St Gallen Consensus Research Articles

Ki-67 gives additional prognostic information on St Gallen 2007 and Adjuvant! Online risk categories in early breast cancer.

Abstract Abstract #1086 Purpose: We sought to determine the significance of Ki-67, one of the tumor cell proliferation indexes, as a useful prognostic factor in early breast cancer.
 Patients and Methods: 1,080 consecutive patients with stage I or II breast cancer operated between 1998 and 2003 were enrolled. Patients were categorized based on the 2007 St. Gallen consensus and Adjuvant! Online. The expression of Ki-67 in the tumor was assayed using immunohistochemistry (cut-off value: 10%).
 Results: Univariate analysis revealed that tumor size, lymph node involvement, histologic grade, estrogen receptor, progesterone receptor, bcl-2, and Ki-67 (≥10%) were significant for both overall survival (OS) and distant metastasis-free survival (DFS). Of them, lymph node involvement and high Ki-67 expression were identified as independent prognostic factors for OS at multivariate analysis. The survivals of intermediate- and high-risk groups according to 2007 St Gallen consensus were further separated by Ki-67 expression level (5-yr DFS rate=93.3% vs 86.6% for Ki-67<10% and ≥10%, respectively in intermediate-risk group (p=.001); 5-yr DFS rate=83.1% vs 61.5% for Ki-67<10% and ≥10%, respectively in high-risk group (p=.006)). The survivals of low- and high-risk groups according to Adjuvant! Online were further separated by Ki-67 expression level [5-yr DFS rate=97.8% vs 89.5% for Ki-67<10% and ≥10%, respectively in low-risk group (p=.010); 5-yr DFS rate=90.4% vs 82.6% for Ki-67<10% and ≥10% in high-risk group (p=.005)).
 Conclusion: Ki-67 was an independent prognostic factor for DFS and OS in early breast cancer, and could give additional prognostic information on the risk grouping by 2007 St Gallen consensus and Adjuvant! Online. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1086.

Aromatase Inhibitors in Early Hormone Receptor-Positive Breast Cancer

Breast cancer is common, affecting one in nine women worldwide. As stipulated by the St Gallen consensus guidelines, hormone therapy is an integral part of treatment for hormone-responsive disease. Previously, this has been with tamoxifen; however, as a result of a number of recent studies, aromatase inhibitors are now competing for use as first-line agents. In addition, there is as yet no firm consensus as to when and how these drugs should be used within the adjuvant setting. This article reviews the use of aromatase inhibitors in early stage hormone-positive breast cancer. It describes the evidence from the studies involving the aromatase inhibitors in an upfront, switch and extended setting. It further discusses the mathematical models proposed to determine the optimum timing of initiation. In light of the ongoing research into predictive biomarkers, this review then concentrates on whether future focus should be on more individualized treatment strategies than the optimum timing of aromatase inhibitors.

Therapeutic impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography in the pre- and postoperative staging of patients with clinically intermediate or high-risk breast cancer

Positron emission tomography with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG-PET) is an accurate imaging modality for the staging of breast cancer. The aim of this study was to determine the potential therapeutic impact of pre- and postoperative FDG-PET in patients with clinically intermediate or high-risk breast cancer. One hundred and fourteen patients with newly diagnosed breast cancer were examined before (73) or after (41) surgery. Patient data were translated into three scoring sheets corresponding to information available before positron emission tomography (PET), after PET and after further diagnostic tests. Three medical oncologists independently reviewed the retrospectively acquired patient data and prospectively made decisions on the theoretically planed treatment for each time point, according to the recommendations of St Gallen Consensus Guidelines 2005. FDG-PET changed the planed treatment in 32% of 114 patients. In 20% of cases, therapeutic intention (curative versus palliative) was modified. Radiation treatment planning was changed in 27%, surgical planning in 9%, chemotherapy in 11% and intended therapy with bisphosphonates in 13% of all patients. Based on current treatment guidelines, FDG-PET, as a staging procedure in patients with newly diagnosed clinically intermediate or high-risk breast cancer examined pre- and postoperatively, may have a substantial therapeutic impact on treatment planning.

