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New Test Aids Lung Cancer Risk Assessment, But Survival Benefit of Comprehensive Sequencing Questioned

Lung cancer-related testing is receiving a lot of attention, but recent results appear to show mixed benefits for these emerging tests.

There is an urgent need to improve lung cancer risk assessment, as current screening strategies miss a large proportion of new cases. A recent small study that used protein-based biomarkers to enhance risk-based screening stratification shows promise.

However, a separate study shows that comprehensive sequencing is penetrating community-based care for lung cancer, yet the effusion of technology is not accompanied by any simultaneous survival benefit, suggesting that the technology adoption has outpaced the utility of results.

Biomarkers Improve Lung Cancer Risk Assessment
Biomarker-based risk profiling has the potential to better identify at-risk patients for lung cancer screening, according to a brief report published July 12 in JAMA Oncology. The proof-of-principle study shows that four protein biomarkers outperform traditional risk prediction models based on smoking history.

“The biomarker panel more accurately identifies at-risk smokers who should proceed to screening, even if they’re not at the highest risk based on smoking history alone,” said lead author Samir M. Hanash, M.D., Ph.D., University of Texas MD Anderson Cancer Center in Houston, in a statement. “A positive blood test means an ever-smoker is as much, if not more so, at risk of having lung cancer as a heavy smoker with a low biomarker score.”

Current U.S. Preventive Services Task Force recommendations call for low-dose computed tomography-based screening for individuals aged 55 to 80 years who have smoked 30 pack-years. Yet, this protocol entirely misses non-smokers who go on to develop lung cancer.

Researchers from the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium for Early Detection of Lung Cancer developed a biomarker risk score based on prediagnostic samples from lung cancer patients. The biomarker score is based on four blood-based protein markers—cancer antigen 125, carcinoembryonic antigen, cytokeratin-19 fragment, and the precursor form of surfactant protein B. The biomarker score, integrated into the smoking-based prediction model, was then validated in a cohort of 63 ever-smoking patients with lung cancer and 90 matched controls.

The researchers found that the integrated risk prediction model significantly outperformed the smoking only-based prediction mode. It had superior sensitivity—identification of smokers who later developed lung cancer—without increasing the number of false-positives.

Twenty-six of the 62 incident lung cancer cases in the validation study qualified for LDCT screening according to USPSTF criteria. The biomarker-based risk prediction model, 40 cases would have been identified. Furthermore, the authors say, the biomarker score could have reduced screening of individuals not destined to develop lung cancer from 15 to four, without affecting the assessment of future lung cancer cases.

“Our findings also indicated that the improvement in discrimination afforded by the biomarker score is more modest beyond the initial year after blood draw, which suggests that an annual biomarker test may be necessary in a screening program,” wrote Hanash and colleagues.

Broad-Based Sequencing Does Not Improve Survival
Broad-based genomic sequencing does not improve survival over routine EGFR and/or ALK testing among patients with advanced non-small cell lung cancer (NSCLC) receiving treatment in the community setting, according to a study published Aug. 7 in the Journal of the American Medical Association. Among those that received broad-based genomic sequencing results informed treatment for a non-EGFR mutation or ALK rearrangement in fewer than 5 percent of patients, raising questions about results’ actionability.

Testing for EGFR and ALK alterations in now standard of care for patients with advanced NSCLC due to the established survival benefit afforded by targeted treatments. However, some recommendations, like those from the National Comprehensive Cancer Network, call for testing using broad-based genomic sequencing to identify rare driver mutations and to facilitate clinical trial eligibility for possible emerging targeted treatments. Yet there is limited evidence to date to evaluate whether broad-based genomic sequencing meaningfully uncovers clinically actionable mutations, affects patient outcomes, and or is cost-effective.

A large study compared the impact of broad-based genomic sequencing versus routine testing (EGFR mutations and/or ALK rearrangements) for 5,688 NSCLC patients treated in the community setting (191 practices; (Jan. 1, 2011, through July 31, 2016) may not currently offer a survival advantage

The researchers found that 15.4 percent of patients in the community setting received broad-based genomic sequencing. All patients received EGFR testing, while 95 percent received ALK testing.

Among the 875 patients who received broad-based genomic sequencing, the vast majority (88.9 percent) had a genetic mutation identified. There were 247 unique genetic mutations identified, including most commonly TP53 (55.1 percent), KRAS (34.2 percent), EGFR (21.9 percent), CDKN2A (15.7 percent), and STK11 (12.2 percent). Other than EGFR and ALK, the most common actionable alterations detected with broad-based genomic sequencing—those for which patients received targeted treatment—were BRAFV600E, MET, and ERBB2.

Of those receiving broad-based sequencing, 4.5 percent received targeted treatment based on testing results, 9.8 percent received routine EGFR/ALK targeted treatment, and 85.1 percent received no targeted treatment. Patients receiving broad-based genomic sequencing were more likely to receive immunotherapy (4.0 percent), even though sequencing is not needed to initiate immunotherapy. Additionally, significantly more patients receiving broad-based sequencing enrolled in clinical trial regimens versus patients receiving routine testing. There were no significant associations between broad-based genomic sequencing and either overall survival or 12-month mortality versus routine testing.

“There is limited availability of targeted treatments that are both effective and have minimal toxicity to target an ever-expanding list of tumor mutations,” write the authors led by Carolyn Presley, M.D., from Ohio State University in Columbus. “This study highlights how broad-based genomic sequencing has disseminated beyond traditional research settings ahead of a demonstrated association with better survival.”

Takeaway: Biomarkers may enhance risk-based screening strategies. But, comprehensive sequencing of advanced NSCLC cases fails to show a survival benefit. Emerging lung cancer tests will benefit from further validation and cost analysis.

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