TY - JOUR
T1 - Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer
AU - Loi, Sherene
AU - Michiels, Stefan
AU - Lambrechts, Diether
AU - Fumagalli, Debora
AU - Claes, Bart
AU - Kellokumpu-Lehtinen, Pirkko Liisa
AU - Bono, Petri
AU - Kataja, Vesa
AU - Piccart, Martine J.
AU - Joensuu, Heikki
AU - Sotiriou, Christos
PY - 2013/7/3
Y1 - 2013/7/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84880230412&partnerID=8YFLogxK
U2 - 10.1093/jnci/djt121
DO - 10.1093/jnci/djt121
M3 - Article
C2 - 23739063
AN - SCOPUS:84880230412
SN - 0027-8874
VL - 105
SP - 960
EP - 967
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 13
ER -