Breaking the Cancer Code

Finding the cure for cancer has long been an aspiration of medical students, researchers and clinicians alike. Yet, despite many major advances in treatment, none has unlocked the code behind the root causes of cancer — until now. In recent years, there has been an avalanche of findings regarding the genetic mutations that lead to malignant tumors, and these findings are producing the first phase of promising drugs that may control — if not cure — certain cancers.

The first gene mutation was discovered in 2004, a mutation in the EGFR (epidermal growth factor receptor) gene. The ALK (anaplastic lymphoma receptor tyrosine kinase) gene mutation was next, identified using advanced DNA-sequencing technology on lung cancer tumors. Prior to that discovery, a pathologist would identify a patient’s lung cancer tumors through a microscope to see if they were of the small-cell or non-small-cell variety. The difference helped determine which regimen of chemotherapy to prescribe.

The discovery of the ALK-gene mutation prompted testing of Xalkori (crizotinib), a brand-named drug manufactured by Pfizer, to see if it worked on the mutation. Pfizer’s study of the first lung cancer patients given the drug showed dramatic improvements, and the U.S. Food and Drug Administration (FDA) approved Xalkori in 2011, four years after the ALK-mutation link was discovered. In an industry accustomed to spending a decade or more waiting for drug approval, the move was a promising one.¹

In the past few years, discoveries of new gene mutations in cancer research have dramatically accelerated. A 2011 report linked a mutation of a gene called RET to lung cancer, prompting researchers at Memorial Sloan-Kettering Cancer Center in New York to partner with Exelixis Inc., a biotechnology company that was developing a drug called Cometriq (cabozantinib) to treat a rare form of thyroid cancer linked to the RET mutation. That mutation is found in only about 1 percent of lung cancer patients, but Sloan-Kettering moved forward and launched a drug trial. The first few patients tested displayed striking improvements, spurring more research. Discoveries of still more lung cancer mutations have continued at a rapid pace, and the current count is 15, accounting for about 60 percent of all lung cancers, according to some estimates, and researchers expect to find more.¹

Understanding Gene Therapy

Gene therapy replaces a faulty gene or adds a new gene in an attempt to cure disease or improve the body’s ability to fight disease. It holds promise for treating a wide range of diseases, including cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS. Researchers are still studying how and when to use gene therapy, and currently in the United States, gene therapy is available only as part of a clinical trial.2

Much of today’s cancer research is devoted to identifying missing or defective genes that cause cancer or increase an individual’s risk for certain types of cancer. Gene research at the University of Texas MD Anderson Cancer Center, for example, has led to many breakthrough discoveries, including the identification of the mutated multiple advanced cancer gene (MMAC1) that is associated with several common cancers. The center also performed the first successful correction of a defective tumor suppressor gene in human lung cancer.¹ Much of the research to date points to specific potential benefits of gene therapy. These include gene-based treatments that attack existing cancer at the molecular level, eliminating the need for drugs, radiation or surgery, and identifying cancer susceptibility genes in individuals or families that can play a major role in preventing the disease before it occurs.

The focus of most gene therapy research is the replacement of a missing or defective gene with a functional, healthy copy, which is delivered to target cells via a “vector.” Viruses are commonly used as vectors because of their ability to penetrate a cell’s DNA. These vector viruses are inactivated so they cannot reproduce and cause disease. Gene transfer therapy can also be done outside the body (ex vivo) by extracting bone marrow or blood from the patient and growing the cells in a laboratory. The corrected copy of the gene is introduced and allowed to penetrate the cells’ DNA before being injected back into the body. Gene transfers can also be done directly inside the patient’s body (in vivo).³

Other types of gene therapy include:

• Injecting cancer cells with special genes that make the tumor more receptive to the effects of anticancer drugs
• Introducing the multidrug-resistant gene into bone marrow to make stem cells more immune to the toxic side effects of anticancer drugs.

