New German S3 Breast Cancer Guideline Confirms Clinical Value of Multigene Tests and Emphasizes Nuanced Interpretation of Randomized Evidence

 

Eurobio Scientific welcomes the update, which emphasizes the value of multigene assays in treatment planning, and encourages a nuanced view of randomized trial data.

 

• The updated German S3 Guideline for Breast Cancer Version 5.0, published within the Leitlinienprogramm Onkologie by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), the Deutsche Krebsgesellschaft e. V. (DKG), and the Stiftung Deutsche Krebshilfe (DKH), reaffirms the role of validated multigene assays in treatment decision-making for patients with early hormone receptor–positive, HER2-negative breast cancer.
• The guideline underscores that accurate risk assessment is essential for therapy planning, as patients with a low absolute risk derive only limited benefit from adjuvant chemotherapy. In cases where classical clinicopathological factors – including Ki-67 – do not allow a clear recommendation for or against chemotherapy, the guideline supports the use of a methodologically standardized and clinically validated multigene test, both in node-negative disease and in patients with 1–3 positive lymph nodes. The guideline does not differentiate between individual assays, but specifies that only one multigene test should be used per treatment decision.

 

Currently, four multigene assays are recognized as clinically validated within the guideline: EndoPredict^®, MammaPrint^®, Oncotype DX^®, and Prosigna^®.

In this context, the guideline highlights that EndoPredict® and Prosigna® were developed using a prospective–retrospective approach. Both assays demonstrate robust long-term prognostic performance extending beyond 5 years, addressing an important clinical need in hormone receptor–positive breast cancer. T The guideline also mentions that EndoPredict provides a binary risk stratification, distinguishing between low- and high-risk groups.

 

While randomized controlled trials (RCTs) exist for several assays, the S3 guideline adopts a differentiated and critical view of randomized evidence. It clearly states that available RCT data are limited to selected subpopulations, such as patients with intermediate genomic risk scores or discordant clinical and genomic risk assessments. As a result, the guideline questions whether findings from these trials can be reliably extrapolated to patients with clearly low- or high-risk profiles.

 

Across all four multigene tests, validation studies include node-negative and node-positive patients as well as pre- and postmenopausal women. These studies consistently show that multigene assays can deliver independent prognostic information beyond standard clinicopathological parameters, improving risk assessment in clinically ambiguous situations. Their prognostic value has further been confirmed in large population-based cohorts and international Health Technology Assessments.

 

Regarding premenopausal patients, the guideline acknowledges ongoing uncertainty in therapeutic interpretation. This uncertainty arises from the fact that key trials – such as RxPONDER, and MINDACT – were unable to distinguish between the cytotoxic effects of chemotherapy and its ovarian suppression–related endocrine effects.

 

Against this backdrop, the S3 guideline explicitly references EndoPredict (EP and EPclin) as providing independent prognostic information in both node-negative and 1–3 node-positive breast cancer, regardless of menopausal status, supported by consistent multivariate analyses. Comparable evidence is acknowledged for MammaPrint^® and Prosigna^®.

 

Overall, the updated S3 Breast Cancer Guideline reinforces the importance of validated multigene assays, recognising the value of all four tests across all patient groups, while calling for a careful, evidence-based interpretation of randomized data, particularly in premenopausal patients. This balanced approach represents a significant step forward in individualized treatment decision-making in early breast cancer.

 

Reference:

S3-Leitlinie: Früherkennung, Diagnostik, Therapie und Nachsorge des Mammakarzinoms, Langversion 5.0 – Dez 2025, AWMF-Registernummer: 032-045OL

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