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Lek cfr prostane a Vitebsk establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR - and ALK -directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.
Writing and advisory panels were constituted from additional experts from these societies. Three unbiased literature searches Lek cfr prostane a Vitebsk electronic databases were performed to capture articles published from January through Februaryyielding articles whose abstracts were screened to identify pertinent articles that were then reviewed in detail for their relevance to Lek cfr prostane a Vitebsk recommendations.
Evidence was formally graded for each recommendation. Initial recommendations were formulated by the cochairs and panel members at a public meeting.
Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel version 1advisory panel version 2and the public version 3 before submission version 4. The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor EGFR or anaplastic lymphoma kinase ALK inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests.
As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
Lung cancer is the leading cause of cancer-related mortality, accounting for approximately 1. Specifically, the discovery of the biologic and therapeutic importance of acquired genetic alterations in 2 genes that encode pharmacologically targetable tyrosine kinases involved in growth factor receptor signaling, epidermal growth factor receptor EGFR and anaplastic lymphoma kinase ALKhas changed the way these cancers are diagnosed and treated. As gefitinib and erlotinib, small-molecule competitive inhibitors of the EGFR tyrosine kinase, were being evaluated in clinical trials of advanced-stage lung cancer in the early part of the last decade, unusual prolonged responses to these medications were recognized in a subset of patients.
This initial exciting observation has led to sustained and continuing laboratory and clinical investigations into the mechanism and clinical consequences of EGFR mutations in lung cancer.
This is likely to be at least partly due to the crossover design of these studies, in that a large fraction of the patients with EGFR -mutated tumors treated initially with chemotherapy crossed over to the EGFR TKI treatment arm, confounding the interpretation of overall Lek cfr prostane a Vitebsk data.
Three years after the initial discoveries of EGFR mutations in lung cancer, inSoda and coworkers 8 reported that an inversion on chromosome arm 2p resulted in the creation of an EML4-ALK fusion gene in lung cancer.
Given the considerable published data on EGFR -mutated lung cancer and the rapid pace of work on ALKrepresentatives of 3 professional organizations with interest in the diagnosis and management of lung cancer—the College of American Pathologists CAPthe International Association for the Study of Lung Cancer IASLCLek cfr prostane a Vitebsk the Association for Molecular Pathology AMP —convened to systematically review the published data and develop evidence-based recommendations for the molecular testing of lung cancers for these 2 critical predictive biomarkers in a clinical practice guideline CPG.
CPGs are systematically developed statements intended to Lek cfr prostane a Vitebsk practitioners and patients in making decisions about appropriate health care options for specific clinical circumstances. Attributes of good CPGs include validity, reliability, reproducibility, clinical applicability, clinical flexibility, clarity, multidisciplinary process, review of evidence, and documentation.
Specifically, utilization of CPG recommendations Lek cfr prostane a Vitebsk provide improvements in outcomes and in medical practice; minimize inappropriate practice variation; provide decision support tools for practitioners, a reference for medical education, criteria for self-evaluation, and indicators and criteria for external quality review; and assist with reimbursement and coverage decisions.
Finally, the process of CPG development can also identify areas where further research is needed. How should molecular testing of lung adenocarcinomas be implemented and operationalized?
Clinical practice guidelines and consensus statements reflect the best available evidence and expert consensus supported in practice. They are intended to assist physicians and patients in clinical decision making and to identify questions and settings for further research.
With the rapid flow of scientific information, new evidence may emerge between the time a practice guideline or consensus statement is developed and when it is published or read. Guidelines and statements are not continually updated and may not reflect the most recent evidence. Guidelines and statements address only the topics specifically identified therein and are not applicable to other interventions, diseases, or stages of diseases.
Furthermore, guidelines and statements cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician, relying on independent experience and knowledge, to determine the best course of treatment for the patient. CAP, Lek cfr prostane a Vitebsk, and AMP make no warranty, express or implied, regarding guidelines and statements and specifically exclude any warranties of merchantability and fitness for a particular use or purpose.
In formulating recommendations for molecular testing in lung cancer, CAP, IASLC, and AMP considered these tenets of guideline development, emphasizing review of data from appropriately conducted and analyzed clinical trials.
Practice guidelines are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The literature and expert review process was directed toward evaluating and selecting the best science for the best possible patient care; a cost analysis was not performed Lek cfr prostane a Vitebsk this guideline.
A detailed account of the methods used to create this guideline can be found in the supplemental digital content at www. The opinions of panel members associated with official government agencies represent their individual views and not necessarily those of the agency with which they are affiliated.
