Gene Test Refines Prognosis For Lung Cancer

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. 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).

On the basis of their findings, Dr. Kratz and his associates proposed a new variation on the conventional tumor size, lymph node status, metastases (TNM) staging system that they called TNMM; the second M stands for multigene assay.

Their revised system designates patients judged stage Ia or Ib by TNM who have a low-risk gene test result as a new class Ia. Patients who had been classified Ia or Ib by the old system who have intermediate- or high-risk gene test results form a new stage Ib, a stage that also includes old IIa patients by TNM who had a low-risk gene test outcome. Finally, the new stage IIa consists of patients scored as IIa by the TNM system who also score as intermediate or high risk on the genetic test.

To further assess the prognostic value of adding the gene test, the researchers ran receiver-operator curves for the standard and revised staging methods in each of the two validation cohorts, and found that adding the gene test led to statistically significant increases in the area under the curve for prognostic accuracy.

In commenting on the study, Dr. Giorgio V. Scagliotti, the designated discussant, said the prognostic factors in current use – tumor size, differentiation, vascular invasion, and surgical margins – are not enough. Additional prognostic factors are needed to identify the completely resected stage I patients who might benefit from adjuvant chemotherapy. "We also need to better identify the stage II patients who have a low risk of recurrence and will not benefit from adjuvant chemotherapy," he said.

Previously reported genetic tests for early-stage non–small cell lung cancer involved complicated microarray test methods and a need for fresh tissue. They lacked reproducibility and validation, and had other problems as well. "The new study avoided these pitfalls, but despite its advances, it remains a set of post hoc analyses that lack prospective, randomized testing. Additional study must prospectively establish the medical utility of the prognostic information before routine use begins. Do patients identified by the test as high risk get any benefit from systemic treatment? Is the genetic test significant in the context of tumor stage, patient age, and treatment with adjuvant chemotherapy? Adjuvant therapy has so far not been included in the analysis," said Dr. Scagliotti, professor of medicine at the University of Torino (Italy).

He said he has been a consultant to Eli Lilly, and has been on the speakers bureaus of AstraZeneca, Eli Lilly, and Roche. Dr. Kratz said that he has been a consultant to and has an equity interest in Pinpoint Genomics, the company that developed the genetic test used in the study.

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. 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).

On the basis of their findings, Dr. Kratz and his associates proposed a new variation on the conventional tumor size, lymph node status, metastases (TNM) staging system that they called TNMM; the second M stands for multigene assay.

Their revised system designates patients judged stage Ia or Ib by TNM who have a low-risk gene test result as a new class Ia. Patients who had been classified Ia or Ib by the old system who have intermediate- or high-risk gene test results form a new stage Ib, a stage that also includes old IIa patients by TNM who had a low-risk gene test outcome. Finally, the new stage IIa consists of patients scored as IIa by the TNM system who also score as intermediate or high risk on the genetic test.

To further assess the prognostic value of adding the gene test, the researchers ran receiver-operator curves for the standard and revised staging methods in each of the two validation cohorts, and found that adding the gene test led to statistically significant increases in the area under the curve for prognostic accuracy.

In commenting on the study, Dr. Giorgio V. Scagliotti, the designated discussant, said the prognostic factors in current use – tumor size, differentiation, vascular invasion, and surgical margins – are not enough. Additional prognostic factors are needed to identify the completely resected stage I patients who might benefit from adjuvant chemotherapy. "We also need to better identify the stage II patients who have a low risk of recurrence and will not benefit from adjuvant chemotherapy," he said.

Previously reported genetic tests for early-stage non–small cell lung cancer involved complicated microarray test methods and a need for fresh tissue. They lacked reproducibility and validation, and had other problems as well. "The new study avoided these pitfalls, but despite its advances, it remains a set of post hoc analyses that lack prospective, randomized testing. Additional study must prospectively establish the medical utility of the prognostic information before routine use begins. Do patients identified by the test as high risk get any benefit from systemic treatment? Is the genetic test significant in the context of tumor stage, patient age, and treatment with adjuvant chemotherapy? Adjuvant therapy has so far not been included in the analysis," said Dr. Scagliotti, professor of medicine at the University of Torino (Italy).

He said he has been a consultant to Eli Lilly, and has been on the speakers bureaus of AstraZeneca, Eli Lilly, and Roche. Dr. Kratz said that he has been a consultant to and has an equity interest in Pinpoint Genomics, the company that developed the genetic test used in the study.

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. 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).

On the basis of their findings, Dr. Kratz and his associates proposed a new variation on the conventional tumor size, lymph node status, metastases (TNM) staging system that they called TNMM; the second M stands for multigene assay.

Their revised system designates patients judged stage Ia or Ib by TNM who have a low-risk gene test result as a new class Ia. Patients who had been classified Ia or Ib by the old system who have intermediate- or high-risk gene test results form a new stage Ib, a stage that also includes old IIa patients by TNM who had a low-risk gene test outcome. Finally, the new stage IIa consists of patients scored as IIa by the TNM system who also score as intermediate or high risk on the genetic test.

To further assess the prognostic value of adding the gene test, the researchers ran receiver-operator curves for the standard and revised staging methods in each of the two validation cohorts, and found that adding the gene test led to statistically significant increases in the area under the curve for prognostic accuracy.

In commenting on the study, Dr. Giorgio V. Scagliotti, the designated discussant, said the prognostic factors in current use – tumor size, differentiation, vascular invasion, and surgical margins – are not enough. Additional prognostic factors are needed to identify the completely resected stage I patients who might benefit from adjuvant chemotherapy. "We also need to better identify the stage II patients who have a low risk of recurrence and will not benefit from adjuvant chemotherapy," he said.

Previously reported genetic tests for early-stage non–small cell lung cancer involved complicated microarray test methods and a need for fresh tissue. They lacked reproducibility and validation, and had other problems as well. "The new study avoided these pitfalls, but despite its advances, it remains a set of post hoc analyses that lack prospective, randomized testing. Additional study must prospectively establish the medical utility of the prognostic information before routine use begins. Do patients identified by the test as high risk get any benefit from systemic treatment? Is the genetic test significant in the context of tumor stage, patient age, and treatment with adjuvant chemotherapy? Adjuvant therapy has so far not been included in the analysis," said Dr. Scagliotti, professor of medicine at the University of Torino (Italy).

He said he has been a consultant to Eli Lilly, and has been on the speakers bureaus of AstraZeneca, Eli Lilly, and Roche. Dr. Kratz said that he has been a consultant to and has an equity interest in Pinpoint Genomics, the company that developed the genetic test used in the study.