31st Annual San Antonio Breast Cancer Symposium.
The 31st Annual San Antonio Breast Cancer Symposium (SABCS) took place from 10-14 December 2008. This symposium continues to be the most important international meeting in the field of translational breast cancer research with over 9000 delegates attending from over 80 countries. The symposium included 700 oral presentations and 1400 abstracts covering all aspects of breast cancer prevention, diagnosis and treatment. The meeting was notable for a number of key presentations, which are discussed below.
Mammographic density and breast cancer risk
The relationship between mammographic breast density and breast cancer risk has been the subject of investigation. The latest addition to the debate was made by Jack Cuzick (Wolfson Institute of Preventative Medicine, London, UK; Abstr. 61) who presented results from the International Breast Cancer Intervention Study (IBIS)-1 trial. This study examined the relationship between breast density and risk reduction in patients taking tamoxifen. A total of 7154 high-risk women were randomly assigned to receive either tamoxifen or placebo for 5 years. The greatest reduction in mammographic density occurred in the first 18 months of treatment. Mammographic density in 126 women who developed breast cancer after their first follow-up mammogram was compared with that of a control group of 942 women who remained disease free. The changes in mammographic density observed at the first follow-up mammogram (12-18 months after baseline) were used to investigate whether a prediction could be made about patient risk.
Where no change in mammographic density was observed, the odds ratio (OR) for developing breast cancer was 1.75. This is in comparison to an OR of 1.06 for women with a 5% reduction in mammographic density, and 0.51 for women with a 10% decrease. Further research is required into the use of mammographic density as a potential surveillance tool to monitor the response to tamoxifen therapy and as an independent predictor of risk. 'If validated, breast density changes would be the first biomarker that could be used by clinicians to determine who stands to benefit from continued tamoxifen prophylaxis', Professor Cuzick said.
SABCS remains at the forefront of providing up-to-date data on the use of the human epidermal growth factor receptor 2 (HER2), which is known to confer a poor prognosis on breast cancer outcome. Two presentations in particular focused on the use of HER2 as a prognostic indicator--the first study evaluated HER2 status in women with early breast cancer and the second investigated the role of HER2 in monitoring response to adjuvant chemotherapy.
In the first presentation, Ronjay Rakkhit (MD Anderson Center, TX, USA; Abstr 701) reported on 965 patients with early breast cancer (T1a/bN0M0). In total, 77% were hormone receptor positive, 13% were triple negative (i.e. oestrogen receptor, progesterone receptor and HER2 negative) and 10% were HER2 positive. Data from a further group of 350 patients with early breast cancer and similar hormone receptor status were collected and used as a validation set. Recurrence-free survival (RFS) and distant RFS were compared using HER2 receptor status (positive versus negative) and HER2 positivity compared to triple negativity as discriminators. RFS and distant RFS were significantly shorter in HER2-positive disease (P<0.0001). Even after adjustment for age, tumour grade and stage, HER2 remained a significant prognostic indicator [hazard ratio (HR): RFS, 2.68, P=0.0002; distant RFS, 5.30, P=0.0002]. These data highlight the importance of HER2 as a prognostic indicator in patients with early breast cancer.
In the second presentation, Angelo di Leo (HER2-TOP2A Meta-Analysis Study Group; Abstr 705) presented results from a planned interim analysis of a meta-analysis of Phase III trials comparing the anthracycline-based chemotherapeutic agents cyclophosphamide, methotrexate and 5-fluorouracil (5FU) in early breast cancer. The four studies in this analysis are the Belgian three-arm trial, the Canadian National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial, the Danish Breast Cancer Cooperative Group (DBCG) trial and the UK National Epirubicin Adjuvant Trial (NEAT) study. HER2 and topoisomerase 2-alpha (TOPO2A) were analysed by fluorescence in situ hybridisation. A total of 1944 patients were recruited. Results from this study showed that HER2 and TOPO2A were only moderately able to predict sensitivity to anthracyclines (HR for disease-free survival 0.7 for HER2 positivity versus 0.9 for HER2 negativity). Further data are awaited following inclusion of the UK NEAT study, raising the final total study cohort to 3500.
Locally advanced breast cancer
The Neoadjuvant Herceptin (NOAH) trial is the largest study to evaluate the use of neoadjuvant trastuzumab in combination with anthracycline--and taxane-based chemotherapy in patients with locally advanced breast cancer (LABC). In the NOAH trial, HER2-positive patients with LABC were randomly assigned to receive either standard neoadjuvant chemotherapy comprising initial doxorubicin/paclitaxel therapy, followed by four cycles of cyclophosphamide/methotrexate/5FU (CMF) combination therapy alone or CMF in addition to trastuzumab (L Gianni, National Cancer Institute, Milan, Italy; Abstr. 31). Dr Gianni said 'These data establish neoadjuvant trastuzumab with chemotherapy as a standard treatment option in women with Her2/neu-positive locally advanced breast cancer.' Event-free survival was significantly better when trastuzumab was included as part of therapy (70.1% versus 53.3%; HR 0.56, P=0.006). Overall survival was also better with trastuzumab but these data failed to reach significance. Adverse events in the two treatment arms were within acceptable limits. Dr Gianni concluded, 'Herceptin, given before surgery, significantly extends survival without recurrence to patients with locally advanced Her2/neu-positive breast cancer. This most likely will translate into an advantage in terms of survival.'
