PMID- 24710307
OWN - NLM
STAT- MEDLINE
DCOM- 20150112
LR  - 20220321
IS  - 1549-490X (Electronic)
IS  - 1083-7159 (Print)
IS  - 1083-7159 (Linking)
VI  - 19
IP  - 5
DP  - 2014 May
TI  - A targeted next-generation sequencing assay detects a high frequency of 
      therapeutically targetable alterations in primary and metastatic breast cancers: 
      implications for clinical practice.
PG  - 453-8
LID - 10.1634/theoncologist.2013-0377 [doi]
AB  - The aim of this study was to assess the frequency of potentially actionable 
      genomic alterations in breast cancer that could be targeted with approved agents 
      or investigational drugs in clinical trials using a next-generation 
      sequencing-based genomic profiling assay performed in a Clinical Laboratory 
      Improvement Amendments-certified and College of American Pathologists-accredited 
      commercial laboratory. Methods. Fifty-one breast cancers were analyzed, including 
      primary tumor biopsies of 33 stage I-II and 18 stage IV cancers (13 soft tissue, 
      3 liver, and 2 bone metastases). We assessed 3,230 exons in 182 cancer-related 
      genes and 37 introns in 14 genes often rearranged in cancer for base 
      substitutions, indels, copy number alterations, and gene fusions. The average 
      median sequencing depth was 1,154x. Results. We observed 158 genomic alterations 
      in 55 genes in 48 of 51 (94%) tumors (mean 3.1, range 0-9). The average number of 
      potentially therapeutically relevant alterations was similar in primary (1.6, 
      range 0-4) and in heavily pretreated metastatic cancers (2.0, range 0-4) (p = 
      .24). The most common actionable alterations were in PIK3CA (n = 9, 
      phosphatidylinositol 3-kinase [PI3K]/mammalian target of rapamycin [mTOR] 
      inhibitors), NF1 (n = 7, PI3K/mTOR/mitogen-activated protein kinase inhibitors), 
      v-akt murine thymoma viral oncogene homolog 1-3 (n = 7, PI3K/mTOR/AKT 
      inhibitors), BRCA1/2 (n = 6, poly[ADP-ribose] polymerase inhibitors), and CCND1,2 
      and CCNE (n = 8)/cycline dependent kinase (CDK)6 (n = 1) (CDK4/6 inhibitors), KIT 
      (n = 1, imatinib/sunitinib), ALK (n = 1, crizotinib), FGFR1,2 (n = 5, fibroblast 
      growth factor receptor inhibitors), and EGFR (n = 2, epidermal growth factor 
      receptor inhibitors). Our sequencing assay also correctly identified all six 
      cases with HER2 (ERBB2) amplification by fluorescence in situ hybridization when 
      tumor content was adequate. In addition, two known activating HER2 mutations were 
      identified, both in unamplified cases. Conclusion. Overall, 84% of cancers 
      harbored at least one genomic alteration linked to potential treatment options. 
      Systematic evaluation of the predictive value of these genomic alterations is 
      critically important for further progress in this field.
FAU - Vasan, Neil
AU  - Vasan N
AD  - Yale University School of Medicine, New Haven, Connecticut, USA; Foundation 
      Medicine, Cambridge, Massachusetts, USA; MD Anderson Cancer Center, Houston, 
      Texas, USA.
FAU - Yelensky, Roman
AU  - Yelensky R
FAU - Wang, Kai
AU  - Wang K
FAU - Moulder, Stacy
AU  - Moulder S
FAU - Dzimitrowicz, Hannah
AU  - Dzimitrowicz H
FAU - Avritscher, Rony
AU  - Avritscher R
FAU - Wang, Baliang
AU  - Wang B
FAU - Wu, Yun
AU  - Wu Y
FAU - Cronin, Maureen T
AU  - Cronin MT
FAU - Palmer, Gary
AU  - Palmer G
FAU - Symmans, W Fraser
AU  - Symmans WF
FAU - Miller, Vincent A
AU  - Miller VA
FAU - Stephens, Philip
AU  - Stephens P
FAU - Pusztai, Lajos
AU  - Pusztai L
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - UL1 TR000142/TR/NCATS NIH HHS/United States
PT  - Journal Article
DEP - 20140407
PL  - England
TA  - Oncologist
JT  - The oncologist
JID - 9607837
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Base Sequence
MH  - Breast Neoplasms/*genetics
MH  - Female
MH  - Genomics
MH  - High-Throughput Nucleotide Sequencing
MH  - Humans
MH  - Middle Aged
MH  - Molecular Targeted Therapy/*methods
MH  - Mutation
MH  - Precision Medicine/*methods
MH  - Sequence Analysis, DNA
PMC - PMC4012963
OTO - NOTNLM
OT  - Molecularly targeted therapy
OT  - Next-generation sequencing
OT  - Precision medicine
OT  - Predictive markers
COIS- Disclosures of potential conflicts of interest may be found at the end of this 
      article.
EDAT- 2014/04/09 06:00
MHDA- 2015/01/13 06:00
PMCR- 2015/05/01
CRDT- 2014/04/09 06:00
PHST- 2014/04/09 06:00 [entrez]
PHST- 2014/04/09 06:00 [pubmed]
PHST- 2015/01/13 06:00 [medline]
PHST- 2015/05/01 00:00 [pmc-release]
AID - theoncologist.2013-0377 [pii]
AID - T13377 [pii]
AID - 10.1634/theoncologist.2013-0377 [doi]
PST - ppublish
SO  - Oncologist. 2014 May;19(5):453-8. doi: 10.1634/theoncologist.2013-0377. Epub 2014 
      Apr 7.