Authors' objectives: High-throughput sequencing technologies enable the simultaneous analysis of multiple genes or the entire genome in a single run and are increasingly used for the detection of clinically relevant genetic alterations. This assessment evaluated the clinical effectiveness, safety, and economic, organisational, and ethical aspects of high-throughput sequencing technologies (synonymously referred to as next-generation sequencing or NGS in the included literature) for the detection of PIK3CA, AKT1, PTEN, and ESR1 genetic alterations in breast cancer diagnostics. The target population comprises adults diagnosed with HR+/HER2–, locally advanced or metastatic breast cancer.

Authors' results and conclusions: Three high-quality systematic reviews, including two meta-analyses and one HTA report, were identified. Five guideline recommendations or informal guidance passages from three international organisations (AWMF, ASCO, SITC) were included in the guideline synopsis. Clinical validity: The evidence shows that NGS outperforms PCR-based methods for PIK3CA detection (2 reviews), while digital PCR is superior to NGS for ESR1 detection (1 review). For the assessment of direct clinical utility, safety outcomes, and the detection of AKT1 and PTEN, no evidence was identified. Economic and organisational aspects: NGS enables multiplexing (simultaneous sequencing of multiple genes in a single run) and unknown variant detection but requires adequate testing infrastructure and specialised bioinformatics expertise. NGS demonstrates volume-dependent cost-efficiency, with per-patient costs becoming comparable to PCR in high-volume settings. The results were based on a Norwegian healthcare context HTA report and may not be directly transferable to Austria. Guideline recommendations: The (German) AWMF S3 guideline recommends comprehensive NGS-based molecular diagnostics based on strong expert consensus, and two (American) ASCO guidelines provide an explicit evidence-based strong recommendation for NGS for PIK3CA detection. Beyond formal recommendations, informal passages within the guidelines also describe and support comprehensive NGS-based testing approaches more broadly. While no explicit recommendations exist for AKT1, PTEN, and ESR1, these mutations are implicitly supported through comprehensive genomic testing approaches.

Authors' recommendations: International guidelines recommend NGS-based testing approaches, however, their transferability to the Austrian healthcare context is limited due to differing healthcare structures and regulatory requirements. No standardised molecular diagnostic pathway currently exists in Austria. Implementation requires local data generation, engagement of relevant stakeholders, and consideration of infrastructural and regulatory requirements.

Authors' methods: A systematic literature search was conducted across five databases. Publications from June 2020 to August 2025 were included, with a focus on systematic reviews and HTA reports. A guideline synopsis was additionally performed, supplemented by manual searches of four further databases. Evidence and guideline recommendations were narratively synthesised.

Project Status: Completed

URL for project: https://aihta.at/page/humangenetische-untersuchungen-in-oesterreich-ein-ueberblick-ueber-massiv-parallele-sequenzierung-mps-anwendungsfelder-nutzen-und-implikationen-fuer-die-versorgung/en

Year Published: 2026

URL for published report: https://eprints.aihta.at/1604/1/HTA-Projektbericht_Nr.176c

URL for additional information: https://eprints.aihta.at/1604/

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Austria

Organisation Name: Austrian Institute for Health Technology Assessment

Contact Address: Josefstaedter Strasse 39, A-1080 Vienna, Austria

Contact Name: office@aihta.at

Contact Email: office@aihta.at