosis to a control condition (standard care) or to the experimental condition (standard care plus relaxation training and imagery). Psychometric tests to evaluate mood and quality of life were carried out before each of the six cycles of chemotherapy and 3 weeks after cycle 6: tests of personality and coping strategy were carried out prior to cycles one and six. Clinical response to chemotherapy was evaluated after six cycles of chemotherapy using standard UICC criteria and pathological response was assessed from the tissue removed at surgery. As hypothesized, patients in the experimental group were more relaxed and easy going during the study (Mood Rating Scale). Quality of life was better in the experimental group (Global Self-assessment and Rotterdam Symptom Checklist). The intervention also reduced emotional suppression (Courtauld Emotional Control Scale). The incidence of clinically significant mood disturbance was very low and the incidence in the two groups was similar. Finally, although the groups did not differ for clinical or pathological response to chemotherapy, imagery ratings were correlated with clinical response. These simple, inexpensive and beneficial interventions should be offered to patients wishing to improve quality of life during primary chemotherapy.

Eremin O, Walker MB, Simpson E, Heys SD, Ah-See AK, Hutcheon AW, Ogston KN, Sarkar TK, Segar A, Walker LG. · United Lincolnshire Hospitals NHS Trust, United Kingdom. · Breast. · Pubmed #19008099 No free full text.

Abstract: Eighty women undergoing multimodality treatment for large (>4cm) or locally advanced (T3, T4, Tx, N2), breast cancers participated in a randomised controlled trial (RCT) to evaluate the immuno-modulatory effects of relaxation training and guided imagery. Patients underwent chemotherapy followed by surgery, radiotherapy, and hormone therapy. Those in the intervention group were taught relaxation and guided imagery. Patients kept diaries of the frequency of relaxation practice and imagery vividness. On 10 occasions during the 37 weeks following the diagnosis, blood was taken for immunological assays CD phenotyping: T cell subsets (helper, cytotoxic), natural killer (NK) and lymphokine activated killer (LAK) cells, B lymphocytes and monocytes; cytotoxicity: NK and LAK cell activities; cytokines interleukin 1 beta (1beta), 2, 4 and 6 and tumour necrosis factor alpha. Significant between-group differences were found in the number of CD25+ (activated T cells) and CD56+ (LAK cell) subsets. The number of CD3+ (mature) T cells was significantly higher following chemotherapy and radiotherapy, in patients randomised to relaxation and guided imagery. Using a median split, women who rated their imagery ratings highly had elevated levels of NK cell activity at the end of chemotherapy and at follow-up. Significant correlations were obtained between imagery ratings and baseline corrected values for NK and LAK cell activity, and IL1beta. Relaxation frequency correlated with the number of CD4+ (T helper) cells, the CD4+:8+ (helper:cytotoxic) ratio, and IL1beta levels. Relaxation training and guided imagery beneficially altered putative anti-cancer host defences during and after multimodality therapy. Such changes, to the best of our knowledge, have not been previously documented in a RCT.

Fite A, Goua M, Wahle KW, Schofield AC, Hutcheon AW, Heys SD. · Section of Surgical Oncology, Department of Surgery, University of Aberdeen, Medical School, Foresterhill, Aberdeen, Aberdeen, Scotland, UK. · Prostaglandins Leukot Essent Fatty Acids. · Pubmed #17900885 No free full text.

Abstract: Response rates of tumours to docetaxel (DOCT) are 45-60% in advanced breast cancer but problems associated with side effects, drug resistance and high costs occur. Conjugated linoleic acids (CLAs) also have anti-tumorigenic activity that elicits similar changes in oncogene expression to DOCT and could augment DOCT efficacy. CLA isomers appear to differ in cytotoxicity toward cancer cells. Effects of two CLA isomers on cytotoxicity of DOCT in breast cancer cells (MCF-7; MDA-MB-231) in vitro were assessed. Cells were incubated up to 72 h with 40 microM each of LA or CLA isomers (cis-9, trans-10 CLA, or trans-10, cis-12 CLA) or a 50:50 isomer mix, alone or with DOCT (0-64 microM); a pilot study determined IC(50) and IC(70) concentrations. Treatments were concurrent (CLA and DOCT together) or sequential (CLA then DOCT). MTT assay determined cell viability. Trans-10, cis-12 CLA was the most effective fatty acid (P<0.001) and increased with treatment time. IC(50) and IC(70) concentrations of DOCT were determined, concurrently or sequentially, with and without fatty acids, in the two cell types. Concurrent treatment with trans-10, cis-12 CLA and DOCT augmented inhibition of cell growth in one or both cell lines (decreased IC(50) and IC(70) in MCF-7; P<0.05 but only IC(50) in MDA-MB-231; P<0.05). CLA mix reduced IC(50) and IC(70) in MDA-MB-231 (P<0.001) but not in MCF-7. Cis-9, trans-11 CLA and LA had no effect. Sequential treatment with CLAs then DOCT reduced IC(50) and IC(70) in MCF-7 but not in MDA-MB-231. The latter had increased IC(50) and IC(70) with LA treatment (P<0.05) and increased IC(70) with cis-9, trans-11 CLA (P<0.05) with sequential but not concurrent treatment. Longer pre-incubation times with trans-10, cis-12 CLA (24-72 h) elicited greater reductions in IC(50) and IC(70) in MCF-7 cells. Results show that CLA isomers augment anti-tumour effects of docetaxel in breast cancer cells and suggest possible dual treatment regimens.

