NEW YORK – St. Jude Children's Research Hospital is ramping up a global effort to bring low-cost genomic sequencing to hospitals in low- and middle-income countries for diagnosing pediatric patients with blood cancers.
The effort is part of St. Jude Global, an initiative to create a global network of institutions focused on improving access to pediatric cancer care worldwide, and is led by Nickhill Bhakta, director of the Sub-Saharan Africa region for St. Jude Global. Bhakta's team is working to install portable sequencing tools, specifically, Oxford Nanopore Technologies' MinIon DNA and RNA sequencing devices, so doctors can use them to improve the diagnosis and treatment of pediatric blood cancers within hospitals in low- and middle-income countries.
The researchers began the groundwork for this program more than two years ago and are expecting to begin sequencing patients in the first hospital in Pakistan in the next month or two, Bhakta said.
There is a wide disparity in diagnosis and survival rates between pediatric cancer patients in high-income countries and those in low- or middle-income countries. Around 80 percent of pediatric cancer patients survive a cancer diagnosis in high-income countries, while globally the survival rate is around 20 percent, Bhakta said. The lack of access to screening tools in many parts of the world makes it difficult to compare pediatric cancer diagnosis rates, though based on one study Bhakta was part of, he estimated that about half of the children globally that develop cancer go undiagnosed.
There are also gaps in the tests that low- or middle-income countries can afford or have access to. Unpublished data from St. Jude's Pediatric Oncology Facility Integrated Local Evaluation Tool, or PrOFILE, which Bhakta presented at the American Association for Cancer Research's annual meeting earlier this month, showed gaps in diagnostic test access across low-, middle-, and high-income countries. According to the analysis, none of the low-income countries included in the dataset had access to fluorescence in situ hybridization, karyotyping, or PCR for pediatric cancer patients. Low-middle income countries fared slightly better, with just under half having access to PCR diagnostics, and between 50 percent and 60 percent having access to flow cytometry, FISH, and karyotyping tests.
"There [are] many reasons for that, but one of them is that the diagnostic process for cancer is incredibly complex," he added. "About 90 percent of children live in low- or middle-income countries, and these are health systems that don't have access to the advanced diagnostics that we have, and, frankly, [we] take [them] for granted here in the United States."
Validating a nanopore sequencing classifier
Last week, Bhakta and other researchers from St. Jude, University of North Carolina, Chapel Hill, and other institutions published a proof-of-concept study in JCO Precision Oncology showing that nanopore sequencing data from Oxford Nanopore's MinIon device could be used to classify genomic subtypes of acute leukemia and help physicians differentiate between acute myeloid leukemia (AML), B-lineage acute lymphoblastic leukemia (B-ALL), and T-lineage acute lymphoblastic leukemia (T-ALL).
In the paper, researchers described using nanopore sequencing and a machine learning-based classification tool to analyze long-read RNA sequencing data in 134 acute leukemia samples from the University of North Carolina, St. Jude, and the ECOG-ACRIN Cancer Research Group. They then developed a classification method to predict the subtypes directly from these gene expression profiles. Using this nanopore sequencing-based method, researchers classified 25 out of 26 (96 percent) of AML cases accurately. With this method, they were also able to correctly classify 64 of 68 (94 percent) B-ALL samples, including identifying patients with favorable prognostic subtypes such as ETV6-RUNX1 and high-hyperdiploid cases; and negative prognostic subtypes like KMT2A-rearranged, hypodiploid, and BCR-ABL1-positive or Ph-like cases.
In resource-strapped areas that have very few diagnostics tools, Bhakta said doctors have to rely on "guesswork" to determine whether a patient has AML or ALL based on clinical features, and figure out how quickly their patients' cancers are proliferating. Often, these cancer centers will go with a high-toxicity treatment upfront on every patient to avoid the risk of relapse, but then may lose patients due to the toxic side effects.
Within St. Jude Global, Bhakta and his colleagues began exploring nanopore sequencing after seeing it used globally by UNC's infectious disease group. While it was not commonly used for cancer diagnostics, the team "took a leap of faith" to explore it as a low-cost option to get basic genetic information, he said.
"We don't need to know every detail, we just need to know [if patients have] AML versus ALL," he continued. "We could even get a little bit more, like risk stratification, so they could potentially de-intensify treatment in some settings. If a hospital doesn't have access to [hematopoietic stem cell transplantation], they only have one shot at treatment."
