While investigators share their latest data in about 6,100 scientifically diverse presentations with nearly 18,000 registered attendees at the 101st annual meeting of the American Association for Cancer Research, a few prominent themes had surfaced by day three in DC — namely, cancer is more complex than was once anticipated and it’s likely time to re-think the design and execution of clinical trials.
Central to each meme is the need to strengthen the marriage between curiosity-driven basic research and patient care-focused clinical investigations. Translating basic discoveries into optimal treatments has historically relied the use of animal models for disease — a practice Ronald DePinho and Scott Lowe maintained the value of during a session moderated by Jill Mesirov on Monday — but some suggest it’s high time to implement translational science alongside clinical trials in order to increase scientific accuracy and improve the pace of progress.
It’s Complicated
Burt Vogelstein’s talk during Monday’s cancer genome plenary session examined the lessons learned from the exomic sequencing of 100 human tumors. By looking at data from 116,432 cancers — derived from all available genomic sequencing projects — Vogelstein and his colleagues identified 130,072 intragenic somatic mutations. Of the 3,142 driver mutations they identified, 286 were tumor suppressor genes and 33 were oncogenes, demonstrating that “90 percent of driver genes in common solid tumors are suppressors,” he told attendees. “Virtually all of these driver genes are part of 12 core cancer pathways,” he continued, saying that while that “considerably simplifies the situation…the elephant in the room is tumor heterogeneity. This is what complicates the picture.”
During his talk in the same session, Arul Chinnaiyan asked “How are we going to personalize cancer therapies when driving mutations may be [occur] in one percent or less in the population?” He also suggested that, in the future, cancers might be classified by their driver mutations rather than their tissue of origin — for example, a patient would be diagnosed and treated for BRCA cancer rather than breast cancer, he elicits. During the Stand Up to Cancer: Maximizing Innovation Through Translational Research and Team Success session moderated by Phillip Sharp, Joe Gray said that in order to understand "how these tumors evolve in the face of treatment," researchers should work toward developing "the capability of biopsying in near real-time," to build an "understanding of their molecular complexities."
Transforming Trials
Martine Piccart-Gebhart shared her lab's clinical strategies with the Breast International Group cohort, during her talk on "building an accelerated path to tailored adjuvant cancer therapy." In it, she outlined her use of the "add-on" treatment approach; in order to achieve progress, she says, it's imperative run clinical trials "accompanied by a very aggressive translational research program," in which drug and biomarker discoveries are performed in tandem.
In a session that followed, Edward Kim reported the results of the BATTLE trial aimed to distinguish personalized therapies for lung cancer patients. In selecting clinical participants, Kim and his colleagues used adaptive randomization, wherein candidate patients are screened for biomarkers to predict tumor response, which "adds to the statistical power," he said. Using real-time tumor profiling, the team was able to not only monitor a patient's disease status, but also identify novel biomarkers for disease states. "BATTLE establishes a new paradigm to investigation BMs [biomarkers] and molecularly targeted treatment in lung cancer patients," the authors conclude.
Elsewhere, Laura van't Veer and Laura Esserman — collaborators in the I-SPY and I-SPY-2 breast cancer trials (the latter is currently recruiting patients) — discussed their use of neoadjuvant trial design, molecular imaging, and adaptive trial design wherein the researchers can "see right away" whether a patient has a "problem with a drug." To enable this, the team is filing multiple Investigational New Drug applications with the Food and Drug Administration — "up to five drugs at once," Esserman said during a panel discussion on biomarker discovery moderated by Anna Barker.
Dennis Slamon and Joe Gray, co-principal investigators of a Stand Up to Cancer grant, "feel convinced that small, focused trials in the appropriate subgroups will generate data much more quickly."