Early Breast Cancer Trialists Research Articles

Adjuvant Taxanes: More to the Story

Breast cancer is a common public health problem, and the most important prognostic factors in survival or recurrence after potentially curative surgery include the number of involved axillary lymph nodes and the biology of the disease. Systemic chemotherapy remains a critical component in the eradication of occult micrometastatic disease in the adjuvant setting. The 2000 Early Breast Cancer Trialists' Collaborative Group overview of polychemotherapy in breast cancer has demonstrated that anthracycline-based regimens are superior to non–anthracycline-based therapies in terms of disease-free survival and overall survival. The taxanes paclitaxel and docetaxel were well established in metastatic breast cancer and lack cross-resistance with anthracyclines and were therefore quickly deemed worthwhile for evaluation in the adjuvant setting. A large meta-analysis showed that the addition of a taxane to an anthracycline-based regimen improves outcomes in high-risk patients regardless of age, menopausal status, number of nodes involved, hormone receptor status, and type of taxane. There are several effective anthracycline/taxane combinations traditionally studied in patients with high-risk disease. In this overview, we will review some of the key trials that have advanced the standard of care in the adjuvant setting with regard to various chemotherapy combinations.

Cost effectiveness of letrozole versus anastrozole in postmenopausal women with HR+ early-stage breast cancer

Background:The Breast International Group (BIG) 1-98 and Arimidex, Tamoxifen Alone or in Combination (ATAC) trials demonstrated that, in postmenopausal women with hormone receptor positive (HR+) early-stage breast cancer, 5 years of initial adjuvant endocrine therapy with letrozole or anastrozole is superior to tamoxifen. With expected generic availability of anastrozole in July 2010 and letrozole in June 2011, there may be financial pressures prior to letrozole's generic availability to start treatment-naïve patients on anastrozole vs. letrozole or to switch patients already receiving letrozole to anastrozole.Methods:A Markov model was used to estimate cost per quality-adjusted life-year (QALY) gained with letrozole vs. anastrozole from the US healthcare system perspective. Cost effectiveness was examined separately in treatment-naïve patients and in patients already receiving letrozole. For the latter, cost effectiveness of continued letrozole vs. therapeutic substitution (TS) to generic anastrozole was evaluated separately in cohorts defined on years of endocrine therapy remaining. TS to generic anastrozole was assumed to result in an additional 5% of patients discontinuing endocrine therapy. Probabilities of distant recurrence and death were taken from reports of BIG 1-98, ATAC, the Early Breast Cancer Trialists’ Collaborative Group meta-analysis of tamoxifen, and other published sources. Carry-over effects of aromatase inhibitors were assumed to be proportional to treatment duration. Costs of aromatase inhibitors were assumed to decline by 75% with generic availability.Results:In treatment-naïve patients, total expected lifetime costs are $3916 greater with letrozole vs. anastrozole. However, initiation of treatment with letrozole results in a gain of 0.15 QALYs. Cost per QALY gained with letrozole vs. anastrozole is $25 846. In patients already receiving letrozole, the increase in total expected lifetime costs with continued letrozole vs. TS to anastrozole is between $4200 and $4500 in all cohorts. QALYs gained with letrozole range from 0.21 in those with 4 years of endocrine therapy remaining to 0.13 in those with 1 year of therapy remaining. Cost per QALY gained ranges from $20 276 to $34 356.Conclusion:For postmenopausal women with HR+ early-stage breast cancer, letrozole is more likely to be cost effective vs. anastrozole in treatment-naïve patients and in patients already receiving letrozole. Limitations of the study include a lack of direct evidence comparing letrozole and anastrozole and lack of data on rates of discontinuation due to therapeutic substitution with aromatase inhibitors.

