Imagine you are a big drug company, testing out a new drug. You pick a group of people who you think are most likely to respond to the drug. If you give the new drug to ten cancer patients and nine of them have progressive disease — their tumors continue to grow — then you’re probably going to shelve that drug. You wouldn’t possibly want to give a drug to a group of patients when 90 percent of them will continue to get worse. But what about that one patient? While the other nine progressed, one patient improved remarkably. You’re probably still going to have to shelve the drug. A 90 percent failure rate is unacceptable. And yet 10 percent of the patient population might be missing out on a phenomenal treatment for their specific tumor.
That one patient is the extraordinary responder — her response was different than the expected, ordinary response based on statistics. If researchers could figure out what made her extraordinary — why she responded to the drug and the others didn’t — perhaps they could tailor a trial to patients with only that “extraordinary” characteristic. By better selecting a target patient population, they could take a drug with a 90 percent failure rate and turn it into a drug with an exceptional success rate!
The current initiatives embracing precision medicine will benefit greatly from the study of extraordinary responders. In fact, Pfizer almost scrapped the drug Xalkori (crizotinib) because of a high failure rate, despite a small group of extraordinary responders. Late in the early stage trial, the identification of the ALK gene and its mutation in non-small cell lung cancer (NSCLC) led to the discovery that Xalkori was actually a specific ALK inhibitor and that the extraordinary responders had an ALK
mutation. Because doctors now know how to better select patients, Xalkori is a successful treatment in NSCLC patients whose tumors carry a mutated ALK gene. (N Engl J Med 2010; 363:1693-1703
The hard thing about studying extraordinary responders is that in any single trial, by definition, there are so few individuals to study. The Metastatic Breast Cancer Project
being launched this month by the Broad Institute and Dana-Farber Cancer Institute has an answer to that problem. By collecting data, tissue and health records from metastatic breast cancer patients treated in any cancer center, oncology practice or community hospital across the country, they will be able to gather a much larger group of extraordinary responders than a researcher could ever find at any individual center. The scientists at Broad have considerable resources and expertise to analyze and compare the genomic data from all these patients — putting them in a tremendous position to find the “extraordinary characteristics” that these patients share. They require very little from the participants: Sign an online consent form and spit in the tube they send you. They do the hard work of acquiring your health records and tissue from your doctors and analyzing everything, and they’ll even keep you informed as the studies progress. If you don’t think your response qualifies as “extraordinary,” they still want to hear from you, too! While they plan to begin by studying extraordinary responders and patients who presented with stage 4 disease, they are reaching out to all metastatic breast cancer patients (men too!) to sign up and share their voice. Starting with the extraordinary responders is a strategic way to quickly impact the most patients, but as the study grows, they will expand to study additional patient groups. They hope to have a robust collection of patients to draw from as soon as they’re ready to start a new group.
I was trained to be a cynic in graduate school. As a PhD science student, I was taught to find the flaws in every paper I read or presentation I attended. This was not to belittle my colleagues or to make myself look better in comparison. Rather, finding the flaws, determining their importance, and figuring out how to compensate for or overcome them helped me to be a better scientist. I was trained to value my cynicism as a skill to improve my research. Naturally, everyone wants to think that their project can cure cancer, yet we all know deep down that we can’t all be right. Many times when people eagerly tout their new exciting project or the media talks about the “next big thing,” I am incredibly skeptical. If a project manages to excite me, it’s overcome some serious hurdles. I really tried, but I can’t pick apart the Metastatic Breast Cancer Project. That doesn’t mean that it will find the cure for all breast cancer within the year. But I truly believe that if all those extraordinary responders have anything in common at the genomic level, this project is the absolute best way to find it. This single project has managed to turn an academically trained skeptic into a raving optimist, and I can’t wait to see what it uncovers! While I’m thankful that with no evidence of disease, I’m not eligible for this study, I am encouraging any of my metastatic friends to be sure to say, “Count me in!”