Best of AACR Journals

Molecular Cancer Therapeutics
Research Article
Genome and Transcriptome Sequencing in Prospective Metastatic
Triple-Negative Breast Cancer Uncovers Therapeutic Vulnerabilities
David W. Craig, Joyce A. O’Shaughnessy, Jeffrey A. Kiefer, Jessica Aldrich, Shripad Sinari, Tracy M. Moses, Shukmei Wong,
Jennifer Dinh, Alexis Christoforides, Joanne L. Blum, Cristi L. Aitelli, Cynthia R. Osborne, Tyler Izatt, Ahmet Kurdoglu,
Angela Baker, Julie Koeman, Catalin Barbacioru, Onur Sakarya, Francisco M. De La Vega, Asim Siddiqui, Linh Hoang,
Paul R. Billings, Bodour Salhia, Anthony W. Tolcher, Jeffrey M. Trent, Spyro Mousses, Daniel Von Hoff, and John D. Carpten
John D. Carpten
Abstract
Triple-negative breast cancer (TNBC) is characterized by
the absence of expression of estrogen receptor, progesterone
receptor, and HER-2. Thirty percent of patients recur after
first-line treatment, and metastatic TNBC (mTNBC) has a poor
prognosis with median survival of one year. Here, we present
initial analyses of whole genome and transcriptome sequencing
data from 14 prospective mTNBC. We have cataloged the
collection of somatic genomic alterations in these advanced
tumors, particularly those that may inform targeted therapies.
Genes mutated in multiple tumors included TP53, LRP1B,
HERC1, CDH5, RB1, and NF1. Notable genes involved in focal
structural events were CTNNA1, PTEN, FBXW7, BRCA2, WT1,
FGFR1, KRAS, HRAS, ARAF, BRAF, and PGCP. Homozygous
deletion of CTNNA1 was detected in 2 of 6 African Americans.
RNA sequencing revealed consistent overexpression of the
FOXM1 gene when tumor gene expression was compared
with nonmalignant breast samples. Using an outlier analysis
of gene expression comparing one cancer with all the others,
we detected expression patterns unique to each patient’s
tumor. Integrative DNA/RNA analysis provided evidence for
deregulation of mutated genes, including the monoallelic
expression of TP53 mutations. Finally, molecular alterations in
several cancers supported targeted therapeutic intervention on
clinical trials with known inhibitors, particularly for alterations
in the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways.
In conclusion, whole genome and transcriptome profiling of
mTNBC have provided insights into somatic events occurring
in this difficult to treat cancer. These genomic data have
guided patients to investigational treatment trials and provide
hypotheses for future trials in this irremediable cancer. Mol
Cancer Ther; 12(1); 104–16. ©2012 AACR.
Mol Cancer Ther January 2013 12:104–16; Published OnlineFirst
November 19, 2012; doi:10.1158/1535-7163.MCT-12-0781
Research Article
EGFR Exon 20 Insertion Mutations in Lung Adenocarcinomas:
Prevalence, Molecular Heterogeneity, and Clinicopathologic
Characteristics
Maria E. Arcila, Khedoudja Nafa, Jamie E. Chaft, Natasha Rekhtman, Christopher Lau, Boris A. Reva,
Maureen F. Zakowski, Mark G. Kris, and Marc Ladanyi
Maria E. Arcila
Abstract
In contrast to other primary epidermal growth factor receptor
(EGFR) mutations in lung adenocarcinomas, insertions in exon
20 of EGFR have been generally associated with resistance to
EGFR-tyrosine kinase inhibitors. Their molecular spectrum,
clinicopathologic characteristics, and prevalence are not
well established. Tumors harboring EGFR exon 20 insertions
were identified through an algorithmic screen of 1,500 lung
adenocarcinomas. Cases were first tested for common mutations
in EGFR (exons 19 and 21) and KRAS (exon 2) and, if negative,
further analyzed for EGFR exon 20 insertions. All samples
underwent extended genotyping for other driver mutations in
EGFR, KRAS, BRAF, ERBB2/HER2, NRAS, PIK3CA, MEK1, and
AKT by mass spectrometry; a subset was evaluated for ALK
rearrangements. We identified 33 EGFR exon 20 insertion cases
[2.2%, 95% confidence interval (CI), 1.6–3.1], all mutually exclusive
with mutations in the other genes tested (except PIK3CA). They
were more common among never-smokers (P < 0.0001). There
was no association with age, sex, race, or stage. Morphologically,
tumors were similar to those with common EGFR mutations but
with frequent solid histology. Insertions were highly variable
in position and size, ranging from 3 to 12 bp, resulting in 13
different insertions, which, by molecular modeling, are predicted
to have potentially different effects on erlotinib binding. EGFR
exon 20 insertion testing identifies a distinct subset of lung
adenocarcinomas, accounting for at least 9% of all EGFR-mutated
cases, representing the third most common type of EGFR mutation
after exon 19 deletions and L858R. Insertions are structurally
heterogeneous with potential implications for response to EGFR
inhibitors. Mol Cancer Ther; 12(2); 220–9. ©2012 AACR.
Mol Cancer Ther February 2013 12:220–9; Published OnlineFirst
January 31, 2013; doi:10.1158/1535-7163.MCT-12-0620
The Best of the AACR Journals 23