Acting on “Actionable Mutations”

The new buzzword in personalized cancer medicine is “actionable mutation”. This label is given to the genetic aberrations that are present in some patients’ tumors, and that are intended targets of new drugs. Increasingly, treatment decisions in routine clinical care, and enrollment in trials are being guided by the concept of “actionable mutations”.

However, determining “actionablility” is an ongoing challenge. The function of a particular mutation, to what degree it is responsible for driving a given malignancy, and how easily it can be targeted by a specific therapy, all affect how “actionable” it is. Further, a tumor’s genomic profiling can vary depending on which tissues are biopsied (ie primary and metastatic tumor sites), or when they are biopsied (before and after particular treatment regiments). “Actionability” of mutations may not be a stable variable that is easily transferred from one clinical setting to another. Instead, the concept of actionability invites further clarification on where a when and these genes should be screened.

Unfortunately, lack of clarity on the definition of “actionable mutations” has not prevented its uptake in either the commercial or scientific medical communities. For example, upon physician request, diagnostics company Foundation One will sequence over 300 genes that are known or likely targets of a specific therapy and provide clinicians with a report listing all of their patient’s actionable mutations. These are mutations they define as all those that can be targeted by both therapies currently approved for their indication as well as those approved for other malignancies (off-label). Further, some mutations are designated “Equivocal” signifying that there is some, but not confirmed evidence, supporting an aberration in a patient’s sample, or “Subclonal” where an abnormality only exists in less than 10% of a patient’s tumor. However, absent clear guidelines or standards surrounding actionable mutations it can be extremely difficult for oncologists to interpret these often ambiguous results.

A number of next generation clinical trials currently underway are allocating patients to treatment arms using similar targeted strategies. Basket trials, like the NCI MATCH study, are assigning mixed-malignancy, advance cancer patients, to off-label targeted therapies based on the presence of “actionable mutations”. However, here too some concerns have been raised. There is little consensus on how to prioritize certain mutations over others – both in terms of their functional importance and rarity – and has raised issues in dealing with patient’s harboring co-mutations and optimizing allotment to ensure sufficient patient accrual to different arms.

These concerns along with the results of a recently published basket trial in the New England Journal of Medicine should lead researchers and physicians to be cautious in blindly treating “actionable mutations”. The phase 2 study looking at Vemurafenib in BRAF V600 mutation positive nonmelanoma patients found variable response among different malignancies – indicating that genomic signatures should not be the only factor playing into treatment selection.

In efforts to give some clarity to the current situation a couple of collaborations have been recently undertaken. Founded in late 2014, The Actionable Genome Consortium, is a collaboration of biotech company Illumina and four leading cancer centers (Dana-Farber Cancer Institute, Fred Hutchinson Cancer Research Center, MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center) with the goal to define the “actionable cancer genome” and create robust standards for next-generation sequencing and treatment decision making.

Another initiative, TAPUR (Targeted Agent and Profiling Utilization Registry), led by ASCO, is a prospective, observational, non-randomized clinical study that will track the off-label performance of commercially available targeted drugs in advanced cancer patients. These therapies are commonly prescribed off-label. However, this will be the first attempt to aggregate data to determine the usefulness of this strategy in regards to targeting actionable mutations.

In time these initiatives should go a long way in drawing the boundaries around “actionable mutations.” In
the interim, however, practicing oncologists and researchers alike are left wondering how, exactly, to interpret the “act” in “actionable.”

2015 September 30 | Leave a comment

@Manual{stream2015-842,
    title = {Acting on “Actionable Mutations”},
    journal = {STREAM research},
    author = {Brianna Barsanti-Innes},
    address = {Montreal, Canada},
    date = 2015,
    month = sep,
    day = 30,
    url = {http://www.translationalethics.com/2015/09/30/acting-on-actionable-mutations/}
}