Obesity and Hormone Therapy in Breast Cancer: An Unfinished Puzzle

The relationship between obesity and breast cancer is a complex one. 1 Obesity is associated with breast cancer risk in qualitatively different ways before and after menopause (with decreased risk in premenopausal women and increased risk in postmenopausal women), whereas similar associations of obesity with prognosis are seen in pre- and postmenopausal women (obese women in both groups experience poorer outcomes). This complexity likely reflects, atleastinpart,thevariablerelationshipsbetweenobesityandestrogen (a major contributor to the growth of hormone receptor‐positive breast cancer) before and after menopause. Before menopause, obesity may interfere with normal menstrual cycling, potentially leading to reductions in estrogen levels; after menopause, increased production of estrogen in excess adipose tissue in obese women is associated with higher estrogen levels. It is likely that the complexity of the relationshipbetweenobesityandbreastcanceralsoreflectsimportant contributions of obesity-related factors other than estrogen to both breast cancer risk and prognosis. 2 These factors include insulin, adipocytokines such as leptin, and adiponectin, as well as inflammatory markers such as C-reactive protein and interleukins. In this issue of Journal of Clinical Oncology, Sestak et al 3 report intriguingresultsofananalysisoftheimpactofobesityontheefficacy of tamoxifen and anastrozole in 5,172 postmenopausal women with hormone receptor‐positive breast cancer who participated in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trial. The population studied was predominantly overweight (body mass index [BMI] 25 to 30 kg/m 2 ; 36.7% of the study population) or obese (BMI 30 kg/m 2 ; 27.3% of the study population). This pattern of obesity is similar to that reported in many recent trials in early breast cancer. The authors reported a significant increase in risk of breast cancerrecurrenceanddeathafterbreastcancerrecurrenceforwomen with higher BMIs but not an increase in the risk of death without recurrence. The authors also demonstrated a significant interaction between treatment and obesity on risk of recurrence—there was a significantlygreaterriskofrecurrenceinoverweightwomenreceiving anastrozole but not in those receiving tamoxifen (Table 4 in Sestak et al 3 ). Furthermore, the relative reduction in risk of recurrence with anastrozole (v tamoxifen) was insignificantly smaller for heavier womenthanforlighterwomen(Fig2inSestaketal 3 ).Theseobserva

Trastuzumab-Related Cardiotoxicity Following Anthracycline-Based Adjuvant Chemotherapy: How Worried Should We Be?

doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. Eur J Cancer 32A:404-412, 1996 7. Buzdar AU, Jones SE, Vogel CL, et al: A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma: Arimidex Study Group. Cancer 79:730-739, 1997 8. Ward HW: Anti-oestrogen therapy for breast cancer: A trial of tamoxifen at two dose levels. Br Med J 1:13-14, 1973 9. Takatsuka Y, Yayoi E, Inaji H, et al: A comparison of two doses of tamoxifen in patients with advanced breast cancer: 20 mg/day versus 40 mg/day [in Japanese]. Gan To Kagaku Ryoho 16:2093-2097, 1989 10. Tamoxifen for early breast cancer: An overview of the randomised trials—Early Breast Cancer Trialists’ Collaborative Group. Lancet 351:14511467, 1998 11. Lonning PE: Pharmacology of new aromatase inhibitors. The Breast 5:202-208, 1996 12. Goodwin PJ, Ligibel JA, Stambolic V: Metformin in breast cancer: Time for action. J Clin Oncol 27:3271-3273, 2009 13. Ballard-Barbash R, Hunsberger S, Alciati MH, et al: Physical activity, weight control, and breast cancer risk and survival: Clinical trial rationale and design considerations. J Natl Cancer Inst 101:630-643, 2009

Adjuvant endocrine monotherapy with tamoxifen or aromatase inhibitors for postmenopausal women with breast cancer: What is the economic impact of CYP 2D6 testing?

6010 Background: The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) has demonstrated significant improvements in breast cancer (BC) outcomes associated with adjuvant tamoxifen (TAM) an...

Potential biologic causes of the racial survival disparity in adjuvant trials of ER-positive breast cancer.

