Impact of KRAS, BRAF, PIK3CA, TP53 status and intraindividual mutation heterogeneity on outcome after liver resection for colorectal cancer metastases

被引:83
作者
Loes, Inger Marie [1 ,2 ]
Immervoll, Heike [3 ]
Sorbye, Halfdan [1 ,2 ]
Angelsen, Jon-Helge [4 ,5 ]
Horn, Arild [5 ]
Knappskog, Stian [1 ,2 ]
Lonning, Per Eystein [1 ,2 ]
机构
[1] Univ Bergen, Dept Clin Sci, Bergen, Norway
[2] Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway
[3] Alesund Hosp, Dept Pathol, Alesund, Norway
[4] Univ Bergen, Dept Clin Med, Bergen, Norway
[5] Haukeland Hosp, Dept Digest Surg, N-5021 Bergen, Norway
关键词
heterogeneity; mutations; colorectal cancer; liver metastases; chemotherapy; PRIMARY BREAST-CANCER; CAPRI-GOIM TRIAL; HEPATIC RESECTION; INTRATUMOR HETEROGENEITY; GENETIC-HETEROGENEITY; SURVIVAL; TUMORS; CHEMOTHERAPY; PROGRESSION; EVOLUTION;
D O I
10.1002/ijc.30089
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
We determined prognostic impact of KRAS, BRAF, PIK3CA and TP53 mutation status and mutation heterogeneity among 164 colorectal cancer (CRC) patients undergoing liver resections for metastatic disease. Mutation status was determined by Sanger sequencing of a total of 422 metastatic deposits. In univariate analysis, KRAS (33.5%), BRAF (6.1%) and PIK3CA (13.4%) mutations each predicted reduced median time to relapse (TTR) (7 vs. 22, 3 vs. 16 and 4 vs. 17 months; p < 0.001, 0.002 and 0.023, respectively). KRAS and BRAF mutations also predicted a reduced median disease-specific survival (DSS) (29 vs. 51 and 16 vs. 49 months; p < 0.001 and 0.008, respectively). No effect of TP53 (60.4%) mutation status was observed. Postoperative, but not preoperative chemotherapy improved both TTR and DSS (p < 0.001 for both) with no interaction with gene mutation status. Among 94 patients harboring two or more metastatic deposits, 13 revealed mutation heterogeneity across metastatic deposits for at least one gene. Mutation heterogeneity predicted reduced median DSS compared to homogeneous mutations (18 vs. 37 months; p=0.011 for all genes; 16 vs. 26 months; p < 0.001 analyzing BRAF or KRAS mutations separately). In multivariate analyses, KRAS or BRAF mutations consistently predicted poor TRR and DSS. Mutation heterogeneity robustly predicted DSS but not TTR, while postoperative chemotherapy improved both TTR and DSS. Our findings indicate that BRAF and KRAS mutations as well as mutation heterogeneity predict poor outcome in CRC patients subsequent to liver resections and might help guide treatment decisions.
引用
收藏
页码:647 / 656
页数:10
相关论文
共 51 条
[1]   Improving resectability of hepatic colorectal metastases: Expert consensus statement [J].
Abdalla, Eddie K. ;
Adam, Rene ;
Bilchik, Anton J. ;
Jaeck, Daniel ;
Vauthey, Jean-Nicolas ;
Mahvi, David .
ANNALS OF SURGICAL ONCOLOGY, 2006, 13 (10) :1271-1280
[2]   Genetic and Phenotypic Diversity in Breast Tumor Metastases [J].
Almendro, Vanessa ;
Kim, Hee Jung ;
Cheng, Yu-Kang ;
Goenen, Mithat ;
Itzkovitz, Shalev ;
Argani, Pedram ;
van Oudenaarden, Alexander ;
Sukumar, Saraswati ;
Michor, Franziska ;
Polyak, Kornelia .
CANCER RESEARCH, 2014, 74 (05) :1338-1348
[3]   Tumour heterogeneity in the clinic [J].
Bedard, Philippe L. ;
Hansen, Aaron R. ;
Ratain, Mark J. ;
Siu, Lillian L. .
