Physician attitudes and prevalence of molecular testing in lung cancer
Background EGFR mutations and EML4-ALK rearrangements are key therapeutic targets in nonsquamous non–small-cell lung carcinoma (nsNSCLC). Current guidelines recommend testing all patients with advanced nsNSCLC (stages IIIB and IV).
Objective To evaluate physician attitudes about molecular testing for nsNSCLC and to determine the rate of testing, the effect of biopsy sample size, and prevalence of driver mutations.
Materials and methods In this retrospective study, 206 cases of advanced nsNSCLC were identified from the tumor registry from 3 hospitals within a health network (February 2011-February 2013). EGFR and ALK testing was performed using commercial laboratories and mutation prevalence was determined. A survey was sent to practitioners who care for patients with lung cancer to evaluate their attitudes toward molecular testing.
Results The prevalence of EGFR mutation (7.8%) and ALK rearrangement (2%) was lower than reported in the literature. Large biopsy samples were more likely to be analyzed for EGFR mutations and ALK rearrangements (P = .023 and P = .007, respectively) than were smaller samples. There was a high level of agreement among survey respondents that mutation testing was essential. Nevertheless, we found that fewer than half of the eligible patients had been tested for these critical driver mutations.
Limitations Small sample size
Conclusion Despite current recommendations to test patients with advanced nsNSCLC for EGFR mutations and ALK rearrangements and physician assertions that they deemed mutation testing essential, fewer than 50% of the patients at the 3 hospitals had been assayed. Our findings imply that large biopsy samples, such as those from surgical or core biopsies, are better than small samples, such as those from needle aspiration for the purpose of molecular testing. In addition, the prevalence of driver mutations among patients who were treated at the cancer center is lower than that published in the literature.
Accepted for publication January 9, 2017
Correspondence Rohit Rao, MD; rohit.rao@ahn.org
Disclosures The authors report no disclosures/conflicts of interest.
Citation JCSO 2017;15(3):e147-e154
©2017 Frontline Medical Communications
doi https://doi.org/10.12788/jcso.0326
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In a similar study, the Association for Community Cancer Centers conducted a project aimed at understanding the landscape and current challenges for molecular profiling in NSCLC. Eight institutions participated in the study, and baseline testing rates were analyzed. The findings demonstrated that high-volume institutions (treating >100 lung cancer patients a year tested 62% and 60% of advanced lung cancer patients for EGFR and EML4-ALK, respectively, and low-volume institutions (treating <100 lung cancer patients a year tested 52% and 47% for EGFR and EML4-ALK, respectively.25,26 In a recent international physician self-reported survey, Spicer and colleagues found that EGFR testing was requested before first-line therapy in patients with stage IIIB or IV disease in 81% of cases, and mutation results were available before start of therapy in 77% of the cases.27 Those percentages are relatively low, given that current guidelines recommend that molecular testing should be done for all patients with stage IIIB or IV nsNSCLC. This highlights the need for objective performance feedback so oncologists can make the necessary practice changes so that molecular testing is done before the start of therapy to ensure high-quality cancer care that will translate into better, cost-effective outcomes and improved patient quality of life.
Our study findings showed that the prevalence of EGFR and ALK mutations is substantially lower among the patients we treat in our network compared with other published data on prevalence. The reason for those low rates is not clear, but it is likely multifactorial. First, Western Pennsylvania, the region our network serves, has a large proportion of older adults – 17.3% of the population is older than 65 years (national average, 14.5%) and advanced age might have contributed to the lower EGFR and ALK rates measured in our study.28 Second, the smoking rate in Pennsylvania is higher than the national average, 20%-24% compared with 18%, respectively.29 Third, the air quality in Western Pennsylvania has historically been very poor as a result of the large steel and coal mining industries. Even though the air quality has improved in recent decades, the American Lung Association’s 2017 State of the Air report ranked Pittsburgh and surrounding areas in Western Pennsylvania among the top 25 most air polluted areas in the United States.30 It is not certain whether air pollution and air quality have any impact on driver mutation rates, but the correlation with smoking, ethnicity, and geographic distribution highlight the need for further epidemiologic studies.
Biopsy sufficiency – getting an adequate amount of sample tissue during biopsy – is a known challenge to molecular profiling, and we found that biopsy sample size had an impact on the testing rates in a large percentage of our cases. To fully understand the impact of biopsy sufficiency, we conducted a subset analysis and compared the testing rates between our large and small biopsy samples. Our analysis showed that larger-sample biopsies were more likely to be tested for mutations than were smaller-sample biopsies (EGFR: P = .023; ALK: P = .007).
