TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer

Grote, Isabel; Bartels, Stephan; Kandt, Leonie; Bollmann, Laura; Christgen, Henriette; Gronewold, Malte; Raap, Mieke; Lehmann, Ulrich; Gluz, Oleg; Nitz, Ulrike; Kuemmel, Sherko; Zu Eulenburg, Christine; Braun, Michael; Aktas, Bahriye; Grischke, Eva-Maria; Schumacher, Claudia; Luedtke-Heckenkamp, Kerstin; Kates, Ronald; Wuerstlein, Rachel; Graeser, Monika; Harbeck, Nadia; Christgen, Matthias und Kreipe, Hans (2021): TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer. In: Cancer Medicine, Bd. 10, Nr. 23: S. 8581-8594

Abstract

Background Whereas the genomic landscape of endocrine-resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non-responsiveness to endocrine treatment in luminal early breast cancer. Methods In this study, 622 estrogen receptor-expressing breast cancer cases treated with short-term preoperative endocrine therapy (pET) from the WSG-ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3-week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post-pET Ki67 <10%) versus slightly, moderately, and severely impaired (post-pET Ki67 10%-19%, 20%-34%, and >= 35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next-generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization. Results ERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53-mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen- and aromatase inhibitor-based pET (p = 0.0005 each). Conclusion We conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53-mutated luminal cancers might not be sufficiently treated by endocrine therapy alone.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2045-7634
• Sprache: Englisch