NEW YORK (GenomeWeb) – A new paper published in the Journal of the National Comprehensive Cancer Network describes the early results of the Intensive Trial of Omics in Cancer (ITOMIC), an initiative that seeks to find more effective cancer therapies by analyzing multiple sources of information and tapping into a network of domain experts.
The current paper provides results from analyzing data from a single patient enrolled in the trial, but also serves as an introduction to the overall initiative and its underlying proposition, according to Anthony Blau, director of the University of Washington's Center for Cancer Innovation and ITOMIC's principal investigator.
ITOMIC is based on the premise that because "clinical trials are based on comparing average results across groups of patients treated differently, randomized trials are probably reaching a point of diminishing returns," he explained to GenomeWeb. "In order to really be able to understand what's going on in patients with cancer with a higher level of granularity, it's going to be important to try to understand some of the basic principles of how cancers evolve and escape treatment. That could only be accomplished by very intensively tracking what's going on in patients with cancer longitudinally over the course of their disease."
Patients who enroll in the study submit to detailed investigations of their tumors. Specifically, ITOMIC researchers analyze genomic, transcriptomic, proteomic, and metabolomic data collected from these patients in addition to monitoring circulating tumor cell levels. Furthermore, external investigators who, by virtue of their expertise in a given area — for example, in-depth knowledge about a particular mutation and its consequences on protein function — are called in to consult on the case.
"There's this large reservoir of untapped expertise that can be brought to bear on patients with cancer who are trying to find any little clue, any little insight that could potentially be brought to bear on their care," Blau said. "The thing that you find is when we contact an expert ... they will always respond. They will not in a single instance say that they can't tell us what they know because it hasn't been published or it's the subject of some kind of patent application." Furthermore, in cases where they do not have the answers, these external researchers frequently recruit their colleagues, students, and post-docs to investigate the question. "That's been an incredibly heartening thing," he added.
For the first of these types of studies, the researchers are focusing on patients with metastatic triple-negative breast cancer but they will eventually expand to other kinds of cancer as well. TNBCs are a subset of breast cancers that lack the conventional markers of breast cancer — HER2, estrogen receptor, and progesterone receptor — making the cancer that much harder to treat since those markers are targets for most chemotherapies. According to Blau, TNBC patients comprise roughly 15 percent of all patients with breast cancer. Currently, "there are no known targets for therapies for patients with triple-negative breast cancers so [it] is largely considered to be an incurable disease," he said.
To date, the ITOMIC investigators have enrolled 12 patients in this first set of studies and were about to add a thirteenth when Blau spoke to GenomeWeb last week — they can enroll up to 20 patients for this iteration of the trial. To be eligible for the study, prospective participants cannot have previously received platinum-based chemotherapies and they and their physicians have to agree that the next course of treatment will be the drug Cisplatin.
The reason for that, Blau explained, is so all patients in the program start off on the same footing. "But as importantly, it's delinking the patient's treatment from the need to wait around for the result of our evaluation," he added. "It's a disease that progresses incredibly quickly; they need treatment right away." The goal is to have completed their analysis and have a treatment suggestion ready to go by the time the patient stops Cisplatin treatments either because they failed or because the patient developed toxicity to the drug. The researchers then perform multiple biopsies of patients' tumors collecting samples from different sites in the body. "One of the goals of this study is to understand how tumors evolve and escape treatment, and in order to do that we try to encompass the heterogeneity at each time point when we biopsy the patient's tumor," Blau said.
The current JNCCN paper described the group's efforts to analyze data from the second patient that was enrolled in the trial — a 56-year-old woman with metastatic TNBC. "We decided to publish our results with a single patient in order to describe the way the clinical trial works," Blau told GenomeWeb in an email. "It just would not have been possible to describe the trial and publish results from all 12 patients enrolled in the trial to date in a single paper."
Over the course of nearly a year, 32 investigators from 14 institutions along with some industry partners sampled circulating tumor cells, performed whole-exome and RNAsequencing, and ran tumor samples through a panel of some 200 cancer-associated genes. They used DNAnexus' platform to share the de-identified data with their all of the researchers involved in the trial — the company made its infrastructure available for free to the ITOMIC consortium.
This is exactly the sort of project that the DNAnexus platform was designed for, according to David Shaywitz, the company's chief medical officer. "For precision medicine to have any meaning, it's not just the raw data, its being able to collaborate and get the shared knowledge that a researcher at one place has [with] a researcher at another place," he told GenomeWeb. "A platform that enables data and people to be brought together in a common place ... is going to be the best way to drive the science and the medicine."
