The new guidelines from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology (CAP/IASLC/AMP) are a significant step toward personalized therapy of patients with lung cancer. More than 226,000 new patients per year are diagnosed with lung cancer in the United States. Therapy with EGFR and ALK tyrosine kinase inhibitors for patients with advanced non–small cell lung cancer (NSCLC) has led to significant improvement in response and progression-free survival for the subgroups of patients with tumors harboring EGFR and ALK abnormalities compared with conventional chemotherapy. Thus, molecular testing is now crucial for choosing therapy in patients with advanced NSCLC.

Paving the Way for Future Testing

The new guidelines are based on a thorough review of evidence from numerous studies published in the period 2004 to 2012. They provide a wide range of recommendations covering tissue acquisition, processing, analysis, reporting, and timeline for analysis. Although the guidelines focus on only the two biomarkers that currently have therapeutic implications, they also pave the way for future biomarker testing for other potential targets and agents, some of which are already being evaluated in clinical trials. Of specific importance is the multidisciplinary approach to biomarker testing and individualized therapy and the importance of establishing multidisciplinary teams including pathologists, diagnostic interventionists, and medical oncologists.

“The tissue is the issue” is a strong theme in the guidelines. They recommend that pathologists should determine the quality of the tumor tissue by assessing cancer cell content and DNA quantity and quality. The quality control of the tumor specimens should be initiated as soon as possible and, most optimally, on site in order to avoid the need for extra or later biopsies from the same patient. It is also important to pay attention to the 2‑week timeline (10 working days) for biomarker testing and reporting recommended in the guidelines. The fact that we are dealing with patients with advanced cancer makes it crucial that the biomarker testing does not delay the initiation of effective therapy.

Who Should Be Tested?

The guidelines recommend molecular testing of all advanced NSCLC patients with a tumor containing an adenocarcinoma component—which seems to be a reasonable and feasible recommendation, although some patients with nonadenocarcinomatous tumors might have either an EGFR mutation or ALK rearrangement. It is important to emphasize that no patients with an adenocarcinoma component should be excluded from specific targeted therapy based on clinical characteristics, unless the patient’s clinical situation makes targeted therapy “not possible.” In such situations, the omnipresent need for good communication between the clinical care team and the testing laboratory is particularly evident.

EGFR Testing

EGFR mutation testing should be performed by a validated EGFR testing method. The guidelines do not specify the assay methodology. However, the guidelines emphasize the importance of quality controls of the testing laboratory through proficiency testing (CLIA-certified) and they recommend use of methodologies that can detect mutations in specimens with at least 50% tumor cells and preferably those able to detect mutations in specimens with as little as 10% cancer cells.

Again, these recommendations call for stringent quality control of the tumor tissue before processing for mutation analysis. Mutation testing should be able to detect all EGFR mutations that have been reported with a frequency of at least 1%, including the “resistant” mutation T790M. The guidelines give strict recommendations in this regard, although the clinical significance of many rare mutations is not entirely established.

ALK Testing

It is recommended that ALK testing be done with ALK fluorescence in situ hybridization (FISH) for eligibility in clinical trials, since this test is currently the only FDA-approved companion diagnostic. However, the question is what to use for a screening test for ALK rearrangement. Numerous studies over the past several years have compared immunohistochemistry (IHC) to FISH and found good sensitivity (~80%–95%) and specificity (90%–100%) with IHC, depending somewhat on methodology and antibody used. The guidelines state that ALK IHC, if carefully validated, may be considered as a screening methodology to select specimens for ALK FISH testing.

The ALK FISH test is still costly and very much skill-dependent, whereas IHC is readily clinically applicable and performed in every pathology department. However, as noted, further validation of the ALK IHC assay is needed, and the assay is not yet FDA-approved for therapeutic applications. Although the ALK FISH assay with specific criteria defined as “positive” is the gold standard, some case reports have already been published concerning patients with tumors that are ALK FISH-negative but IHC-positive and show significant response to ALK inhibition. Thus, it may be that the future will call for a combined diagnostic paradigm including both IHC and FISH.

Clinical Practice

Now that molecular testing of patients with advanced NSCLC is required and guidelines are established, the next step will be the implementation of these guidelines into clinical practice. According to the most optimistic reports, only 60% to 70% of patients with advanced NSCLC undergo molecular testing, more commonly in the academic environment than in community practices. In order to capture all the patients who will benefit from personalized therapy, a wide range of educational activities have to be implemented.

While molecular testing for patients with advanced NSCLC is already implemented in many places in the United States and many other countries, the new guidelines should have a significant impact on the overall future management of all patients with lung cancer, since they cover a broad range of crucial aspects of molecular testing. It is important to emphasize that molecular testing is complex. Standardization in testing is crucial if patients are to be able to take advantage of therapeutic progress; “failed” molecular testing or false-negative results can lead to a detrimental effect in individual patients.

And while the new guidelines are expected to lead to a significant improvement in patient care, their success in this regard is entirely dependent on success in establishing a multidisciplinary team approach to the management of patients with lung cancer—also stressed by the new guidelines. With the continued rapid movement toward personalized medicine, such guidelines will need to be continuously monitored and modified as diagnostic and therapeutic progress occurs.

Barriers to Implementation

The implementation of the new guidelines carries some financial implications. However, the prices for molecular testing and the applied assays have dropped significantly over the past several years and continue to drop. In any case, costs of testing must be viewed in the context of the price associated with offering a patient ineffective or less-effective therapy due to lack of testing or failed testing due to lack of guidelines and/or standardization.

Another potential barrier for molecular testing is the fact that many patients with advanced NSCLC often have only very small biopsy or cytology specimens, making testing difficult or impossible, particularly if the sparse material has already been exhausted for routine diagnostic purposes. Despite the fact that technology is rapidly evolving and assays become more and more applicable to small biopsies and cytology specimens, there will still be some patients for whom molecular profiling will not be possible and for whom standard chemotherapy is the only option. The implementation of the new guidelines will in many cases lead to a tough prioritization of sparse available tumor material—although ongoing development of multiplex technologies covering several biomarkers will help remedy this situation in the future. It needs to be emphasized that the prioritization of sparse tumor material should be addressed based on a multidisciplinary approach.

Conclusion

The new CAP/IASLC/AMP guidelines for molecular testing represent a significant step toward standardization and implementation of personalized medicine for patients with lung cancer. Successful implementation of the guidelines into clinical practice should significantly improve clinical care and secure for many patients the most optimal therapeutic options. Further, the guidelines provide an important framework for incorporating the new recommendations and standards that will be needed as progress toward personalized medicine continues. ■

Dr. Hirsch is Professor of Medicine and Pathology, University of Colorado Cancer
Center, Aurora.

Disclosure: Dr. Hirsch has participated in advisory boards for Pfizer, Boehringer-Ingelheim, Roche/Genentech; his laboratory has (through University of Colorado) research funding from Genentech, Lilly/Imclone, Ventana-Roche; and he is a member of Board of Directors for The International Association for the Study of Lung Cancer (IASLC) and has been advisor for the guidelines.