Abstract IA15: Bringing personalized therapy into the clinic: Can pathology deliver?

The rapidly evolving area of personalized medicine in the treatment of non-small cell lung cancer (NSCLC) raises many questions, not the least of which is posed in the title of this abstract. The short answer is ‘yes’, but there are, inevitably, some caveats. But it is essential that Pathology does deliver, in support of this vital and exciting development.

The recognition that some drugs have differential efficacy (pemetrexed) or toxicity (bevacizumab), depending on the histological subtype of NSCLC was a key factor in focusing the lung oncology community on the importance of pathological diagnosis in NSCLC. The rapid emergence of molecular targeted therapies, which appear to be primarily effective against tumors which bear, and are driven by, particular molecular/genetic changes has increased the demand upon Pathology to deliver a molecular as well as morphological diagnosis. This demand will only increase, as more targets are identified. Whilst the assessment of some such predictive markers is a clinical reality right now, the development of clinically applicable prognostic markers, primarily to determine adjuvant therapy is less advanced, but ‘on the agenda’.

The portfolio of possible tests is thus rapidly expanding. In NSCLC, the accuracy and specificity of morphological diagnosis is aided by immunohistochemically (IHC) determined molecular profiles. IHC also has a potential role in identifying some predictive markers, such as ALK, EGFR, MET, mutant EGFR and ERCC1 proteins. Some have advocated an alternative approach to some of these, and other markers; the assessment of mRNA rather protein. In some instances, the potentially important predictive information appears to be gene copy number (PI3K, C-MET, possibly EGFR or HER2, FGF2 etc), making in situ hybridization (ISH) approaches an important part of testing strategy. ISH is also a key factor in detecting ALK gene rearrangements. Gene mutations are, of course, of key importance; activating mutations of several genes may give rise to tumors ‘addicted’ to a hyperactive tyrosine kinase which can be targeted. Multiplex approaches, allowing the parallel assessment of several gene sequence or copy number alterations are being developed. Multi-gene expression signatures have been used to generate both predictive, but more usually prognostic data which may yet find a secure clinical niche. Multiple different testing modalities may be required, on the same tissue sample.

‘Tissue is the issue’. Tissue diagnosis of lung cancer is particularly challenging, not only because of the complexity and variability in NSCLC morphology, but also because the tissue samples on which diagnosis is made are frequently very small, contaminated by non-neoplastic tissue and sometimes of poor quality. Poor patient cardiorespiratory fitness and tumor location often conspire to limit access to tumor tissue; most patients present with advanced disease so that whole tumor resection is inappropriate. One of the greatest challenges in Pathology is the most efficient and appropriate utilization of this very limited tissue resource. A culture shift around tissue acquisition may be required; away from minimal intervention producing only the bare minimum for diagnosis, towards maximizing tissue yield as safely as possible in each patient. Repeat biopsy may be indicated. Nonetheless, it will not be possible to ‘test for everything’ on these limited samples, for some patients testing will be suboptimal due to inadequate material for testing. Testing algorithms are urgently needed to address the needs of individual patients. Allied to these are questions around who decides which tests should be prioritized? At which point in the investigation cycle should they be performed? Where should these tests be performed and by whom? These points raise further issues relating to communication between oncologists, pathologists and patients. Reimbursement is also an issue.

Does the ‘result’ of the test adequately and accurately reflect the relevant marker status of the patient's entire tumor burden? The uncomfortable truth is that it may not. Both pathologists and oncologists have a responsibility to understand the limitations of the tests, make certain that the patient is given the best possible chance of an informative diagnosis, and ensure the highest quality in testing methodology and outcome. Tumor heterogeneity and sampling error may conspire to render a non-representative test outcome. Tissue handling and processing may compromise the outcome of the test. Unless great care is taken, the tissue used for extraction of DNA or RNA may not contain sufficient cellular tumor tissue to allow the test methodology in use to provide a relevant result. External quality assurance measures are important to ensure and maintain the highest standards in laboratory practice. Validated, reliable and meaningful testing methods must be employed.

Pathology can and must deliver on this important new aspect of lung cancer diagnosis. Education and training of ALL those involved in the diagnostic process is required – awareness of the issues will help eliminate errors and improve outcomes for patients. Time, technological and tissue resources may be in short supply; collaboration and communication between all parties is essential for the most efficient and effective use of available diagnostic material.