Genetic tests for cancer have come a long way since they first entered the clinic in 1995. Back then, mutations in two genes—known as BRCA1 and BRCA2—hinted at the crucial role that genetics can play in treatment decisions. Women carrying one of those mutations (and having a family history of breast or ovarian cancer) were much more likely than the general population to develop tumors in their breasts or ovaries. Then, as now, some of these women opted to have their breasts and ovaries removed before any malignant growths could arise.
In the intervening decades, researchers have come to recognize that most cancers are driven largely by abnormalities in genes. Genetic analysis of tumors has, therefore, become standard practice for many malignancies—such as breast, lung and colon cancer—because the information may help guide therapy. Clinicians have amassed a modest arsenal of drugs able to counteract some of the most common mutations.
Yet many patients learn that their cancers have mutations for which no drug exists. In fact, the roles many of these genetic changes play in cancer growth are poorly understood. Complex analyses of DNA done across a range of cancer types have revealed a landscape rife with genetic mutations, and very little of this encyclopedic information is helping doctors to make treatment decisions. To date, the U.S. Food and Drug Administration has approved just 29 tests for specific mutations that can directly influence therapy.
Several major research collaborations are now making heroic efforts to identify more mutations that can serve as drug targets and to collect the information that will allow doctors to match many more patients with such targeted therapies. And earlier this year President Barack Obama announced the National Cancer Moonshot, a $1-billion initiative that includes funding for such efforts. The task is so large and complicated, however, that the gap between genetic knowledge and patient benefit is likely to widen for some time before the promised revolution in care becomes a reality for most people afflicted by cancer. “We're in a transition period,” says Stephen Chanock, who directs the Division of Cancer Epidemiology and Genetics at the National Cancer Institute.
Drivers vs. Passengers
The genetic changes that eventually trigger cancerous growth fall into two main groups. First, there are hereditary germ-line mutations, which people inherit from their parents. Second, there are somatic mutations, which arise over the course of one's life as a result of advancing age, cigarette smoking or other environmental influences. Although hereditary changes in DNA often lead to aggressive tumors, including some childhood cancers, these kinds of germ-line mutations are relatively uncommon. The vast majority of human cancers arise from somatic mutations.
Most somatic mutations turn out to be harmless; many are even repaired by the body's own quality-control processes. But some manage to wreak havoc, causing cells to reproduce uncontrollably. Many genes code for proteins, which do much of the work in cells. In the case of cancer, the harmful mutations tend to result in proteins that either actively promote excessive replication or fail in their usual job of putting the brakes on cell proliferation.
Researchers refer to the abnormal changes that are integral to a tumor's growth and survival as driver mutations; the others are known as passenger mutations because they appear to be unimportant and seemingly are just along for the ride. No one knows how many driver mutations are needed to promote each of the different kinds of cancers. One study determined that the average tumor requires as few as two or as many as eight driver mutations, whereas other studies found that tumors may frequently contain as many as 20 driver mutations.
Despite the difficulties of figuring out which genetic mutations are important in a given tumor, researchers began making progress in targeting specific cancer mutations by the late 1990s. Among the first such treatments were imatinib mesylate (brand name Gleevec), which undermines a common driver of chronic myeloid leukemia, and trastuzumab (brand name Herceptin), which addresses the HER2 mutation responsible for about a quarter of breast cancers. Other customized therapies soon followed.
For the past three years patients with lung cancer have routinely been tested for an abnormality in a gene known as ALK. In as many as 7 percent of such patients, a genetic mistake that melds the ALK gene with another gene yields an abnormal protein that drives the tumor's growth. Drugs that block this mutant protein typically do a better job than standard chemotherapy at slowing the disease. Patients with normal ALK genes in their tumors do not benefit from anti-ALK drugs at all.
Routine genetic tests have also helped people with melanoma, a form of skin cancer. About half of patients with melanoma have a mutation in the BRAF gene, which plays a role in the spread of cancer from the tumor to other parts of the body. In 2011 the FDA approved the first drug that inhibits the mutant BRAF protein. A recent study found that nearly 80 patients with metastatic melanoma who responded to the new treatment lived for an average of two years, much longer than the 5.3 months typically seen in such patients whose skin cancer has spread.
