Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer.
Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer.
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DOI：
10.1093/jnci/djt121
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发表时间：
2013-07-03
期刊：
影响因子：
--
通讯作者：
Sotiriou C
中科院分区：
文献类型：
--
作者：
Loi S;Michiels S;Lambrechts D;Fumagalli D;Claes B;Kellokumpu-Lehtinen PL;Bono P;Kataja V;Piccart MJ;Joensuu H;Sotiriou C
乳腺癌的某些体细胞改变可以决定预后和对治疗的反应。本研究使用随机、辅助、III期临床试验数据集调查了已知癌症体细胞突变的频率、预后效应和预测效应。FinHER试验是一项III期随机辅助乳腺癌试验，涉及1010名女性。将人表皮生长因子受体2（HER 2）阳性乳腺癌患者进一步随机分配至9周曲妥珠单抗组或无曲妥珠单抗组。1010个肿瘤中有705个具有足够的DNA，可使用质谱法对20个基因中的70个体细胞热点突变进行基因分型。采用Kaplan-Meier和考克斯回归分析探讨了无远处疾病生存期（DDFS）、总生存期（OS）以及与曲妥珠单抗的相互作用。所有统计学检验均为双侧检验。中位随访时间为62个月。在705个肿瘤中，687个成功地进行了基因分型。PIK 3CA突变（外显子1、2、4、9、13、18和20）存在于25.3%（687例中的174例）中，TP 53突变存在于10.2%（687例中的70例）中。其他突变很少发现：三个ERBB 2和KRAS，ALK，STK 11/LKB 1和AKT 2的单一病例。PIK 3CA突变与雌激素受体阳性相关（P <0.001）和管腔-A表型（P = .04），但与预后无统计学显著相关性（DDFS：风险比[HR] = 0.88，95%置信度[CI] = 0.58至1.34，P = 0.56; OS：HR = 0.603，95%CI = 0.32至1.13，P = 0.11），尽管DDFS观察到统计学显著的非比例预后效应（P = 0.002）。PIK 3CA突变与曲妥珠单抗获益无统计学显著相关性（P相互作用：DDFS P = .14; OS P = .24）。在该数据集中，靶向基因分型仅显示了频率大于10%的两个改变，其他突变很少观察到。PIK 3CA突变与更好的结局相关，但这种效应在3年后消失。与曲妥珠单抗获益无统计学显著相关性。
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. 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. 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 (P interaction: DDFS P = .14; OS P = .24). 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.
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影响因子：
64.8
作者：
Ellis, Matthew J.;Ding, Li;Shen, Dong;Luo, Jingqin;Suman, Vera J.;Wallis, John W.;Van Tine, Brian A.;Hoog, Jeremy;Goiffon, Reece J.;Goldstein, Theodore C.;Ng, Sam;Lin, Li;Crowder, Robert;Snider, Jacqueline;Ballman, Karla;Weber, Jason;Chen, Ken;Koboldt, Daniel C.;Kandoth, Cyriac;Schierding, William S.;McMichael, Joshua F.;Miller, Christopher A.;Lu, Charles;Harris, Christopher C.;McLellan, Michael D.;Wendl, Michael C.;DeSchryver, Katherine;Allred, D. Craig;Esserman, Laura;Unzeitig, Gary;Margenthaler, Julie;Babiera, G. V.;Marcom, P. Kelly;Guenther, J. M.;Leitch, Marilyn;Hunt, Kelly;Olson, John;Tao, Yu;Maher, Christopher A.;Fulton, Lucinda L.;Fulton, Robert S.;Harrison, Michelle;Oberkfell, Ben;Du, Feiyu;Demeter, Ryan;Vickery, Tammi L.;Elhammali, Adnan;Piwnica-Worms, Helen;McDonald, Sandra;Watson, Mark;Dooling, David J.;Ota, David;Chang, Li-Wei;Bose, Ron;Ley, Timothy J.;Piwnica-Worms, David;Stuart, Joshua M.;Wilson, Richard K.;Mardis, Elaine R.
通讯作者：
Mardis, Elaine R.
影响因子：
158.5
作者：
Joensuu, H;Kellokumpu-Lehtinen, P;Isola, J
通讯作者：
Isola, J
影响因子：
11.2
作者：
Carracedo A;Alimonti A;Pandolfi PP
通讯作者：
Pandolfi PP
影响因子：
45.3
作者：
Joensuu, Heikki;Bono, Petri;Kellokumpu-Lehtinen, Pirkko-Liisa
通讯作者：
Kellokumpu-Lehtinen, Pirkko-Liisa
影响因子：
50.3
作者：
Junttila, Teemu T.;Akita, Robert W.;Sliwkowski, Mark X.
通讯作者：
Sliwkowski, Mark X.