AMSTERDAM – A commercially available gene-expression test significantly improved discrimination between low- and high-risk stage I and IIa lung cancer patients in a pair of validation tests, leading investigators to propose routine use of the test to identify early-stage patients who should get adjuvant chemotherapy.
"The multigene assay can outperform conventional risk factors and staging, and may lead to personalized therapies for patients with early-stage nonsquamous non–small cell lung cancer," Dr. Johannes Kratz said at the World Conference on Lung Cancer.
Dr. Johannes Kratz
Dr. Kratz conceded that no prospective, randomized study has yet tested whether identification of high-risk stage I patients singled out a subgroup that would definitely benefit from adjuvant chemotherapy. But the prognostic information that the genetic test already provides justifies its routine use in stage I and II patients, said Dr. Kratz, a surgeon who performed this study while at the University of California, San Francisco (UCSF), but who is now at Massachusetts General Hospital in Boston.
"I think [the test] is certainly ready for prognosis, to give patients information," he said in an interview. "We’ll start using it routinely for prognosis at UCSF. We believe the strength of the results show it’s ready for prime time. Whether it should also be used to guide treatment, especially for stage I patients, is up to each health care provider, but it opens an interesting possibility before anything is proven in a randomized, controlled trial. The hope is that by identifying high-risk patients, you’ll improve their survival by giving them adjuvant chemotherapy. And in some of the low-risk stage II patients, you can avoid some of the toxicities of adjuvant chemotherapy."
Although several different genetic tests for stage I lung cancer have been studied over the past decade, none have wound up as marketed tests. Dr. Kratz and his associates set out to develop a practical and commercially viable test. They worked in collaboration with Pinpoint Genomics, the company that has now begun marketing the test.
The test they developed uses polymerase chain reaction–based gene expression assays for 11 different genes, based on results from prior studies that identified genes critical to key causal pathways leading to lung cancer. "We took a truly blinded, one-shot approach" in putting together the genetic test panel, without any tinkering during the validation phase to boost the prognostic strength of the test, he explained at the conference sponsored by the International Association for the Study of Lung Cancer. They also focused on tests that use paraffin-embedded specimens.
"I don’t think a prospective validation study is needed" before routine prognostic use of the test begins, he said. The validation studies "were done retrospectively, but in a very controlled way that was equivalent to prospective validation. I think we have powerful evidence that these markers provide additional prognostic information. We’re not saying to abandon traditional staging, but this adds useful prognostic information."
The initial test development cohort consisted of 361 stage I, II, and III patients treated and followed at UCSF. Validation used two independent cohorts, 433 stage I patients treated by physicians from Kaiser Permanente of Northern California, and a second cohort of 1,006 patients with stage I, II, or II disease treated at hospitals affiliated with the China Clinical Trials Consortium. Median follow-up in the three cohorts ranged from just over 3 years to just short of 6 years. Five-year mortality was about 42% in each of the three cohorts. About 80% of the nonsquamous non–small cell lung cancer patients in the three cohorts had adenocarcinomas.
The genetic test used to discriminate among three risk levels in the UCSF cohort identified a low-risk group with a calculated 5-year survival of 78%, an intermediate group with a 5-year survival of 60%, and a high-risk group with a survival rate of 30%. Between-group differences were statistically significant (P = .00005). The U.S. and Chinese validation cohorts each led to identification of three very similar prognostic subgroups, "suggesting that the assay was based on principles of lung cancer biology that are fundamental to the disease and remain constant despite the diverse genetic backgrounds of the populations studied," Dr. Kratz said.
In a multivariate analysis that controlled for age, sex, tumor size, and smoking history, high-risk identification using the genetic test led to a near doubling of the mortality risk in the Kaiser cohort (hazard ratio = 1.93, P = .010) and a more than tripling of the mortality risk in the Chinese cohort, compared with the low-risk tertile (HR = 3.25, P less than .001).