Somatic mutations and immune checkpoint biomarkers

Abstract

The development of molecular testing for identifying somatic mutations and immune checkpoint biomarkers has directed treatment towards personalized medicine for patients with non‐small cell lung cancer. The choice of molecular testing in a clinical setting is influenced by cost, expertise in the technology, instrumentation setup and sample type availability. The molecular techniques described in this review include immunohistochemistry (IHC), fluorescent in situ hybridization, direct sequencing, real‐time polymerase chain reaction (PCR), denaturing high‐performance liquid chromatography, matrix‐assisted laser desorption/ionization time of flight mass spectrometry and next‐generation sequencing (NGS). IHC is routinely used in clinical practice for the classification, differentiation, histology and identification of targetable alterations of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and programmed death ligand‐1 (PD‐L1). Recently, the PD‐L1 pathway was identified as being exploited by tumour cells, allowing immune resistance and tumour evasion. The development of immune checkpoint inhibitors as treatment for tumours expressing checkpoints has highlighted the need for standardized IHC assays to inform treatment decisions for patients. Direct sequencing was historically the gold standard for mutation testing for EGFR, KRAS (Kirsten rat sarcoma viral oncogene homologue) and BRAF (v‐Raf murine sarcoma viral oncogene homologue B1) requiring a high ratio of tumour to normal cells, but this has been superseded by more sensitive methods. NGS is a new emerging technique, which allows high‐throughput coverage of frequently mutated genes, including less common BRAF and MET mutations and alterations in tumour suppressor genes. When an NGS platform is unavailable, PCR‐based technologies offer an efficient and cost‐effective single gene test to guide patient treatment. This article will review these techniques and discuss the future of molecular platforms underpinning clinical management decisions.

Chronic obstructive pulmonary disease (COPD) and lung cancer: common pathways for pathogenesis

“…EGFR and KRAS are two of the most commonly mutated oncogenes in adenocarcinoma, with EGFR being found to be over-expressed in 40-80% of NSCLC cases and associated with higher metastatic and tumour proliferation rate, advanced staging and poorer prognosis (75,76). Further mutant forms of EGFR (deletion in exon 19 and L858R in exon 21) with tyrosine kinase activity have been identified to play a role in lung carcinogenesis and further have been considered targets for treatment (77,78). This led to the development of specific EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib which were approved by the FDA as therapeutics for advanced and metastatic NSCLC (79,80).…”

Path Less Traveled: Targeting Rare Driver Oncogenes in Non–Small-Cell Lung Cancer

“…The means of detecting ROS1 fusions have been variable from reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). 28 Currently, the companion diagnostic test for ROS1 rearrangement approved by the US Food and Drug Administration (FDA) is NGS (Oncomine Dx Target test, PMA number P160045), but FISH is still routinely used to detect ROS1 fusion. IHC screening followed by either FISH confirmation 29 or RT-PCR confirmation (AmoyDx ROS1 gene fusion detection kit) is also used.…”

Identification of immune subtypes and response prediction to immune-checkpoint inhibitors for MDM4 gain/amplification luminal A type breast cancer

“…Increasingly the literature [22][23][24]suggests that response of cancer immune check-point therapy was predicted by a series of biomarkers, including PD1/PD-L1, DNA damage response related gene, major histocompatibility complex (MHC), IFN responses and so on.…”