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ECCO 2017 webcasts - Part 2

'Identifying the right patient: histological and molecular profiling challenges' by Keith Kerr

Identifying the right patient - Keith Kerr

Keith Kerr
University of Aberdeen

“We are very adventurous in identifying new targets for treatment of lung cancer. As we learn more about the characteristics and biology of tumours we can develop new therapeutic opportunities to target different aspects of malignant diseases and new biomarkers will evolve to identify the best patient”, outlines Keith Kerr, University of Aberdeen, Scotland.

Many cancers are driven by multiple genetic and epigenetic alterations. Despite this complexity a single abnormality may play a more dominant role and is driving the cancer, a concept known as oncogene addiction. This is a feature of adenocarcinomas of the lung in the European population that are mostly not tobacco-related, nearly no squamous cell carcinomas fall in this category. These addictive oncogenes can be targeted by drugs and patients receiving a genotype-directed therapy respond with an increase in median overall survival.

On the basis of particular molecular abnormalities lung adenocarcinomas can be subdivided into ever smaller groups of potential targetable treatments. But so far only few of them are of clinical importance such as the epidermal growth factor receptor (EGFR) and the anaplastic lymphoma kinase (ALK) fusion gene. Testing for and treating EGFR mutation and ALK gene fusion are standard of care for patients with advanced non-small cell lung carcinoma (NSCLC) and recommended by the guidelines. Emerging targets in adenocarcinoma are ROS1, already approved in Europe, BRAF with breakthrough status of the FDA and further biomarkers such as RET rearrangement, NTRK1 fusion, HER2 mutation, KRAS mutation and MET Exon 14 skip mutations.

Patients treated with tyrosine kinase inhibitors (TKI) can develop resistence to first-line therapy over time like the T790M mutation. “Therefore we need to understand much more about the different mechanism of resistence,” explains Keith Kerr. “This will open up a panel of new testing challenges for pathology in order to identify the next appropriate step in the treatment”.

In contrast to adenocarcinomas squamous cell carcinomas are less driven by mutations than by upregulation of the wild type genes e.g. through amplification of EGFR. There are only few addictive oncogenes detected. The commonest are inactivation mutations in tumour surpressor genes, which are no suitable targets for therapeutic intervention.

Current diagnostic algorithms involve – once lung cancer is diagnosed and the subtype specified – two parallel pathways: a “teste-tube” with extracted DNA test to detect mutations like EGRF, KRAS, or BRAF, and morphology-based tests such as fluorescent in situ hybridization (FISH) or immunohistochemistry (IHC) for biomarkers as ALK, ROS1 or programmed death-ligand 1 (PD-L1). A challenge is the limited availability of tumour material and that most clinical samples are diluted by non-tumour fragments.

Newer technologies like next-generation sequencing (NGS) are certainly powerful but at the moment the experience is mixed: “We get a large array of genetic data for one single sample but currently they are of no clinical value. It is hard to justify the costs if you test only for EGFR or ALK. But with more biomarkers available multiplex testing will have certainly a future”, notes Keith Kerr.