City of Hope
Research by City of Hope, other experts suggests next-gen DNA sequencing identifies drug-sensitive lung tumors previously missed by conventional screen
DUARTE, Calif. — A major breakthrough of the last decade is identification of drugs targeting patient-specific mutations that cause cancer. These discoveries are beginning to allow oncologists to prescribe treatments based on a tumor's unique genetic signature and form the very basis of personalized medicine.
A striking example is crizotinib, a drug effective in treating a subset of nonsmall cell lung cancer (NSCLC) patients. Their tumor cells are distinguished by mutations that hyperactivate a gene called ALK to promote tumorigenesis. Detection of these ALK mutations not only alerts an oncologist that their patient has this type of NSCLC but means that crizotinib, which acts by blocking ALK activity, is the appropriate therapy to treat that patient. It follows that crizotinib is not approved to treat NSCLC patients with an undamaged ALK gene (sometimes termed "ALK-negative"); simply, they lack the drug's target.
Now a study by co-corresponding authors Ravi Salgia, M.D., Ph.D, professor and chair of City of Hope's Department of Medical Oncology & Therapeutics Research, and Siraj M. Ali, director of clinical development and medical affairs with Foundation Medicine Inc. reports a finding that could impact NSCLC patients once diagnosed as ALK-negative. The team found that a third of NSCLC patients believed to have a normal ALK gene based on a conventional lab test actually harbored cancer-associated and potentially crizotinib-sensitive ALK mutations, as revealed by state-of-the-art DNA sequencing.
The study, published in a recent issue of The Oncologist, means that, at least in this case, genomic profiling is potentially another way to identify lung cancer patients who might benefit from targeted therapy. The paper also illustrates the urgent need for accurate diagnostic tests of any cancer.
"This seminal article reports that despite previous negative results revealed by standard diagnostic tests, we were able to detect an abnormal genetic marker for ALK," says Salgia, a lung cancer specialist who holds the Arthur & Rosalie Kaplan Endowed Chair in Medical Oncology at City of Hope. "Our study illustrates that we must be able to identify more appropriate therapeutic biomarkers. Currently, the diagnostics we have in hand are not enough."
An estimated 5 percent of NSCLCs display chromosomal damage called ALK "rearrangements." In these cases, the end of chromosome 2, which contains the ALK gene, breaks off and reconnects at the wrong place, most often fusing to a gene called EML4 and creating an oncogenic hybrid gene that drives unchecked cell proliferation. A microscopy technique called fluorescence in situ hybridization, or FISH, allows diagnosticians to literally see pieces of a broken ALK gene inside a cell, providing them with a Food and Drug Administration-approved method of determining which patients would likely respond to and benefit from ALK blockers like crizotinib. (And, by extension, which ones would not.)
The team strongly suspected that FISH analysis might be missing some ALK mutations. So they decided to analyze tumor samples from lung cancer patients using state-of-the-art DNA sequencing to search for break points along the DNA strand, regions that serve as undeniable evidence that a chromosome broke off and pinpoint where it reconnected. DNA sequencing revealed that of 1,000 patients analyzed, 47 showed exhibited ALK rearrangements, a number that made sense given that about 5 percent of NSCLC tumors are estimated to emerge from this class of ALK mutations.
Of note, 31 of the 47 had previously undergone FISH testing, and that data was available for the team to review. If FISH were 100 percent accurate, all 31 should, in theory, test positive for the rearrangement. But remarkably, 11 had been scored as normal and nonmutant following FISH analysis. In other words, slightly over a third represented "false negatives" for ALK rearrangement and were patients who might have benefited from crizotinib therapy, but did not receive the drug.
A gratifying end of this story is that nine of the 11 misdiagnosed patients then became eligible to receive crizotinib and showed at least a partial positive response — among them a 38-year-old woman who, having suffered disease progression after six months and several cycles of chemotherapy, showed a partial response to crizotinib and is currently participating successfully in a clinical trial of a next-generation ALK blocker.
The study also identified genes other than EML4 that can fuse to "rearrange" ALK in cancer cells. Unorthodox ALK fusion partners had been reported before, but three tagged in the study are novel. The paper notes that non-EML4 ALK hybrids are expressed in lung tumors of patients who respond positively to crizotinib, meaning that they likely drive tumor growth in a manner similar to EML4/ALK, a finding of great interest to cancer biologists.
The take-home message of Salgia's paper is nonetheless sobering: FISH as standard-of-care testing for NSCLC therapies is simply insufficient to identify all cases of ALK rearrangement. Until new diagnostics, such as DNA sequencing, are routinely applied, some patients may not receive an available drug that could save them.
"Even in instances where diagnostic tests may already exist, we must create additional tests that will detect abnormality in every patient that harbors a particular genetic alteration in the tumor," says Salgia, whose research centers on biomarkers for early detection of thoracic cancers. "It is imperative that we not only utilize the current tests, but that we perform further research to optimize our tests."
Salgia joined City of Hope in January of this year. The current study was conducted prior to that, when he served as professor at the University of Chicago Medical Center and Pritzker School of Medicine and was director of the Thoracic Oncology Program.
About City of Hope
City of Hope is an independent research and treatment center for cancer, diabetes and other life-threatening diseases. Designated as one of only 45 comprehensive cancer center, the highest recognition bestowed by the National Cancer Institute, City of Hope is also a founding member of the National Comprehensive Cancer Network, with research and treatment protocols that advance care throughout the nation. City of Hope is located in Duarte, California, just northeast of Los Angeles, with community clinics throughout Southern California. It is ranked as one of "America's Best Hospitals" in cancer by U.S. News & World Report. Founded in 1913, City of Hope is a pioneer in the fields of bone marrow transplantation, diabetes and numerous breakthrough cancer drugs based on technology developed at the institution.