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ASCO Endorses Guideline for Molecular Testing to Select Lung Cancer Patients for EGFR and ALK Inhibitor Treatment

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Key Points

  • The guidelines recommend that EGFR and ALK testing be offered to all patients with lung adenocarcinoma, irrespective of characteristics such as gender, race, and smoking status.
  • Laboratories can use a range of different testing methods, provided they meet certain technical requirements.
  • Laboratories should adhere to guidance regarding specimen processing, testing validation, quality assurance, and turnaround times for reporting results.

ASCO has endorsed the recently developed joint College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and Association of Molecular Pathologists (AMP) guideline on molecular testing for selection of patients with lung cancer for EGFR and ALK inhibitor treatment.

The endorsement, reported in the Journal of Clinical Oncology by Natasha B. Leighl, MD, of Princess Margaret Cancer Centre, and colleagues, follows review of the guideline by an ASCO Expert Panel cochaired by Dr. Leighl and Natasha Rekhtman, MD, PhD, of Memorial Sloan Kettering Cancer Center.

The guideline, summarized below, provides CAP/IASLC/AMP expert panel recommendations (evidence grades A and B), consensus opinions (opinions), and suggestions.

Which patients should be tested for EGFR mutations and ALK rearrangements?

Recommendation: EGFR and ALK molecular testing should be used to select patients for EGFR-targeted and ALK-targeted tyrosine kinase inhibitor therapy, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics.

Recommendation: For lung cancer resection specimens, EGFR and ALK testing is recommended for adenocarcinomas and mixed lung cancers with an adenocarcinoma component, regardless of histologic grade. For fully excised lung cancer specimens, EGFR and ALK testing is not recommended in lung cancers that lack any adenocarcinoma component, such as pure squamous cell carcinomas, pure small cell carcinomas, or large cell carcinomas lacking any immunohistochemistry evidence of adenocarcinoma differentiation.

Recommendation: For more-limited lung cancer specimens (biopsies, cytology) in which an adenocarcinoma component cannot be completely excluded, EGFR and ALK testing may be performed in cases that show squamous or small cell histology, but clinical criteria (eg, younger age, lack of smoking history) may be useful in selecting a subset of these samples for testing.

Recommendation: To determine EGFR and ALK status for initial treatment selection, primary tumors or metastatic lesions are equally suitable for testing.

Opinion: For patients with multiple, apparently separate, primary lung adenocarcinomas, each tumor may be tested, but testing of multiple different areas within a single tumor is not necessary.

When should a patient specimen be tested for EGFR mutation or ALK rearrangement?

Recommendation: EGFR mutation testing should be ordered at the time of diagnosis for patients who present with advanced-stage disease (stage IV) who are suitable for therapy or at time of recurrence or progression in patients who originally presented with lower-stage disease but were not previously tested.

Suggestion: ALK rearrangement testing should be ordered at the time of diagnosis for patients who present with advanced-stage disease (stage IV) and are suitable for therapy, or at time of recurrence or progression in patients who originally presented with lower-stage disease but were not previously tested.

Opinion: EGFR and ALK testing of tumors at diagnosis from patients who present with stage I, II, or III disease is encouraged, but the decision should be made locally by each laboratory in collaboration with its oncology team.

Recommendation: Tissue should be prioritized for EGFR and ALK testing.

How rapidly should test results be available?

Opinion: EGFR and ALK results should be available within 2 weeks (10 working days) of receiving the specimen in the testing laboratory.

Opinion: Laboratories with average turnaround times > 2 weeks need to make available a more rapid test—either in-house or through a reference laboratory—in instances of clinical urgency.

Opinion: Laboratory departments should ensure that specimens that have a final histopathologic diagnosis are sent to outside molecular pathology laboratories within 3 working days of receiving requests and to intramural molecular pathology laboratories within 24 hours.

How should specimens be processed for EGFR mutation testing?

Opinion: Formalin-fixed, paraffin-embedded specimens or fresh, frozen, or alcohol-fixed specimens should be used for polymerase chain reaction (PCR)-based EGFR mutation tests.

Other tissue treatments (eg, acidic or heavy metal fixatives, or decalcifying solutions) should be avoided. Cytologic samples are also suitable for EGFR and ALK testing, with cell blocks being preferred over smear preparations.

What are the specimen requirements for EGFR testing?

Opinion: Adequacy of specimens for EGFR testing should be determined by assessing cancer cell content and DNA quantity and quality. Each laboratory should establish the minimum proportion and number of cancer cells needed for mutation detection during validation. A pathologist should assess the tumor content of each specimen and either perform, or guide a trained technologist to perform, microdissection for tumor cell enrichment as needed.

How should EGFR testing be performed?

Recommendation: Any validated EGFR testing method with sufficient performance characteristics may be used.

Opinion: Laboratories should use EGFR test methods that are able to detect mutations in specimens with ≥ 50% cancer cell content, although laboratories are strongly encouraged to use (or have available at an external reference laboratory) more sensitive tests that are able to detect mutations in specimens with as little as 10% cancer cells.

Opinion: Clinical EGFR mutation testing should be able to detect all individual mutations that have been reported with a frequency of ≥ 1% of EGFR-mutated lung adenocarcinomas.

Recommendation: Immunohistochemistry for total EGFR is not recommended for selection of EGFR tyrosine kinase inhibitor therapy. EGFR copy number analysis (ie, fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization) is not recommended for selection of EGFR tyrosine kinase inhibitor therapy.

Recommendation: KRAS mutation testing is not recommended as a sole determinant of EGFR tyrosine kinase inhibitor therapy.

What additional testing considerations are important in the setting of secondary or acquired EGFR tyrosine kinase inhibitor resistance?

Recommendation: Testing on specimens from patients with acquired resistance to EGFR kinase inhibitors should be able to detect the secondary EGFR T790M mutation in as few as 5% of cells.

What methods should be used for ALK testing?

Recommendation: Laboratories should use an ALK FISH assay using dual-labeled break-apart probes for selecting patients for ALK tyrosine kinase inhibitor therapy; ALK immunohistochemistry, if carefully validated, may be considered as a screening methodology to select specimens for ALK FISH testing.

Recommendation: Reverse transcriptase PCR is not recommended as an alternative to FISH for selecting patients for ALK inhibitor therapy.

Opinion: A pathologist should be involved in the selection of sections for ALK FISH testing, by assessing tumor architecture, cytology, and specimen quality. A pathologist should participate in the interpretation of ALK FISH slides, either by performing the analysis directly or by reviewing the interpretations of cytogeneticists or technologists with specialized training in solid tumor FISH analysis.

Opinion: Testing for secondary mutations in ALK associated with acquired resistance to ALK inhibitors is not currently required for clinical management.

For full disclosures of the study authors, visit jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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