McDermott GM, Welch A, Staff RT, Gilbert FJ, Schweiger L, Semple SI, Smith TA, Hutcheon AW, Miller ID, Smith IC, Heys SD. · School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. · Breast Cancer Res Treat. · Pubmed #16897427 No free full text.

Abstract: We have compared 2-deoxy-2-[(18)F]-fluoro-D-glucose positron emission tomography (FDG-PET) images of large or locally advanced breast cancers (LABC) acquired during Anthracycline-based chemotherapy. The purpose was to determine whether there is an optimal method for defining tumour volume and an optimal imaging time for predicting pathologic chemotherapy response. METHOD: PET data were acquired before the first and second cycles, at the midpoint and at the endpoint of neoadjuvant chemotherapy. FDG uptake was quantified using the mean and maximum standardized uptake values (SUV) and the coefficient of variation within a region of interest. Receiver-operator characteristic (ROC) analysis was used to determine the discrimination between tumours demonstrating a high pathological response (i.e. those with greater than 90% reduction in viable tumour cells) and low pathological response. RESULTS: Only tumours with an initial tumour to background ratio (TBR) of greater than five showed a difference between response categories. In terms of response discrimination, there was no statistically significant advantage of any of the methods used for image quantification or any of the time points. The best discrimination was measured for mean SUV at the midpoint of therapy, which identified 77% of low responding tumours whilst correctly identifying 100% of high responding tumours and had an ROC area of 0.93. CONCLUSION: FDG-PET is efficacious for predicting the pathologic response of most primary breast tumours throughout the duration of a neoadjuvant chemotherapy regimen. However, this technique is ineffective for tumours with low image contrast on pre-therapy PET scans.

Heys SD, Smith IC, Ross JA, Gilbert FJ, Brooks J, Semple S, Miller ID, Hutcheon A, Sarkar T, Eremin O. · Department of Surgery, University of Aberdeen, Scotland. · Undersea Hyperb Med. · Pubmed #16602255 No free full text.

Abstract: Work in an animal cancer model suggests that pretreatment with hyperbaric oxygen can improve tumor vascularity rendering chemotherapy more effective. Accordingly 32 subjects with locally advanced breast carcinoma (>5cm diameter) entered into a randomized clinical trial where a course was administered of six intravenous pulses of cyclophosphamide 1000mg/m2 i.v., doxorubicin 50mg/m2 i.v. and vincristine 1.5mg/m2 i.v. In the case group this was preceded by ten, once daily, sessions of hyperbaric oxygen therapy (HBO2) administered either at 2.4 or 2.0 atmospheres absolute. Eleven out of 15 subjects tolerated a full course of HBO2 and chemotherapy. All 17 control subjects tolerated a full course of chemotherapy. Tumor extravascular extracellular or edema fluid was reduced after HBO2 but there was no reduction in tumor cell volume and no indication of increased vascularity on MRI. Clinical and pathological responses to chemotherapy were the same in both groups and there was no evidence of neovascularisation. Five year survival in those who tolerated the trial regime was 73% and did not differ between the groups. This mortality was cancer related.

Chaturvedi S, McLaren C, Schofield AC, Ogston KN, Sarkar TK, Hutcheon AW, Miller ID, Heys SD. · Department of Surgery, Medical School, University of Aberdeen, UK. · Breast Cancer Res Treat. · Pubmed #16187235 No free full text.

