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Old 07-07-2013, 05:03 PM   #3
gdpawel
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Targetable genetic alterations detected by next-generation sequencing

Needle biopsies assay on 33 pretherapy primaries and 17 mBCs. NGS of 3,230 exons in 182 cancer-related genes and 37 introns in 14 genes. 117 "potentially" targetable driver mutations were identified (mean: 2.3 in primary tumors, 2.8 in mBCs); however, further research is needed.

According to Dr. Neil Love of Research To Practice, one of several presentations at the ASCO trade show was in a variety of solid tumors on the now commercially available FoundationOne assay. This study of 50 patients with breast cancer — like similar reports in lung, prostate and colorectal cancer — documented that fine needle biopsies provided enough tissue to adequately perform the test. Even more relevant was that multiple potentially “targetable” mutations were found in all these specimens. Although the authors suggest that some of these targets may correlate with benefit from approved agents (eg, crizotinib for ALK translocations), and it might be tempting to consider ordering the assay for patients who have run out of conventional options, this concept has not yet been tested. In that regard, it is worth reflecting on the wholly disappointing experience with BRAF inhibitors for patients with V600E mutation-positive colorectal cancer and appreciating that the term “targetable” is highly theoretical at this point in time.

Use of next-generation sequencing (NGS) to detect high frequency of targetable alterations in primary and metastatic breast cancer (MBC).

Sub-category:
Genomic and Epigenomic Biomarkers

Category:
Tumor Biology

Meeting:
2012 ASCO Annual Meeting

Session Type and Session Title:
General Poster Session, Tumor Biology

Abstract No:
10559

Citation:
J Clin Oncol 30, 2012 (suppl; abstr 10559)

Author(s):

Lajos Pusztai, Roman Yelensky, Bailiang Wang, Rony Avritscher, William Fraser Symmans, Doron Lipson, Gary A. Palmer, Stacy L. Moulder, Philip Stephens, Yun Wu, Maureen T. Cronin; University of Texas M. D. Anderson Cancer Center, Houston, TX; Foundation Medicine, Cambridge, MA; University of Texas, Houston, TX; Department of Radiology, University of Texas M. D. Anderson Cancer Center, Houston, TX

Abstract:

Background:

The aim of this study was to assess the frequency of genomic alterations in breast cancer potentially treatable with approved targeted agents or investigational drugs in clinical trials. NGS was performed in a CLIA setting (Foundation Medicine).

Methods:

DNA was extracted from needle biopsies of 33 pre-therapy primary and 17 MBCs (mean age 52 yrs; 58% ER+, 20% HER2+, 30% triple negative) obtained prospectively for biomarker discovery and preserved in RNAlater. Patients with MBC received an average of 7 drugs (range 5-17) including adjuvant therapy before biopsy for this research; 13 biopsies were from soft tissues, 3 from liver and 1 from bone. Sequencing was targeted to 3230 exons in 182 cancer-related genes and 37 introns in 14 genes often rearranged in cancer. Average median depth was >1200x.

Results:

All biopsies yielded sufficient DNA. NGS revealed a total of 117 known driver mutations across 36 genes (per-tumor average=2.5, range 1-6), including 37 base substitutions (32%), 28 indels (24%), 42 amplifications (36%) and 10 homozygous deletions (9%). NGS identified HER2 gene amplification in 6/7 cases scored HER2+ by FISH. The average number of functionally important alterations was surprisingly similar, 2.3 in primaries vs 2.8 in heavily treated MBCs (p=0.32). Remarkably, 25/33 (76%) of primary and 14/17 (82%) of MBCs had at least 1 genomic alteration targetable with an FDA approved drug or novel agent in clinical trials. These included: ERBB2 alterations (n=9), PIK3CA mutations (n=8), NF1 mutations (n=4, candidate for PI3K/MEK inhibitors), AKT1-3 mutations (n=5, PI3K inhibitors), BRCA1/2, (n=6, PARP inhibitors), and CCND2 (n=3)/CDKN2A (n=3) mutations (CDK inhibitors). Numerous other alterations with less apparent therapeutic implications were also observed.

Conclusions:

Comprehensive NGS profiling in breast cancer needle biopsies showed high frequency of genomic alterations linked to a clinical treatment option or clinical trials of targeted therapies. These results demonstrate it is feasible to use NGS to guide targeted therapy. Prospective testing of the diagnostic/predictive value of this patient selection approach is currently under way.
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