Until recently, cancer treatment was based on where the disease began, such as the breast, lung or colon. Now, small pills called “smart drugs” and a sophisticated new type of diagnosis pioneered by the Massachusetts General Hospital Cancer Center that identifies tumors’ genetic mutations are creating a new era in cancer medicine. What’s more, the new treatments are easier for patients to manage, have fewer side effects and may offer improved outcomes.
“Cancer cells require certain genes to survive,” says Leif Ellisen, MD, PhD, co-director of the Mass General Translational Research Lab. The lab launched two years ago to develop the technologies and infrastructure necessary to support broadly testing high volumes of tumors and to move new targeted therapies into clinical trials. “If you have a drug that can inhibit these genetic pathways, you can treat the cancer more effectively than with traditional therapies.”
Traditional chemotherapy works by killing off all rapidly dividing cells, including tumor cells. Smart drugs, however, work by targeting a specific genetic mutation, a kind of “molecular fingerprint” in a cancer cell, and essentially arresting the disease process by turning it off. Imagine a light switch: the light is on, cancer; flip the switch, turn the cancer off. These new treatments, while not a cure, offer a promising new approach to treat cancer.
Molecular Fingerprinting: The Key to Personalized Cancer Care
FINDING A TUMOR'S ACHILLES' HEEL
To know which genetic mutation is active in a patient’s tumor, Cancer Center researchers analyze a tumor’s genetic makeup gene by gene. Cumbersome in the past, molecular fingerprinting (also known as “genotyping”) at the Cancer Center has become a highly automated, efficient process that rapidly evaluates tumors for known genetic mutations. Read FAQs about molecular fingerprinting and smart drugs
In fact, since March 2010, the Mass General Cancer Center has genotyped tumors in patients diagnosed with advanced lung, metastatic breast, colorectal or brain tumors, as well as leukemia and melanoma, the most aggressive form of skin cancer. By the end of the year, the Cancer Center expects to routinely profile the tumors of most of the approximately 7,000 new patients seen annually.
Unlike other cancer centers, which generally test only for mutations most commonly associated with a particular tumor, the Mass General Cancer Center aims to test all tumors for a large variety of cancer-causing mutations – currently more than 130 mutations on 15 genes.
“Genetic testing is assuming an increasingly important role in the care of select patients with lung cancer,” says Alice Shaw, MD, PhD, a Cancer Center thoracic oncologist. “Patients whose tumors have specific genetic mutations have access to new therapies – typically pills – that target their tumors much more effectively.”
“We’re tapping into this idea that there’s going to be a structural reorganization of how we classify cancers,” says Jeffrey Engelman, MD, PhD, director of the Center for Thoracic Cancers at the Mass General Cancer Center. “It’s not so important as to whether a person has breast cancer or lung cancer, but rather which type of mutated breast gene or mutated lung gene they have. There may be some lung cancers and breast cancers that are treated identically and others that are treated completely differently. It’s based on a tumor’s specific genetic mutation.”
Understanding What Makes Each Tumor Unique
Six years ago, the Cancer Center made a breakthrough discovery by asking the simple question “why.” Results from a 2003 study showed that some lung cancer patients experienced a significant reduction in the size of their tumors after taking the drug Iressa.
Why did these patients experience such a profound response? Several months later, the team found their answer in a genetic mutation called EGFR, first discovered by Mass General Cancer Center researchers.
In the United States, only 10 percent of lung cancer patients have the EGFR mutation, although it is found in 50 percent of nonsmokers who develop lung cancer. Research conducted at Mass General showed that 70 percent of patients with an EGFR mutation responded to Iressa, resulting in significant improvement in survival compared with patients who received traditional chemotherapy for lung cancer.
Based on this success, Cancer Center researchers have been instrumental in developing two additional smart drugs: the ALK inhibitor for other subtypes of lung cancer and the B-RAF mutation inhibitor for melanoma. About 900 people with these cancers – the types for which molecular diagnosis is currently most useful – will have their tumors tested this year at Mass General.
“We now know that no two tumors are likely to be identical,” says José Baselga, MD, PhD, the new chief of hematology oncology and associate director of the Mass General Cancer Center. “A massive effort is needed to identify what makes each tumor unique. The Cancer Center’s initiative to provide genotype snapshots of tumors as part of routine medical care is critical to this effort, as is the commitment to collaboration across academic disciplines and institutions.”
Matching Smart Drugs to Mutations
Of course, the third leg of this approach involves pharmaceutical companies that develop new targeted therapies, and the Cancer Center is playing a fundamental role in working with these companies to place promising drugs into clinical trials sooner.
“Clinical trials typically take an inhibitor drug and try it on all patients with, for example, lung cancer. That takes years. Instead, why not just test the new drug on those patients whose tumors have the genetically abnormal pathways the drug is supposed to inhibit?” asks Ellisen. “We believe this is the quickest and most efficient way to find highly effective inhibitors and get them to the patients who can most benefit from them.”
One such drug, PLX4032, is a “smart drug” for the B-RAF mutation in melanoma. Keith Flaherty, MD, a Cancer Center oncologist, has seen this drug increase survival in his patients. Flaherty’s work focuses on getting major drug companies to work together to bring drugs that target the same mutations to trials, believing that combinations of drugs will create even better outcomes for patients. “We just need to find the right combinations,” he says.
The Mass General Cancer Center is also developing a bank of tumor samples that can be re-tested as new mutations are documented. “So in a year or two, if a new genetic mutation is identified, there might be a drug available to us,” says Ellisen. “We can re-test the tumor sample, tell you whether you have the mutation and whether you might be treated with a certain smart drug at that time.”
“For many of these treatments, we don’t expect they will cure metastatic disease,” reflects Engelman. “However, we do think smart drugs can help patients with specific cancers go into remission and live much longer than if they had undergone traditional therapies.”
“It used to take 10 years for cancer research results to be translated from bench to bedside,” says Ellisen. “Now it takes just months to bring new therapies to patients. It’s a whole new era.”