In community oncology practices, where most cancer in the United States is treated, broad-based genetic testing does not offer survival advantages compared with routine genetic testing for patients with advanced non-small cell lung cancer (NSCLC), concludes a new retrospective study. But lung cancer experts challenge this conclusion, pointing out that few of the patients who were found to have actionable mutations on broad-based genetic testing actually received targeted therapy and some received targeted therapy not matched to the mutations.
The study, conducted by researchers at the Yale Cancer Center, New Haven, Connecticut, was published August 7 in JAMA Oncology.
Using an "instrumental variable analysis," the retrospective analyses from a Flatiron Health Database showed that 12-month mortality was 41.1% for patients who received broad-based sequencing and 44.4% for those who received routine testing, and the difference between the two groups was not statistically significant.
The Flatiron Database provided data for 5688 patients with advanced NSCLC from 191 community oncology practices. Routine testing included testing for EGFR and/or ALK mutations, and broad-based testing included any multigene panel that tested more than 30 genes.
The results mean that "use of broad-based genomic sequencing in the community setting for advanced non-small cell lung cancer may not currently offer a survival advantage," the researchers conclude, implying that broad-based genetic testing in the community setting may not be warranted.
This conclusion may come as a shocker to those who treat NSCLC because in the current landscape of patient management, broad-based genetic testing has evolved as a tool to provide precision treatment and is recommended to match an actionable mutation with appropriate therapy. Indeed, guidelines for broad-based genetic testing are based on a plethora of studies that show an improvement in survival and/or clinical outcomes for patients who receive treatment that matches with a driver or actionable mutation in their tumor.
In an accompanying editorial, lung cancer expert Paul A. Bunn Jr, MD, and his pathologist colleague, Dara L. Aisner, MD, PhD, both from the University of Colorado, Denver, concede that there is value in understanding how precision oncology is practiced in the community. "[But] the study should not lead to the conclusion that broad-based genomic sequencing should be avoided in nonsquamous NSCLC," they write.
Study Limitations Challenge Conclusions
"The limitations of this investigation do not allow one to make this conclusion," Bunn told Medscape Medical News.
The limitations of this investigation do not allow one to make this conclusion. Dr Paul A Bunn Jr
Lung cancer expert Alice T. Shaw, MD, PhD, from the Massachusetts General Hospital in Boston, echoed Bunn's sentiments. "As a clinician who practices precision medicine I do not believe in and am troubled with the conclusions they [the researchers] draw from their data, given the number of important limitations of the study." She explained that it is important to understand these limitations, which may not be entirely clear to all readers.
The Yale researchers acknowledge eight limitations, some importantly related to treatment decisions, outcome measures, and treatment availability. In the Flatiron Database, electronic health record (EHR) data capture during routine care is less complete and potentially less accurate, the researchers note.
Bunn pointed out that outcome measures, such as progression-free survival (PFS), objective response rates, quality of life (QOL), and drug-related toxicities, are not captured in the Flatiron Database. Specific targeted therapies in the first-line setting improve these outcomes, and using 12-month survival as the sole endpoint underestimates other forms of benefit conferred by targeting therapies in the setting of broad-based testing, Bunn and Aisner note.
Bunn told Medscape Medical News that about 125 patients had an actionable mutation from broad-based testing, yet very few (36 patients, less than a third) were treated with an appropriate targeted therapy. "Identifying driver or actionable mutations, but not offering appropriate treatment, is not going to improve survival," he said.
Bunn suggested that there is a gap in community oncology practices between getting mutational data and acting appropriately on it — a gap that may be associated with lack of clinician education or the unavailability of the appropriate therapy during the timeframe of the study. This gap results "in a potential study bias against broad-based genomic sequencing," Bunn and Aisner comment.
Shaw agreed that not all patients were matched to the appropriate targeted therapy. For example, she pointed out that patients with tumors that harbored MET or KRASmutations were given erlotinib and patients who had CCNE1 or TAF1 mutations were given crizotinib (Xalkori, Pfizer). "Overall, the proportion of patients who received targeted treatment is small enough (4.5%) that even a few cases like these could skew the results," she said.
Bunn and Aisner point out that the time frame of the study (January 2011 to July 2016) predated the routine use of US Food and Drug Administration (FDA)–approved therapies for ROS1 rearrangements and BRAF mutations and included the period following the approval of targeted therapy for ALK rearrangements.
They further point out that since the start of this study, the FDA has approved new tyrosine kinase inhibitors for EGFR and ALK alterations, crizotinib for ROS1-rearranged lung cancer, and a combination of BRAF/MEK inhibitors for BRAFV600E mutation.
Shaw similarly noted that the timing of this study may have also confounded the results. "Since the data cutoff of July 2016, we have a number of new and highly effective therapies," she said. In addition to the examples above, she noted that there are now effective therapies for NSCLC with RET rearrangements, which occur in about 1% of NSCLC.
Bunn told Medscape Medical News that some of these newer therapies may not have been available to patients whose data were used in the analysis. The Flatiron Database does not capture the oral therapies patients received, Bunn noted.