511 Background: An analysis of SWOG adjuvant breast cancer clinical trials (n = 6,676) found African American (AA) patients (pts, n = 662) had significantly worse survival than others (adjusting for treatment, tumor factors, BMI and SES) overall and in ER-positive (ER+) and ER-negative cohorts separately (JNCI 2009; 101:984). As triple negativity could not fully explain the disparity, we analyzed the ER+ S8814 phase III study to assess if level of ER-positivity or expression of single genes within the 21-gene Recurrence Score (RS) assay might inform this critical issue. Methods: S8814 (ER+, node+, postmenopausal: tamoxifen vs. CAF plus tam; Lancet 2009; 374:2055) was analyzed for disease-free survival (DFS) and overall survival (OS) for AA vs. others, adjusting for other factors. Within the subset available for RS analysis of prognosis/prediction of CAF benefit (Lancet Oncol 2010; 11:55), outcome of AA vs. others was assessed overall; and by ER level, the composite RS, and each of the genes analyzed by RT-PCR. Results: Of 1,477 pts, 139 (9%) were AA, who derived similar benefit from CAF as did others. However, outcomes were worse for AA after adjusting for treatment and other prognostic factors: DFS AA vs. others HR = 1.44 and for OS = 1.70. 27 of 367 pts in the RS sample were AA, for whom DFS was also worse (logrank p = 0.073; adjusted HR 1.65; 5-year DFS 67% AA, 79% others). There was no significant difference in RS by race, although fewer AA had low RS (33% vs. 40%) and more had high RS (41% vs. 32%). There was no significant difference by race in ER level by Allred IHC score or by RT-PCR for each of the 4 ER genes. However, all 5 genes in the proliferation group by RT-PCR had higher quantitative gene expression in AA vs others (p < 0.05 for CCNB1, MKI17, MYBL2, BIRC5; p = 0.051 for AURKA). While Cox regression models that adjusted for nodes, CAF and RS made a marginal impact on the DFS HR by race (1.60), the HR decreased substantially to 1.23 upon adjustment for proliferation. Conclusions: AA on ER+ early breast cancer trials have worse survival than others, due in large part to tumors with higher proliferation and not to differences in degree of endocrine responsiveness. If confirmed in other studies, this finding might impact choice of adjuvant therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genomic Health Genomic Health Agendia, Genomic Health

How Improved Local-Regional Therapy Impacts Survival

Findings from the 2005 Early Breast Cancer Trialists Collaborative Group overview of the effects of more extensive local therapy on breast cancer survival provide strong evidence supporting a causal link between local-regional cancer control and subsequent breast cancer survival. This article reviews the evidence supporting this link and discusses both the conditions that must be met for improved local-regional therapy to confer a survival benefit and the potential magnitude of the survival benefit from improved local-regional therapy.

The androgen receptor in breast cancer: learning from the past

Care of the cancer patient is becoming increasingly individualized. At the fulcrum of such therapeutic decisionmaking lies a relevant and accurate understanding of unique patient characteristics and preferences, and of tumor biology. In a pure sense, prognostic factors reflect tumor biology that may be used to estimate outcome independent of systemic treatment, whereas predictive factors reflect a relative resistance or sensitivity to specific therapy(ies) and are increasingly used to select optimal treatments for an individual patient. Perhaps the best and oldest example of a biomarker with proven clinical utility is the estrogen receptor alpha (ER), the expression of which on breast tumors has served both as a prognostic and predictive biomarker for the last three decades [1]. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 2005 overview clearly demonstrated that tamoxifen substantially reduces the risk for breast cancer recurrence and death across all age groups in patients with ER-positive earlystage breast cancer, whereas patients with ER-negative disease do not benefit from tamoxifen [2, 3]. ER status also predicts response to endocrine therapy in the metastatic setting [4]. In this issue of Breast Cancer Research and Treatment, a well designed and thorough study by Castellano et al. [5] explores the concept of androgen receptor (AR) as a novel prognostic factor in ER-positive breast cancer, and suggests that it may have additional clinical utility in identifying a better prognosis subgroup of luminal B breast cancers.

E17. Modern radiotherapy planning in the treatment of breast cancer

Radiotherapy (RT) is an integral part of the management of early stage breast cancer following breast-conserving surgery and after mastectomy in patients at moderate to high risk for loco-regional recurrence. Absolute improvements in breast cancer-specific and overall survival have been demonstrated by the Early Breast Cancer Trialists’ Collaborative Group due to improvements in loco-regional control with RT and are approximately 4−5% at 15 years. 1 The gains in survival would likely be greater were it not for excess mortality observed from causes other than breast cancer, which have been shown to be primarily cardiac in nature. Therefore, treatment planning approaches which minimise treatment of uninvolved tissues are critical to the ultimate success achieved with RT. Radiation treatment planning for breast cancer has changed dramatically through the years with modifications in clinical target volumes, treatment delivery systems, and techniques. Early target volumes reflected a Halstedian philosophy in which extensive loco-regional fields were felt to be necessary for cure but through successive studies, volumes have been refined that maintain high rates of loco-regional control while minimising toxicity. Treatment delivery systems have evolved from orthovoltage units where skin dose and shallow depth dose distributions limited dose delivery to deep seated lesions to sophisticated computer-controlled treatment delivery systems which allow highly conformal therapy by the creation of dose distributions that closely conform to the shape of the target in three dimensions. While improvements in target definition, treatment delivery systems and changes in techniques are all critical in radiation delivery, the remainder of the discussion will be devoted to modern treatment planning techniques. Two-dimensional (2D) planning systems utilising tangential fields to the breast have resulted in high rates of tumour control. However, dose homogeneity across the entire breast is difficult to achieve with 2D planning due to variations in breast contour and tissue density. Use of wedges with lung density correction significantly reduced dosimetric hot spots along the central axis 2 ; however, lack of homogeneity within the entire field was still problematic particularly in large-breasted women,