Those results suggest that larger-sample biopsies should be encouraged, but procedural risks, tumor location, and patient age and wishes need to be considered before tissue acquisition.21 Furthermore, clinicians who are responsible for tissue procurement need to be properly educated on the tissue sample requirements and the impact these results have on treatment decisions.31 Our institution, like many others, has adopted rapid onsite evaluation (ROSE) of biopsy samples, whereby a trained cytopathologist reviews sample adequacy at the time of tissue procurement. Although there is scant data directly comparing molecular testing success rates with and without the ROSE protocol, a meta-analysis conducted by Schmidt and colleagues concluded that ROSE improved the adequacy rate of fine-needle aspiration cytology by 12%.32,33 Given that molecular profiling depends on both the absolute and relative amount of tumor cells present in the sample, the ROSE protocol likely enhances the procedural success rate and reduces the need for repeat and subsequent biopsies.
It is interesting to note that our data also demonstrated that we are obtaining large-sample biopsies in most of our patients (about 70%). However, we are still failing to test more than half of our cases for driver mutations (Figure, A and C). This strongly suggests there are additional factors beyond tissue adequacy that are contributing to our high failure rate. It is essential to understand the dynamics and system practices that influence testing rates if we are to improve the care and outcomes of our cancer patients. To better understand those barriers, we surveyed 110 practitioners (including medical oncologists, pulmonologists, thoracic surgeons, and interventional radiologists) about the molecular profiling process and their responses highlighted several important areas that deserve special attention (Tables 1, 4, 5).
In our institution, testing initiation is primarily the responsibility of the treating medical oncologist. This presents a challenge because there is often a significant delay between tissue acquisition, histologic confirmation, and oncologic review. Many institutions have adopted pathology-driven reflex testing to help overcome such delays. Automatic testing after pathologic confirmation streamlines the process, increases testing rates, and eliminates unnecessary delay between the time of diagnosis and the time of test ordering.34 It also allows for the molecular and histologic diagnosis to be integrated into a single pathology report before therapy is initiated.
Another barrier to timely testing according to the respondents, was the CMS’s 14-day rule. The 14-day rule requires hospitals to wait 14 days after the patient is discharged for the lab to receive reimbursement for molecular testing and was frequently identified as a cause for significant delay in testing and having an impact on first-line treatment decisions.35,36
Often clinicians will choose to defer testing until this time has elapsed to reduce the financial burden placed on the hospital but by that time, they might well have initiated treatment without knowing if the patient has a mutation. This is a significant challenge identified by many of our oncologists, and is a limitation to our analysis above as it is unclear what percentage of patients received follow up testing once care was established at an outside facility and once the 14-day time period had elapsed.
The data from our institution suggests there is discordance between physician attitudes and molecular testing practices. However, there are several limitations in our study. First, most of the survey respondents agreed that molecular testing is an important aspect of treating advanced lung cancer patients, but the retrospective nature of the study made it difficult to identify why testing was deferred or never conducted. Second, the absence of a centralized reporting system for molecular testing results at our institution, may have resulted in an overestimation of our testing failure rate in cases where results were not integrated our electronic medical record.
Third, the low survey response rate only allowed us to make generalizations regarding the conclusions, although it does provide a framework for future process improvements.
We believe the poor testing rates observed in our study are not isolated to our institution and reflect a significant challenge within the broader oncology community.27 A system of best practices is essential for capturing this subset of patients who are never tested. There is agreement among oncologists that improving our current testing rates will require a multidisciplinary approach, a refined process for molecular evaluation, a push toward reflex testing, and standardization of biopsy techniques and tissue handling procedures. In our institution, we have initiated a Lean Six Sigma and PDSA (plan, do, study, act) initiative to improve our current molecular testing process. In addition, because obtaining larger-sample biopsies or additional biopsies is often not feasible for many of our advanced cancer patients, we have started using whole blood circulating tumor cells (CTC) and plasma ctDNA (cell-free circulating DNA) for molecular testing. Recent studies have shown high concordance (89%) between tissue biopsies and blood-based mutation testing, which will likely have a positive impact on the cancer care of our patients and help to capture a subset of patients who are not candidates for traditional biopsies.37