Which is the Better Pathological Prognostic Factor, the Nottingham Histological Grade or the Japanese Nuclear Grade? A Large Scale Study with a Long-term Follow-up

We compared the Nottingham histological grade (H-grade) and the Japanese nuclear grade (N-grade) to select the better prognostic factor for breast cancers. The series included 1786 patients with breast cancers with the exception of non-invasive and stage 4 cancers. They were classified according to the H- and N-grade. We analyzed their survival curves and also performed multivariate Cox regression analyses. According to the H-grade classification, 476 cases were grade 1, 647 cases were grade 2 and 663 cases were grade 3. According to the N-grade, 381 cases were grade 1, 215 cases were grade 2, and 1129 cases were grade 3. In the survival curves of those cases with lymph node metastases (N+) and recurrent cases, there were statistically significant differences in different categories of the H-grades, but not in the N-grades. The survival curves of all the cases and those cases without lymph node metastases (N-) always exhibited statistically significant differences. According to the 2003 St Gallen consensus, the N- group was classified as a minimal risk and an average risk groups. Both H- and N-grade exhibited statistically significant differences between the minimal risk and the average risk groups in the disease-free survival. The multivariate analyses proved that the H-grade was a statistically significant prognostic factor in all the cases and N+ group, but the N-grade was not significant in any of the studies. The H-grade is clearly proved to be a more significant prognostic factor for wider stage cases than the N-grade.

Expression profiling as a prognostic and predictive factor in breast cancer

Microarray gene expression profiling combined with advanced bioinformatics is beginning to show its power in delineating disease entities that are otherwise indistinguishable. This refinement in tumor classification allows a more accurate prediction of outcome of disease for patients that present with the same stage of disease based on conventional clinical and histopathological criteria. Gene activities determining the biological behaviour of the tumor may indeed be more likely to reflect the aggressiveness of the tumor than general parameters such as tumor size, age of the patient, or even tumor grade. The immediate clinical consequences are therefore that treatment schemes can be tailored based on the gene activity patterns of the primary tumor. Using gene expression profiling with cDNA microarrays, Perou and colleagues showed that there are several subgroups of breast cancer patients based on unsupervised cluster analysis: those of 'basal type' and those of 'luminal type'. These subgroups differ with respect to outcome of disease in patients with locally advanced breast cancer. In addition, microarray analysis has been used to identify diagnostic categories (e.g. BRCA1 and BRCA2, estrogen receptor status). We used gene expression profiling with DNA microarrays harboring 25,000 genes on 78 primary breast cancers of young lymph-node-negative patients to establish a signature, predictive for a short interval to distant metastases. This 'poor prognosis' signature consists of genes involved in the cell cycle, invasion and angiogenesis. The prognosis signature is superior to currently available clinical and histopathological prognostic factors in predicting a short interval to distant metastases (odds ratio = 18 [95% confidence interval = 3.3-94], P < 0.001, multivariate analysis). We have validated our findings of this poor prognosis profile on a large unselected consecutive series of LN0 as well as lymph-node-positive (LN+) young breast cancer patients (n = 295). The analyses confirm that the profile is a strong independent factor in predicting outcome of disease for LN0 patients in general (10-year overall survival for the good prognosis profile 96% vs 50% for the poor prognosis profile). Furthermore, the profile is also powerful for LN+ patients. At present, the prognostic significance of the 70 genes is tested in older breast cancer patients. Nowadays, consensus guidelines in the management of breast cancer select up to 95% of lymph-node-negative young breast cancer patients for adjuvant systemic therapy (e.g. NIH and St Gallen consensus criteria). As 70–80% of these patients would have remained disease-free without this adjuvant treatment, these patients are 'overtreated'. The 'poor prognosis' signature provides a novel strategy to accurately select patients who would benefit from adjuvant systemic therapy and can greatly reduce the number of patients that receive unnecessary treatment. Our data revealed that already small tumors display the metastatic signature, and recent results show that the molecular program established in a primary breast carcinoma is highly preserved in its distant metastasis. These findings suggest that metastatic capability in breast cancer is an inherent feature, and is not based on clonal selections. The results further imply that neo-adjuvant treatment given to patients based on (yet to be established) response expression profiles of their primary breast tumor might indeed prevent the outgrowth of micrometastases. Currently, the EORTC breast group is preparing a 5000-patient randomized trial to compare the efficacy of guidance of breast cancer patients for adjuvant chemotherapy based on either 'conventional' St Gallen consensus criteria or the microarray prognosis test (MINDACT trial within the EU-TRANSBIG program). The aim of the study is to confirm that the microarray test will save up to 30% of the patients from unnecessary chemotherapy and to identify 5% of them who are nowadays 'undertreated'.

