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brought into routine clinical practice the analysis of mutations in the <span class="elsevierStyleItalic">EGFR</span> and <span class="elsevierStyleItalic">KRAS</span> genes&#44; and the detection of chromosomal translocations involving the <span class="elsevierStyleItalic">ALK</span> and <span class="elsevierStyleItalic">ROS1</span> genes&#46; Specific activating mutations in exons 18&#44; 19&#44; 20 and 21 of the <span class="elsevierStyleItalic">EGFR</span> gene allow selection of 10-20&#37; of patients for treatment with the EGFR inhibitors gefitinib&#8482; or erlotinib&#8482;&#46; In contrast&#44; patients with other <span class="elsevierStyleItalic">EGFR</span> mutations&#44; namely insertions and deletions in exon 20&#44; and mutations in the <span class="elsevierStyleItalic">KRAS</span> gene&#44; are not likely to respond to the same EGFR inhibitors&#44; and as such should receive alternative treatment&#46; In addition&#44; 3-5&#37; of patients not eligible for EGFR-inhibitor treatment may still benefit from treatment with ALK-inhibitor crizotinib&#8482; as long as they can be confirmed to carry chromosomal translocations involving the <span class="elsevierStyleItalic">ALK</span> or <span class="elsevierStyleItalic">ROS1</span> genes&#46;</p><p class="elsevierStylePara">Currently&#44; lack of integration between molecular assays&#44; requires all the above described mutation and chromosomal translocations to be analysed sequentially in multiple assays&#46; Each step demands its own biological aliquot for analysis and has its own turnaround time&#44; challenging both sample requirement and laboratory diagnostics turnaround time&#46; Typically&#44; the biological material will be used first for histopathology analysis&#44; which may include the study of protein markers such as TTF1 and p63 using immunohistochemistry &#40;IHC&#41;&#46; This step will typically take 5-10 working days&#46; If diagnosis of non-small cell lung carcinoma is confirmed &#40;80-85&#37; of the cases&#41;&#44; first-line therapy with EGFR inhibitors should be considered&#44; especially for adenocarcinomas&#46; The second step will therefore include mutation screening for the <span class="elsevierStyleItalic">EGFR</span> gene alone or in conjunction with the <span class="elsevierStyleItalic">KRAS</span> gene&#46; This step will typically take 5-10 working days&#46; If not eligible for anti-EGFR therapy there will be further testing for <span class="elsevierStyleItalic">ALK</span> and <span class="elsevierStyleItalic">ROS1</span> translocations using fluorescence in-situ hybridization &#40;FISH&#41; alone&#44; or a combination of IHC and FISH&#46; This third step takes additional 5-10 working days&#46; Altogether&#44; this three-step testing strategy may take something between 15 and 30 working days&#44; delaying timely oncology treatment initiation and incurring patient insecurity&#46; Additional delays may occur if samples need to be transferred between laboratories&#46;</p><p class="elsevierStylePara">While we all eagerly await technological developments that allow for single-assay methods&#47;devices coping with the current challenges of minimizing both the need for analytical biological material and turnaround time&#44; there is a pressing need to prioritize the type and number of companion tests in lung cancer diagnosis&#46; In that respect&#44; current recommendations are very straightforward&#58; as long as lung cancer diagnosis has been confirmed&#44; all available biological material shall be prioritized for the analysis of molecular biomarkers with predictive value to therapy response which&#44; at the time of this writing&#44; include and are limited to <span class="elsevierStyleItalic">EGFR</span> and <span class="elsevierStyleItalic">KRAS</span> mutations&#44; and <span class="elsevierStyleItalic">ALK</span> and <span class="elsevierStyleItalic">ROS1</span> translocations&#46; International organizations&#44; such as the CAP&#47;IASLC&#47;AMP&#44; clearly state physicians should order predictive testing at the time of diagnosis for patients with advanced stage lung adenocarcinoma&#44; regardless of their clinical history&#46; That is how much is enough&#46;</p>"
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Routine characterization of biomarkers in non-small cell lung carcinoma: how much is enough?
