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Recommended Testing for Mutations      

Of primary importance, EGFR and ALK testing is recommended for all patients presenting with lung adenocarcinoma or mixed adenocarcinoma, regardless of their clinical characteristics. Furthermore, testing is recommended at diagnosis not only for stage IV disease but also at diagnosis for disease at earlier stages. “This came as a surprise,” according to Dr Spigel, “I expected the guidelines to restrict testing to advanced disease, as earlier guidelines have.”

Tests used to identify EGFR mutations and ALK rearrangements differ. Deletions or point mutations in EGFR have been identified that lead to activation of the EFGR TK domain and confer sensitivity to EGFR TKI.3 In contrast, a specific rearrangement of the ALK gene has been identified that both initiates and maintains tumor growth when present.5 The guidelines specify that testing for EGFR mutations should use real-time qualitative polymerase chain reaction (qRT-PCR), whereas fluorescence in situ hybridization (FISH), not PCR, should be used to identify ALK rearrangements.2,3

Only recently have antibodies with sufficient sensitivity and specificity been identified for ALK immunohistochemistry (IHC). The guidelines state that a well-validated, sensitive ALK IHC may be used to screen patients prior to FISH testing; those who have a negative IHC screening result need not undergo FISH testing.2 “These guidelines point out that while the story of ALK IHC testing is still evolving, it may become an accessible and less expensive way to screen patients who then subsequently could get FISH testing,” noted Dr Spigel.

EGFR mutations and ALK rearrangements are mutually exclusive, with each other and with KRAS mutations in lung cancer.3,4  This mutual exclusivity, coupled with the ready availability of KRAS-mutation testing kits had, in some cases, resulted in the use of KRAS testing to rule out EGFR mutations.2

However, the absence of KRAS mutations is not specific for identification of EGFR mutation or ALK rearrangement, meaning additional tests are required, further adding to delays and tissue usage, according to Dr. Spigel. The new guidelines prioritize molecular testing based on its relevance to treatment decision-making: EGFR testing takes top priority, followed by ALK testing. KRAS testing is not recommended for EGFR-TKI patient selection.2

Overall, these new guidelines, developed with consensus from pathologists and oncologists involved in the study of lung cancer, represent a step forward in formalizing clinicians’ approach to molecular testing. “From a practical point of view, these guidelines help everyone to understand that EGFR and ALK testing is a priority and should be performed on all patients diagnosed with lung adenocarcinoma,” said Dr. Spigel. “They bring attention to the importance of this testing, re-educate and re-energize the whole lung cancer care community, and provide a road map for incorporating these tests into patient care.”


References

1. American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013.
2. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors. Arch Pathol Lab Med. 2013;doi: 10.5858/arpa.2012-0720-OA.

3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non–Small Cell Lung Cancer. Version 2.2013. www.nccn.org. Accessed March 5, 2013.

4. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non–small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27(26):4247-4253. Li Y, 5. Li Y, Yang T, et al. Clinical significance of EML4-ALK fusion gene and association with EGFR and KRAS gene mutations in 208 Chinese patients with non–small cell lung cancer. PLoS One. 2012;8(1):e52093.