An Analysis of PIK3CA Hotspot Mutations and Response to Neoadjuvant Therapy in Patients with Breast Cancer from Four Prospective Clinical Trials.

Autor:	Jank P; Institute of Pathology, Philipps University Marburg and Marburg University Hospital (UKGM), UCT Frankfurt-Marburg, Marburg, Germany., Karn T; Department of Gynecology and Obstetrics, University of Frankfurt, UCT Frankfurt-Marburg, Frankfurt, Germany., van Mackelenbergh M; Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Schleswig-Holstein, Kiel, Germany., Lindner J; Institute of Pathology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany., Treue D; Institute of Pathology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany., Huober J; Kantonsspital St. Gallen, Brustzentrum, Departement Interdisziplinäre Medizinische Dienste, St. Gallen, Switzerland., Engels K; Zentrum für Pathologie, Zytologie und Molekularpathologie, Neuss, Germany., Solbach C; Department of Gynecology and Obstetrics, University of Frankfurt, UCT Frankfurt-Marburg, Frankfurt, Germany., Diebold K; Institute of Pathology, St. Barbara-Klinik Hessen Hamm, Hamm, Germany., Marmé F; Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Müller V; Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany., Schneeweiss A; National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany., Sinn HP; Institute of Pathology, University of Heidelberg, Heidelberg, Germany., Fehm T; Universitaetsklinikum Düsseldorf, Düsseldorf, Germany., Schem C; Mammazentrum Hamburg am Krankenhaus Jerusalem, Germany., Stickeler E; Klinik für Gynäkologie und Geburtsmedizin, Uniklinik Aachen, Aachen, Germany., Fasching P; Universitätsklinik Erlangen, Erlangen, Germany., Budczies J; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany., Felder B; German Breast Group, Neu-Isenburg, Germany., Nekljudova V; German Breast Group, Neu-Isenburg, Germany., Holtschmidt J; German Breast Group, Neu-Isenburg, Germany., Untch M; Helios Kliniken Berlin-Buch, Berlin, Germany., Denkert C; Institute of Pathology, Philipps University Marburg and Marburg University Hospital (UKGM), UCT Frankfurt-Marburg, Marburg, Germany., Loibl S; German Breast Group, Neu-Isenburg, Germany.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Sep 03; Vol. 30 (17), pp. 3868-3880.
DOI:	10.1158/1078-0432.CCR-24-0459
Abstrakt:	Purpose: The PI3K signaling pathway is frequently dysregulated in breast cancer, and mutations in PIK3CA are relevant for therapy resistance in HER2-positive (HER2pos) breast cancer. Mutations in exons 9 or 20 may have different impacts on response to neoadjuvant chemotherapy-based treatment regimens. Experimental Design: We investigated PIK3CA mutations in 1,691 patients with early breast cancer who were randomized into four neoadjuvant multicenter trials: GeparQuattro (NCT00288002), GeparQuinto (NCT00567554), GeparSixto (NCT01426880), and GeparSepto (NCT01583426). The role of different PIK3CA exons and hotspots for pathologic complete response (pCR) following neoadjuvant chemotherapy (NACT) and patient survival were evaluated for distinct molecular subgroups and anti-HER2 treatment procedures. Results: A total of 302 patients (17.9%) of the full cohort of 1,691 patients had a tumor with a PIK3CA mutation, with a different prevalence in molecular subgroups: luminal/HER2-negative (HER2neg) 95 of 404 (23.5%), HER2pos 170 of 819 (20.8%), and triple-negative breast cancer 37 of 468 patients (7.9%). We identified the mutations in PIK3CA exon 20 to be linked with worse response to anti-HER2 treatment (OR = 0.507; 95% confidence interval, 0.320-0.802; P = 0.004), especially in hormone receptor-positive HER2-positive breast cancer (OR = 0.445; 95% confidence interval, 0.237-0.837; P = 0.012). In contrast, exon 9 hotspot mutations p.E452K and p.E545K revealed no noteworthy differences in response therapy. Luminal/HER2neg patients show a trend to have worse treatment response when PIK3CA was mutated. Interestingly, patients with residual disease following neoadjuvant treatment had better survival rates when PIK3CA was mutated. Conclusions: The PIK3CA hotspot mutation p.H1047R is associated with worse pCR rates following NACT in HER2pos breast cancer, whereas hotspot mutations in exon 9 seem to have less impact. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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