Lung Cancer Treatment on Brink of New Molecular Era

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Although testing for EGFR mutations and ALK rearrangements in patients with NSCLC has become widespread, the time has come to translate into clinical practice next-generation sequencing assays that provide exponentially more information about tumor biology.

Maria E. Arcila, MD

Although testing for EGFR mutations and ALK rearrangements in patients with non—small cell lung cancer (NSCLC) has become widespread, the time has come to translate into clinical practice next-generation sequencing (NGS) assays that provide exponentially more information about tumor biology, according to Maria E. Arcila, MD.

“New molecular diagnostic technology will change the diagnosis and treatment of lung cancer, ” Arcila, acting director of the Diagnostic Molecular Pathology Laboratory at Memorial Sloan Kettering Cancer Center, said during a presentation at the 9th Annual New York Lung Cancer Symposium Saturday.

Arcila cited a number of advantages offered by commercially available NGS services, ranging from the conservation of biopsy tissue to the conservation of caregiver time, but said the primary benefit was therapeutic. NGS finds relevant mutations in a highly heterogeneous malignancy that single-mutation tests and multiplex sequencing are not designed to ascertain.

“For patients who are negative by all other testing, you can find genetic alterations that may be targetable,” said Arcila, who noted that the FDA has approved the use of 20 biomarkers in cancer diagnostics and treatment.

“You can treat directly with agents that are approved to treat these mutations, or, with promising agents that are not yet approved, you may be able to get access in the setting of a clinical trial,” she said.

Arcila said she often hears doctors object that there’s no practical use right now for most of the information that NGS provides. They get mountains of data that obscure the small amount of information that really matters.

Arcila conceded that it can be hard to pick out valuable information from pages filled with genetic sequences and pathway analysis, but said that there’s no other way at present to get all the relevant data.

Moreover, she continued, the complexity of the readouts is offset by the simplicity of the process. Practices send a single sample to a single lab rather than cutting tissue up and sending it to different places. Better still, newer tests cost about the same as pair of simpler tests that provide no information about anything beyond EGFR mutations and ALK translocations.

The move from single-mutation tests to those that measure dozens of biomarkers also makes better use of the biopsy tissue and reduces the need to do repeat biopsies, a key consideration in lung cancer since tissue for testing is often difficult to obtain, Arcila noted.

Nevertheless, Arcila noted that NGS testing as a clinical tool remains a work in progress.

“There is high variation among platforms right now, so you have to know what kind of information each assay will give you,” said Arcila.

She said NGS testing could mean custom panels with amplicon capture, custom panels with hybridization capture, whole exome sequencing, or whole genome sequencing.

She said that tests evolve frequently, so oncologists should double-check frequently and then to make sure that particular multiplex assays still offer whatever information they want.

For the most part, however, changes tend to bring more information rather than less. A multiplex assay that Memorial Sloan Kettering has developed, for example, is about to increase the number of cancer genes it checks from 341 to 420.

Another frequent problem with NGS is speed. It often takes 2 to 4 weeks to get results—far longer than clinicians typically want to wait for vital data about EGFR and ALK aberrations. Test developers are working to speed up the process, but doctors who want the extra information but don’t want to wait for the basics must currently order both the single-mutation tests and a new one.

Another potential issue, getting reimbursement for the cost of testing, should become easier when the New Year arrives. Companies and institutions that offer NGS tend to bill as if they were providing a number of single-mutation tests, Arcila said, but a new reimbursement code for the new breed of tests will take effect on January 1.

“Biomarkers in current practice are simplistic. They underestimate the high complexity of cancer,” Arcila said. “Today, patients who exhibit EGFR mutations get EGFR TKIs, while patients who exhibit ALK rearrangement get ALK inhibitors. Future algorithms will not be based on this one-to-one relationship.”

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