By Lee B. Riley, MD, PhD, FACS
Medical Director, Oncology Services, St. Luke’s University Health Network
Cancer has been around for tens of thousands of years, but only in the last few years have we started to understand what causes it.
Of the 25,000 genes in a human cell, only about 500 of them can cause cancer, but only a few of them cause cancer in a single individual. The hope of cancer care is to identify the few genes that cause a specific patient’s cancer. Armed with this knowledge, the cancer team will be able to develop a personalized strategic plan to kill the cancer.
The human genome project, which identified the entire sequence of the all the human DNA, was completed in 2000. This project cost three billion dollars and took 13 years to complete. Identifying the codes for each of the 25,000 genes allowed science and technology to rapidly advance so that now thousands of different cancers have been sequenced. This technology has impacted every part of cancer care including screening, diagnosis, prognosis and therapy.
Identifying Cancer-Causing Genes
One of the best ways to beat cancer is to never get it. Some people like Angelina Jolie inherit a mutated gene for breast or ovarian cancer from one of their parents. Having one copy of this gene makes the patient much more likely to develop breast or ovarian cancer. Other inherited mutant genes place people at risk for colon cancer, melanoma, pancreatic cancer, etc. Genomic testing can now identify which members of a family have one of these cancer-causing genes. Armed with this information, patients and their physicians can discuss ways to minimize their risk. Options include more intensive screening programs, preventative medicines or surgery.
Genomics and Cancer Diagnosisv
Typically, cancer is diagnosed by obtaining a sample of the tumor and looking at it under a microscope. The pathologist then decides, based on several features, whether the cells are cancerous or not. They also try to discern what type of cancer it is (e.g. breast vs. colon, vs. lung). Currently, we cannot use genomic tests to tell for certain if tissue is cancerous or not; this still remains the responsibility of the pathologist. However, today the pathologist can use several different genomic tests to help clarify the diagnosis.
Tumors of Unknown Origin
Occasionally, the pathologist may see a cancer in a lymph node, but cannot find where it came from. These “tumors of unknown origin” present challenging problems for medical oncologists, because chemotherapy for breast cancer is different than chemotherapy for liver cancer or lymphoma. The genomic tests for “tumors of unknown origin” used genetic signatures for each type of tissue and help the physician team decide what type of treatment to recommend.
Other genomic tests in the arena of cancer diagnosis include tests that define the genomic sub-type of the tumor. Breast cancer, for instance, has now been divided into several genetic subtypes, each with their own unique features, prognosis and treatment options. Similar studies have genomically classified other cancers including prostate cancer, colon cancer and lung cancer. Some of these tests are commercially available and being used today.
Genomics and Prognosis
Most cancers are detected before there is any evidence of spread. These patients often undergo surgical treatment to remove their cancer. However, some of these patients already have cancer cells that have already spread (metastatized) to other organs, but the microscopic metastasis is not detectable. Consequently, physicians often recommend additional systemic therapy (hormonal therapy or chemotherapy) “just in case” to be on the safe side. Many, if not the majority, of these patients don’t have any spread of cancer but get chemotherapy because we can’t determine who will and who won’t come back with cancer.
Genomic tests that look at a wide variety of genes in several different cancer types are now helping us determine which cancers are more likely to have already spread. In breast cancer for example, two tests (Oncotype® and MammaPrint®) can predict who is most likely to have a recurring cancer. By identifying patients who have a very low risk of recurrence, we can safely withhold chemotherapy. These tests have safely reduced the use of chemotherapy in over 25% of breast cancer patients.
Genomic tests help with prevention, diagnosis and prognosis, but the greatest hope for genomic medicine is the potential to identify what genes/mutations caused a particular patient’s cancer and identifying a drug that could specifically target that defect. This is very similar to identifying what antibiotic to use to treat a specific type of infection. Fungi have different genes compared to bacteria or protozoans; we use different antibiotics to effectively attack their unique genetics properties and kill the invading organism.
Cancers can now be classified into one of two major types of genetic defects, those with mutations (M-class) of which there are 17 sub-classes (M1-17) and those tumors with larger genetic changes termed copy number (C-class) of which there are 14 sub-classes (C1-14). Within each of these classes, there are similar defective biochemical pathways. Knowing the specific defective pathway, specific chemotherapy agents can potentially be used against these cancers’ Achilles heel.
Next Generation Sequencing and Clinical Trials
In the past, we have determined which chemotherapy drug or combination of drugs is most effective against a group of cancers. We have grouped the cancers based on where they originated, e.g. breast, colon, lung, etc. However, each of the groups of cancer can be divided into very different subgroups, some of which respond to one type of treatment but not another. This new classification, based on genomics and defective biochemical pathways, is a paradigm shift that we have been evolving towards for some time.
But we can’t simply ignore the decades of information about which drugs work on which cancers. We must use clinical trials to test and prove the hypothesis: Do we treat cancers based on where they came from, or what genes are causing the cancer? Now with the ability to identify the cancer-causing genes in a particular patient’s tumor (next generation sequencing, nextgen for short), we can test whether the “standard of care drugs,” are more or less effective than drugs that we think will target the cause.
Fortunately, we are already in this paradigm shift, testing targeted therapies verus “standard of care” through the use of clinical trials. Further, we are rapidly starting to appreciate the importance of knowing as much as we can about what is driving an individual’s cancer. The advancement of our care will only be limited by our ability to create new targeted drugs based on newly identified genetic changes and, most importantly, to enroll patients with those changes on appropriate clinical trials. The hope for a cure is through the doors of a clinical trial.