NATURE, 2013, 501 (7467) :355-364
[4]   Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions [J].
Brannon, A. Rose ;
Vakiani, Efsevia ;
Sylvester, Brooke E. ;
Scott, Sasinya N. ;
McDermott, Gregory ;
Shah, Ronak H. ;
Kania, Krishan ;
Viale, Agnes ;
Oschwald, Dayna M. ;
Vacic, Vladimir ;
Emde, Anne-Katrin ;
Cercek, Andrea ;
Yaeger, Rona ;
Kemeny, Nancy E. ;
Saltz, Leonard B. ;
Shia, Jinru ;
D'Angelica, Michael I. ;
Weiser, Martin R. ;
Solit, David B. ;
Berger, Michael F. .
GENOME BIOLOGY, 2014, 15 (08)
[5]   Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases [J].
Brudvik, K. W. ;
Kopetz, S. E. ;
Li, L. ;
Conrad, C. ;
Aloia, T. A. ;
Vauthey, J. -N. .
BRITISH JOURNAL OF SURGERY, 2015, 102 (10) :1175-1183
[6]   The causes and consequences of genetic heterogeneity in cancer evolution [J].
Burrell, Rebecca A. ;
McGranahan, Nicholas ;
Bartek, Jiri ;
Swanton, Charles .
NATURE, 2013, 501 (7467) :338-345
[7]   CHEK2 Mutations Affecting Kinase Activity Together With Mutations in TP53 Indicate a Functional Pathway Associated with Resistance to Epirubicin in Primary Breast Cancer [J].
Chrisanthar, Ranjan ;
Knappskog, Stian ;
Lokkevik, Erik ;
Anker, Gun ;
Ostenstad, Bjorn ;
Lundgren, Steinar ;
Berge, Elisabet O. ;
Risberg, Terje ;
Mjaaland, Ingvil ;
Maehle, Lovise ;
Engebretsen, Lars Fredrik ;
Lillehaug, Johan Richard ;
Lonning, Per Eystein .
PLOS ONE, 2008, 3 (08)
[8]   Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial [J].
Ciardiello, F. ;
Normanno, N. ;
Maiello, E. ;
Martinelli, E. ;
Troiani, T. ;
Pisconti, S. ;
Giuliani, F. ;
Barone, C. ;
Carteni, G. ;
Rachiglio, A. M. ;
Montesarchio, V. ;
Tonini, G. ;
Rizzi, D. ;
Cinieri, S. ;
Bordonaro, R. ;
Febbraro, A. ;
De Vita, F. ;
Orditura, M. ;
Fenizia, F. ;
Lambiase, M. ;
Rinaldi, A. ;
Tatangelo, F. ;
Botti, G. ;
Colucci, G. .
ANNALS OF ONCOLOGY, 2014, 25 (09) :1756-1761
[9]  
COX DR, 1972, J R STAT SOC B, V34, P187
[10]   Mutations of the BRAF gene in human cancer [J].
Davies, H ;
Bignell, GR ;
Cox, C ;
Stephens, P ;
Edkins, S ;
Clegg, S ;
Teague, J ;
Woffendin, H ;
Garnett, MJ ;
Bottomley, W ;
Davis, N ;
Dicks, N ;
Ewing, R ;
Floyd, Y ;
Gray, K ;
Hall, S ;
Hawes, R ;
Hughes, J ;
Kosmidou, V ;
Menzies, A ;
Mould, C ;
Parker, A ;
Stevens, C ;
Watt, S ;
Hooper, S ;
Wilson, R ;
Jayatilake, H ;
Gusterson, BA ;
Cooper, C ;
Shipley, J ;
Hargrave, D ;
Pritchard-Jones, K ;
Maitland, N ;
Chenevix-Trench, G ;
Riggins, GJ ;
Bigner, DD ;
Palmieri, G ;
Cossu, A ;
Flanagan, A ;
Nicholson, A ;
Ho, JWC ;
Leung, SY ;
Yuen, ST ;
Weber, BL ;
Siegler, HF ;
Darrow, TL ;
Paterson, H ;
Marais, R ;
Marshall, CJ ;
Wooster, R .
NATURE, 2002, 417 (6892) :949-954