Tyrosine kinase inhibitors
Lapatinib is a tyrosine kinase inhibitor (TKI) that competes with ATP for the kinase binding domain within the HER2 molecule thus inhibiting its downstream effects. Cross-talk between the growth factor receptor and steroid hormone receptor pathways has been implicated in endocrine resistance in breast cancer. The addition of lapatinib in patients with hormone receptor-positive disease, receiving aromatase inhibitors (AIs), may improve endocrine response and delay the onset of endocrine resistance (S Johnston, Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK; Abstr. 46). In the EGF30008 trial, a double-blind, placebo-controlled, first-line Phase III trial to explore the benefit of letrozole with or without lapatinib, 1286 patients were randomly assigned to receive oncedaily treatment with letrozole plus lapatinib or letrozole plus placebo. This study is the largest clinical trial designed to evaluate whether the addition of targeted HER2 receptor blockade with endocrine therapy improves outcome in HER2-positive metastatic cancer. Median progression-free survival (PFS) in the 219 HER2-positive patients was increased (8.2 versus 3.8 months; HR 0.71, P=0.19). No difference was observed between treatment arms for HER2-negative patients. Dr Johnston said, 'There is a statistically significant 29% reduction in risk of progression, which is manifested in the median PFS.' These data add to evidence supporting the use of lapatinib in hormone-positive, HER2-positive metastatic breast cancer.
The performance of AIs continues to form a major part of the SABCS meeting. Data from a number of major clinical trials were presented here, either as published data or updates.
James Ingle, on behalf of the Aromatase Inhibitors Overview Group (AIOG), presented data from a large-scale meta-analysis comparing tamoxifen with one of three AIs--letrozole, anastrozole or exemestane (Abstr 12). Patients were divided into two groups: agents were given as monotherapy upfront in cohort 1, and after initial tamoxifen therapy for 2 or 3 years with a total of 5 years' hormonal therapy in cohort 2. The meta-analysis included 9956 patients with a follow-up period of 5.9 years. Cohort 2 included 9015 patients with follow-up for 3.9 years. In patients receiving an AI for 5 years, a lower recurrence rate was seen in comparison with patients receiving tamoxifen initially (9.6% versus 12.6% at 5 years and 15.3% versus 19.2% at 8 years). With regard to cohort 2, patients who switched from tamoxifen therapy to an AI at 2 years had lower recurrence rates than patients who remained on tamoxifen therapy throughout (5.0% versus 8.1% at 5 years and 12.0% versus 16.1% at 8 years). Cohort 2 also showed absolute benefits in overall mortality. The advantage of the AI over tamoxifen decreased over time in both cohorts, which Dr Ingle suggested highlights the remaining question with AIs, namely duration of adjuvant treatment.
Stephen Jones (US Oncology Research Inc, Houston, Texas, USA; Abstr 15) presented data from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) study, which is a randomised Phase III trial recruiting hormone-sensitive postmenopausal women with early breast cancer. Initial aims of this study were to compare tamoxifen versus exemestane as monotherapy. However, during the study, results of the Intergroup Exemestane Study (IES) became available showing that patients who crossed over from tamoxifen to exemestane had a better disease-free survival, and lower rates of contralateral breast cancer. The TEAM study was then adjusted to compare sequential exemestane therapy after 2-3 years of initial tamoxifen monotherapy with a single 5-year course of exemestane alone. With 9775 patients, the TEAM trial is the largest AI study conducted to date. At SABCS, the data from the 2.75-year point were presented. At present, the exemestane arm shows a trend towards improved disease-free survival (HR 0.89; adjusted log-rank P=0.12) and better relapse-free survival (HR 0.85; adjusted log-rank P=0.05) and time to distant metastasis (HR 0.81; adjusted log-rank P<0.03). Adverse events, particularly gynaecological side effects, were more commonly identified in the tamoxifen arm, as were hot flushes and thromboembolic events, but no difference was observed in cardiac toxicity. Patients undergoing exemestane therapy were more likely to have hypertension. The rate of fractures was reported equally between the two treatment groups. In summary, Dr Jones said that 'the TEAM trial is the largest aromatase inhibitor study ever to be done. The overall results are positive with an improvement in outcome measured by several parameters and a favourable safety profile for exemestane relative to a worldwide standard, tamoxifen.'
Henning Mouridsen presented data on behalf of the Breast International Group (BIG) 1-98 trial (Abstr 13). In this Phase III study, postmenopausal women with hormone receptor-positive breast cancer were randomly assigned to receive single-agent therapy with either tamoxifen or letrozole for 5 years or tamoxifen for 2 years followed by letrozole for the remaining 3 years. Updated results presented at SABCS after a median follow-up of 76 months demonstrated that patients treated with letrozole monotherapy had an improved overall survival (HR 0.87, P=0.08), a better disease-free survival (HR 0.88, P=0.03) and longer time to distant recurrence (HR 0.85, P=0.05) in comparison with those patients who switched from tamoxifen to letrozole. By contrast, patients who switched from tamoxifen to letrozole had a higher risk of recurrence than those who received letrozole monotherapy (9.1% versus 7.3% at 5 years). Given these findings, Dr Mouridsen suggested that 5 years of letrozole upfront rather than tamoxifen ought to be the standard of care.
The SABCS continues to be a world-class congress and is the largest scientific meeting dedicated to advances in breast cancer. Further details can be obtained from the SABCS website .
All the abstracts appear in Cancer Research, 2009, 69 (Supplement).
[1.] San Antonio Breast Cancer Symposium. www.sabcs.org (accessed 12 March 2009).
Sascha Dua and Mohammed Keshtgar
Royal Free Hospital, London, UK
Correspondence to: Sascha Dua Department of Surgery, Royal Free Hospital, Pond Street, London NW3 2QG (email:firstname.lastname@example.org)
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|Author:||Dua, Sascha; Keshtgar, Mohammed|
|Publication:||Advances in Breast Cancer|
|Article Type:||Conference news|
|Date:||Mar 1, 2009|
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