The researchers admit that decision support for oncologists in the community setting is needed and add that even if there is a potential clinical trial with an appropriate targeted therapy available, patient enrollment from a community setting is low. "Efforts to increase access to broad-based genomic sequencing should be paired with efforts to facilitate clinical trial enrollment," the Yale researchers write. They also note that in the community setting the prohibitive cost of targeted therapies may result in financial burden and limit drug access.
More broadly, Shaw noted that a retrospective study, such as this one, that uses EHR data can be misleading because of confounders that we may not even be aware of. "While the study is interesting and provocative, a retrospective study cannot replace the rigors of a randomized clinical trial," she said.
In addition, Shaw was also troubled with the message this study is sending to community oncologists. "The targeted therapies that have been developed for specific molecular subsets of lung cancer have prolonged the lives of many thousands of patients. The implication of the study — that broad-based genomic testing may not benefit patients in the community setting — is misleading," she told Medscape Medical News.
The implication of the study — that broad-based genomic testing may not benefit patients in the community setting — is misleading. Dr Alice T. Shaw
Study Details
The retrospective study from the Yale researchers analyzed patient data from the Flatiron Database, which at the time of analyses represented more than 250 cancer clinics with 1.5 million active patients.
Routine testing included testing for EGFR and/or ALK mutations, while broad-based testing included any multigene panel that tested more than 30 genes.
The group that had only EGFR and ALK testing is not necessarily a valid control group, Shaw told Medscape Medical News. With respect to the broad-based testing cohort, she noted that seven different platforms were used.
"Not all next-generation sequencing platforms have the same degree of validation," she said. In addition, she noted that Guardant Health, which provided the broad-based sequencing for 14.5% of the samples, is used for sequencing circulating tumor DNA from a liquid biopsy and is not equivalent to the standard sequencing of tumor tissue, she explained.
Patients diagnosed with stage IIIB/IV or recurrent nonsquamous NSCLC who received first-line treatment and either broad-based or routine testing were included in the study.
Of 5688 patients, 875 received broad-based testing and 4813 received routine testing. In the instrumental variable analysis confounding variables were accounted for. These included timing of testing compared with therapeutic line, comorbidities, socioeconomic factors, age, and sex.
All patients were tested for EGFR mutations; 95% were tested for ALK mutations.
In addition, the patients who received broad-based genetic testing were also tested for ROS1, KRAS, and PD-L1.
For the entire cohort of 5688 patients, 12-month mortality was significantly higher for patients receiving routine testing (49.2% vs 30.5% for routine testing; hazard ratio [HR], 0.69; P < .001). But the instrumental variable analysis made the difference nonsignificant (44.4% for routine testing vs 41.1% for broad-based testing).
Despite a significant association between patients receiving immunotherapy and broad-based testing as well as between receipt of immunotherapy and improved survival, the differential receipt of immunotherapy across the two groups was an important confounder that required adjustment in the analyses. The researchers point out that a clinician obtains PD-L1 testing rather than broad-based testing to guide use of immunotherapy in the first-line setting of advanced NSCLC.
An analysis was also conducted among 519 propensity-matched pairs, which had well-matched characteristics. For these 1038 patients, 12-month mortality was also not significant — 42% for broad-based testing and 45.1% for routine testing (HR, 0.92; P = .40). Rate of immunotherapy use was 21.2% in both groups.
All patients received first-line treatment and 47.3% received second-line treatment. Among the 875 patients who underwent broad-based testing, only 36 (4.5%) received informed targeted therapy, 75 (9.8%) received treatment with EGFR/ALK-targeted treatment, and 674 (85.1%) received no targeted treatment.
"Our ability to sequence has outpaced our ability to get targeted therapy to patients," the researchers comment in a Yale news statement. Coauthor Roy S. Herbst, MD, chief of medical oncology at the Yale Cancer Center, noted that over the past decade, with science moving so quickly, therapies for patients have improved substantially. "I hope and expect when this study is repeated in a few years we will see improved outcomes and we now have a baseline from which to build," he said.
However, editorialists Bunn and Aisner prefer to reframe the issue: The question that remains is not whether to test but how to do so and how optimally to direct therapy based on the results of the testing.
Bunn told Medscape Medical News that in NSCLC, there are currently about 10 actionable mutations, yet the broad-based testing included more than 30 genes, and the study compared the value of testing 30 genes vs testing 2 genes (EGFR and ALK). "While the optimal number of genes is not known and is likely to be ever-changing, benefit in this context, with regard to overall survival, PFS, objective response rates, and QOL may reside in the difference between 2 and 10 genes…rather than below and above 30 genes," the editorialists conclude.
Many of the authors list conflict of interest disclosures, as shown in the paper, and several authors are employees of Flatiron Health, New York. Bunn reported receiving consulting fees from AstraZeneca, Bristol-Myers Squibb, Genentech, Lilly, Merck, Merck-Serono, Pfizer, Novartis, and Takeda. Shaw receives honoraria from Pfizer, Roche, Genentech, Novartis, and Foundation Medicine; serves in a consulting or advisory role for Pfizer, Roche, Genentech, Novartis, Ariad/ Takeda, Ignyta, Daiichi Sankyo, Taiho Pharmaceutical, EMD Serono, Loxo Oncology, Blueprint Medicines, KSQ Therapeutics, Natera, TP Therapeutics; and receives research funding from Pfizer, Roche, Genentech, and Novartis.
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