Researchers used three mutation-calling methods to analyze the patient's sequence information. Specifically, investigators at UW ran the data through MuTect, a Broad Institute-developed method for identifying somatic point mutations in cancer. Meanwhile researchers at the University of California, Santa Cruz used a computational method that they developed, called RNA and DNA Integrated Analysis (RADIA), which uses a combination of patient-matched normal and tumor data with tumor RNA to detect somatic mutations.
Lastly, Data4Cure used its proprietary methods to analyze the data including a new ensemble variant calling pipeline that it added to its platform in the last year, Janusz Dutkowski, the company's co-founder and CEO, told GenomeWeb. Data4Cure markets a cloud-based platform that lets users combine and analyze omics datasets to better understand the activities of genes and pathways in diseases. Participating in the ITOMIC initiative appealed to Data4Cure because of the different kinds of data involved and the experimental design. "There is a lot of data and there are rich datasets ... taken at multiple time points which makes it really interesting for analysis and finding interesting somatic mutations and variants in the data," Dutkowski said. The project also offered an opportunity to test some of the new capabilities that the company was developing for its platform, he added.
Based on their efforts, the investigators came up with two possible treatments to which they thought the patient's tumor might respond. One of these is the drug crizotinib (Pfizer's Xalkori), which the US Food and Drug Administration has approved to treat some forms of lung cancer. The reason for suggesting this as a potential treatment is that the researchers found a mutation in ROS1, a gene associated with non-small cell lung cancers, in the patient's tumor. Previous studies have shown, according to the JNCCN paper, that some two percent of non-small cell lung cancers mutations in ROS1 are susceptible to crizotinib.
Crizotinib costs nearly $10,000 per month. Since the drug is not approved for treating breast cancer, the patient's insurance company refused to pay for it. Furthermore, the ROS1 mutations observed in NSCLC always occur in the context of fusions, but almost never as point mutations as was the case of the ITOMIC patient, Blau added — they only found one lung cancer patient mentioned in the literature with this specific point mutation.
The ITOMIC group consulted with an expert in ROS1 mutations who thought that crizotinib might be effective. "He thought that this point mutation might prevent the binding of an E3 ubiquitin ligase that would degrade the protein and ... that there was a chance that this point mutation might result in persistence of the protein in the cell [resulting] in higher-level activity of the protein [that] might confer susceptibility to crizotinib," Blau explained.
Unfortunately, the tumor did not respond to the new treatment: in fact, the patient's condition worsened. But the attempt did yield valuable data that will hopefully benefit future patients. "What we've done in essence is close a learning loop; 'you have a prediction, you tested it, it was wrong, and you record that instance,'" Blau said. It does not mean that another breast cancer patient with a similar mutation would not respond to crizotinib. "We don't know enough about what's going on ... but I would say that if you did this two or three or four times and it consistently didn't work, you might at some point lose enthusiasm for that approach."
The ITOMIC analysis also turned up a second treatment option. By screening circulating tumor cells from the patient against a 160-drug panel, the researchers found evidence that the tumor might respond to two drugs that are inhibitors of the B-cell lymphoma 2 gene. These drugs are currently in phase III clinical trials for hematological malignancies with a TNBC-specific clinical trial planned for the future, Blau said. However, efforts to obtain these drugs from the pharmaceutical developer failed and the patient died.
"It's really a lost opportunity," Blau said. "We had a reasonably strong suggestion that she might respond to the drug and if we had been able to get access to it and she had responded, that might help inform the drug company about how they might proceed with their clinical trial."
Blau said that the ITOMIC team plans to publish more results from its trials. It also plans to share the expert opinions it has gathered for each of the ITOMIC enrollees via an open-access platform that will be available to cancer researchers and clinicians. The group currently has a prototype of the system up and running called the Tumor Crowd Modeling platform that is currently being used to post patients' results, with their consent, for review and comment by oncologists and clinicians.
Blau also said that group would be willing to share the raw data that they have stored on the DNAnexus cloud with interested researchers. "I think as we publish our first 12 patients, it will go on to more conventional databases. But if anyone wants to see our data now, I'm happy to share it," he said.
The group is also applying for federal research dollars to support more single-patient investigations. To date the project has largely been supported by grants from foundations and private donors "It's been hard to get traction in federal funding without having preliminary data [but] I think now, after having enrolled 12 patients, we are in a better position to be competitive for traditional grants," Blau said.