If Patient X were like most people with advanced bladder cancer, she would probably be dead by now. After her first diagnosis, she received standard chemotherapy. It failed. Then she entered a clinical trial for a drug that was originally approved to treat other tumour types: would it also work in metastatic bladder cancer? Apparently not — none of the other patients in the trial did well.
Yet Patient X thrived. Her tumour completely disappeared, says computational biologist Barry Taylor at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, where Patient X was treated. Today, a little more than five years after treatment, she is healthy and has no evidence of disease1.
Patient X (her identity is shielded to protect her privacy) is an exceptional responder, one of those rare individuals who have a dramatically positive response to a therapy that does little or nothing for most other patients. This response is not unique to cancer. Immunologists, for example, have discovered why some individuals can be HIV-positive and yet avoid the symptoms of AIDS.
By definition, exceptional responses are rare, which makes them hard to study. Their anecdotal nature seems to contradict the teachings on statistically sound results in biomedical research. In a clinical trial, even if there are several exceptional responders, a drug will fail to achieve approval because it does not improve the health of the majority of patients. This means there has been little incentive for researchers or drug companies to investigate thoroughly why a few people respond so well.
But that neglect is starting to be addressed as more cases of exceptional responses in cancer reach the published scientific literature and techniques emerge for profiling patients at the molecular level2. In Patient X’s case, genome sequencing revealed a mutation in her tumour that explains why her cancer is specifically vulnerable to the drug she received on the clinical trial1. Such successes indicate that searching for and profiling these patients can potentially help researchers to predict many other patients’ responses to potential therapies.
The relatively new ability to comprehensively characterize a tumour’s genome, transcriptome (its gene expression) and metabolome (its metabolic processes) increases the chance of discovering the reasons behind outlier results, says Kenneth Kinzler, a cancer researcher at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. “The hope is that a signal seen in an exceptional responder will be seen in other cancer patients and be a predictor of therapeutic response regardless of tumour type,” he says.
The exceptional profile
There is no universally accepted definition of exceptional responders, says Barbara Conley of the US National Cancer Institute (NCI) in Rockville, Maryland. Conley directs the Exceptional Responders Initiative (ERI), which profiles these patients. The ERI considers a drug response to be exceptional when a tumour disappears or when a patient shows an exceptional response to treatment and lives longer than 90% of others treated similarly. In tough-to-treat and advanced cancers, an exceptional response is when treatment causes a tumour to regress by at least 30% for at least six months, but only in less than 10% of people on the same treatment.
In the case of Patient X, for example, her sequenced tumour genome revealed a mutation in a gene called tuberous sclerosis complex 1, which is one of several genes involved in a pathway that regulates cell growth and proliferation. The drug that worked for Patient X, but not for the other patients in the clinical trial, inhibits signalling in that pathway……