Sometimes a particular mutation allows doctors to steer clear of prescribing certain drugs. For example, colorectal cancers with mutations in the KRAS or NRAS gene typically do not respond to particular medicines because these genetic changes render those agents ineffective.
But there are several obstacles to further progress. Finding a genetic abnormality in a cancer is not enough—the aberration must be integral to the cancer's growth and survival. A reliable test for the mutation and a treatment that can exploit the mutation must exist. These requirements, it turns out, are a very tall order. Beyond the difficulty of figuring out which mutations drive the cancer, researchers also need to know which mutations tend to act later on. As a tumor grows, new mutations may appear. Each crop of abnormalities means separating the drivers from the passengers all over again, so that if one drug stops working, a subsequent genetic test can steer physicians to the next option.
Creating drugs to block driver mutations, likewise, is no small feat. Many abnormal proteins encoded by somatic mutations sit on the surface of cancer cells, within easy reach of drugs. But others are buried deep within cells, and compounds small enough to slip inside a cell are typically too small to stick to their target proteins. This conundrum has left the most common driver mutations, such as p53, RAS and MYC, impossible to combat.
And the drugs that do successfully target somatic mutations have often led to meager extensions in survival time. If a single drug targeted to a specific driver mutation manages to shrink a tumor but leaves even one cell resistant to the drug behind, that cell can proliferate and create additional tumors unresponsive to the medicine. It may be, then, that certain cancers, as is true of HIV, will need to be treated with multiple drugs. Yet each drug that is added will come with its own costs and potential side effects. Researchers will need to figure out the optimal strategies.
The rarity of many somatic mutations also slows the transition from the laboratory to the clinic. Some mutations occur in less than 1 percent of patients with a certain type of cancer. Evaluating whether a drug could possibly address that mutation requires a clinical trial, but finding enough patients willing and able to enroll in such a study can take a long time.
All these challenges are spurring research methods, drug designs and infrastructure meant to hasten the expansion of precision genetic medicine. The approaches are also taking into account a new realization. Traditionally cancer has been defined by the location of where it first arose in the body—for example, in the breast or lung. But it turns out that mutations known to drive a particular type of malignancy in one part of the body are sometimes involved in cancers typically found elsewhere in the body.
Defining cancer not only by its body part but also its genes is prying treatment options loose from old restrictions. A drug conventionally used for one cancer may turn out to work in another driven by the same abnormality. When the drugs trastuzumab and lapatinib, approved for breast cancer harboring a HER2 mutation, were given to a group of patients with late-stage colorectal cancer with the same mutation, for example, nearly half lived for about a year, an unusually long time. Although such connections are still rare and preliminary, they indicate that it may be time to reconsider standard definitions of cancer.
The NCI launched one of the new collaborations—called MATCH—in August 2015. This study, which expects to enroll 840 volunteers, aims to provide the data needed for doctors to prescribe drugs to more patients based on tumor genetics. DNA from up to 5,000 tumor specimens will be sequenced to find suspicious abnormalities with matching gene-targeted drugs. When the trial started, eligible patients received one of 10 gene-drug combinations; that number has now expanded to 24. Meanwhile the American Association for Cancer Research has put an initial $2 million into a two-year project called GENIE, which will collect both tumor gene profiles and medical results for many thousands of patients from seven major cancer centers in the U.S. and Europe. This registry aims to provide information that investigators can use for many purposes, including identifying more mutations that might be amenable to targeted drugs and finding markers that can help with diagnosis or staging of tumors.
These and other efforts augur well for future improvements in genetically customized care for cancer patients. At present, however, they are dogged by skepticism about how quickly they will lead to meaningful changes. In addition, the push for targeted drugs could be undermined if pharmaceutical companies shift their focus to other up-and-coming approaches, such as immunotherapy. For now the gulf between the promise of precision medicine and the reality remains frustratingly large.