Progress in systemic therapy for breast cancer: an overview and perspectives

This review will focus on progress for advanced and early breast cancer in systemic medical therapy, which consists of three main modalities: endocrine therapy (ET), chemotherapy (CT) and biological therapies (BTs). In advanced disease, we did witness two consecutive shifts in our classical sequence of ET: in the first one, the potent third-generation aromatase inhibitors took the second place after tamoxifen failure (a shift that is level 1 evidence based), making megestrol acetate a third option, while in the second, they are challenging tamoxifen as the ‘gold standard’ first line ET (a shift that is level 2 evidence based). As far as CT is concerned, most of the progress has been seen in anthracycline-resistant disease with the taxanes (docetaxel in particular) becoming the preferred treatment option on a level 1 evidence basis. In patients with no or limited anthracycline exposure, at least 10 randomised clinical trials involving the taxanes have been conducted, but in view of their conflicting results, no new standard of care has emerged. Third-line CT following anthracyclines and taxanes remains a wide-open research opportunity, with oral capecitabine being the only agent approved in this indication. Herceptin® (trastuzumab) is the first BTs available for the treatment of breast cancer. Its impressive clinical activity in metastatic breast cancer (MBC) prompted the registration of the drug for use as monotherapy in patients with HER-2 overexpressing MBC who have failed anthracyclines and taxanes, as well as for use upfront in combination with paclitaxel. There is substantial room for further progress with the use of Herceptin® in the management of breast cancer and much hope is placed in the combination of Herceptin® with other agents targeting important signaling pathways, such as the MAPKinase pathway or the PI 3 kinase cell survival pathway. Such strategies will be briefly discussed. In the area of early breast cancer management, BTs (namely Herceptin® and bisphosphonates) are being evaluated in randomised clinical trials, while ET has consolidated its prominent role for all women whose tumours express hormone receptors, as outlined in the 2000 NIH Consensus Conference and in the latest treatment guidelines proposed by the St-Gallen consensus panel in 2001. Substantial mutations in our standards of care are also expected in the field of adjuvant ET, with the early positive results of the large ATAC trial showing superior efficacy and tolerability of anastrozole over tamoxifen. The added benefits from adjuvant CT in patients receiving optimal ET remain difficult to ascertain and may be quite small in certain sub-groups. Only translational research efforts carry the hope for a much needed understanding of this complex interplay between ET and CT. With further improvement expected with new hormonal agents, it is possible that the role of CT will diminish in the future management of endocrine-responsive breast cancer, while the role of ET±BTs will grow.

Are international guidelines for the prescription of adjuvant treatment for early breast cancer followed in clinical practice? Results of a population-based study on 1547 patients.

The results of several randomized trials and meta-analyses have been reported on adjuvant treatment for early breast cancer and treatment guidelines have been defined accordingly, but detailed data are lacking on the appropriateness of treatment prescription in clinical practice. We performed a prospective, observational, multicenter study to monitor the prescription, delivery and effectiveness of radiotherapy following conservative surgery for early breast cancer; 1610 patients treated with postoperative radiation to the breast in 1997 were entered by 12 centers in Lombardy, Italy. Here we report the results of a secondary analysis focused on the prescription of medical adjuvant treatment (1547 eligible patients). Chemotherapy only was prescribed to 526 patients (33%), hormonal therapy only to 539 (33%), and both treatments to 85 patients (5%); 460 women (29%) received no medical adjuvant treatment. We compared the collected data with guidelines defined in 1995 by the St Gallen Consensus Conference. Undertreatment was most frequent in node-negative patients at intermediate/high risk, no treatment (instead of tamoxifen or chemotherapy) being prescribed in 21-45% of cases. Node-negative patients at low risk, on the other hand, were overtreated with tamoxifen in 31% of cases. In node-positive, premenopausal women compliance with guidelines was far better, with a 91-96% rate of chemotherapy prescription. In node-positive, postmenopausal, estrogen receptor-positive patients chemotherapy was unduly prescribed in as many as 56% of cases. Comparison of clinical practice with the next version of the guidelines (1998) showed a somewhat better compliance. Despite the availability of official and authoritative guidelines, adjuvant treatment prescription for early breast cancer in Lombardy in 1997 was suboptimal, especially in well-defined subgroups of patients.

Choosing between endocrine therapy and chemotherapy--or is there a role for combination therapy?

Results from many randomized trials of adjuvant breast cancer therapy have been presented in several overviews and at subsequent meetings. This manuscript reviews the current status of both chemo- and endocrine therapy and the prospects for combination therapy, as summarized at the NIH and St Gallen Consensus meetings. In conclusion, treatment selection should be based primarily on endocrine responsiveness; however, a collaborative approach involving the development of new agents and investigation of their optimal integration into therapy programs will ensure progress and improved patient care.