Unique molecular signatures as a hallmark of patients with metastatic breast cancer: Implications for current treatment paradigms

// Jennifer J. Wheler 1 , Barbara A. Parker 2 , Jack J. Lee 3 , Johnique T. Atkins 1 , Filip Janku 1 , Apostolia M. Tsimberidou 1 , Ralph Zinner 1 , Vivek Subbiah 1 , Siqing Fu 1 , Richard Schwab 2 , Stacy Moulder 4 , Vicente Valero 4 , Maria Schwaederle 5 , Roman Yelensky 6 , Vincent A. Miller 6 , M Philip J. Stephens 6 , Funda Meric-Bernstam 1 , Razelle Kurzrock 2 1 Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX 2 Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California at San Diego Moores Cancer Center, 3 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 4 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 5 Center for Personalized Cancer Therapy, Moores Cancer Center, University of California San Diego, La Jolla, CA 6 Foundation Medicine, Cambridge MA Correspondence: Jennifer Wheler, email: // Keywords : Genomics, Breast Cancer, PI3K, Clinical Trials Received : February 7, 2014 Accepted : April 30, 2014 Published : May 2, 2014 Abstract Our analysis of the tumors of 57 women with metastatic breast cancer with next generation sequencing (NGS) demonstrates that each patient’s tumor is unique in its molecular fingerprint. We observed 216 somatic aberrations in 70 different genes, including 131 distinct aberrations. The most common gene alterations (in order of decreasing frequency) included: TP53, PIK3CA, CCND1, MYC, HER2 (ERBB2), MCL1, PTEN, FGFR1, GATA3, NF1, PIK3R1, BRCA2, EGFR, IRS2, CDH1, CDKN2A, FGF19, FGF3 and FGF4. Aberrations included mutations (46%), amplifications (45%), deletions (5%), splices (2%), truncations (1%), fusions (0.5%) and rearrangements (0.5%), with multiple distinct variants within the same gene. Many of these aberrations represent druggable targets, either through direct pathway inhibition or through an associated pathway (via ‘crosstalk’). The ‘molecular individuality’ of these tumors suggests that a customized strategy, using an “N-of-One” model of precision medicine, may represent an optimal approach for the treatment of patients with advanced tumors.