All members of the expert author panel were required to disclose financial and personal conflicts of interest see below. All searches were limited to the English language. Systematic reviews with or without meta-analyses, randomized controlled trials, cohort studies, case-control studies, case series, and method comparisons were eligible for Lek cfr prostane a Vitebsk study.
Also included were testing guidelines and proficiency testing strategies of various US and international organizations. Articles were eligible for inclusion if they met the following criteria:. Letters, commentaries, editorials, reviews, and case reports were excluded. Other outcomes of interest included accuracy in determining EGFR or ALK status, concordance across technical platforms, sensitivity, and specificity of different tests.
The panel reviewed the results of randomized controlled trials in lung cancer, evaluating therapies targeting EGFR or ALK, such as gefitinib, erlotinib, and crizotinib. The panel also reviewed unblinded trials comparing various testing methods, describing test characteristics, and defining strategies for quality assurance of testing in the literature. At the December conference, individuals representing regulatory agencies FDA also provided information about the regulatory framework.
This information was used to help the panel specify testing requirements and exclusions, and the necessary quality assurance monitoring that will make the testing less variable and more accurate.
Grading of recommendations was based on overall ratings of individual components of the evidence, such as strength of evidence, its consistency, clinical impact, generalizability, and applicability to the international health care system. The overall grade of the recommendation was obtained by rating all components of the evidence.
The overall grade indicates the strength of the body of evidence to assist the users of clinical practice guidelines in making appropriate and informed clinical judgments. This guideline will be reviewed Lek cfr prostane a Vitebsk, as mandated by publication of substantive and high-quality medical evidence that could potentially alter the original guideline recommendations.
If necessary, the entire panel will reconvene to discuss potential changes. When appropriate, panel members will recommend revision of the guideline to their respective organizations for review and approval. The potential members completed the conflict of interest disclosure form conservatively, listing any relationship that could be interpreted as constituting an actual, potential, or apparent conflict.
Regarding members declaring potentially perceived or real conflict, guideline cochairs agreed that these individuals Lek cfr prostane a Vitebsk best serve as advisory panel members for the guideline, but not authors on the expert panel.
The expert author panel cochairs N. Full-text articles were then reviewed for all selected abstracts by 2 members of the expert author panel; discrepancies were Lek cfr prostane a Vitebsk by a cochair. Evidence tables were developed from selected studies that met the criteria for inclusion.
A third literature review was performed by the authors of each section of the guideline, to verify that the highest levels of evidence supported each of their recommendations and, if not, to reevaluate the recommendation and modify or defend it. The purposes of the panel meeting were to refine the questions addressed by the guideline, solicit input and testimony from the nonwriting advisory panel, and make writing assignments for the respective sections. All members of the expert panel participated in the preparation of the draft guideline, which was then disseminated for review by the entire panel.
Feedback from external reviewers was also solicited. The recommendations are summarized in Table 3. Recommendation: EGFR molecular testing should be used to select patients for EGFR-targeted TKI therapy, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics. Recommendation: ALK molecular testing should be used to select patients for ALK-targeted TKI therapy, Lek cfr prostane a Vitebsk patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics.
Recommendation: In the setting of lung cancer resection specimens, EGFR and ALK testing is recommended for adenocarcinomas and mixed lung cancers with an adenocarcinoma component, regardless of histologic grade. In the setting of fully excised lung cancer specimens, EGFR and ALK testing is not recommended in lung cancers that lack any adenocarcinoma component, such as pure squamous cell carcinomas, pure small cell carcinomas, or large cell carcinomas lacking any immunohistochemistry IHC evidence of adenocarcinoma differentiation.
Recommendation: In the setting of more limited lung cancer specimens biopsies, cytology where an adenocarcinoma component cannot be completely excluded, EGFR and ALK testing may be performed in cases showing squamous or small cell histology but clinical criteria eg, young age, lack of smoking history may be useful in selecting a subset of these samples for testing. Recommendation: To determine EGFR and ALK status for initial treatment selection, primary tumors Lek cfr prostane a Vitebsk metastatic lesions are equally suitable for testing.
Expert consensus opinion: For patients with multiple, apparently separate, primary lung adenocarcinomas, each tumor may be tested but testing of multiple different areas within a single tumor is not necessary. Recommendation: EGFR mutation testing should be ordered at the time of diagnosis for patients presenting with advanced- stage disease stage IV according to the 7th edition TNM staging Lek cfr prostane a Vitebsk who are suitable for therapy or at time of recurrence or progression in patients who originally presented with lower-stage disease but were not previously tested.
