Three Leading Medical Societies Update Molecular Testing Guideline for Lung Cancer TKI Treatment

Targeted therapy with tyrosine kinase inhibitors (TKIs) can provide significant benefit for patients with lung cancer whose tumors harbor certain molecular alterations. New evidence regarding therapies, technologies, and targetable genes in the ever-evolving lung cancer molecular pathology landscape spurred an evaluation and update of the evidence-based guideline on molecular testing for the selection of patients with lung cancer for treatment with TKIs.

First published in 2013 by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology, the updated guidance is the culmination of a reconvening of representatives from the 3 medical societies, and includes 18 new recommendations, as well as 3 revisions to the existing information.

Among the new recommendations are several key changes. One is to test for ROS1 rearrangements in all patients with advanced adenocarcinoma of the lung. “Although relatively rare, accounting for less than 2% of non–small cell lung carcinomas and 2% to 3% of lung adenocarcinomas, structural rearrangements involving the ROS1 gene generate an oncogenic fusion that can be treated successfully with targeted inhibitors,” the authors wrote in their explanation of the new guidance.

Another important recommendation was the call for multiplexed next-generation sequencing (NGS) panels, as opposed to single-gene assays, to allow for the inclusion of additional genes that could help in identifying treatment options for patients with lung cancer. “NGS enables the simultaneous assessment of all 3 of the ‘must-test’ genes in lung cancer—EGFR, ALK, ROS1—as well as each of the genes suggested for inclusion in larger panels—BRAF, RET, ERBB2 (HER2), KRAS, MET—and hundreds to thousands of other genes that may have potential roles in cancer development,” the authors wrote.

The authors also recommended immunohistochemistry (IHC) as a viable alternative to fluorescence in situ hybridization in testing for ALK and ROS1 alterations. In addition, the new guidance states that laboratory testing for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors should have the capability to detect the genetic alterations in as little as 5% of viable cells.

Another new recommendation is to use cell-free plasma DNA testing to identify targetable mutations in settings where tissue is insufficient for molecular testing.

Although the expert panel reaffirmed much of the original guideline, 3 changes emerged from the re-evaluation.    

The first change allows for the testing of any cytology sample with adequate cellularity, a departure from the original recommendation, which preferred cell blocks over smears. “A recent systematic review identified by the literature search has indicated that numerous studies have been published showing excellent performance of smear preparations, such that this preference is no longer appropriate,” the authors wrote.

The second change to the guideline is a recommendation for improved assay sensitivity. The authors state that molecular testing must have the capability of detecting mutation in a sample comprised of ≥20% malignant cells.

“Given the widespread availability of technology capable of reliably detecting lower-frequency mutational events in small samples, it is no longer appropriate to offer a low-sensitivity test that cannot test tumors with 20% to 50% tumor content and requires patients to undergo more procedures, and potentially more invasive procedures, solely to procure a tissue sample with high tumor content,” the authors noted.

The third change is a recommendation against the use of IHC in testing for EGFR mutations, in light of advances in molecular diagnostic technology.                 

Source
Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol. 2018;13:323-358.