Over the past decade, prospective studies have clearly demonstrated that certain specific mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) are associated with dramatic response to EGFR TK inhibitors in patients with non-small cell lung cancer (NSCLC). Since the initial recognition six years ago, the presence of EML4-ALK translocation has now been shown to identify a subgroup of patients likely to respond to crizotinib. However, as is nearly always the case, translating these research findings to clinical practice remains a challenge.
Several questions linger despite copious amounts of research work in this area. For starters:
- Should we screen all patients with NSCLC for molecular alterations?
- What specific molecular tests should be done?
- Can KRAS mutation analysis be used to select patients for anti-EGFR therapy?
- What standards should the laboratories follow?
- What is the optimal turn around time?
These issues transcend the traditional boundaries of medical practice and involve pathologists (anatomical, molecular), pulmonologists, thoracic surgeons, interventional radiologists, and medical and radiation oncologists.
In the absence of well-defined prospective clinical trials to address each and every one of these practice issues related to molecular testing, a comprehensive review of the published literature overseen by unbiased experts cutting across a wide variety of disciplines is perhaps the best way to guide practicing physicians and the lung cancer community. Accordingly, a team of experts convened by the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association of Molecular Pathology (AMP) has recently completed such an endeavor.
The team reviewed published data before developing guidelines for EGFR and ALK molecular testing in patients with lung cancer. These findings were published jointly in Archives of Pathology and Laboratory Medicine, The Journal of Molecular Diagnostics and the Journal of Thoracic Oncology.
The expert panel screened 1,533 abstracts to identify 521 pertinent articles for detailed review. The members of the panel formulated initial recommendations at a public meeting. An advisory panel reviewed draft versions of the recommendations. Based on the strength of the data the recommendations were graded. Grades A or B were assigned when the available data are strong enough to support clinical practice in all or most situations. When the data are insufficient (Grades C or D), expert consensus option was used. All members completed the CAP conflict-of-interest process. Only members with no real or perceived conflict of interest served as authors on the expert panel. The CAP, IASLC, and AMP organizations provided the funding for this effort. No industry funding was used for this project.
The clinical practice guideline (CPG) with regard to molecular testing of EGFR and ALK in patients with lung cancer addressed five principal and 14 corollary questions. The key questions:
1. When should molecular testing for NSCLC performed?
2. How should EGFR testing be performed?
3. How should ALK testing be performed?
4. Should other genes be routinely tested in lung adenocarcinoma?
5. How should molecular testing of lung adenocarcinoma be implemented and operationalized?
The panel felt there was sufficient evidence to recommend that EGFR molecular testing and ALK testing in patients with lung adenocarcinoma. The clinical characteristics (age, gender, ethnicity, and smoking status) are not sufficiently specific to identify a subgroup of patients more likely to harbor these molecular alterations. However, in the setting where only a limited amount of material is available (small core biopsies and cytological specimens) where an adenocarcinoma component cannot be completely ruled out, EGFR and ALK testing are recommended in patients who are young and report no history of tobacco smoking.
The panel felt that the quality of specimens (tumor content and preservation) matters more than whether they are obtained from primary or metastatic lesions. The recommendation is that EGFR and ALK testing be done at the time of the diagnosis of metastatic disease. The tissue should be prioritized for EGFR and ALK testing after a diagnosis of lung adenocarcinoma is established.
In the absence of data, the consensus opinion from this expert panel determined that the optimal turn-around time was two weeks (10 working days). The panel also addressed the issues of how the specimens should be processed for EGFR mutation testing, the minimum proportion and number of cancer cells needed for mutation detection.
The panel advised against using EGFR testing using immunohistochemistry or copy number analyses (FISH or chromogenic in situ hybridization) instead of EGFR mutation testing. The panel does not recommend using KRAS mutation testing alone as a sole determinant of anti-EGFR therapy given the lack of significant benefit in EGFR wild subgroup (regardless of KRAS mutation status) with upfront EGFR TK inhibitors.
The panel recommends use of an ALK FISH assay using dual-labeled break-apart probes. The consensus opinion favors the involvement of a pathologist to choose the most appropriate slides for the ALK FISH test. The expert panel felt that the published data are insufficient at the present time to develop guidelines for testing other molecular markers in lung cancer. In addition, the panel addressed other issues related to testing, validation, reporting, and quality assurance.
Reflex testing, an approach that does not require a specific order from the clinician, was deemed appropriate by the panel if agreed upon by the (institutional) lung cancer care team in order to expedite the test results. However, it is worth remembering that sometimes the initial core biopsies with limited material may be followed by a more complete resection. A reflex testing done on a smaller core needle biopsy with a poor-quality specimen may not yield optimal results compared with the test done on a larger resected specimen.
A robust communication system should be put in place in order to optimize the process between the clinicians and pathologists. I commend the panel for taking this opportunity to remind the pathology community that the term “non-small cell lung carcinoma” is no longer an acceptable pathological diagnosis for resected specimens.
This set of guidelines, distilling many years of research to optimize molecular testing in lung cancer, is obviously only the beginning of a new approach to standardize testing for individualized therapy. Large-scale genomic studies through The Cancer Genome Atlas (TCGA) and other groups undoubtedly will identify several additional molecular targets for therapy. With further advances in molecularly targeted therapies, the number of targets to be tested will only expand incrementally.
It is likely that multiplex testing for a large set of molecular markers will soon become a reality in the clinic.