Suggestion: ALK rearrangement testing should be ordered at the time of diagnosis for patients presenting with advanced- stage disease stage IV according to the 7th edition TNM staging system who are suitable for therapy or at time of recurrence or progression in patients who originally presented with lower-stage disease but were not previously tested.
Expert consensus opinion: EGFR testing of tumors at diagnosis from patients presenting with stage I, II, or III disease Lek cfr prostane a Vitebsk encouraged but the decision to do so should be made locally by each laboratory, in collaboration with its oncology team. Expert consensus opinion: ALK testing of Lek cfr prostane a Vitebsk at diagnosis Lek cfr prostane a Vitebsk patients presenting with stage I, II, or III disease is encouraged, but the decision to do so should be made locally by each laboratory, in collaboration with its oncology team.
Expert consensus opinion: EGFR and ALK results should be available within 2 Lek cfr prostane a Vitebsk 10 working days of receiving the specimen in the testing laboratory. Expert consensus opinion: Laboratories with average turnaround times beyond 2 weeks need to make available a more rapid test—either in-house or through a reference laboratory—in instances of Lek cfr prostane a Vitebsk urgency.
Lek cfr prostane a Vitebsk consensus opinion: Laboratory departments should establish processes to ensure that specimens that have a final histopathologic Lek cfr prostane a Vitebsk are sent to outside molecular pathology laboratories within 3 working days of receiving requests and to intramural molecular pathology laboratories within 24 hours. Other tissue treatments eg, acidic or heavy metal fixatives, or decalcifying solutions should be avoided in specimens destined for EGFR testing.
Expert consensus opinion: Pathologists should determine the adequacy of specimens for EGFR testing by assessing cancer cell content and DNA quantity and quality. Expert consensus opinion: Each laboratory should establish the minimum proportion and number of cancer cells needed for mutation detection during validation.
Expert consensus opinion: A pathologist should assess the tumor content of each specimen and either perform, or guide a trained technologist to perform, microdissection for tumor cell enrichment as needed. Recommendation: Laboratories may use any validated EGFR testing method with sufficient performance characteristics.
Expert consensus opinion: A pathologist should be involved in the selection of sections for ALK FISH testing, by assessing tumor architecture, cytology, and specimen quality. Expert consensus opinion: A pathologist should participate in the interpretation of ALK FISH slides, either by performing the analysis directly or by reviewing the interpretations of cytogeneticists or technologists with specialized training in solid tumor FISH analysis.
Expert consensus opinion: Testing for secondary mutations in ALK associated with acquired resistance to ALK inhibitors is not currently required Lek cfr prostane a Vitebsk clinical management. Expert consensus opinion: Laboratories may implement testing algorithms to enhance the efficiency of molecular testing of lung adenocarcinomas, provided the overall turnaround time requirements are met.
Expert consensus opinion: EGFR mutation testing reports and ALK FISH reports should include a results and interpretation section readily understandable by oncologists and by nonspecialist pathologists. Expert consensus opinion: Laboratories should follow similar quality control and quality assurance policies and procedures for EGFR and ALK testing in lung cancers as for other clinical laboratory assays.
EGFR molecular testing should be used to select patients for EGFR-targeted TKI therapy, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics. ALK molecular testing should be used to select patients for ALK-targeted TKI therapy, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics. Clinical characteristics eg, age, sex, ethnicity, smoking history are not sufficiently sensitive or specific to be used to select or exclude patients for treatment or testing.
Multiple studies have established that EGFR mutations are more common in women than men, in patients who have never smoked tobacco than in patients who have smoked tobacco, and in East Asians than in other ethnic groups. In the setting of lung cancer resection specimens, EGFR and ALK testing is recommended for adenocarcinomas and mixed lung Lek cfr prostane a Vitebsk with an adenocarcinoma component, regardless of histologic grade.
This evolution is also reflected in the version 3. EGFR mutations have been detected in several histologic lung cancer types, but most tumors with EGFR mutations are adenocarcinomas or mixed carcinomas with an adenocarcinoma component, including adenosquamous carcinomas. While there is some evidence that EGFR mutations are more likely in low-grade adenocarcinomas with lepidic, papillary, or acinar histology than in poorly differentiated, mucinous, or solid adenocarcinomas, EGFR mutations are found at significant frequencies in adenocarcinomas of all grades.
Therefore, adenocarcinoma subtype should not be used as a determinant of which samples should, or should not, be tested. ALK rearrangements are also associated with adenocarcinoma histology, without any single subtype being strongly predictive.
Abbreviation: n, number of squamous cell carcinoma samples tested.