Doubling back on centromere 17 in early breast cancer

Anthracycline chemotherapy produces a modest improvement in survival for women with early-stage breast cancer. 1 Early Breast Cancer Trialists' Collaborative GroupEffects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005; 365: 1687-1717 Summary Full Text Full Text PDF PubMed Scopus (6304) Google Scholar However, these drugs are associated with serious long-term side-effects—eg, secondary congestive heart failure and leukaemia—and careful selection is needed to ensure that anthracyclines are given only to patients who may benefit from them. A meta-analysis 2 Gennari A Sormani MP Pronzato P et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst. 2008; 100: 14-20 Crossref PubMed Scopus (322) Google Scholar of eight randomised trials concluded that the benefit of anthracyclines was limited to patients with HER2 amplification. However, not all studies are consistent and a clear mechanistic link between HER2 amplification and anthracycline sensitivity remains elusive. TOP2A, which neighbours HER2 on chromosome 17 (Ch17), is frequently co-amplified in HER2-positive tumours and encodes a TOP2A DNA replication protein that is inhibited by anthracycline therapy. Alterations of TOP2A have been associated with differential anthracycline benefit, 3 O'Malley FP Chia S Tu D et al. Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst. 2009; 101: 644-650 Crossref PubMed Scopus (169) Google Scholar although this finding has not always been recorded. 4 Bartlett JM Munro A Cameron DA Thomas J Prescott R Twelves CJ Type 1 receptor tyrosine kinase profiles identify patients with enhanced benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial. J Clin Oncol. 2008; 26: 5027-5035 Crossref PubMed Scopus (87) Google Scholar Thus potentially only a subset of HER2-positive breast cancers might benefit from anthracycline therapy. Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/BR9601)In women with early breast cancer receiving adjuvant chemotherapy, the most powerful predictor of benefit from anthracyclines is Ch17CEP duplication. In view of the location of HER2/TOP2A on chromosome 17, Ch17CEP duplication might explain the inconsistencies in previous studies of factors predicting benefit from anthracyclines. Full-Text PDF Open Access

Benefit of adjuvant chemotherapy in elderly ER-negative breast cancer patients: benefits and pitfalls

Approximately 50% of breast cancer (BC) cases occur in women aged 65 and older, and more than 30% occur in those aged over 70, yet very old (older than 70) patients are under-represented in clinical trials. In the Oxford meta-analysis, the hazard ratios for recurrence and BC mortality in women aged over 70 were 0.88 and 0.87, respectively, suggesting a benefit from chemotherapy in this group of patients as well; however, the large confidence intervals surrounding reductions in this subgroup reflect the small number of older patients recruited in randomized trials in Early Breast Cancer Trialists’ Collaborative Group meta-analyses. If we consider the tumor biology of BC in older adults, we will see that they are more likely to develop a tumor with high estrogen receptor (ER)- and/or progesterone receptor-positive status and a lower proliferative index. However, the biology of these tumors appears to change according to chronological age into aggressive forms diagnosed in these patients as well. This subgroup analysis for the benefit of adjuvant chemotherapy in elderly patients (at least 65 years) is reported in a few studies, even though a limited statistical significance has been revealed. Retrospective evidences suggest that even more aggressive treatments such as taxanes and dose-dense schedule appear feasible (but probably more toxic) in the elderly. Age is no longer considered the only criterion for choosing the right treatment for patients with BC; in fact, functional status and comorbidity have to be taken into consideration as well. Fit elderly patients with more aggressive forms (node-positive and ER-poor disease) seem to obtain the same benefits as younger patients, and thus have to be treated in the same manner.

