To search for the mutant version of the ALK gene, technicians at NIH employed a test called fluorescence in situ hybridization, or FISH. The test uses dyes—in this case orange and green—that bind to separate halves of the ALK gene. Pathologists peer through a microscope and look for the two colors. If the two dyes are superimposed on each other, the tissue looks yellow and the gene is intact. But if the colors are separated, this indicates ALK damage. Abbott Laboratories developed the ALK -FISH test in partnership with the Pfizer team developing Xalkori. It was one of the first times that a big pharmaceutical company teamed up with a large diagnostics lab to create a cancer drug-biomarker combo.
The NIH and Mass General are at the vanguard of a major effort to identify and treat cancer based on causative gene mutations like the one found in ALK . The convergence of several factors explains the trend: cheaper genetic sequencing technologies, the discovery of new oncogenes (genes that can cause a normal cell to become cancerous), a new generation of computers and bioinformatics that can analyze vast amounts of data, and a multibillion-dollar effort by researchers inside and outside the pharma industry to develop targeted drugs and companion diagnostics for cancer.
Mass General geneticist Dora Dias-Santagata explains that she and other pathologists at the hospital’s Translational Research Laboratory examine patients’ tumors for more than 150 cancer-inducing mutations. She says they can now identify the mechanisms that cause tumor growth in half of all adenocarcinomas, a family of cancer that affects skin and other tissue, including the lungs. Adenocarcinomas account for some 40 percent of all lung cancers diagnosed. All of the known mechanisms driving adenocarcinoma in the lungs (more than eight have been discovered to date) are powered by kinase genes like ALK which, when healthy, regulate cell growth. When the genes go rogue, cells multiply out of control.
Identifying the cause of a tumor does not always mean that doctors know which drug will work best. Only a quarter of the patients who test positive for one of the oncogenes identified at Mass General can be matched to a specific treatment. “We don’t have companion diagnostics for most of these,” Dias-Santagata explains, though her lab is working hard to formulate the tests.
As the cost of DNA sequencing continues to plummet, the lab will move ever closer to a once-elusive goal: economically processing every patient’s complete genome in both tumors and healthy cells. Right now technicians target only a few crucial genes. But “probing all relevant cancer genes will mean we can find new mutations and areas of interest,” Dias-Santagata says.
A robotic device the size of a dishwasher is humming nearby as dozens of tiny tubes move tumor samples through the sequencing process. In another room of the Translational Research Lab, DNA amplifiers nicknamed John, Paul, George, and Ringo help process genes from 5,000 to 6,000 patients a year. “We’re looking for multiple mutations across tumors, mutations that turn on genes and promote cell growth,” Dias-Santagata says. “In half of patients we have found new mutations, which makes this very individualized.”
Nearby, a young technician in a white lab coat watches a computer screen for one particular patient’s signs of mutation. Anomalies appear as upward spikes on a graph line. “This is for melanoma,” the technician says. She points at an uptick on the screen. “This is a BRAF mutation [associated with melanoma] right here.”
The research behind the melanoma finding and Martensen’s ALK test began in the 1970s, when a young oncologist named Dennis Slamon became obsessed with the genetics of breast cancer. He wanted to understand why 25 percent of breast cancer patients had an identifiable, unusually fatal mutation in a gene called HER2—and to find a drug that might target this gene. His ensuing two-decade quest led to the discovery and 1998 approval of the breast cancer drug Herceptin, and to a companion diagnostic test that looks for an overproduction of her2 proteins. It was the first-ever personalized treatment for cancer.
Herceptin works by blocking the receptors for the protein produced by the cancer-causing HER2 gene for those who test positive for her2 overproduction, but it does nothing for patients who are negative. Before the advent of Herceptin, women with the mutated HER2 gene had among the worst survival rates. With Herceptin, they can now do very well. (In clinical trials, HER2-positive patients receiving Herceptin and standard combination chemotherapy had a 52 percent decrease in disease recurrence compared with patients treated with chemotherapy alone.)
Herceptin and the her2 test arrived at a heady moment for biology, when the race to sequence the human genome was close to completion and optimism ran high that more biomarker-targeted cancer drugs were close at hand. But the expected rush of personalized drugs failed to materialize because the biology driving cancer turned out to be far more complex than researchers expected.
The next round of biomarker-drug combos didn’t appear until 2004, when Genomic Health, a small start-up in Silicon Valley, launched a test called OncotypeDx. Using a panel of 21 genes, this test helped physicians target which type of cancer therapy would work best for breast cancer patients. The test identifies the 25 percent of patients who are likely to benefit from chemo and the 50 percent who should get hormonal treatments only.
At the same time, the years of research were beginning to produce a deeper understanding of the mechanisms underlying different cancers, including lung cancer. Alice Shaw recalls a signal moment in 2004—just as she was finishing her oncology fellowship at MIT—when scientists discovered that mutations in a gene for epidermal growth factor receptor (EGFR) were the culprits in about 10 to 15 percent of lung cancer patients. Perhaps more important, a diagnostic test that identified the EGFR mutation was paired with the Genentech drug Tarceva. Patients testing positive registered similar response rates to those currently taking Xalkori. “This completely transformed the field of lung cancer,” Shaw recalls.
Since 2004, a wealth of new research has produced a deluge of oncology drugs in development and human trials; more than 900 are being tested today. This is good news, although research has lagged in coming up with companion diagnostics like those for ALK or EGFR—which means that many of the new drugs are still administered in a trial-and-error fashion to determine which will work for individual patients.
In 2006 Pfizer started early human testing on one of these new, targeted drugs called crizotinib (now sold as Xalkori), concentrating on a mutation of a gene called MET, implicated in several cancers, including esophageal and stomach cancer. The link between this drug and ALK and lung cancer was not suspected until 2007, when a team in Japan published a study in Nature that made the connection. “It became clear after reading the paper that crizotinib might also work in patients with the ALK mutation in lung cancer,” Shaw says.
By December 2007 Shaw had joined the clinical team testing Xalkori at Mass General and soon enrolled her first few ALK -positive lung cancer patients. “Some had failed multiple lines of treatment and were very, very sick, with advanced-stage lung cancer,” Shaw says. The drug worked almost immediately. “One woman who had been on oxygen reported that even in the first week she could breathe better.” Physicians at Mass General and several other clinical test sites enrolled a few dozen more patients that June. They, too, did remarkably well.
“Lung cancer patients are usually treated with chemo, and they can do well, but you seldom see dramatic turnarounds,” Shaw says. “It was electrifying when we saw these reactions.”
A few days after the NIH received Martensen’s tumor, the lab issued its result. “Incredibly, it was positive,” Martensen says—he was among the fortunate few with the well-defined ALK mutation. “In my case, this was even more rare since I have a different version of lung cancer than most people who were being tested on Xalkori,” he adds. That distinction meant that Martensen still might not respond to the drug. He would soon find out as he traveled up to Boston to meet with oncologist Shaw.