Gene therapy is a complicated area of research, and there are many variables that can affect outcome. Complications may arise because some cancers are caused by more than one gene, and some vectors, if used incorrectly, can actually cause cancer or other diseases.³

Breakthrough Results in Leukemia Study

A study published in The New England Journal of Medicine and Science Translational Medicine last August spotlighted a clinical trial that took five patients with untreatable cancer and, using their own immune systems, injected genetic material into their white cells, turning them into cancer fighters. The modified white cells then went out in the body and destroyed all the cancer cells. “Cancer cells are similar enough to your normal cells that the T cells cannot recognize it,” said Dr. Richard M. Stone, program director of the Adult Leukemia Program at the Dana-Farber Cancer Institute. “By injecting genes into these cells, you’re educating the immune system to recognize the cancer.”⁴

The treatment success came in a pilot study that was only meant to find out whether the treatment was safe, and to determine the right dose to use in later studies. But, the therapy was significantly more effective than University of Pennsylvania researchers David L. Porter, MD, Carl H. June, MD, and colleagues ever imagined. “Our results were absolutely dramatic. It is tremendously exciting,” said Dr. Porter in an interview with WebMD. “These kinds of outcomes don’t come around very often. We are really hopeful that we can now translate this into treatment for much larger numbers of patients and apply this technique to other diseases and many more patients.”⁴

The study reviewed only outcomes of patients with acute lymphoblastic leukemia (ALL), but the results could represent a major breakthrough in the fight against all different kinds of cancer. “We have a clinical trial at the University of Pennsylvania with an anti-mesothelin molecule (which marks mesothelioma, ovarian and pancreatic tumors)” explained Dr. Porter. “There are other trials around the country trying to target renal cell carcinoma and myeloma. We are hoping to identify other tumor targets, particularly in other leukemias, to adapt this technology.”⁴

A Closer Look at Lung Cancer

Lung cancer is one of the most common and deadliest forms of cancer. Much of the genetic research to date has targeted this particular disease, and the breakthroughs in this area are significant because for decades, lung cancer remained highly resistant to drugs that could extend an average patient’s life by even a few weeks. Three decades of research starting in the 1970s uncovered hundreds of potential lung cancer drugs, but produced dismal results; the progress made in diagnosis and treatment increased a lung cancer patient’s median survival prognosis by only one month. But, in a recent case study, Kellie Carey, a 45-year-old female patient who was diagnosed with a rare type of lung cancer, underwent experimental treatment that improved her prognosis significantly. Given just three months to live initially, Carey persuaded her physicians to genotype her tumor, and they uncovered that she had an ALK gene mutation that could be targeted by Pfizer’s drug Xalkori. By pinpointing her cancer, the drug may have added years to her life, and offered a much better outcome than chemotherapy; within six weeks, two of three cancerous nodules in her lungs had disappeared, and the third had shrunk significantly.¹

Carey’s situation was unique. She was “fortunate” enough to be diagnosed with lung cancer in the midst of a revolution in treatment. One thing cancer patients have a limited supply of is time, and when a patient is diagnosed with a cancer mutation that has no approved precision drugs associated with it, the options are to search for a drug in development and then attempt to join its trial. It’s a process that could take months or even years, while in some cases there may be off-label (non-FDA-approved) drug options that show promise, but insurers will be unlikely to pay for coverage of such treatments. The good news is that rapid diagnostic advances are making it easier for any doctor to test for the newfound cancers. Tests now can hunt for more than 200 mutations — of lung and other cancers — in one biopsy.

Evidence that precision medicine works will likely broaden its use quickly. A June 2013 report on 1,007 patients with advanced lung cancer whose tumors were sequenced by a group of researchers called the Lung Cancer Mutation Consortium found that 62 percent had alterations suspected of being driver mutations. Currently, there are three drugs on the market for newly discovered lung cancer mutations, while dozens more are in clinical trials. Some approved for other cancers appear effective for specific lung cancers, and drug companies are targeting other mutations of all cancer types.¹

Promise in the Pipeline

Decoding DNA in tumors is a similar process to how DNA is analyzed to identify criminal suspects. The newly discovered variants in cancer genes have led major cancer centers to revamp their approach to treating cancer and have spurred a rush among drug companies to bring breakthrough medications to market. Companies like Pfizer, Roche Holding AG and Merck & Co. have all thrown their hats in the ring in the race to develop cancer-specific drugs. In 2013 alone, nearly 1,000 cancer drugs were in clinical development, up 52 percent from 2006, according to Pharmaceutical Research and Manufacturers of America. The vast majority of that growth is from drugs targeted at genetic mutations.¹

