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Hotspot mutations in PIK3CA associate with first-line treatment outcome for aromatase inhibitors but not for tamoxifen |
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| Authors: | Diana E Ramirez-Ardila Jean C Helmijr Maxime P Look Irene Lurkin Kirsten Ruigrok-Ritstier Steven van Laere Luc Dirix Fred C Sweep Paul N Span Sabine C Linn John A Foekens Stefan Sleijfer Els M J J Berns Maurice P H M Jansen |
| Institution: | 1. Department of Medical Oncology, Erasmus MC Cancer Institute, Room Be424, PO Box 2040, 3000 CA, Rotterdam, The Netherlands 2. Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands 3. Department Oncology, Catholic University Leuven, Leuven, Belgium 4. Translational Cancer Research Unit, Laboratory of Pathology, Oncology Centre, Antwerp University, GZA Hospitals St-Augustinus, Antwerp, Belgium 5. Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 6. Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 7. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands |
| Abstract: | PIK3CA mutations occur frequently in breast cancer, predominantly in exons 9 and 20. The aim of this retrospective study is to evaluate the PIK3CA mutation status for its relationship with prognosis and first-line endocrine therapy outcome. PIK3CA exon 9 and 20 were evaluated for mutations in 1,352 primary breast cancer specimens by SnaPshot multiplex analyses. The mutation status was studied for their relationship with metastasis-free survival (MFS) in 342 untreated lymph node-negative (LNN) patients and to time to progression (TTP) in estrogen receptor (ER)-positive patients with metastatic disease treated with first-line tamoxifen (N = 447) or aromatase inhibitors (AIs; N = 84). We detected in 423 patients hotspot mutations for PIK3CA (31 %). Mutations in exon 20 were detected in 251 patients (59 %), with H1047L and H1047R mutations in 37 (15 %) and 214 (85 %) cases, respectively. Mutations in PIK3CA exon 9 were discovered in 173 patients (41 %), with E542K and E545K mutations in 57 (32 %) and 104 (60 %) cases as most prevalent ones. Evaluation of the untreated LNN patients for prognosis showed no relationship between MFS and PIK3CA mutations, neither for exon 9 HR = 1.04 (95 % CI 0.57–1.89), P = 0.90] nor for exon 20 HR = 0.98 (95 % CI 0.63–1.54); P = 0.94] when compared to wild-type. The PIK3CA mutation status was also not associated with treatment outcome after first-line tamoxifen. On the other hand, patients treated with first-line AIs showed a longer TTP when having a PIK3CA mutation in exon 9 HR = 0.40 (95 % CI 0.17–0.95); P = 0.038] or exon 20 HR = 0.50 (95 % CI 0.27–0.91); P = 0.024] compared to wild-types, both significant in uni- and multivariate analysis including traditional predictive factors. All results remained when only HER2-negative patients were evaluated for each cohort. PIK3CA mutations in ER-positive tumors were significantly associated with a favorable outcome after first-line AIs, which needs further confirmation in other datasets. Mutations were not associated with prognosis in untreated LNN patients nor predictive outcome after first-line tamoxifen therapy in advanced disease patients. |
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