Cancer genomes and clinical care

Abstract

Stratifying individual patients for specific therapies based on the clinical stage and morphological features (phenotype) of their disease is the basis of modern clinical oncology. Appropriate therapeutic regimens are selected in light of the characteristics of an individual’s cancer based on imaging and histopathology, which are indirect ‘surrogate’ measures of disease biology. Advances in molecular pathology and our understanding of cancer biology have led to refinement of existing clinico-pathological phenotypes, and in some cases such as leukaemia and breast cancer, a new molecular taxonomy has emerged which is integral to the modern management of these diseases. Increasingly, the development of a novel targeted therapy involves defining drug-diagnostic combinations where the presence of a molecular marker identifies patients who are most likely to respond to treatment. This model of developing treatment and diagnostic/companion biomarker combinations in order to target patient populations with a greater chance of benefiting from treatment is the emerging paradigm for new drug and diagnostic development. This strategy is facilitating significant advances in some cancer types, with one of the more recent examples being the successful use of the BRAF inhibitor PLX4032, which targets a specific mutation (V600E) in melanoma. The number of target-drug combinations with efficacy is growing, and some are suggesting that the era of personal genomic cancer therapy is already here. This emerging paradigm is changing the focus from therapeutic strategy development to diagnostics and will create significant challenges in the development and delivery of personalised medicine strategies. The Australian Pancreatic Cancer Genome Initiative, a part of the International Cancer Genome Consortium, aims to define, interpret and apply cancer genomic data. Direct potential clinical applications include the delineation of phenotypes based on patterns of genomic aberrations co-segregating with clinico-pathological endpoints and identifying druggable mutations. In addition, other approaches such as the detection of tumour specific genomic abnormalities in blood would have applications in early detection of recurrence and surrogate markers of therapeutic responsiveness. These advances are rapidly altering diagnostic and therapeutic strategies for cancer, and potentially other diseases, paving the way to genomic health. These advances in genetic pathology have the potential to refine, and possibly replace current morphology based diagnostic approaches.