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AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2016

For the last 12 years, the Breast Committee of the Arbeitsgemeinschaft Gynakologische Onkologie (German Gynaecological Oncology Group, AGO) has been preparing and updating evidence-based recommendations for the diagnosis and treatment of patients with early and metastatic breast cancer. The AGO Breast Committee consists of 43 gynaecological oncologists specialized in breast cancer and interdisciplinary members specialized in pathology, radiological diagnostics, medical oncology and radiotherapy. The update is performed according to documented rules by thoroughly reviewing and scoring chapter by chapter the recent publications for their scientific validity (Oxford Level of Evidence, LoE; www.cebm.net[1]) and clinical relevance (AGO Grades of Recommendation; table ​table1).1). Here we present the 2013 update of these guidelines focussing on the modifications that were performed this year. The full version of the update is available online as a PDF file in an English and a German version [2]. 
 
 
 
Table 1 
 
AGO grades of recommendation 
 
 
 
 
Prognostic and Predictive Factors 
Currently, the indication for adjuvant chemotherapy is mainly driven by prognosis and to a much lesser extent by prediction. Since the publication of the molecular classification of breast cancer, the role of classical pathology and immunohistochemistry (IHC) has been questioned as a sole instrument for adjuvant decision making. According to ASCO-CAP guidelines, discordances for central versus local immunohistochemical staining of hormone receptors (HR) and human epidermal growth factor receptor 2 (HER2) are reported in about 20%, major discrepancies in grading for 40% [3,4,5]. Furthermore, in 2012, Mirror trialists reported an upgrade of 22% of pN0 cases to pN1 in central pathology [6]. In the context of these data, and because of the lack of consideration of HER2 over-expression as a prognostic and predictive factor, the AGO guidelines have downgraded the available version 8.0 of Adjuvant! online (LoE 2bB; AGO+/-). Considering immunohistochemical tumour markers, Ki-67 is a reliable prognostic factor especially after neoadjuvant chemotherapy (NACT)/short-term endocrine treatment. Data for prediction of chemotherapy outcome are less convincing. The committee nevertheless recommends the clinical use of Ki-67 under the prerequisite of meticulous quality control (LoE 1aA; AGO+). As long as nationwide standardization and quality assurance are not implemented, cut-off levels cannot be reliably defined for routine use. 
 
uPA/PAI was tested in prospective trials and is suggested as a reliable prognostic marker and a predictive marker for the usefulness of chemotherapy in N0 cases (LoE 1aA; AGO+). 
 
New molecular tools (mRNA, DNA level) have the advantage of higher accuracy, reproducibility and lower inter-observer variability compared to IHC. To allow for adequate evaluation of available molecular markers/genomic signatures, the AGO Breast Committee valued prospective-retrospective evidence, generated by retrospective analyses using archived tissue from prospective trials, to LoE IB as proposed by Simon et al. in 2009 [7]. Validated molecular signatures may be used in individual cases in which classical prognostic factors provide contradictory results; however, a general recommendation cannot be given for lack of prospective data (LoE 2bB; AGO+/-). The largest prospective-retrospective body of evidence exists for Oncotype DX® (Genomic Health Inc., Redwood City, CA, USA) (LoE IB, prognostic and predictive for chemotherapy) in HR+/N0-1 breast cancer [8,9]. Endopredict® (Sividon Diagnostics GmbH, Cologne, Germany) (LoE IB for prognosis) was evaluated in HR-positive postmenopausal patients receiving endocrine therapy only and cannot be used for prediction of chemotherapy outcome [10]. Mammaprint® (Agendia BV, Amsterdam, Netherlands) has been evaluated in N0-1 breast cancer (LoE IIC for prognosis) [11]. Additionally, PAM50, a gene expression signature which reproduces molecular subtypes (LoE IIB for prognosis), will soon be commercially available in Germany [12].