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Mayo Study Highlights How Concurrent NSCLC Mutations May Complicate Genetic Testing Strategies

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A small Mayo Clinic study has added new data to a growing body of evidence that mutations in EGFR and other genes do occur concurrently with ALK rearrangements in non small-cell lung cancer, although relatively infrequently.

In 25 ALK-positive patient samples, the group found five overall to have a second mutation: one in EGFR, and four in MET.

According to the researchers, whose study appeared in the Journal of Thoracic Oncology this week, the presence of these double mutants — though rare — in the overall lung cancer population creates challenges in deciding on appropriate molecular testing strategies, such as whether it is appropriate to use clinical or pathological features to limit the number of patients who are tested, or whether testing positive for either ALK or EGFR should preclude additional testing for the second gene.

Recently released guidelines from The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology support testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an EGFR or ALK inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and recommend prioritizing EGFR and ALK testing over other molecular predictive tests (PGx 4/10/2013).

However, these recommendations counter some research that has found that administering ALK testing without the help of enrichment strategies to home in on patients who are more likely to harbor such rearrangements may not be cost-effective.

In the study, the Mayo researchers used an array-based screening panel to gauge 179 mutations in 10 genes in 25 tumor samples confirmed to be ALK positive by FISH. The array-based screening panel gauged mutations in EGFR, KRAS, BRAF, JAK2, AKT1, AK2, KIT, MET, and PIK3CA.

According to the Mayo study authors, the true incidence of coexisting EGFR and ALK mutations is still unknown. In the group's study, one of the 25 ALK-positive cases, or 4 percent, showed a mutation in EGFR. Previous studies the group cited have found other single incidences in similarly small cohorts— one in 12 ALK-positive cases in one study, and one in eight in another.

Considering these results, the study authors wrote, it seems that EGFR/ALK double mutants are likely relatively rare, "probably less than 10 percent of ALK-positive cases" overall, but definitely in existence.

Knowledge of EGFR and ALK co-mutated status may have important implications for therapeutic decision-making, the authors wrote as well. Some patients with both mutations have had good responses to EGFR inhibitors, while at least one has shown resistance to such drugs in previous research, according to the study.

More research into whether inhibition of one of these pathways can be effective in the presence of another cancer-implicated pathway will be necessary to determine whether EGFR inhibitors and ALK inhibitors, like Pfizer's Xalkori (crizotinib), should be administered in a sequential fashion or together, the researchers wrote.

In addition to the single EGFR mutation, the study also found four co-occurring MET mutations. Though the clinical and therapeutic importance of co-existing ALK and MET mutations is not yet known, the researchers suggested that this finding could also have implications for therapeutic decision-making, since Xalkori inhibits both ALK and the protein encoded by the MET gene.

According to the Mayo study authors, the development of appropriate testing strategies in NSCLC is "a complicated and controversial issue."

In a paper published in the British Journal of Cancer last year, University of Colorado researchers found that applying an enrichment strategy, where clinicians target testing to patients with certain characteristics that make them more likely to harbor ALK mutations — such as those negative for EGFR mutations — could decrease the cost of testing per quality-adjusted life year gained significantly (PGx Reporter 3/28/2012).

Test makers and drug developers criticized this analysis at the time, pointing out that enrichment strategies would still miss patients who would benefit from targeted treatment.

According to the Mayo team, its recent study results and other emerging data, suggest that "the co-existence of EGFR and ALK mutations would be missed in any algorithm omitting ALK testing in tumors showing EGFR mutation or vice versa." However, the group wrote, "some may argue that the incidence of [these double mutants] is low enough to justify such an algorithm."

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