CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Dr. Finley
The subset of EGFR-driven NSCLC patients has certain clinical characteristics, Dr. Finley noted. “They are often Asian, because the prevalence of mutations in Asians is high. They’re often women, and they are often never-smokers, and they have this nonsquamous or adenocarcinoma histology.”
Some large studies of those with EGFR driver mutations (LUX-Lung 3 and LUX-Lung 6 trials) have shown no difference in overall survival rates between those who were initially treated with targeted therapy and those whose initial treatment was chemotherapy. But many of the patients in those studies were switched at time of initial progression to targeted therapy after starting on chemotherapy, Dr. Finley said, which is the likely explanation for the same overall survival.
“Subsequent subset analysis demonstrated that if you have the most sensitive mutation of the EGFR driver mutations—that is, the deletion in exon 19—you in fact had an overall survival benefit if you started with the appropriate targeted agent—in this case, afatinib [Gilotrif], or you could imagine using Tarceva [erlotinib] or Iressa [gefitinib] as well.”
The subset with this targeted therapy has unusually high median overall survival of about 2.5 to three years, he said. “This to me is a very striking result, and it continues to drive my thinking around molecular testing and the importance of it.”
Unfortunately, when he and others searched the registry data at two of Allegheny Health Network’s hospitals, of about 200 patients with nonsquamous NSCLC, “we found we were only testing about half of the patients for these important drivers and that the frequency of driver mutation was lower than what was seen in the published literature”—eight percent versus about 15 percent for EGFR and two percent versus about five percent for ALK. One finding that fell out of the data was that the hospitals were testing more patients with large biopsies than patients who had small biopsies. And this was true for both EGFR and ALK FISH testing.
He set out to determine via surveys and more why AHN’s 50 percent testing rate was lower than the 70 to 80 percent in the literature. One of the barriers to molecular testing was the Medicare 14-day rule. Another was the physicians’ unwillingness to subject the patient, who often had multiple comorbidities, to repeat testing. “So we had a number of meetings to try to increase awareness and stakeholder education, and we came up with some pathways to encourage large tissue biopsies, to re-biopsy if necessary, and if unable to re-biopsy, to use blood-based testing. And we’ve been incorporating this into our general practice both at the community and the academic level.”
Demographics were part of the explanation for the lower prevalence of the driver mutations, Dr. Finley noted. Allegheny Health Network extends from tertiary or quaternary care sites in large Pittsburgh hospitals all the way to community sites in rural Punxsutawney, but western Pennsylvania as a whole has few Asians and a large population of Caucasians, the elderly, and smokers, all of whom have low mutation rates. “So the idea of using blood-based testing is very appealing because it would then allow us to interrogate more tumors without the patient having to undergo an invasive biopsy.” Tumor heterogeneity as well is occasionally seen and is another reason to opt for a blood-based assay.
“The advantage of a blood-based assay is that as all cells within the tumor mass itself undergo apoptotic or necrotic cell death, they release their contents into the blood, and this can be detected as cell-free plasma DNA through a variety of techniques.” This liquid biopsy, Dr. Finley said, is likely to be used more and more in the future, to look for driver mutations and to use tumor cell capture techniques that might allow interrogation of cells for PD-L1 expression. “Exosomes, which contain DNA, RNA, and protein, and perhaps will have some interesting signatures with respect to either proteins or microRNAs, may be useful in stratifying our patients.”
With the goal of testing all adenocarcinomas or nonsquamous cancers for the key genes, Allegheny Health Network is now requiring that all stage IIIB and stage IV be tested and is looking at reflexive testing for all lung cancers. “We are moving toward reflexive testing of all nonsquamous cancers. We prefer large tissue biopsies. We like to avoid the delay associated with the Medicare 14-day rule and we’ve sort of eliminated that as a barrier. We do re-biopsy, and we have used blood-based testing very successfully.”
Whether they start with chemotherapy and move on to targeted therapy or start with targeted therapy alone, “patients with driver mutations have a better prognosis in general.” They’re a “lucky subgroup of patients,” he said, and “it behooves us to identify them.”
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‘A marriage of virtual and real bronchoscopy’
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As a community hospital, Southside Regional Medical Center in Petersburg, Va., has some differences in resources, said David R. Penberthy, MD, MBA, medical director of radiation oncology at Southside Regional, which serves an area that has high cancer incidence. But the cancer care program where he works has received a “gold” level Outstanding Achievement Award for the last two survey cycles from the American College of Surgeons’ Commission on Cancer. “When ACCC [Association of Community Cancer Centers] approached us about looking at our rates of molecular testing, we wanted to compare ourselves to the standard benchmarks out there and see how we’re doing.”
A process improvement plan was eventually the result. In looking at cases between Nov. 2, 2012 and Oct. 31, 2013, “we found that we performed molecular testing on only four of six stage IIIB and seven of 17 stage IV lung adenocarcinomas.” But collecting the data was difficult.
“We thought we could answer the question more efficiently and it was suggested that we add molecular test results as a data field in the lung cancer registry, then track the molecular testing in a pathology database.” Southside Regional’s pathologists did exactly that, and the subsequent analysis was more easily obtained.
In the second assessment, in 2015, there were 138 cases in the lung cancer registry; of those, 47 were adenocarcinomas and three had mixed histologies (adenosquamous). Molecular testing was performed on 80 percent of stage I, 60 percent of stage II, 58 percent of stage III, and 61 percent of stage IV. The higher percentage in stage I is owing to the stage often having been undetermined at the time of biopsy, Dr. Penberthy pointed out. “So we’ve gotten into the habit of testing any sample that is nonsquamous.”
Dr. Penberthy
As frequently happens, collecting the data helped trigger improvement. “We had an average of about 6.6 days turnaround time for the first year, so it was taking almost a week to get results back. But the most recent six-month period showed we’re starting to improve, and we got a little smarter as we went along with our process, partly due to some improvements such as reflexive testing.” The goal, he said, is a turnaround time of five working days. “Typically, the oncologist will order the molecular testing and then schedule follow-up about two weeks later to discuss the results and formulate the treatment plan.”
The hospital found there were many reasons molecular testing was not performed. “Sometimes a test was ordered and the sample was inadequate, and sometimes patients have significant comorbid conditions and did not want to re-biopsy. We also had some physicians not ordering the test because the patient was end-stage or referred to a tertiary care facility.” Some patients refused treatment and one refused to be evaluated by medical oncology.
Other challenges are third-party payment issues and the limited time that’s available before the management decision must be made. “And we have run into the Medicare 14-day rule on more than one occasion,” Dr. Penberthy said. If there’s a potential delay in obtaining results, that can be a problem for the patient who wants treatment to begin quickly.
“Our molecular testing process is moving toward reflex testing,” he said, “but it’s not happening all the time.”
So what can be done to standardize testing and reduce the delays? Document the reasons molecular testing isn’t done so it can be tracked (“we need a better documentation process,” he said), analyze testing rates, set a protocol for mode of biopsy (“right now that’s still operator choice,” he said), and move to reflex testing to expedite clinical decision-making. But as for so many other things, “I would say it all boils down to people and collaboration,” Dr. Penberthy said. For them and others, that means tumor boards and telephone calls.
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Anne Paxton is a writer and attorney in Seattle.