NEW YORK – The first phase of France's Genomic Medicine Plan 2025 will wrap up this year, but the effort, which has introduced whole-genome sequencing for patients with rare diseases and cancer nationwide, is far from over, according to its organizers.
Discussions are now underway within the French government as to where to steer the initiative next, with questions on the table such as how to best distribute sequencing resources throughout the country, what disease categories to address, how to manage issues related to variants of unknown significance, and what diagnostic strategies to employ.
"The consensus in France is to continue," said Frédérique Nowak, the operational coordinator of the initiative, who is based at Inserm, France's National Institute of Health and Medical Research. "There will not be a sharp end at the end of 2025," Nowak said.
France embarked on its plan, shorthanded as PFMG2025, a decade ago when the government proposed a plan to establish access to genetic diagnoses in France and called for a 10-year prospective review. The initiative formally commenced the following year. According to Nowak, France was partially inspired by the launch of the UK's 100,000 Genomes Project in 2012.
The results of the endeavor to date were outlined last month in an article in the Lancet Regional Health. As of Dec. 31, 2023, the French government had invested €239 million (about $250 million) in its plan. Nowak said money has since continued to flow into the effort from various government sources and could not provide an updated investment figure.
As noted in the article, the government decided to focus on patients with rare diseases and those with a genetic predisposition to or currently with cancer. To offer sequencing to these patients, two laboratories were established within the country: one called SeqOIA in Paris to serve patients in the north of France and another called Auragen in Lyon to serve the south. According to Nowak, both facilities began to offer sequencing services in mid-2020 following the first COVID-19 pandemic lockdown, which lasted from March to July.
Nowak underscored that there were organizational challenges in implementing sequencing within the French healthcare system to serve the country's 67 million people. While healthcare in France is centralized, organizers had to ensure equal access to the genomic analyses provided, make the platforms economically sustainable, and demonstrate medical benefits for the patients undergoing sequencing.
Aligning with France's eternal focus on "liberté, égalité, fraternité," organizers worked to ensure equal access by providing genome sequencing free of charge for patients and by guaranteeing nationwide coverage by having the new labs serve agreed-upon areas with France, including its overseas territories. This took time and involved defining genomic healthcare pathways for each indication, as well as a correlated diagnostic strategy. The organizers also needed to agree upon lab protocols, integrate international best practices, and draft model reports for clinical biologists.
In general, the organizers view the outcome as positive. As of Dec. 31, 2023, they had returned 12,737 results to patients with either rare diseases or a genetic predisposition to cancer. The median delivery time was 202 days, and the diagnostic yield was about 31 percent, which Nowak said is in line with what a literature review concluded researchers should expect to see.
Orders for cancer genome sequencing were about a quarter of the laboratories' test volume. Altogether, 3,109 cancer patients had their tumors sequenced within about three years of operation, with a medium delivery time of 45 days. In the paper it was noted that organizational changes in 2022 and 2023, including the creation of genomic pathway managers, led to a spike in new orders for whole-genome sequencing, as they grew by about 50 percent year over year.
Still, the organizers said that about 420,000 new cancer patients were diagnosed between 2020 and 2023, meaning that the amount of orders for sequencing were a drop in the bucket.
"For rare diseases, it has been a great success," said Nowak. "But for cancers, it has been more complicated, as it is ordered less than for rare diseases," she said.
One issue facing the initiative is that tumor tissue samples are preserved in different ways throughout France, with some clinicians relying heavily on formalin-fixed, paraffin-embedded samples. As of November 2023, such samples have been sequenced according to best practices.
Another issue in general is that clinical geneticists continue to be the source of most orders for sequencing, accounting for about 70 percent of orders. According to organizers, more clinicians need to be educated to integrate sequencing into their practice, especially as the government considers adding complex diseases to the menu.
The project's organizers also seek to improve diagnostic yields. In the article, they suggested developing functional assays to classify variants of unknown significance as well as improving the genetic diversity of France's databases so that they are more representative of the population. This could help to improve the performance of polygenic risk scores and other tools that assess cancer genetic predisposition.
Finally, the capacity of the SeqOIA and Auragen laboratories is also an issue, though Nowak said the implementation of new sequencing instruments at both sites has helped to address this. SeqOIA currently has four Illumina NovaSeq 6000 and two NovaSeq X instruments. Nowak said that capacity could be increased at the existing labs, or labs could be set up in other regions of France, noting that "these are political questions."
As PFMG2025 is government-funded, it will be up to France's Ministry of Health and Ministry of Research to lay the groundwork for the second phase of the initiative by setting up working groups.
"We will see if we will broaden the scope of the initiative," said Nowak, "and if we will interrogate complex diseases and integrate different technologies along with sequencing."
Amaury Martin, the deputy director of Institut Curie and coordinator of the SeqOIA laboratory, said that the main difficulty facing organizers is not technological or financial but organizational. He said that setting up sample recovery hospitals, having these samples sequenced, and then having them analyzed by medical biologists, with reports returned, remains an "arduous task."
"For cancer in particular, tumor analysis must be carried out within a time frame compatible with therapeutic decision-making, such as between two and four weeks, which is possible but difficult to organize," Martin commented. He also noted that in the majority of cancer cases, whole-genome sequencing is not necessary, and that relying on targeted panels is "very useful."
Looking ahead, Martin said that organizers aim to offer sequencing to as many cancer and rare disease patients as possible. To do so will require different approaches. "We could, for example, move towards in silico panel approaches and then, depending on the mutations identified, carry out a complete genome analysis or, on the contrary, just an RNA-seq," he said.
As in every field, artificial intelligence is looming, and could speed up genome analysis, Martin said, especially given the shortage of medical geneticists. Discussions are also ongoing about moving patients who are sequenced into clinical trials.
Finally, data-sharing issues loom. "The data generated must be able to be studied as widely as possible and matched with other local or international databases," said Martin, "which raises the question of system interoperability and differences in regulatory regimes."
This latter issue is being addressed in part through France's participation in the 1+ Million Genomes initiative, a European endeavor to make whole-genome data shareable to researchers around the region. France is now a full member of the initiative and "very active," Nowak underscored, and is taking part in its Genomic Data Infrastructure (GDI) and Genome of Europe (GoE) projects.