An increasing number of anticancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Recent evidence suggests that the selection of patients whose tumors harbor specific genetic alterations identifies the subset of patients who are most likely to benefit from the use of such agents. As the number of genetic alterations that provide diagnostic and/or therapeutic information increases, the comprehensive characterization of cancer genomes will be necessary to understand the spectrum of distinct genomic alterations in cancer, to identify patients who are likely to respond to particular therapies, and to facilitate the selection of treatment modalities. Rapid developments in new technologies for genomic analysis now provide the means to perform comprehensive analyses of cancer genomes. In this article, we review the current state of cancer genome analysis and discuss the challenges and opportunities necessary to implement these technologies in a clinical setting.Significance: Rapid advances in sequencing technologies now make it possible to contemplate the use of genome scale interrogation in clinical samples, which is likely to accelerate efforts to match treatments to patients. However, major challenges in technology, clinical trial design, legal and social implications, healthcare information technology, and insurance and reimbursement remain. Identifying and addressing these challenges will facilitate the implementation of personalized cancer medicine. Cancer Discovery; 1(4): 297-311. ©2011 AACR.
THE CASE FOR INDIVIDUALIZED CANCER MEDICINEWork from many laboratories has identified genetic alterations that occur at an appreciable frequency in specific types of cancers. For example, a reciprocal translocation between chromosome 9 and 22, known as the Philadelphia chromosome and resulting in the BCR-ABL fusion gene, occurs in ~9 5% of chronic myelogenous leukemias (CML; refs. 1 , 2 ); oncogenic KIT mutations are present in ~8 5% of gastrointestinal stromal tumors (GISTs; refs. 3 , 4 ); mutations in the serine-threonine kinase BRAF are present in >50% of cutaneous melanoma ( 5 ); activating mutations in the epidermal growth factor receptor ( EGFR) have been identified in ~1 5% of non-small cell lung cancers (NSCLC; refs. 6-8 ), and ERBB2 is amplified in 15-20% of breast cancers ( 9-12 ). Biochemical studies confirmed that these genetic alterations result in constitutively active molecules, and tumors that harbor such mutations depend on the activity of these proteins for survival.On the basis of these observations, efforts to target these molecules with either small-molecule inhibitors or antibodies have led to several agents that induce significant clinical responses. For example, the tyrosine kinase inhibitor (TKI) imatinib induces clinical responses in Philadelphia chromosome-positive CML ( 13 ) and GISTs that harbor KIT mutations ( 14 , 15 ); PLX4032 has been shown to induce responses in cutaneous melanomas with BRAF mutations ( 16 , 17 ); the EGFR TKIs erlotinib...