Abstract: This study aimed to evaluate patterns of local and distant disease recurrence in patients having primary chemotherapy and compared patterns of relapse in patients with a complete pathological response with those who had residual breast disease. This is an observational study using a sequential series of patients treated with primary chemotherapy. They were followed up for a minimum of 5 years. All data was collected prospectively. Three hundred forty-one consecutive patients with breast cancer were treated with up to eight cycles of doxorubicin-based chemotherapy. Clinical and pathological response rates were evaluated and patients were followed up for disease recurrence (local and distant) and overall survival. Fifty-two patients (16.5%) had a complete pathological response to chemotherapy. Distant disease recurrence occurred in nine patients (17.3%) but no local recurrence was observed. In patients not having a complete pathological response, 86 patients (32.6%) subsequently developed metastases. Local recurrence of disease occurred in 12 (4.5%). There was a statistically significant difference in overall survival between patients whose tumours had a complete pathological response compared with patients who had residual disease in the breast following chemotherapy (88% versus 70% at 5 years, p = 0.036). Following primary chemotherapy, about 84% of patients had residual disease in the breast. Surgery is necessary to ensure complete removal of residual tumour and excellent rates of local control are achievable. A complete pathological response is associated with fewer local and distant recurrences as well as improved survival although there are no differences in time to development of metastatic relapse.

Shalli K, Brown I, Heys SD, Schofield AC. · School of Medicine, College of Life Sciences and Medicine, University of Aberdeen, Medical School, Foresterhill, Aberdeen, UK. · FASEB J. · Pubmed #15946994 links to  free full text

Abstract: Docetaxel is one of the most active drugs used to treat breast cancer. The cellular target of docetaxel is the microtubule, specifically the beta-tubulin subunit, that comprises a series of isotypes and that can modulate function. This study has examined the role of alteration in beta-tubulin isotypes in vitro and has sequenced the beta-tubulin gene to determine if there were mutations, both of which may represent important mechanisms of acquired resistance to docetaxel. Breast cancer cells, MCF-7 (oestrogen-receptor positive) and MDA-MB-231, (oestrogen-receptor negative) were made resistant to docetaxel in vitro. Expression of beta-tubulin isotypes (class I, II, III, IVa, IVb, and VI) was determined at the RNA and protein level using RT-PCR and western analysis, respectively. DNA sequencing evaluated the beta-tubulin gene. At the mRNA level, class I, II, III, and IVa beta-tubulin mRNA isotypes were over-expressed in docetaxel-resistant MCF-7 cells when compared with the docetaxel-sensitive parental cells. However, class VI beta-tubulin mRNA isotype expression was decreased in resistant cells. In MDA-MB-231 cells, there was a decrease in expression of the class I and class IVa beta-tubulin mRNA. However, there were increased expressions in class II, IVb, and VI beta-tubulin mRNA isotypes in resistant cells. Western analysis has confirmed corresponding increases in beta-tubulin protein levels in MCF-7 cells. However, in MDA-MB-231 cells, there were decreased protein levels for class II and class III beta-tubulin. This study demonstrates that altered expression of mRNA beta-tubulin isotypes and modulation of beta-tubulin protein levels are associated with acquired docetaxel resistance in breast cancer cells. This allows further understanding and elucidation of mechanisms involved in resistance to docetaxel.

McDonald SL, Stevenson DA, Moir SE, Hutcheon AW, Haites NE, Heys SD, Schofield AC. · School of Medicine, College of Life Sciences and Medicine, University of Aberdeen, Medical School, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. · Eur J Cancer. · Pubmed #15862759 No free full text.

Abstract: Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. In this study high-level, docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) were created, and comparative genomic hybridisation was used to identify genomic regions associated with resistance to docetaxel. MCF-7 resistant cells showed an amplification of chromosomes 7q21.11-q22.1, 17q23-q24.3, 18, and deletion of chromosomes 6p, 10q11.2-qter and 12p. MDA-MB-231 resistant cells showed a gain of chromosomes 5p, 7q11.1-q35, 9, and loss of chromosomes 4, 8q24.1-qter, 10, 11q23.1-qter, 12q15-q24.31, 14q and 18. Whole chromosome paints confirmed these findings. Amplification of 7q21 and loss of 10q may represent a common mechanism of acquired docetaxel resistance in breast cancer cells. This study is the first description of a genomic approach specifically to identify genomic regions involved in resistance to docetaxel.

