Heidi Ledford in Nature:
A landmark cancer drug approved last year seemed to herald a long-anticipated change in the treatment of some tumours: with medicines selected on the basis of molecular markers, rather than the tissue in which the cancer first took root. But clinicians and researchers are struggling to put that theory into practice. Although the drug itself works well in a variety of tumour types, some of the tests used to identify the molecular markers, it turns out, do not. On 15 April at the American Association for Cancer Research annual meeting in Chicago, Illinois, researchers and representatives from the US Food and Drug Administration (FDA) will discuss how best to tackle the situation. “If you get a false negative result, you’re not going to give that patient the therapy, which is terrible,” says Zsofia Stadler, an oncologist at the Memorial Sloan Kettering Cancer Center in New York City. “That’s why there’s such a debate.” The drug in question, pembrolizumab (Keytruda), works by firing up the body’s immune responses against tumours. First approved by the FDA in 2014 to treat melanoma, it has since been given the go-ahead to treat a handful of other cancers, including lung cancer. But last year, researchers reported that patients whose tumours had a disabled DNA-repair system also responded to the drug, regardless of where the tumour originated1. Damaged DNA can yield mutant proteins, which the immune system could target as potential invaders. Scientists think this increases the chances that immune cells unleashed by pembrolizumab will find and attack the tumour.
In May 2017, the FDA allowed pharmaceutical giant Merck of Kenilworth, New Jersey, to market pembrolizumab to people with advanced-stage cancer who had any solid tumour with that particular DNA-repair defect. “This is absolutely a breakthrough approval,” says Razelle Kurzrock, an oncologist at the University of California, San Diego. “We have seen some dramatic responses in our patients.” But the three kinds of tests commonly used to look for the DNA damage that arises from that defect can produce conflicting results, says Heather Hampel, a genetic counsellor at Ohio State University in Columbus. One relies on PCR, a process that amplifies specific regions of the genome; a second looks for certain proteins; and a third relies on DNA sequencing. “Which is the best? Is any positive on any test sufficient?” Hampel says. “Does that mean you should try them all? No one wants to miss a patient who might benefit from pembrolizumab.”