pathology and diagnostics The new kid on the block
Next generation sequencing is practical and reliable to use on tissue specimens and potentially on liquid biopsies , which potentially will further revolutionise the diagnostic landscape of lung cancer
Marvin Lim Chang Jui MBBCh BAO BA MRCPUK
Anne-Marie Baird BSc ( Hons ) PG Dip ( Statistics ) PhD
Stephen Finn MB BAO BCh FDS PhD FRCPath FFPATH Trinity College Dublin , School of Medicine , Dublin , Ireland
Lung cancer continues to be the major cause of cancer-related death globally . 1 More than two-thirds of lung cancer patients present with advanced disease , 2 , 3 which excludes the option of potentially curative treatments . Another important reason accounting for the high mortality rate is excessive mutational load in patients with smoking history , a phenomenon central to the pathogenesis of lung cancer progression , compared with patients with age-related cancers . 4 Five-year survival of all patients with lung cancer is only 18 %. 5 Recently , great advances have been made in terms of screening , minimally invasive techniques for diagnosis and new treatments . 6 – 9
The recognition of genetic driver mutations in NSCLC has paved the way for the development of targeted therapies , which often provides outstanding responses in patients harbouring specific genetic mutations . 10 , 11 Approximately two thirds of lung adenocarcinomas contain actionable driver mutations , which can be detected using comprehensive molecular profiling . 11 – 13 ALK gene rearrangement in NSCLC was first discovered by Japanese researchers a decade ago . 14 This gene rearrangement , which precipitates expression of oncogenic fusion proteins , is found in approximately 3 – 7 % of patients with metastatic lung carcinoma based on early studies using reverse transcriptionpolymerase chain reaction ( RT-PCR ) and
14 , 15
fluorescence in situ hybridisation ( FISH ). ALK gene fusion with echinoderm microtubuleassociated protein like 4 ( EML 4 ) represents the most frequent rearrangement among the ALK alterations . 12 , 16 Other fusion partners have also been reported such as TPR , HIP 1 , FAM 179 A
17 – 20 and COL25A1 .
Drug discovery The discovery of ALK rearrangement led to advent of crizotinib , a tyrosine kinase inhibitor ( TKI ) with powerful activity against ALK . Crizotinib showed a response rate of 74 % with progression-free survival ( PFS ) of 10.9 months compared with a response rate of 45 % with PFS of 7 months in standard platinum doublet chemotherapy ( either carboplatin or cisplatin plus pemetrexed ). 21 This superior outcome
The recognition of genetic driver mutations in NSCLC has paved the way for the development of targeted therapies
compared with standard platinum doublet chemotherapy laid the foundation for targeted therapy as the first-line treatment for ALK-positive NSCLC . 21 Second-generation ALK inhibitors such as ceritinib and alectinib have not only been shown to be effective in the first-line treatment setting but are also effective in patients who develop crizotinib resistance . 22 – 24 In 2013 , FDA granted the approval of crizotinib for treatment of metastatic ALK-positive NSCLC with FISH as companion diagnostic based on efficacy and safety data of Phase II and III
21 , 25 studies .
Benchmark technique FISH is currently the benchmark technique for diagnosis of ALK rearrangements ; however , meticulous preparation and skillful interpretation according to guidelines is necessary for achieving accurate results . Thus , it is expensive , labourintensive and requires a high level of pathology expertise . 26 – 29 On rare occasions , FISH may produce equivocal results because in 5 – 10 % of NSCLC , the rate of rearrangement of positive cells falls within the range of 10 – 20 %; however , the current accepted cut-off for positive cells is 15 % or more . 30 , 31 Immunohistochemistry ( IHC ) is another method that can be used for ALK diagnosis in lung cancer . An IHC companion diagnostic assay was approved in 2015 based on its ability to accurately
32 , 33
identify patients with ALK-rearranged NSCLC . Although IHC has been extensively used in laboratories due to the cost effectiveness , its interpretation requires experience and rarely protein expression may be absent in cases with atypical ALK
34 , 35
rearrangement . Despite these limitations , ALK IHC is gaining momentum in Europe as the primary test usually in a two-step approach with FISH being performed only to confirm positive or equivocal IHC results . 36 – 38 However , a few studies have reported false negative results using IHC , which potentially risk excluding patients from receiving standard of care treatment . 39 , 40 , 41 Molecular diagnosis could surpass the limitations of both FISH and IHC either as a stand alone assay or in concert with either FISH
14 HHE 2018 | hospitalhealthcare . com