Bannerbild German Brest Group

Mutational landscape and therapy response in GeparSepto trial

22.05.2019

Results of a next-generation sequencing (NGS) analysis conducted in the neoadjuvant GeparSepto study (GBG 69) have been published in the Clinical Cancer Research.

Translational studies investigating mutational landscape of breast cancer after neoadjuvant chemotherapy (NACT) in large clinical trial cohorts are limited. In this study a total of 851 pretherapeutic formalin-fixed paraffin-embedded (FFPE) samples from the neoadjuvant GeparSepto trial were sequenced by targeted NGS. A breast cancer-specific hotspot panel of 24 genes including 16 genes for mutation (AKT1, BRAF, CDH1, EGFR, ERBB2, ESR1, FBXW7, FGFR2, HRAS, KRAS, NRAS, SF3B1, TP53, HNF1A, PIK3CA, PTEN) and 8 genes for copy-number alterations (CAN) (CCND1, ERBB2, FGFR1, PAK1, PIK3CA, TOP2A, TP53, ZNF703) was used to investigate the prevalence of alterations in different breast cancer subgroups as well as the role for response to NACT. Three genes, PIK3CA, TP53 and ERBB2 were analyzed for both mutations and CNAs. The most common genomic alterations were mutations of TP53 (38.4%) and PIK3CA (21.5%), and 8 different amplifications (TOP2A 34.9%; ERBB2 30.6%; ZNF703 30.1%; TP53 21.9%; PIK3CA 24.1%; CCND1 17.7%; PAK1 14.9%; FGFR 12.6%). The genetic heterogeneity in different breast cancer subtypes [lum/HER2-negative vs. HER2-positive vs. triple-negative breast cancer (TNBC)] was significantly linked to differences in NACT response. PIK3CA-mutated tumors showed a significantly reduced pathological complete response (pCR) rate compared with wild-type tumors (23.0% vs. 38.8%; p<0.001), in particular in the HER2-positive subcohort (multivariate OR=0.43 [95%CI 0.24–0.79]; p=0.006). This study is the first comprehensive FFPE-based NGS analysis of different breast cancer subtypes after NACT and provided evidence for using NGS to dissect molecular heterogeneity in clinical trial samples. Furthermore, the findings pointed to PIK3CA mutations as a therapy resistance parameter in the HER2-positive breast cancer.

Loibl S, Treue D, Budczies J, Weber K, Stenzinger A, Schmitt WD, Weichert W, Jank P, Furlanetto J, Klauschen F, Karn T, Pfarr N, von Minckwitz G, Möbs M, Jackisch C, Sers C, Schneeweiss A, Fasching PA, Schem C, Hummel M, van Mackelenbergh M, Nekljudova V, Untch M, Denkert C. Mutational Diversity and Therapy Response in Breast Cancer: A Sequencing Analysis in the Neoadjuvant GeparSepto Trial. Clin Cancer Res. 2019 Apr 12. [Epub ahead of print]

Link in PubMed

News

  • 05.11.2018 October 2018: Long-term survival analysis of GeparSixto trial

    The survival analysis of patients with triple-negative and HER2-positive early breast cancer enrolled in the neoadjuvant GeparSixto (GBG 66) phase II trial have been published in the Annals of Oncology.

    Mehr ...
  • 15.10.2018 GBG Research at ESMO

    Data of several GBG trials and translational research projects will be presented at the upcoming ESMO 2018 Congress, which will take place from 19 to 23 October in Munich, Germany.

    Mehr ...
  • 11.10.2018 BIG newsletter no 9 is out

    We’re delighted to announce that the BIG newsletter BIG Research in Focus, Issue 9 is out and has been published on BIG’s website.

    Mehr ...
  • 27.09.2018 Paper of the month: models for pCR

    Paper of the month: models for pCR

    A statistical research study that aimed to develop an empirical model for predicting the magnitude of the treatment effects on survival endpoints based on the treatment effects on pathological complete response (pCR) has been published in the Contemporary Clinical Trials.

    Mehr ...

GBG Forschungs GmbH
Martin-Behaim-Str. 12 | 63263 Neu-Isenburg | Fax +49 6102 7480-440

+49 6102 7480-0 | nfGBGd