An Inside Look at Diagnostics
This case study illustrates the evolution of the diagnostic industry across different continents, diagnostic companies' evolving business models, stak...
In August 2016, a team of experts from Diaceutics submitted a response to the IASLC Molecular Testing Guideline for Selection of Lung Cancer Patients, during the public open comment period1. Here they share a summary of their thoughts and concerns.
The open comment period offered by the International Association for the Study of Lung Cancer (IASLC) for the Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK gave us the chance to analyse the suggested changes and to put forward our opinion in an area where Diaceutics has industry expertise.
Molecular testing of EGFR and ALK
We welcome the 2016 draft reclassification to a ‘strong recommendation’ that physicians must use EGFR and ALK molecular testing for lung adenocarcinoma patients at the time of diagnosis presentation with advanced stage disease. It is relevant and appreciated that they include ‘molecular testing’ of EGFR and ALK, and not just a particular mutation or rearrangement as before. Molecular testing embraces additional mutation testing, which can also cover mutations known to be involved with disease resistance. This is a growing problem facing oncologists as they become more used to ALK inhibitors and new generations of EGFR inhibitors. They are finding many patients not responding at all to treatment or the disease progressing quickly, when they are eligible for the respective treatments for their EGFR mutant or ALK rearranged profile. Resistance mutations are often present and detectable at diagnosis and some doctors are starting to request this test upfront.
We agree it is good to continue to encourage testing in the early stages, but feel the recommendation is too wide. Leaving doctors with the decision to test will, all too often, end up with patients not being tested, for different possible reasons. There may be a lack of time or urgency to treat the patient, the doctor may lack understanding or knowledge around the cost or be concerned about reimbursement. The physician could simply be sticking to protocol and doing what is required rather than recommended, and there could be other factors such as delays in treatment. It will be helpful to see some additional guidance to help doctors narrow the target populations that will benefit from particular testing at early diagnosis, such as non-smokers.
The use of cfDNA
The recommendations regarding the use of cfDNA seem somewhat contradictory. We suggest that 9, 12 and 13 in the analytical section are revisited to clarify the situations in which cfDNA could be tested:
With regards to a laboratory turnaround time (TAT) anything beyond two weeks should be considered unacceptable, but this is a personal perception from the clinical standpoint. From the lab
operational standpoint, a reduced TAT of less than two weeks is achievable, even for more esoteric or cumbersome techniques. Taking any longer than this is likely to be caused by lab operations not being efficiently managed, and/or the lab batching for economic reasons. In this case, we question if it should be acceptable to keep a NSCLC patient waiting more than two weeks for the result just so that a particular lab can be profitable. There must be a balance between clinical impact and lab profitability.
Responsibility for testing
The responsibility and decision for testing lies primarily with the physician as he or she decides which tests to use to guide therapeutic decisions. However, depending on the amount of sample left, pathologists are in a better position to evaluate the remaining tissues and the possibilities they offer. The role of the pathologist regarding the tests to be performed, and in supporting physicians in their decisions, should not be neglected.
We don’t believe that it should be at the discretion of the physician to choose which test has to be used, according to the sample available. It will often be the case that a physician is unaware of sample availability or indeed how much sample is required for a specific test. That should be the responsibility of the pathologist, so in the analytical section 7, instead of ‘Physicians should use molecular testing for the appropriate genetic targets on either primary or metastatic lung lesions to guide initial therapy selection’, we would prefer it to say, ‘Pathologists should choose the most clinically appropriate sample, either primary or metastatic lung lesions, on which to perform molecular testing.’
Confirmation by FISH where a result is uncertain
The choice of antibody clone is critical for ALK IHC. Given the lower sensitivity for some clones and in samples with a limited number of tumor cells, we think it wise to recommend confirmation by FISH where a result is uncertain, as is recommended for ROS1 IHC. In the context of ALK (where FISH is used) the proportion of tumor cells is not as important as the number. The current analytical protocol used (Vysis package insert) recommends that in equivocal cases a minimum of 100 tumor cells should be analysed. We believe this is sound practice and that it should be included in the guidelines for ALK and also ROS1.
Interpretation of results
The recommendation that a pathologist should interpret a FISH result is not always practical and will differ between organizations and countries. It is agreed that ultimately pathologists will have the final say, but cytogeneticists or technologists highly trained in FISH analysis and interpretation may have the best understanding of this technique. It is imperative though that if interpretation is to be done by a scientist rather than a pathologist then they should have a thorough training in the identification of tumor cells. If there is any doubt, advice should be sought from a pathologist.
Considering the recommendations overall, Neil Atkey, Director of Scientific Operations at Labceutics, said, “These revised guidelines add clarity to the issues regarding the increasingly important area of biomarker testing in NSCLC. They should enable laboratories to ensure they are offering the appropriate tests for clinical decision-making. A number of details on the use of ctDNA for EGFR testing do, however, need to be harmonised.”
The CAP/IASLC/AMP Molecular Testing Guideline Public Open Comment Period ran from June 28 to Aug. 2, 2016.
It states: This information is time-limited and does not represent the final content of the Expert Panel recommendation statements.
Draft statements are not valid as of August 2, 2016.