Molecular profiling is emerging as an important analytical approach for finding specific biomarkers in cancerous tumors by helping physicians choose the best treatment based on a tumor's molecular expression pattern. Molecular profiling applies the most powerful gene and protein analytical tools for identifying alterations in patient tumors, relying on a team of skilled laboratory professionals to determine the best possible, personalized treatment for each patient.
Beyond Tumor Pathology
Cancer is a devastating illness; more than 1,500 people in the U.S. die of some type of cancer every day (source: American Cancer Society, Cancer Facts and Figures, 2012.) Traditionally, cancer treatment has been determined largely based on tumor pathology, as viewed under the microscope. This has led to a "one-size-fits-all" approach such that tumors with similar pathology will typically receive the same treatment. However, tumor pathology provides only limited information. Advances in analytical techniques have shown that tumors are extremely complex at the molecular level with vast numbers of genes and proteins dysregulated in tumor cells. Thus tumors that appear very similar under the microscope may have very different gene and protein expression patterns. Moreover, this tumor heterogeneity explains why tumors that appear similar by microscopic analysis may respond very differently to the same treatment.
Molecular profiling is a comprehensive approach for finding specific biomarkers in a patient's tumor and choosing systemic treatments that specifically will attack that biomarker or pathway (Table). Enabled by the development of high-throughput techniques that reveal the expression status of specific genes and proteins, molecular profiling can now be performed rapidly, accurately, and on a wide scale.
Chromosomal aberrations, such as gene amplification or chromosomal deletion, can
be revealed by fluorescent or chromogenic in situ hybridization (FISH/CISH). With DNA and RNA microarray technology, hundreds of genes, including entire regulatory pathways, can be examined; comparison with a control shows which genes have increased or decreased expression. Quantitative real-time polymerase chain reaction (qRT-PCR) can uncover gene duplications or deletions, while DNA sequencing may be used to discover point mutations. Immunohistochemistry (IHC) continues to be a standard diagnostic and analytical technique for examining the expression levels of known proteins. Taken together, these techniques uncover a remarkable level of detail on the molecular workings of tumors that go far beyond simple microscopic observation.
As advanced molecular techniques have revealed the aberrant pathways that allow tumors to thrive, novel treatments have been developed in parallel to harm tumor cells by specifically attacking identified biomarkers. Some tumors are known to commonly harbor certain molecular abnormalities. For example, up to 25 percent of breast cancer tumors overexpress the HER2 protein, which can be detected by IHC. HER2 overexpression is mediated by HER2 gene amplification, which can be detected via FISH or CISH. Patients whose tumors are positive for either one of these tests are eligible for treatment with trastuzumab, a targeted therapy that specifically attacks the HER2 protein. Trastuzumab is part of the standard of care for patients with this particularly aggressive form of breast cancer.
Standard diagnostic tests for specific tumor types include only a few biomarkers. For example, breast cancer tumors are routinely analyzed for expression of HER2 as well as the estrogen and progesterone receptors. However, with advanced molecular profiling, it is now known that most tumors contain dozens of molecular abnormalities. Major advances in cancer treatment have been achieved through this method. The approach has been validated with many biomarkers for a wide range of tumor types, and targeting of specific markers has improved outcomes for many patients; nonetheless, treatment failure remains common. Disease resistance often leaves the patient with few or no treatment choices. In addition, common molecular aberrations have yet to be identified for rare tumor types, and optimal treatments have not been established.
Customizing Cancer Treatment
Molecular profiling also has demonstrated that cancer arising from a single tissue is not a uniform disease. Tumors arising from the same tissue in different patients may have very different gene and protein expression patterns. This tumor heterogeneity helps to explain why some cancer in some patients is resistant to standard treatment and why patients may develop resistance to treatment over time.
With the wealth of knowledge provided by state-of-the-art molecular analysis, a new treatment paradigm is evolving that matches treatment to the tumor's molecular profile. In addition, by showing the activity of hundreds of drug targets, broader molecular profiling has the potential to greatly expand the range of treatment options for an individual patient. This individualized approach is actively being investigated and has already shown promise in cancer patients. In a pilot study, molecular profiling that included IHC, FISH and microarray analysis, was performed on the tumors of 86 patients who had progressed on treatment. Patient tumor samples were screened against dozens of genes implicated in cancer and for which targeted treatments are available. A molecular target was detected in 98 percent of patients, and 66 patients received treatment based on their profiling results. For 18 of these treated patients, progression-free survival was longer on the treatment regimen selected through molecular profiling compared with prior treatment regimens.
In addition to pinpointing treatments that are likely to be effective, such screening can determine treatments that should be avoided, thus shielding the patient from unnecessary stress, time, costs, and side effects that often accompany cancer therapy. At this time, only a few assays are commercially available for molecular analysis of multiple genes. For oncologists, a hallmark of a robust molecular analytical tool is the ability to utilize multiple integrated technologies to derive the greatest amount of information possible from the analysis, thus enabling physicians to determine the optimal therapeutic choices for cancer patients. One offering that encompasses this approach is the Caris Target Now™ molecular profiling service. Selective analysis of biomarkers that are strongly implicated in the disease is available for non-small cell lung cancer (NSCLC), melanoma, and cancers of the breast, colon, and ovary.
The comprehensive analysis encompasses a wider range of biomarkers and can be applied to any tumor type, including rare cancers. Findings are correlated with the latest scientific literature that helps remove some of the ambiguity commonly faced by oncologists when making treatment decisions. Additionally, both the selective and the comprehensive approaches identify open clinical trials that may be appropriate for the patient. This particular approach facilitates oncology care at an individual level and is highly personalized for the patient.
Dr. Ashfaq is director of oncologic profiling at Caris Life Sciences in Irving, Texas.