Oncology Enters Era of Genomics: Sledge Calls for Overhaul of Clinical Trials System

George W. Sledge, Jr, MD

As the genomic era in oncology unfolds, the development of new therapeutics increasingly will involve targeting a range of mutations simultaneously, requiring a “next-generation clinical trials system” to match the advances that technology is delivering, according to George W. Sledge, Jr, MD.

Sledge told attendees at the 30th Annual Miami Breast Cancer Conference Saturday that last year marked a leap forward in understanding breast cancer as the results of many genomic analyses became available. The range of mutations uncovered in individual tumors will necessitate moving beyond battling cancer by identifying a particular molecular process, as has been the case in the targeted therapy era, to multiple driver mutations.

“We’re clearly entering a new age and that age is what I consider to be the genomic era,” said Sledge, who is chief of the Oncology Division at Stanford University School of Medicine in California and a past president of the American Society of Clinical Oncology. “This is an era of great promise. We’re at the point where we’ll be able to tell an individual what’s driving their cancer but it’s going to require a whole lot more of us.”

In developing new therapeutics, researchers will have to focus not only on qualitative mutations but also quantitative aberrations, Sledge said. “We don’t need a magic bullet, we need a magic shotgun,” he said. “We need something that can shoot pellets at a lot of different targets and do so more or less simultaneously.”

He said the current clinical trials system is poorly equipped to take advantage of advances in knowledge about cancer genomics and that many changes are needed. His ideas for overhauling the system include trials designed around multitargeting, greater collaboration among research entities, an information network for clinical trials, a redesigned informed consent process, and a “fundamentally different regulatory apparatus.”

“We have next-generation sequencing. We need a next-generation clinical trials system, “ Sledge said. Sledge noted that technological advances have delivered an explosion of information at an ever-decreasing cost. He said the sequencing of the first human genome took 13 years and cost approximately $3 billion; in the next several years, researchers likely will be able to sequence a genome in less than two weeks at a cost of about $1000. He said the price would drop further and that the challenge would be using the information generated.

“The evaluation of that gene chip that you order will be incredibly complicated and will require a significant amount of playing out over the next decade in terms of how we use it,” he said. Sledge said genomics research has revealed that cancers can be described broadly as either “stupid” or “smart.”

Cancers that are stupid have a single dominant mutation and a small mutational load, meaning that monotherapy will be effective and that resistance to therapy will occur rarely and along the same pathway.

In contrast, smart cancers show multiple mutational drivers with a large mutational load, requiring multitargeted therapy to which resistance is common and occurs early in treatment.

Chronic myeloid leukemia, with bcr-abl as a target and a relatively small mutational load, is an example of a stupid cancer, Sledge said. Smart cancers with a greater mutational load include those where patients’ lifestyles play a role, such as lung cancer and melanoma.

Breast cancer falls in the middle of the mutational spectrum, with subtypes that reflect the genomic complexities of the malignancies, Sledge said. “This distinction between stupid cancers and smart cancers drives a lot of what we know about the prognosis of human cancers, and it increasingly will drive how we approach these cancers from a therapeutic standpoint,” he said.

For example, Sledge said, an analysis of triple-negative breast cancer found 32 somatic mutations,1 showing a “genomic chaos” that makes the malignancy a collection of orphan diseases. Attacking a tumor type with so many mutations becomes an oncology version of the Whack-a- Mole arcade game, he said.

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“We’re dealing with this rapid emergence of compensatory mechanisms of resistance that have a deep genomic basis which we now for the very first time in human history can measure and increasingly will be able to measure by an individual basis,” Sledge said. “One has to think this will change how we think about the cancer and how we approach cancer from a therapeutic standpoint.”

1. Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486(7403):395-399.

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