Variations Among Experienced Surgeons in Cancer Control After Open Radical Prostatectomy

Complications and functional outcomes after prostate surgery vary among surgeons to a greater extent than may be accounted for by chance. This excessive variation is known as heterogeneity. We explored whether there is also heterogeneity among high volume surgeons with respect to cancer control after surgery. The study cohort consisted of 7,725 patients with clinically localized prostate cancer treated with open radical prostatectomy at 4 major American academic medical centers from 1987 to 2003 by 1 of 54 surgeons. We defined biochemical recurrence as serum prostate specific antigen 0.4 ng/ml or greater followed by a higher level. Multivariate random effects models were used to evaluate prostate cancer recurrence heterogeneity among surgeons after adjusting for case mix (prostate specific antigen, pathological stage and grade), surgery year and surgeon experience. We found statistically significant heterogeneity in the prostate cancer recurrence rate independent of surgeon experience (p = 0.002). Seven experienced surgeons had an adjusted 5-year prostate cancer recurrence rate of less than 10% while another 5 had a rate that exceeded 25%. Significant heterogeneity remained on sensitivity analysis adjusting for possible differences in followup, patient selection and stage migration. Patient risk of recurrence may differ depending on which of 2 surgeons is seen even if the surgeons have similar experience levels. Surgical randomized trials are imperative to determine and characterize the roots of these variations.

Abstract CN05-03: Energy balance in cancer patients: Are we ready to intervene?

Abstract There is growing evidence that aspects of energy balance, including overweight/obesity and physical inactivity are associated with poor outcomes in some cancers, notably breast and colorectal. In breast cancer, evidence is strongest for overweight/obesity; recent evidence suggests physical activity may have important independent associations with outcomes. In colorectal cancer, evidence is strongest for physical activity. Clinical mechanisms that have been postulated for these associations include presentation of cancer at a more advanced stage or receipt of less than optimal therapy in overweight or obese individuals. Potential biologic mechanisms have included sex hormones, insulin and related IGFs, adipocytokines and inflammatory markers. In breast cancer there is growing evidence that insulin (and associated insulin resistance) may play a key role in mediating these prognostic associations - high insulin levels have been associated with increased risk of breast cancer recurrence or death. Breast cancer cells commonly overexpress insulin receptors (frequently a fetal form of the receptor that may hybridize with the IGF-1 receptor) that are not downregulated by circulating insulin; as a result, cancer cell growth may be stimulated by high circulating insulin levels. Observational clinical studies linking energy balance to prognosis of breast and colorectal cancer will be reviewed, along with early intervention work demonstrating the feasibility, short-term benefits (e.g. on QOL) and biologic (mechanistic) changes associated with lifestyle interventions in breast and colon cancer survivors. The impact of the available evidence on clinical practice and the role of large scale clinical trials of energy balance modification with recurrence or survival endpoints (completed, ongoing and planned) will be reviewed, with an emphasis on issues relating to feasibility, cost and the need for embedded correlative research to investigate biologic mechanisms for any survival effects that are identified. Related metformin trials (which target insulin and AMPK/mTOR signaling), notably NCIC MA.32, an adjuvant trial in early breast cancer that will be activated early in 2010, will also be reviewed. Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN05-03.

Breast Conservation Treatment With Radiation: An Ongoing Success Story

Breast Conservation Treatment With Radiation: An Ongoing Success Story

New radiation therapy technique for breast cancer: should the IOERT boost be a standard technique?

The standard treatment for early breast cancer comprises wide local excision, sentinel lymph node biopsy or axillary lymph node dissection and whole-breast radiotherapy (WBRT), including boost radiation if indicated, and adjuvant medical treatment. Multiple randomized clinical trials and meta-analyses demonstrated the effectiveness and safety of WBRT, and revealed that local control plays a crucial role in overall survival [1,2]. The European Organisation for Research and Treatment of Cancer (EORTC) boost versus no boost trial demonstrated that the additional dose escalation to the tumor bed, the tumor bed boost, further improved local control rates [3]. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG [Oxford, UK]) overview suggested that differences in local treatment that substantially affect local recurrence rates would avoid approximately one breast cancer death over the next 15 years for every four local recurrences avoided and should reduce 15-year overall mortality [2]. The local recurrence rate is estimated for 1% per year, and varies according the literature between 4 and 7% after 5 years and up to 10–20% in the long-term follow-up [1,4–6]. The majority of patients who develop local recurrences do so within 2–5 years [1,7]. Patients with local recurrences have an increased risk of distant metastases, and local recurrence seems to be an independent predictor of distant metastasis [7–15]. Patients who develop recurrences in the short term have a worse prognosis than patients who develop recurrences in the long term [1,7]. Based on these data the reduction of local recurrence rates should be one of our treatment goals. Many factors contribute to the reduction of local recurrence rates, such as improved diagnostic tools, modern surgical techniques, the extensive pathologic evaluation of specimen and margins, the increasing use of adjuvant systemic therapies and the extensive use of radiation therapy. Standard radiation therapy comprises 50–55 Gy in daily fractionations for 5–6 weeks. The additional application of an external boost radiation of 10–16 Gy to the tumor bed can reduce the local failure rate by 40% [3,16–19]. With this therapy an excellent local tumor control can be achieved.

