Tackling the Testing Challenge in Lung Cancer

Lung cancer remains one of the world’s most significant causes of death, with the disease accounting for approximately one-fifth of all cancer mortality worldwide. As with most cancers, it’s possible that we could reduce those numbers with the help of appropriate testing to detect lung cancer early, stratify patients by risk, and identify appropriate treatments for each patient’s unique disease. Molecular testing can help – but to take full advantage of its scope and power, we need up-to-date testing recommendations to help guide its use.

Whys and wherefores

We always knew that the existing guidelines for molecular testing in lung cancer would need revision – just like we know that these new guidelines will need another revision at some point. The field moves very rapidly, with new discoveries emerging and new technologies maturing at an astonishing rate. We felt in 2016 that – between the importance of ROS1, the emergence of next generation sequencing and liquid biopsies, and the advances in immunohistochemistry (IHC) – enough significant changes had “declared themselves” that the time was right to launch this revision.

One of the major changes is the introduction of new genetic tests to the lung cancer repertoire. For instance, we now have compelling published evidence of clinical response to ROS1 inhibition that has translated into real-world clinical practice – in fact, the ROS1 story was beginning to emerge even while we were finishing off the initial guideline. We also have extensive published evidence of clinical responses to ALK inhibition when IHC was used as biomarker, of the value of next generation sequencing as an efficient way to detect multiple alterations concurrently, and of the response of EGFR-resistant lung cancers with the acquired T790M mutation to third-generation EGFR inhibitors.

I think the more challenging thing to explain – and to implement – is the recommendation regarding the “intermediate” genes: ERBB2, MET, BRAF, RET, and KRAS. For these, we felt there was good clinical evidence from small, single-arm studies that indicated medical necessity… but it wasn’t compelling evidence from large, controlled studies – and this was a fine line. In the end, we believe that it is necessary to offer investigational therapies to lung cancer patients when the standard treatments are not appropriate, and this expanded testing is the portal to those therapies.

Continuous change

Collectively, we look forward to the continuing evolution of diagnostics and care for lung cancer patients as technology, scientific understanding, and clinical practice advance. Because these recommendations represent current best practice in a rapidly developing field, we anticipate an ongoing need for additional updates in the future. I think one of the big challenges is to provide these updates rapidly, as the field outpaces our ability to generate the recommendations! We are also seeing a transition in care, with lesser levels of evidence being used as a basis for treatment strategies.

One example, might be the approval of the BRAF/MEK1 targeted inhibitor combination for lung cancers with the BRAF V600E mutation. That came just a little too late for us to incorporate it into the new guidelines, but we knew it was unpublished even as we were finishing off our recommendations. We fully expect this alteration to be a standard part of lung cancer diagnostics by the time we develop the next guideline – and we’ll probably see other up-and-coming tests such as MET splicing variants, too.

Quis custodiet?

The international, multidisciplinary panel was established jointly by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. It included pathologists, oncologists, pulmonologists, a methodologist, laboratory scientists, and patient representatives who collaborated to develop the guideline following the Institute of Medicine’s evidence-based process. We really tried to adhere to the formal evidentiary basis of the recommendations, and to avoid falling back on opinion statements. The rigor of the process takes time, but in the end, we are confident that our recommendations are robust.

This update process began approximately 18 months after the publication of the 2013 guidelines, due to the rapid pace of discovery in the field. The panel reviewed the evidence published since the 2013 recommendations had been made and found that the literature either still supported or even strengthened some of those initial recommendations. We also reviewed all available evidence to address the new “key questions” that we had defined with regard to consideration of new genes, new technologies, and new subtypes of lung cancer. A public open comment period provided feedback on the draft guidance, which the authors considered in writing the final guideline recommendations. Finally, a rigorous, independent scientific peer review completed the publication process, with the final guideline appearing in all three organizations’ journals (1).

New techniques; new technologies

Our recommendations are determined by the strength of the available evidence at the time of their writing. At the moment, the evidence does not support the use of cell-free DNA for routine initial diagnosis, despite its growing popularity. In some clinical settings, however, tissue-based EGFR analysis cannot be performed – either because tissue biopsy material is unavailable or insufficient, or because tissue re-biopsy is not feasible. In these situations, a cell-free DNA assay to identify activating EGFR mutations is recommended as an alternative molecular diagnostic procedure. However, in progression, testing for EGFR T790M is required, and good evidence supports the use of either biopsy or cell-free circulating DNA methods in this context. As technologies and testing methodologies continue to advance and more evidence becomes available, we will continue to update the recommendations as needed.

One particularly exciting area is the notion of quantitative monitoring of disease burden by analyzing mutations in cell-free DNA. I expect that this will emerge in the coming years, and, in the next guidelines, we may be looking into the standardization of quantitative cell-free DNA assays for mutation load assessment, in a manner analogous to BCR-ABL1 fusion testing in chronic myeloid leukemia.

Need to know

The guideline’s purpose is to set the standards for the molecular analysis of lung cancers to guide targeted therapy treatment decisions, but it’s a rapidly evolving field. We base our recommendations on the evidence that has been published at the time, and what that evidence indicates is necessary to provide adequate care for lung cancer patients today. New findings will emerge, practices will evolve, and we will issue new recommendations when the evidence to do so has accumulated satisfactorily – but, in the meantime, all providers who care for lung cancer patients are advised to keep abreast of advances in the field.

As with any evidence-based clinical practice guideline, following these recommendations is not mandatory – but we encourage pathologists and laboratories to review and adopt them so that we can provide patients battling lung cancer with the greatest possible treatment benefit. The guideline was a successful collaboration of international, multidisciplinary experts from CAP, IASLC, and AMP, all of whom spent countless hours working to assess the available evidence and determine the best path forward to ensure clinicians stay apace and provide optimal patient care.

Neal Lindeman is AMP Co-chair and Member, Director of Molecular Diagnostics at Brigham and Women’s Hospital, and Associate Professor of Pathology at Harvard Medical School in Boston, USA.