Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers

Libero Santarpia, Yuan Qi, Katherine Stemke-Hale, Bailiang Wang, Elliana J. Young, Daniel J. Booser, Frankie A. Holmes, Joyce O'Shaughnessy, Beth Hellerstedt, John Pippen, Tatiana Vidaurre, Henry Gomez, Vicente Valero, Gabriel N. Hortobagyi, W. Fraser Symmans, Giulia Bottai, Angelo Di Leo, Ana M. Gonzalez-Angulo, Lajos Pusztai

Research output: Contribution to journalArticlepeer-review


The mutation pattern of breast cancer molecular subtypes is incompletely understood. The purpose of this study was to identify mutations in genes that may be targeted with currently available investigational drugs in the three major breast cancer subtypes (ER+/HER2-, HER2+, and Triple Negative). We extracted DNA from fine needle aspirations of 267 stage I-III breast cancers. These tumor specimens typically consisted of >80 % neoplastic cells. We examined 28 genes for 163 known cancer-related nucleic acid variations by Sequenom technology. We observed at least one mutation in 38 alleles corresponding to 15 genes in 108 (40 %) samples, including PIK3CA (16.1 % of all samples), FBXW7 (8 %), BRAF (3.0 %), EGFR (2.6 %), AKT1 and CTNNB1 (1.9 % each), KIT and KRAS (1.5 % each), and PDGFR-α (1.1 %). We also checked for the polymorphism in PHLPP2 that is known to activate AKT and it was found at 13.5 % of the patient samples. PIK3CA mutations were more frequent in estrogen receptor-positive cancers compared to triple negative breast cancer (TNBC) (19 vs. 8 %, p = 0.001). High frequency of PIK3CA mutations (28 %) were also found in HER2+ breast tumors. In TNBC, FBXW7 mutations were significantly more frequent compared to ER+ tumors (13 vs. 5 %, p = 0.037). We performed validation for all mutated alleles with allele-specific PCR or direct sequencing; alleles analyzed by two different sequencing techniques showed 95-100 % concordance for mutation status. In conclusion, different breast cancer subtypes harbor different type of mutations and approximately 40 % of tumors contained individually rare mutations in signaling pathways that can be potentially targeted with drugs. Simultaneous testing of many different mutations in a single needle biopsy is feasible and allows the design of prospective clinical trials that could test the functional importance of these mutations in the future.

Original languageEnglish
Pages (from-to)333-343
Number of pages11
JournalBreast Cancer Research and Treatment
Issue number1
Publication statusPublished - Jul 2012


  • Breast cancer
  • Drug targets
  • Gene mutations
  • Mutation detection
  • Signaling pathways

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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