Zoledronic Acid: Its Use in the Treatment of Breast Cancer

Breast cancer is a very common diagnosis in women; approximately 30% of patients with breast cancer will develop bone metastases. In addition, breast cancer patients experience adjuvant treatment related bone loss. Bisphosphonates (BPs) are the standard of care for maintaining bone health in patients with cancer. The purpose of this paper is to review the evidence on the use of zoledronic acid (ZA) in breast cancer. Therapy with ZA is generally safe and well tolerated. ZA has become established in the management of patients with breast metastatic bone disease (MBD), reducing the morbidity by decreasing the rate of skeletal-related events (SREs) and the time to develop first and subsequent SREs. Among different BPs, the strongest evidence in this setting is available for ZA. However, emerging data is currently addressing the benefit of anti-RANKL therapy versus ZA. Several trials in early breast cancer have also investigated ZA in other settings, such as for protection of bone density and in adjuvant therapy.

International Breast Cancer Research: Launching an Expedition to the Moon.

Abstract In his State of the Union address in 1971, President Nixon launched a "war on cancer" by calling for the "same kind of concentrated effort that split the atom and took man to the moon" to be turned towards conquering cancer. Since this landmark address, great strides have been made in the war on breast cancer. Lumpectomy with adjuvant radiotherapy, sentinel lymph node dissection, and adjuvant systemic therapy in the form of chemotherapy, hormonal therapy and trastuzumab have improved the quality of life and long-term survival of women diagnosed with early breast cancer. International collaboration involving research groups and initiatives such as the Early Breast Cancer Trialists' Collaborative Group quinquennial overviews has provided the clinical trials infrastructure and framework necessary to synthesize the evidence-based data upon which these gains have been achieved. Despite these successes, the pathway to new drug development and improved medical effectiveness today is costly, labor-intensive, and far too slow for our patients. Over the last decade, the advent of molecular technologies has dramatically improved our understanding of the biology of breast cancer. We now have targeted therapies available to inhibit specific signaling pathways that are aberrant in subpopulations of breast cancer. To further improve breast cancer care, we must fundamentally rethink how translational research is performed in clinical trials. The challenge of making personalized medicine a reality demands the launch of an expedition taking us to and beyond the moon: it will involve clinicians, basic scientists, bioinformaticians, statisticians, industry sponsors, regulators, and patients in new partnership that is committed to changing the vision, culture and methodology of breast cancer research. The Breast International Group's efforts in this direction will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr W1-1.

Overview of the Randomised Trials of Radiotherapy in Early Breast Cancer.

Abstract The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) was set up in the mid-1980s to co-ordinate 5-yearly meta-analyses of centrally collated individual patient data from women in all randomised trials of the treatment of early breast cancer. The present cycle considers trials that began by 2000 and includes follow-up to 2006 where available. The latest results from the overview of trials of radiotherapy versus the same management but without radiotherapy will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr MS3-1.

Who would have thought it! Influence on outcome of radiotherapy, Ki67 and stroma. Introduction to Session 5