Brown I, Shalli K, McDonald SL, Moir SE, Hutcheon AW, Heys SD, Schofield AC. · Department of Surgery, University of Aberdeen, Medical School, Aberdeen, UK. · Breast Cancer Res. · Pubmed #15318941 links to  free full text

Abstract: INTRODUCTION: Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. However, apoptosis and cell cycle regulation are key mechanisms by which most chemotherapeutic agents exert their cytotoxic effects. METHODS: We created two docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) and performed cDNA microarray analysis to identify candidate genes associated with docetaxel resistance. Gene expression changes were validated at the RNA and protein levels by reverse transcription PCR and western analysis, respectively. RESULTS: Gene expression cDNA microarray analysis demonstrated reduced p27 expression in docetaxel-resistant breast cancer cells. Although p27 mRNA expression was found to be reduced only in MCF-7 docetaxel-resistant sublines (2.47-fold), reduced expression of p27 protein was noted in both MCF-7 and MDA-MB-231 docetaxel-resistant breast cancer cells (2.83-fold and 3.80-fold, respectively). CONCLUSIONS: This study demonstrates that reduced expression of p27 is associated with acquired resistance to docetaxel in breast cancer cells. An understanding of the genes that are involved in resistance to chemotherapy may allow further development in modulating drug resistance, and may permit selection of those patients who are most likely to benefit from such therapies.

Semple SI, Gilbert FJ, Redpath TW, Staff RT, Ahearn TS, Welch AE, Heys SD, Hutcheon AW, Smyth EH, Chaturvedi S. · Department of Radiology, University of Aberdeen, Lilian Sutton Building, AB252ZD Aberdeen, Scotland, UK. · Eur Radiol. · Pubmed #15316743 No free full text.

Abstract: The objective of this study was to investigate the relationship between vascular and metabolic characteristics of breast tumours in vivo, using contrast-enhanced dynamic MRI and 2-[(18)F] fluoro-2-deoxy- d-glucose (FDG) PET imaging. Twenty patients with large or locally advanced primary breast cancers were imaged prior to therapy. MRI data were acquired using a dynamic gradient echo sequence and analysed using two pharmacokinetic models. Static PET data were acquired in 2D mode. A significant association ( P<0.05) was observed between the calculated exchange rate constants of both pharmacokinetic models and calculated PET FDG dose uptake ratios (DUR). Statistical analysis showed that the exchange rate constants can explain between 27 and 44% of the variance observed in the PET FDG uptake ratios. A relationship was demonstrated between the vascular and metabolic characteristics of primary breast tumours showing that any assessment of tumour metabolic activity using PET may be controlled at least in part by delivery of uptake agent due to the vascular characteristics of the tumour. MRI and PET provide methods of assessing breast tumour vascularity and metabolism in vivo using the exchange rate constants of dynamic MRI, and DUR of PET, respectively, these measures being related but not equivalent.

Semple SI, Gilbert FJ, Redpath TW, Ahearn TS, Welch AE, Hutcheon AW, Heys SD, Smyth EH, Miller ID, Smith IC. · Department of Radiology, University of Aberdeen, Foresterhill, Scotland, UK. · Lancet Oncol. · Pubmed #14662432 No free full text.

This publication has no abstract.

Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD. · Section of Surgical Oncology, University of Aberdeen, Foresterhill, Aberdeen, Scotland AB9 2ZD, UK. · Breast. · Pubmed #14659147 No free full text.

Abstract: The clinical and complete pathological response of a primary breast cancer to chemotherapy has been shown to be an important prognostic for survival. However, the majority of patients do not experience a complete pathological response to primary chemotherapy and the significance of lesser degrees of histological response is uncertain and the prognostic significance is unknown. The purpose of this study was to evaluate a new histological grading system to assess response of breast cancers to primary chemotherapy and to determine if such a system has prognostic value.A consecutive series of 176 patients with large (> or =4cm) and locally advanced breast cancers were treated with multimodality therapy comprising primary chemotherapy, surgery, radiotherapy and tamoxifen. All underwent assessment of the primary breast tumour before and after completion of chemotherapy. Residual tumour was excised after completion of chemotherapy (mastectomy or wide local excision with axillary surgery). The removed tissue was assessed and response to chemotherapy graded using a five-point histological grading system based with the fundamental feature being a reduction in tumour cellularity; comparison being made with a pre-treatment core biopsy. All patients were followed up for 5 years or more. Pathological responses were compared to 5 year overall survival and disease-free survival using log rank tests.The overall 5-year survival for all patients was 71%, and 5 year disease free interval was 60%. There was a significant correlation between pathological response using this new grading system and both overall survival (P=0.02) and disease-free interval (P=0.04). In a multivariate analysis of known prognostic factors, the Miller/Payne grading system was an independent predictor of overall patient survival.This grading system, which assesses the histological response to primary chemotherapy, can predict overall survival and disease-free interval in patients with large and locally advanced breast cancers treated with such therapy. The relationship of degree of histological response to overall and disease-free survival has been shown in univariate and multivariate analyses and could potentially have an important role in the clinical management of patients with locally advanced breast cancer undergoing primary chemotherapy.