A retrospective analysis of patients with advanced non–small cell lung cancer treated in community clinics found no benefit of broad genomic testing over routine testing for abnormalities in EGFR and ALK. However, the reason may have more to do with patients not receiving targeted therapy than with any inherent flaws in genomics-guided precision medicine.

Broad-based genomic testing may not be all it's cracked up to be. According to a large retrospective analysis in the United States, survival outcomes for patients with advanced non–small cell lung cancer (NSCLC) were similar whether their disease was profiled for dozens to hundreds of cancer-related genes via next-generation sequencing (NGS), or routinely evaluated for common EGFR and ALK alterations only (JAMA 2018;320:469–77).

Lead author Carolyn Presley, MD, of The Ohio State University in Columbus, and her colleagues wanted to probe the question: Does more genetic information yield better outcomes for patients? They dug into the Flatiron Health database, a longitudinal collection of clinical and genetic records, focusing on 5,688 patients with inoperable or metastatic nonsquamous NSCLC treated at 191 community oncology practices between 2011 and 2016.

The researchers compared the outcomes of two groups: 875 patients who underwent broad sequencing of 30 or more genes, and another 4,813 patients who were tested for EGFR mutations and ALK rearrangements only. Looking at 1-year mortality rates or at a survival score that corrected for differences in patient characteristics between the two groups, they reported that NGS-based multigene testing yielded no statistically meaningful benefit over routine EGFR/ALK profiling.

“Testing for many more genes is not translating into a survival difference,” Presley says.

The findings suggest that “we should temper our breathless enthusiasm” for genomics-guided precision medicine, says H. Jack West, MD, of the Swedish Cancer Institute in Seattle, WA, who was not involved in the research. However, he adds, the study is “not a castigation of NGS.”

If anything, Presley notes, it's a “wake-up call” that oncologists need to more proactively use genetic data to match patients to targeted therapies. The problem is not the type of test, she says. “The problem is what's happening after testing is done.”

As Dara Aisner, MD, PhD, of the University of Colorado in Denver, points out: “You can only expect the testing to provide benefit if it's being acted upon.” Among the patients for whom broad sequencing identified alterations in ROS1, MET, BRAF, ERBB2, NTRK, or RET—all known drug targets—only 27% received genomically informed therapy. Use of targeted therapy was only a little better among those with more common ALK or EGFR defects—41% in the same group that received NGS testing.

Presley suspects that cost considerations are precluding patients from getting the personalized therapies they need. “Targeted treatments are prohibitively expensive for most patients,” she says.

Both Aisner and West, who each penned commentaries on the article, point to one limitation of Presley's study that could make the findings already obsolete (JAMA 2018;320:445–6; JAMA Oncol 2018 Aug 16 [Epub ahead of print]). During most of the time period considered, the only targeted therapies approved for NSCLC were those directed against EGFR and ALK—so it's perhaps no surprise that multigene sequencing had limited utility, especially in community clinics where patients have limited access to clinical trials for experimental agents.

Since 2016, however, the FDA has approved therapies for patients with ROS1- and BRAF-mutant NSCLC, and there are at least half a dozen more actionable targets for patients with access to drugs off-label or through a clinical protocol. The benefit of broad genomic testing in NSCLC could therefore “be a little different now,” West says. “It's really just a matter of when we'll get to that tipping point” of NGS-based profiling leading to better outcomes. –Elie Dolgin

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