Seeing Cancer in Its DNA: The Origins of Precision Medicine

« Great advances in oncology » – Episode 3/4. Now considered indispensable in oncology, molecular profiling of tumours is one of the cornerstones of precision medicine. As early as 2011, three physician-researchers at Gustave Roussy outlined its key principles in an article published in the Journal of Clinical Oncology, with a clear ambition: to direct every patient towards the targeted therapies best suited to their disease.

In 2011, oncology was at a turning point. For several years, the success of certain therapies had demonstrated that it was possible to treat cancer by targeting some of its molecular characteristics. For researchers and clinicians, one question therefore became unavoidable: how could they identify, in each patient, the genetic abnormalities that might be targeted by these new treatments?

“At the time, we were seeing a growing number of targeted therapies being evaluated in Phase I clinical trials. However, the techniques available for directing patients towards the right treatment could only sequence one gene at a time, whereas we needed to sequence the entire tumour to identify all actionable alterations. These new therapies were excellent news for patients, but they also presented a major diagnostic challenge,” recalls Professor Fabrice André, Director of Research at Gustave Roussy.

Indeed, as new mutations continued to be identified, it became impossible to investigate them gene by gene in individual patients. At the same time, clinical trials continued to enrol very large patient populations, even though some alterations were present in only a small proportion of patients. For oncologists, another question was increasingly pressing: how could the right patient be identified quickly for the right treatment?

A pioneering publication

To address this issue, Professor Fabrice André, Dr. Suzette Delaloge and Professor Jean-Charles Soria, then all physician-researchers at Gustave Roussy, set out to consolidate the emerging knowledge in a landmark publication. Their objective was to draw lessons from recent advances in molecular biology and propose a new model for selecting patients for clinical trials. On 1 April 2011, the Journal of Clinical Oncology published their article, Biology-Driven Phase II Trials: What Is the Optimal Model for Molecular Selection?[1]

“The central idea of this article was to translate genomic research tools into clinical practice, enabling a much more rapid and comprehensive mapping of tumours for each patient. Initial experiments had already shown that high-throughput technologies could simultaneously analyse a large number of genetic alterations present in a tumour. The publication proposed a paradigm shift: moving away from an approach based on a handful of isolated biomarkers towards a broader analysis of the tumour’s molecular landscape,” explains Professor Fabrice André.

Today, this approach is one of the foundations of precision medicine. However, in 2011, neither the value of analysing large numbers of genes nor the need to understand the biology of disease for diagnostic purposes had yet been established. By advocating the systematic molecular profiling of tumours to guide access to innovative treatments, Gustave Roussy became one of the first centres to formalise this paradigm shift, one that would profoundly transform both oncology research and patient care.

The first clinical applications

By the time the article was published, the vision it promoted was already beginning to take shape in clinical research. In 2010, Gustave Roussy launched its first multidisciplinary molecular tumour board dedicated to patients with metastatic lung cancer. The aim was to discuss cases in which tumours displayed mutations of interest and to direct patients towards the most appropriate targeted therapy or clinical trial.

At the same time, the Institute initiated several research programmes designed to evaluate the value of high-throughput tumour sequencing. Among them was the SAFIR01 study, launched in 2011, which subsequently demonstrated[2] that large-scale molecular profiling of metastatic breast cancers could be carried out to direct certain patients towards suitable targeted therapies.

Also launched in 2011, the MOSCATO study pursued the same ambition among patients with advanced cancers of various types. Between 2011 and 2016, more than a thousand patients were enrolled in the programme. The results, published in Cancer Discovery[3] in 2017, provided some of the first prospective evidence suggesting that large-scale molecular profiling is not only feasible within clinically relevant timeframes, but can also improve survival for a proportion of patients with advanced cancers.

“I remember setting up, with Unicancer, the first national molecular boards. As part of the SAFIR trials, we met every Tuesday evening to review cases of patients whose tumours had been sequenced, in order to determine whether a mutation or copy number alteration could be acted upon therapeutically. It was one of the defining moments of my career, when I felt I was taking part in something genuinely innovative. This weekly meeting marked a new way of practising medicine, based on understanding the disease itself. We felt we were paving the way for an approach that we already sensed would become a lasting feature of oncology,” recalls Professor André.

A story that continues

Fifteen years after its publication, the 2011 article now appears as a record of a pivotal moment. Its authors did not predict the disappearance of traditional oncology but rather the emergence of a new perspective for understanding disease more effectively. Subsequent developments proved them right. Molecular oncology has gradually established itself as a major component of cancer care without replacing existing therapeutic approaches. “In the end, we found the right balance,” says Professor André today. The challenge for the future is to develop classifications based on biology, potentially independent of the organ of origin[4].

This vision now continues through the PRISM University Hospital Institute (IHU PRISM). The ambition remains fundamentally the same as that expressed in 2011: to understand each cancer in all its biological complexity, alongside its clinical complexity, in order to tailor treatment as accurately as possible for every patient. Whereas the work at the time focused primarily on genomics, current approaches now incorporate additional biological dimensions, particularly at the cellular level. The IHU is the direct heir to the vision formulated fifteen years earlier: to acquire the most detailed possible understanding of each tumour to better comprehend the disease and build the medicine of tomorrow.