Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer

Sherene Loi, Stefan Michiels, Diether Lambrechts, Debora Fumagalli, Bart Claes, Pirkko Liisa Kellokumpu-Lehtinen, Petri Bono, Vesa Kataja, Martine J. Piccart, Heikki Joensuu, Christos Sotiriou

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    Résumé

    Background Certain somatic alterations in breast cancer can define prognosis and response to therapy. This study investigated the frequencies, prognostic effects, and predictive effects of known cancer somatic mutations using a randomized, adjuvant, phase III clinical trial dataset. Methods The FinHER trial was a phase III, randomized adjuvant breast cancer trial involving 1010 women. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer were further randomized to 9 weeks of trastuzumab or no trastuzumab. Seven hundred five of 1010 tumors had sufficient DNA for genotyping of 70 somatic hotspot mutations in 20 genes using mass spectrometry. Distant disease-free survival (DDFS), overall survival (OS), and interactions with trastuzumab were explored with Kaplan-Meier and Cox regression analyses. All statistical tests were two-sided. Results Median follow-up was 62 months. Of 705 tumors, 687 were successfully genotyped. PIK3CA mutations (exons 1, 2, 4, 9, 13, 18, and 20) were present in 25.3% (174 of 687) and TP53 mutations in 10.2% (70 of 687). Few other mutations were found: three ERBB2 and single cases of KRAS, ALK, STK11/LKB1, and AKT2. PIK3CA mutations were associated with estrogen receptor positivity (P <. 001) and the luminal-A phenotype (P =. 04) but were not statistically significantly associated with prognosis (DDFS: hazard ratio [HR] = 0.88, 95% confidence [CI] = 0.58 to 1.34, P =. 56; OS: HR = 0.603, 95% CI =. 32 to 1.13, P =. 11), although a statistically significant nonproportional prognostic effect was observed for DDFS (P =. 002). PIK3CA mutations were not statistically significantly associated with trastuzumab benefit (Pinteraction: DDFS P =. 14; OS P =. 24). Conclusions In this dataset, targeted genotyping revealed only two alterations at a frequency greater than 10%, with other mutations observed infrequently. PIK3CA mutations were associated with a better outcome, however this effect disappeared after 3 years. There were no statistically significant associations with trastuzumab benefit.

    langue originaleAnglais
    Pages (de - à)960-967
    Nombre de pages8
    journalJournal of the National Cancer Institute
    Volume105
    Numéro de publication13
    Les DOIs
    étatPublié - 3 juil. 2013

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