“Where we are now is that genetic sequencing of cancers has enabled us to redefine some diseases completely. Lung cancer is the best example. What we find is that lung cancer is a number of different diseases that have very distinct gene mutations,” says Hervé Hoppenot, president of the Novartis Oncology Unit. “Once a tumor has been analyzed genetically, we can target each of these mutations very specifically.”⁵

Just last year, the FDA established a “breakthrough therapy” designation to hasten approval of experimental drugs that show striking benefits in early trials, including those targeted at cancer mutations. While these new drugs don’t yet cure cancer, doctors are encouraged by the possibilities presented by a “precision medicine” approach to treatment that can treat tumors far more effectively than commonplace chemotherapy. A June 2013 study found that lung cancer patients who were treated with drugs targeted at their genetically identified varieties lived 1.4 years longer than patients on chemotherapy whose cancers weren’t genetically identified. “What we’re seeing is the beginning of a revolution in therapeutics,” says Janet Woodcock, director of Center for Drug Evaluation and Research. “We can only hope that this gets us to where cancer is managed or curable.”¹

Research hospitals like MD Anderson, Vanderbilt University and Massachusetts General Hospital are among a growing number of cancer practices that routinely decode the tumor DNA of most patients with advanced cancer. In addition to lung cancer, scientists have decoded tumor DNA from breast, colon, kidney, skin and other cancers, and they are discovering numerous variations they didn’t know existed before.

The Role of Genetic Counseling

In May 2013, actress Angelina Jolie announced she had undergone a prophylactic double mastectomy after genetic testing revealed she carried the BRCA1 gene, giving her a roughly 87 percent risk of contracting breast cancer. The news instantly increased awareness of hereditary forms of cancer caused by genetic mutations.

BRCA testing is a genetic test that looks at the sequence, or code, of the BRCA1 and/or BRCA2 genes. Changes or mutations in the genetic code indicate increased cancer risks. The test can be performed on a blood or saliva sample, and genetic counselors and other healthcare providers are tasked with determining whether genetic testing is appropriate for individual patients. Factors that influence the appropriateness of testing include the patient’s personal and family history of cancer, age and ethnicity. In general, individuals with a personal or family history of breast cancer appearing before age 50; ovarian cancer at any age; breast cancer in both breasts; male breast cancer; multiple cases of breast cancer within a family; and breast cancer in individuals of Ashkenazi Jewish ancestry should get genetic counseling to determine whether they should be tested.⁶

As was the case with Jolie, a positive test result in BRCA1 or BRCA2 means that the person has a genetic mutation that increases cancer risk. A positive BRCA1 result gives a woman a 60 percent to 80 percent lifetime risk of breast cancer and a 30 percent to 45 percent lifetime risk of ovarian cancer. A positive BRCA2 result gives a woman a 50 percent to 70 percent lifetime risk of breast cancer and a 10 percent to 20 percent lifetime risk of ovarian cancer. In some instances, BRCA2 mutations are also associated with an increased risk of prostate cancer, pancreatic cancer and male breast cancer.⁷

The good news for patients is that BRCA testing is usually covered by insurance if certain criteria are met. Costs can range from $475 to as much as $4,000, and genetic counselors are influential in determining the type of testing required.

Hope on the Horizon

Precision medicine is showing great promise for various types of cancer, although researchers are quick to point out it is not a cancer cure. For one thing, a tumor with a pinpointed mutation doesn’t always respond to the drugs used to target it; while the drug often shrinks tumors within weeks, some aggressive tumors can develop resistance and come back with a vengeance, as was the case with Kellie Carey. Carey’s lung cancer returned in 2012, and she went off the crizotinib for another regimen of brain radiation, followed by another drug trial for a “next-generation” crizotinib. As of this writing, Carey was also considering a new class of drugs called PD-1 inhibitors that enlist the immune system. Such agents from Merck, Roche and Bristol-Myers Squibb Co. have been creating a buzz among oncologists for use in parallel with the genomic strategy. “The tumor will keep evading our best therapies,” said Trever Bivona, a lung cancer researcher at University of California, San Francisco. “Ultimately, we’re going to have to get to combination approaches.”¹