CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and professor, Department of Pathology, University of California, San Diego; John A. Thorson, MD, PhD, associate professor of pathology, director of the Clinical Genomics Laboratory, Center for Advanced Laboratory Medicine, UCSD; Sarah S. Murray, PhD, professor, Department of Pathology, and director of genomic technologies, Center for Advanced Laboratory Medicine, UCSD; and James Solomon, MD, PhD, resident, Department of Pathology, UCSD.
Tumor profiling and patient outcomes in genotype-matched clinical trials
Molecular profiling of tumors with next-generation sequencing can provide important diagnostic and prognostic information that can be used to inform treatment strategies. There is an abundance of information in the literature about molecular and genomic characteristics of solid tumors, but less is known about how these characteristics could influence clinical care for individual patients. In two prospective studies—the Integrated Molecular Profiling in Advanced Centers Trial (IMPACT) and Community Molecular Profiling in Advanced Cancers Trial (COMPACT)—conducted at the Princess Margaret Cancer Centre, in Toronto, Canada, oncologists use molecular profiling information on solid tumors to enroll patients in clinical trials with targeted therapies. In studies conducted from March 2012 to July 2014, formalin-fixed, paraffin-embedded archival tumor and matched peripheral blood samples from 1,893 patients were analyzed by three molecular profiling assays: a MALDI-TOF mass-spectrometry platform to genotype 279 mutations in 23 genes, MiSeq sequencer covering regions of 48 genes, and Ion Proton sequencer covering regions of 50 genes. Variants were then classified using a five-class scheme. Tumor profiling was successful in 1,640 of the patients, and these patients’ molecular information was entered into their electronic medical records. Treating oncologists, often with the aid of a multidisciplinary molecular tumor board, used this information to plan treatment strategies. A total of 245 patients were subsequently enrolled in therapeutic clinical trials, including 84 in genotype-matched trials. The latter were defined as trials restricted to specific somatic mutations, trials in which a targeted drug inhibited a biological pathway linked to the specific somatic mutation, or trials in which targeted drugs had been shown to have increased activity in patients with the specific somatic mutations. Most of the patients enrolled in genotype-matched trials had somatic mutations in PIK3CA, KRAS, BRAF, and EGFR. When comparing patients enrolled in genotype-matched trials with those enrolled in genotype-unmatched trials, no significant difference was found in age or gender distribution or number of previous treatments. However, genotype-matched trials were significantly more likely to be phase one studies and significantly more likely to involve treatment with targeted drug combinations without chemotherapy or immunotherapy. The overall response rate, as measured by tumor shrinkage, was significantly higher in genotype-matched trials—19 percent versus nine percent in genotype-unmatched trials—although no significant difference in overall survival was seen. While the difference in response rate was significant, a rate of only 19 percent in the genotype-matched trials suggests a potential for improvement, possibly by refining models or using synergistic therapies or alternative treatment strategies. In addition, a multivariate analysis showed that the only significant predictors of tumor response were enrollment in a genotype-matched trial and female gender. One disappointing outcome was that only five percent of patients enrolled in the IMPACT or COMPACT trials were ultimately enrolled in a genotype-matched clinical trial, a finding seen in many similar studies at academic cancer centers. Overall, however, although the study is a nonrandomized comparison, it demonstrated that patients are more likely to achieve tumor response if selected for a clinical trial based on molecular tumor profiling.
Stockley TL, Oza AM, Berman HK, et al. Molecular profiling of advanced solid tumors and patient outcomes with genotype-matched clinical trials: the Princess Margaret
IMPACT/COMPACT trial. Genome Med. 2016;109. doi:10.1186/s13073-016-0364-2.
Correspondence: Philippe L. Bedard at philippe.bedard@uhn.ca