Reflecting on a Decade of Genomics Research on Cancer Care

With the anniversary of the sequencing of the entire human genome a decade ago, the NEJM has published a review of how the first 10 years of genomic research has impacted the field of oncology (N Engl J Med 2011; 364:340-350).

From the Human Genome Sequence to Cancer Genomics

The draft human genome sequence was published in February 2001 and in 2011, scientists and clinicians are reflecting on the path that genomics has taken us and the paths we should be taking next.

Structure of the BRCA1 protein. Based on PyMOL rendering of PDB 1jm7, Courtesy of User Emw, Wikimedia Commons

BRCA1-Gene located on chromosome 17, Courtesy of Armin Kbelbeck, Wikimedia Commons

One such path is the systematic effort to sequence human cancer genomes. The goal is to find all somatic cancer mutations to generate comprehensive, publically available catalogues. The hope is that this will result in a better grasp of the many processes of human cancers and will be the foundation of understanding the causes of cancer, its development, and insights into its prevention and treatment.

One of the central dogmas of oncology is the idea that the evolution of a cancer requires multiple driver mutations that allow for its robust growth advantage. Identifying these driver mutations that reside in “cancer genes” and have a causal effect on oncogenesis is one of the goals of cancer genome sequencing. However, cancer evolution is complex and it can be difficult to interpret whether a specific mutation is one of the causes of cancer or just happens to be present in the genome due to an error in replication. Cancer genomes contain numerous mutations called passenger mutations that confer no growth advantage and do not contribute to cancer development. Deciphering between driver and passenger mutations can be extremely difficult, requiring the sequencing of many cancer genomes, making these projects time-consuming and expensive.

This is why this large-scale undertaking, partly funded by government agencies, has been highly debated. How many resources should researchers be expending to retrieve these catalogues, and will they actually lead to crucial knowledge that will justify the concentration of cost, time, and effort of the endeavor?

The International Cancer Genome Consortium (ICGC) (http://www.icgc.org/home) was established in 2008 with the aim of comprehensively characterizing all somatic cancer mutations in at least 50 classes of cancers from 25,000 cancer genomes. Having an umbrella program to coordinate this grandiose task is important to prevent duplication of efforts and allow a parsimonious allocation of resources.

7 Ways Genomics Has Impacted Cancer Care

Biological classification
A few distinct cancers such as leukemia and breast cancer have been classified based on the presence of a mutated cancer gene, most cancer classification still relies on histological tissue or cell staining rather than a molecular assay.

Progress in genomics has particularly impacted the classification of breast cancer.  Breast tumor expression profiling, or measuring levels of mRNAs expressed in the tumor are now widely used to sub-classify tumors along with standard histological analysis and immunostaining.

Additionally, gene expression tools can now classify the origin of metastatic tumors, a major problem that histological analysis could not address accurately.

Prognostic markers
Gene expression tools are being used in clinical practice to define whether a patient is at risk for relapse. For breast cancer, 3 profile tools are able to give a prognosis, including the Oncotype DX assay, which is part of the American Society of Clinical Oncology guidelines for breast cancer patients. Expression profile analyses are also available for colon cancer, acute myeloid leukemia, and diffuse large-B-cell lymphoma.

Incorporation of these gene-expression assays into routine practice requires randomized, controlled trials to confirm their efficacy. Currently, the Oncotype DX and MammaPrint assays are being tested in large-scale trials for their efficacy in predicting the benefit of adjuvant chemotherapy in breast cancer.

Optimizing the Use of Therapeutics
There are now multiple cancer therapeutics that are given to patients who have a specific mutation in a cancer gene such as trastuzumab (Herceptin), an antibody targeted against HER2, a protein that is overexpressed and amplified in 20-30% of breast cancers.

Many new agents entering clinical trials are targeted against driver mutations in cancer genes that have been identified using genomic approaches. One example is the development of inhibitors against epidermal growth factor receptor (EGFR) kinase. EGFR is overexpressed in many cancers and activating somatic mutations have been identified in non-small cell lung cancers that have had good responses to these inhibitors. A 2009 prospective study found that patients with these mutations in EGFR had a 71% response rate to the inhibitors compared to 1% for non-EGFR mutated lung cancers.

The analysis of tumor biopsy samples for key mutations in cancer genes is becoming more prevalent and will likely become a routine diagnostic test in all cancer centers over the next few years. The field is going in the direction of creating diagnostic genetic tests in conjunction with targeted therapies allowing patients to receive treatments tailored to their specific cancer profile. This method is allowing better results in clinical trials since only the subset of patients who harbor the specific mutation that a treatment targets are selected, increasing the chance of patient response.

Development of new therapeutics
As discussed in the previous section, the development of treatments that target tumors with specific mutations in a cancer gene is a promising area of cancer drug development. The paradigm example is imatinib (Gleevec), an inhibitor of an abnormal protein in chronic myeloid leukemia (CML) produced due to a genomic alteration known as the Philadelphia chromosome. imatinib is superior to chemotherapy for CML and is FDA-approved as a first-line treatment.

A current example of a targeted treatment is Roche’s BRAF inhibitor, RG7204, for melanoma that targets a specific mutation in the BRAF gene found in 40% of melanoma tumors. RG7204 has completed Phase 3 clinic trials and Roche plans to announce the results at a scientific meeting this year. The BRAF mutation in melanoma was discovered due to systematic sequencing of cancer genomes and its discovery through the development of the inhibitor and late-stage clinical trials has taken less than a decade.

Two recent studies published in Nature that sequenced tumors as they progressed from primary to metastatic showed that the mutation spectrum of the tumor changes. Studies such as these will aid in parsing out genes that may be important for progression to a metastatic phase, leading to potentially important drug targets.

Acquired resistance to therapy
A negative consequence of chemotherapy and targeted treatments is tumor-resistance and relapse. Tumor resistance to targeted therapies can be the acquisition of a different mutation in the same gene, in a gene that functions in the same pathway as the targeted gene, or in an entirely different cancer gene. For example, mutations in the target of imatinib result in resistance to imatinib. These novel mutations can now be sequenced and second-generation inhibitors, nilotinib (Tasigna) and dasatinib (Sprycel) are now being used to treat relapsed CML patients. Sequencing may detect these mutations early in a small subset of cells, allowing proper treatment decisions.

Monitoring Disease Burden
Cancer can be monitored with imaging methods for solid tumors, measurement of specific circulating markers such as prostate-specific antigen for prostate cancer, and recently, the detection of tumor-specific genetic mutations in blood samples. The last example is especially useful for blood cancers for which highly sensitive genetic testing is now routine. This technique is used to monitor the response and potential resistance development to imatinib in CML patients.

Sequencing methods to monitor solid tumor burden and relapse are currently being developed. Early detection is still the best hope, however, as detection of early relapse has so far only been beneficial in terms of improved survival for relapsed cancers that can be treated with surgical resection such as colorectal cancer.

Susceptibility to Cancer
Genetic testing for mutations discovered prior to 2000, BRCA1, BRCA2 mutations that confer an increased risk of breast and ovarian cancers, and MLH1 and MSH2 for colorectal cancers, is now routine clinical practice. Taking advantage of the human genome sequence, efforts are being made to identify new genes that confer cancer susceptibility using genome-wide analyses of cancer patients and control subjects.

Technology is progressing to allow research tools to become inexpensive and provide rapid diagnostics, and next-generation sequencing is becoming increasingly less expensive, on the par of a few hundred dollars per cancer genome sequence. These tools will facilitate our knowledge of cancer development, the design of personalized treatments, more targeted approaches, and ways to predict treatment outcomes for patients.