There are similar challenges diagnosing pediatric solid tumors in low- and middle-income countries as well.
Bhakta and colleagues are also exploring a nanopore classifier for tumor tissue samples to differentiate between cancers like Ewing sarcoma, neuroblastoma, or rhabdomyosarcoma, or to classify high- versus low-risk patients.
In St. Jude's bid to improve access to genomic sequencing for pediatric blood cancers globally, the institution has recognized that hospitals in low-income countries may not have access to the powerful computers needed to analyze RNA data, and therefore, it is also making its cloud computing services available to local pathologists so they can analyze the sequencing results and quickly turnaround reports. St. Jude Global also conducts virtual molecular tumor boards with partner hospitals to help physicians interpret these reports.
Implementing precision oncology tools
With the sequencing method and classifier established, the next step is implementing the process in these hospitals. Bhakta highlighted that the Indus Hospital and Health Network in Karachi, Pakistan will be the first place where young patients with blood cancer will have access to genomic sequencing through this effort, and noted that his team is working to do the same at partner hospitals in Guatemala, Brazil, Uganda, and other countries.
While the challenges of implementation vary between countries, regulations are a common barrier for an effort like this. St. Jude must comply with each country's laws governing the privacy of genetic information and the exchange of DNA data internationally, especially if the hospitals plan to use St. Jude's cloud computing software to analyze sequencing data.
Furthermore, upfront costs for sequencing samples, including reagent costs, may be prohibitive for some institutions if they have limited patient volume. A benefit of nanopore sequencing is its low cost relative to other platforms. The MinIon device costs about $1,000 and can be run in small batches on either frozen or formalin-fixed, paraffin-embedded (FFPE) tumor tissue or blood samples, Bhakta said, estimating that in can cost as much as $200,000 to install a more comprehensive sequencing platform.
"Illumina and other platforms are built for multiplexing because people are trying to do high-throughput, whereas nanopore lets us do low-throughput at a reasonable price," Bhakta said. "That's important because childhood cancer is rare, so you may get only one or two diagnoses a week and it could take four or five weeks to pool enough samples to use any of the other high-throughput platforms. By being able to [analyze a] single sample or a couple of samples at a time, it lets us use the resources efficiently."
The team must also consider the needs of each hospital and tailor the effort accordingly. For instance, some hospitals in low- or middle-income countries may be sending samples for flow cytometry or even molecular analysis to labs in other countries. But other hospitals, particularly those in Sub-Saharan Africa, don't even have the basic tests needed to accurately diagnose the leukemia type, Bhakta said.
"There's multiple levels to consider as we go in and start working with hospitals," Bhakta said. "We're starting with nanopore, but [it] is one solution. From an equity standpoint there are upper-middle income countries that could benefit from an Illumina sequencing platform. That's not to deny the importance of that for centers that have [stem cell] transplant capabilities or may have genetic predisposition centers and that want that deeper data."
Once the researchers have shown proof-of-concept with nanopore sequencing, Bhakta suggested they may employ similar efforts to expand access to other sequencing platforms for more in-depth analysis for hospitals that want to expand their capabilities.
While access to targeted therapies is not expressly part of this project, Bhakta hopes getting more genomic sequencing capabilities into low- and middle-income countries will help on this front, too.
He acknowledged there's a "vicious cycle" of access issues between sequencing tools and targeted therapies. The hospitals in low- and middle-income countries can't identify which patients will benefit from targeted therapies because they don't have the sequencing tools needed, but these advanced diagnostics won't be utilized to their fullest extent if patients in these countries can't access the targeted therapies in the first place, he said.
In December, St. Jude separately partnered with the World Health Organization (WHO) for a program to increase access to childhood cancer drugs in lower middle-income countries. That program dedicated $200 million over six years to develop purchasing structures and a global fund to help hospitals in low- and middle-income countries afford novel targeted therapies.
By addressing disparities in access to basic cancer diagnostic and targeted treatments first, these low-resource hospitals can begin to move toward a future where precision oncology is more readily available to pediatric cancer patients.
"We can then start advocating for additions to the essential medicines list or the essential diagnostics list," he said. "If we can say we have the diagnostics in place, [then we can ask] why aren't certain targeted therapies on the essential medicines list when we've shown they have efficacy for these [blood cancer] subtypes, and they potentially could have impact in these countries? Then, suddenly the game changes, and we break that vicious cycle to an extent."