In breast cancer there are clearly a number of factors that counter-intuitively influence outcome or for which there is a change, after a considerable time, in longstanding evidence that outcome was not affected. The latter is well represented by the effect of postoperative radiotherapy in early breast cancer on overall survival. There was clear evidence that such treatment reduced local recurrence risk (by about two-thirds) and risk of death from breast cancer (by one-sixth [1]), but until 1997 evidence suggested treatment would not improve overall survival. The results in that year of two randomised trials in high-risk patients showed that the addition of postmastectomy radiotherapy to adjuvant chemotherapy improved overall survival [2,3]. Ragaz argues from the updated results of these pivotal Canadian and Danish trails, from survival trends observed in British Columbia, Canada and from the data presented consistently from 1990 to 2005 by the Early Breast Cancer Trialists' Collaborative Group that this effect on outcome is real [4]. The reality is explained by the record reduction over this period in post-radiotherapy acute and late morbidity due to improved techniques and dosimetry. Ragaz also indicates that, due to lack of radiotherapy trials, there is no clarity on what needs to be irradiated, while the question of who needs to be irradiated can no longer be answered simplistically on the basis of the number of nodes involved. The histopathological extent of nodal involvement judged by the percentage of involved nodes, by the spread within a node and by the presence of extracapsular spread - all indicators of risk of systemic relapse - is more critical than the indicators of increased risk of local failure. The need for more trials in radiotherapy is underlined by the fact that this paradigm shift in attitude and assessment of benefit occurred when the results of the pivotal randomised trials were published in 1997 showing that postoperative radiotherapy could improve long-term overall survival and not just cause long-term morbidity. That a single measurement of Ki67 does predict long-term outcome is discussed by Dowsett and colleagues [5], but with the caveat that such a single assay may not deliver all of the required information. For prognosis alone, a single pretreatment assay suffices - but for predictive information, a second post-treatment assay in the neoadjuvant case is needed. Further assays offer even more information for drug development studies or of drug resistance mechanisms. While breast stroma has been of passing interest to pathologists since at least the 1960s, when elastosis was considered a possible marker of prognosis, the hypothesis that malignant epithelial cells alone are prognostic and the supporting (stromal) tissues are of no prognostic influence has generally been the focus of research and clinical interest. This no longer stands up to scrutiny. Howell and colleagues describe well how stroma is recruited by tumours, is variable from tumour to tumour, and how tumour genes may be downregulated (for adhesion) or upregulated (facilitating cell movement) [6] - all potentially affecting outcome. Stroma does not, however, integrate with other prognostic factors. Stroma is already targeted in various ways in clinical situations. Bevacizumab and the bisphosphonates are already in regular and effective use. There is, therefore, opportunity for further improvement in outcomes as other stromal targets are explored. 'Who would have thought it!' is a statement and not a question. Many did think it, and that is why the critically important trials in postmastectomy radiotherapy were carried out even though some trialists expected the old paradigm to be confirmed. Newer technologies now enable pathologists and clinicians to revisit hypotheses on stroma mooted 40 years ago. Neoadjuvant treatments also facilitate assessment of the prognostic effects of molecular and genetic factors. Clearly, it is having the thought that counts.

Meta-Analysis of Breast Cancer Outcomes in Adjuvant Trials of Aromatase Inhibitors Versus Tamoxifen

To conduct meta-analyses of randomized trials of aromatase inhibitors (AIs) compared with tamoxifen either as initial monotherapy (cohort 1) or after 2 to 3 years of tamoxifen (cohort 2). Data submitted to the Early Breast Cancer Trialists' Collaborative Group were used in separate meta-analyses of two cohorts. Primary analyses involve postmenopausal women with tumors reported to be estrogen receptor positive. Log-rank P values are two-sided. Cohort 1 comprised 9,856 patients with a mean of 5.8 years of follow-up. At 5 years, AI therapy was associated with an absolute 2.9% (SE = 0.7%) decrease in recurrence (9.6% for AI v 12.6% for tamoxifen; 2P < .00001) and a nonsignificant absolute 1.1% (SE = 0.5%) decrease in breast cancer mortality (4.8% for AI v 5.9% for tamoxifen; 2P = .1). Cohort 2 comprised 9,015 patients with a mean of 3.9 years of follow-up. At 3 years from treatment divergence (ie, approximately 5 years after starting hormonal treatment), AI therapy was associated with an absolute 3.1% (SE = 0.6%) decrease in recurrence (5.0% for AI v 8.1% for tamoxifen since divergence; 2P < .00001) and an absolute 0.7% (SE = 0.3%) decrease in breast cancer mortality (1.7% for AI v 2.4% for tamoxifen since divergence; 2P = .02). There was no convincing heterogeneity in the proportional recurrence reduction with respect to age, nodal status, tumor grade, or progesterone receptor status and no indication of an increase in nonbreast deaths with AIs in either cohort. CONCLUSION AIs produce significantly lower recurrence rates compared with tamoxifen, either as initial monotherapy or after 2 to 3 years of tamoxifen. Additional follow-up will provide clearer information on long-term survival.