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Lung Cancer Molecular Testing Guidelines Updated by CAP, AMP, IASLC

NEW YORK (360Dx) – The College of American Pathologists, The International Association for the Study of Lung Cancer, and the Association for Molecular Pathology have released new molecular testing guidelines for lung cancer that includes 18 new recommendations and three updates since the joint guidelines were first released in 2013.

The guidelines, published online on Tuesday, are intended to identify patients for treatment with tyrosine kinase inhibitors. A key change introduced in the current guidelines is the addition of ROS1 as the third gene that should be offered "by all laboratories that test lung cancers, as an absolute minimum." The 2013 guidelines had only included EGFR and ALK in that necessary category, and had named the gene KRAS as conditionally necessary because of its "ease of analysis and mutual exclusivity with EGFR and ALK." The updated guidelines put KRAS, BRAF, MET, RET, and ERBB2, commonly referred to as HER2, into a second group of genes that should be included in any expanded panel offered for lung cancer patients. KRAS may also be offered as a single gene test.

According to the guidelines, patients can be either offered the expanded panel, or offered the targeted panel of EGFR, ALK and ROS1 first, with the expanded panel or single-gene KRAS tests offered as secondary tests when necessary. The guidelines currently consider all other genes investigational, based on available published evidence at this time.

Other key changes include the addition of immunohistochemistry as an equivalent alternative to fluorescence in situ hybridization for ALK testing. When the original guidelines were released, an ALK FISH break-apart assay was the only assay that had evidence of clinical utility from prospective studies to select patients for crizotinib, which is marketed by Pfizer under the brand name Xalkori.

Beyond testing for EGFR, ALK and ROS1, the guidelines identify multiplexed genetic sequencing panels as preferred over multiple single-gene tests to identify other treatment options. That recommendation was made as an "expert consensus opinion" because of limitations in the amount of evidence available.

While the original recommendations preferred cell block testing over smears, more recently published studies have shown excellent performance of smear testing, and the new guidelines no longer indicate a preference between the two.

A key challenge to developing the new guidelines that the guideline authors noted is the increasingly small size of populations affected by a treatment that can be identified by genomic analysis.

"When a dramatic clinical response is seen in 0.5 percent of patients with a condition – even a common condition such as lung cancer – how do we recruit enough patients to study to prove that the dramatic response is a general truth that should change practice, and how do we decide that everyone in the world should get the test that can determine if they are in that 0.5 [percent]?" they wrote in their conclusion.

The updated guidelines were published in the Archives of Pathology & Laboratory Medicine, Journal of Thoracic Oncology, and Journal of Molecular Diagnostics. The guidelines were developed by a panel that included pathologists, oncologists, a methodologist, laboratory scientists, and patient representatives, and was led by Neal Lindeman, director of molecular diagnostics at Brigham and Women's hospital and associate professor of pathology at Harvard Medical School.

"We hope that these updated guidelines will help providers around the world better interpret the effectiveness of therapies that are designed to target an individual cancer's genetic vulnerabilities," Lindeman said in a statement.

The groups said that the guidelines will be reviewed at least every four years, or earlier, if high-quality evidence that could alter guideline statements is published in the interim.