Tumor profiling: Shifting from DNA to RNA sequencing

Personalized biopsy-driven treatment based on DNA sequencing has been tested in various settings for over ten years. Unfortunately, the response rate is disappointing, with only a small percentage of patients displaying a DNA alteration that can be used to identify a useful therapy for them. A recent study shows that profiling RNA, instead of DNA, allows the more advanced cancer patients to benefit from personalized therapies, compared to the standard analysis of DNA alterations alone.

All healthy human body cells (more than 10,000 billion) share the same genes. What differs from one tissue to another and therefore from one cell to another is the expression of these genes. A gene can be compared to a word in the genetic code: it is quite schematically a functional unit of the genome.  A human gene contains between 500 and several thousand bases, the famous A, T, C and G letters. It is estimated that our genome contains around 19,000 to 22,000protein-coding genes, which represents a total of around 3.2 billion base-pairs.

A cancer cell, independently of its tissue of origin, is a cell whose genome is seriously and irreversibly altered. It has become an unruly cell, both morphologically and behaviorally: it is insatiable (feeding on sugar and oxygen), aggressive and invasive. The genome of a cancer cell is, therefore, a corrupt version of that of our own healthy cells: from mutation to mutation, cellular DNA changes until it has the characteristics of an irreversible unpredictable genome.

No two cancers are the same. There are a large number of possible genetic mutations for a tumor. Each tumor, therefore, each patient, is unique and treatments must be individualized. DNA sequencing performed on tumors makes it possible to shed light on genetic mutations that may cause the appearance and multiplication of cancer cells. Precision medicine aims to target these specific genetic differences that may cause the development and progression of cancer. It doesn't matter which tumor, as long as the genomic analysis identifies the genetic alteration whose effect, can then be modulated by a given treatment. Precision medicine has the advantage of inducing fewer side effects as the most effective and/or best tolerated treatment will be chosen based on the tumor genome. Precision medicine means offering the right treatment at the right time for the right group of patients.

Personalized biopsy-driven treatment based on DNA sequencing has been tested in various settings for over ten years. Unfortunately, the response rate is disappointing, with only a small percentage of patients displaying a DNA alteration that can be used to identify a useful therapy for them.

In the SAFIR-01trial testing the effectiveness of using DNA analysis for therapeutic decision, Dr. André and colleagues biopsied metastatic lesions from 423 breast cancer patients, and performed DNAbased molecular characterization of the tumors. A precision therapy could be used in only 55 patients (13% of all patients in the trial). In another clinical trial, IMPACT (Initiative for Molecular Profiling and AdvancedCancer Therapy), testing the use of DNA for identifying the optimal therapy, DNA analysis was carried out on the tumors of 3,743 patients. Of those, for only 711 (19% of all patients) the analysis led to the identification on a therapy adapted to their specific genetic alteration.

To date, most clinical trials testing the ability to select therapies using DNA profiling only have shown that potential treatments could be identified for only 5% to 25% of patients.

Although DNA is the carrier of our genetic code, it is the proteins that are key cellular entities, responsible for driving the majority of cellular activity. Genes encoded in DNA are used as a recipe for making individual proteins. RNA is used in cells as an intermediary, enabling the cells to translate genes into proteins. Most approved drugs exert their function by binding to and modifying a protein(s) function.

DNA testing attempts to identify a number of genomic alterations that impact proteins. However, if a mutation is present in a gene that is not expressed, it is unlikely to lead to a defective protein. Drugs targeting that specific protein may therefore have no therapeutic benefit.

This and the lack of known links between most DNA alterations and the effect of drugs could explain the low success rate of Precision Medicine based only on DNA sequencing.

A recent study published on April 2019 in the journal Nature Medicine shows that profiling RNA, instead of DNA, allows more advanced cancer patients to benefit from personalized therapies, compared to standard DNA sequencing tests.

The goal of this study (the WINTHER trial) was to test the effectiveness of using DNA and RNA analysis for therapeutic decision. A total of 107 advanced multi-resistant metastatic patients (including 25% that had received and had been found to be resistant to five or more therapies) were biopsied and both DNA (using Foundation One™panel) and RNA analysis were performed. If an actionable DNA alteration was identified, it was used for therapeutic decision. If not, RNA was used as a backup to provide a therapeutic recommendation for all remaining patients.

The study showed that in thecontext of the WINTHER trial, 40% of patients did not have a therapeutic recommendationusing DNA profiling only, whereas with RNA profiling, a therapeuticrecommendation could be provided for all patients. Due to the small samplesize, the numbers were not statistically significant, however the studyrevealed that the overall survival of patients treated based on the  RNA analysis was 45% higher than thosetreated based on the  DNA.

Overall he study demonstrated that the use of RNA expression can be used to effectively expand patients’ treatment options.

Deciphering tumor’sRNA should make it possible to bring more actionable insights to each individual patient.