DNA sequencing lays foundation for personalised cancer treatment
Mapping the genetic evolution of cancer and monitoring response to treatment
Scientists at Washington University School of Medicine in St. Louis are using DNA sequencing technology not only to identify mutations at the root of a patient's tumour -- considered key to personalising cancer treatment -- but to map the genetic evolution of disease and monitor response to treatment.
Genome analysis can play a role at multiple time points during a patient's treatment, to identify driver mutations in the tumour genome and to determine whether cells carrying those mutations have been eliminated by treatment. According to Elaine Mardis, PhD, co-director of The Genome Institute at the Washington University School of Medicine, scientists are searching for clinically relevant information in the tumour samples they are sequencing for discovery-oriented research studies.
This work is helping to guide the design of future cancer clinical trials in which treatment decisions will be based on results of sequencing, according to Mardis, who was speaking at the opening plenary session of the American Association for Cancer Research Annual Meeting in Chicago (31 March – 4 April 2012). She also is affiliated with the Siteman Cancer Centre at the School of Medicine and Barnes-Jewish Hospital.
Genome discovery-oriented research studies
To date, Mardis and her colleagues have sequenced the genome of tumour cells from more than 700 cancer patients. By comparing the genetic sequences in the tumour cells to healthy cells from the same patient, they can identify mutations underlying each patient's cancer.
Already, information gleaned through whole-genome sequencing is pushing researchers to reclassify tumours based on their genetic make-up rather than their location in the body. In patients with breast cancer, for example, Mardis and her colleagues have found numerous driver mutations in genes that have not previously been associated with breast tumours.
A number of these genes have been identified in prostate, colorectal, lung or skin cancer, as well as leukaemia and other cancers. Drugs that target mutations in these genes, including imatinib, ruxolitinib and sunitinib, while not approved for breast cancer, are already on the market for other cancers.
Mardis predicts, however, that it may require a paradigm change for oncologists to evaluate the potential benefits of individualised cancer therapy. While clinical trials typically involve randomly assigning patients to a particular treatment regimen, a personalised medicine approach calls for choosing drugs based on the underlying mutations in each patient's tumour. In a recent study, Mardis and her team mapped the genetic evolution of leukaemia and found clues to suggest that targeted cancer drugs should be aimed at mutations that develop early in the course of the disease.
Using deep digital sequencing, a technique developed at The Genome Institute, they sequenced individual mutations in patients' tumour samples more than 1,000 times each. This provides a read-out of the frequency of each mutation in a patient's tumour genome and allowed the researchers to map the genetic evolution of cancer cells as the disease progressed.
They found that as cancer evolves, tumours acquire new mutations but always retain the original cluster of mutations that made the cells cancerous in the first place. Their discovery suggests that drugs targeted to cancer may be more effective if they are directed toward genetic changes that occur early in the course of cancer. Drugs that target mutations found exclusively in later-evolving cancer cells likely may not have much effect on the disease because they would not kill all the tumour cells.
Sequencing the entire genome of cancer cells is essential to piecing together an accurate picture of the way cancer cells evolve. If the researchers had sequenced only the small portion of the genome that involves genes, they would not have had the statistical power to track the frequency of mutations over time (only 1 to 2% of the genome consists of genes).
No one has ever looked at treatment response at this level of resolution
In another study, a phase III clinical trial of post-menopausal women with oestrogen-receptor positive breast cancer, the Washington University researchers have shown that sequencing can help to predict which women will respond to treatment with aromatase inhibitors. Only about half of women with oestrogen-receptor positive breast cancer respond to these oestrogen lowering drugs, and doctors have not been able to predict which patients will benefit.
Interestingly, by sequencing patients' breast tumours before and after aromatase inhibitor therapy, the researchers identified substantive genomic changes that had occurred in responsive patients, whereas the genomes of unresponsive patients remained largely unchanged by the therapy.
In addition, the researchers have identified a series of mutations in the breast tumours that have corresponding small-molecule inhibitor drugs that target defective proteins. This finding indicates that for women who are not responding to aromatase inhibitors, treatment options may include combining conventional chemotherapy with the indicated small-molecule inhibitor.
The research is funded by the National Cancer Institute (USA), the National Human Genome Research Institute (USA) and the National Heart, Lung and Blood Institute (USA), and the Washington University Cancer Genome Initiative.
Thank you for rating!
You have already rated this page, you can only rate it once!