José Carlos Machadoa
a Department of Pathology and Oncology, Medical Faculty of Porto, Porto, Portugal
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    "textoCompleto" => "<p class="elsevierStylePara">In recent years there was an extraordinary development in targeted therapies for cancer&#46; This development was quickly followed by the realization that successful application of these therapies is highly dependent on the identification and routine use of predictive biomarkers of therapy response&#46; In this context&#44; the fine characterization of tumours&#44; both at the molecular and histopathological levels&#44; might provide fundamental insight&#46; In the study by Sousa et al&#46;&#44;<a href="&#35;bib1" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> published in the current issue of the Portuguese Journal of Pulmonology&#44; the authors show adenocarcinomas of the lung are highly heterogeneous from the histopathological standpoint and show different patterns of expression of immunohistochemical and genetic biomarkers&#46; In their study the authors used a set of 10 immunohistochemical biomarkers and 3 genetic biomarkers&#46; The authors further reinforce the need to carefully identify lung adenocarcinoma histological patterns with putative implications in diagnosis and pathogenesis understanding&#46; Unfortunately&#44; the study does not include data on the clinical follow-up of the patients precluding the analysis of the predictive value of the data presented&#46; Nevertheless&#44; the publication of this study may constitute a good opportunity to discuss the clinical impact of routine characterization of biomarkers in non-small cell lung carcinoma&#46;</p><p class="elsevierStylePara">The diagnosis of lung cancer involves a variety of approaches ranging from pathology to medical imaging and molecular biology&#46; As our understanding of the disease grows&#44; and new knowledge is translated into clinically relevant procedures&#44; there is an increasing pressure on diagnostic turnaround times and relevant sample material for the increased number of companion tests prior to decision-to-treat&#46; Advanced lung cancer diagnostics are a showcase for this challenge&#59; biological material for diagnostics procedures is often limited &#40;cytology and biopsy material&#41;&#44; and timely responses are needed for optimal therapeutic decisions&#46; In this cancer model&#44; tumour samples are necessary for routine pathology evaluation combined with advanced molecular biology analysis&#46;</p><p class="elsevierStylePara">The diagnosis and histological classification of lung cancer into its major subtypes - small cell lung carcinoma&#44; adenocarcinoma and squamous carcinoma - relies on morphological characterization and on the use of differentiation biomarkers&#46; Although several markers are available for routine diagnosis&#44; the immunohistochemical expression of TTF1 and p63 are currently markers of choice to put forth differential diagnosis between squamous carcinoma and adenocarcinoma of the lung&#46; Expression of TTF1 favours the diagnosis of adenocarcinoma&#44; whereas expression of p63 favours diagnosis of squamous carcinoma&#46;</p><p class="elsevierStylePara">The addition of tyrosine kinase inhibitors into the therapeutic arsenal of non-small cell lung carcinoma&#44; brought into routine clinical practice the analysis of mutations in the <span class="elsevierStyleItalic">EGFR</span> and <span class="elsevierStyleItalic">KRAS</span> genes&#44; and the detection of chromosomal translocations involving the <span class="elsevierStyleItalic">ALK</span> and <span class="elsevierStyleItalic">ROS1</span> genes&#46; Specific activating mutations in exons 18&#44; 19&#44; 20 and 21 of the <span class="elsevierStyleItalic">EGFR</span> gene allow selection of 10-20&#37; of patients for treatment with the EGFR inhibitors gefitinib&#8482; or erlotinib&#8482;&#46; In contrast&#44; patients with other <span class="elsevierStyleItalic">EGFR</span> mutations&#44; namely insertions and deletions in exon 20&#44; and mutations in the <span class="elsevierStyleItalic">KRAS</span> gene&#44; are not likely to respond to the same EGFR inhibitors&#44; and as such should receive alternative treatment&#46; In addition&#44; 3-5&#37; of patients not eligible for EGFR-inhibitor treatment may still benefit from treatment with ALK-inhibitor crizotinib&#8482; as long as they can be confirmed to carry chromosomal translocations involving the <span class="elsevierStyleItalic">ALK</span> or <span class="elsevierStyleItalic">ROS1</span> genes&#46;</p><p class="elsevierStylePara">Currently&#44; lack of integration between molecular assays&#44; requires all the above described mutation and chromosomal translocations to be analysed sequentially in multiple assays&#46; Each step demands its own biological aliquot for analysis and has its own turnaround time&#44; challenging both sample requirement and laboratory diagnostics turnaround time&#46; Typically&#44; the biological material will be used first for histopathology analysis&#44; which may include the study of protein markers such as TTF1 and p63 using immunohistochemistry &#40;IHC&#41;&#46; This step will typically take 5-10 working days&#46; If diagnosis of non-small cell lung carcinoma is confirmed &#40;80-85&#37; of the cases&#41;&#44; first-line therapy with EGFR inhibitors should be considered&#44; especially for adenocarcinomas&#46; The second step will therefore include mutation screening for the <span class="elsevierStyleItalic">EGFR</span> gene alone or in conjunction with the <span class="elsevierStyleItalic">KRAS</span> gene&#46; This step will typically take 5-10 working days&#46; If not eligible for anti-EGFR therapy there will be further testing for <span class="elsevierStyleItalic">ALK</span> and <span class="elsevierStyleItalic">ROS1</span> translocations using fluorescence in-situ hybridization &#40;FISH&#41; alone&#44; or a combination of IHC and FISH&#46; This third step takes additional 5-10 working days&#46; Altogether&#44; this three-step testing strategy may take something between 15 and 30 working days&#44; delaying timely oncology treatment initiation and incurring patient insecurity&#46; Additional delays may occur if samples need to be transferred between laboratories&#46;</p><p class="elsevierStylePara">While we all eagerly await technological developments that allow for single-assay methods&#47;devices coping with the current challenges of minimizing both the need for analytical biological material and turnaround time&#44; there is a pressing need to prioritize the type and number of companion tests in lung cancer diagnosis&#46; In that respect&#44; current recommendations are very straightforward&#58; as long as lung cancer diagnosis has been confirmed&#44; all available biological material shall be prioritized for the analysis of molecular biomarkers with predictive value to therapy response which&#44; at the time of this writing&#44; include and are limited to <span class="elsevierStyleItalic">EGFR</span> and <span class="elsevierStyleItalic">KRAS</span> mutations&#44; and <span class="elsevierStyleItalic">ALK</span> and <span class="elsevierStyleItalic">ROS1</span> translocations&#46; International organizations&#44; such as the CAP&#47;IASLC&#47;AMP&#44; clearly state physicians should order predictive testing at the time of diagnosis for patients with advanced stage lung adenocarcinoma&#44; regardless of their clinical history&#46; That is how much is enough&#46;</p>"
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ISSN: 08732159
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