Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology
이런 제목으로 무려 3개의 저널(Arch Pathol Lab Med, J Mol Diagn, J Thorac Oncol)에서 개재된 논문이다.
전문을 읽어보지는 않았고 대충 요약을 해보면 다음과 같다.
권고 등급이 서로 다르다는 것을 알고 볼 것.
Summary of Guideline Recommendations
Section I: When Should Molecular Testing of Lung Cancers Be Performed?
검사 꼭 해야함?
Question 1: Which Patients Should Be Tested for EGFR Mutations and ALK Rearrangements?
1.1a: 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.
1.1b: Recommendation: 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.
임상 양상과 상관없이 targeted therapy 를 할 경우에는 할 것.
1.2: 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.
ADC 에서 혹은 ADC의 분화의 증거가 있는 분위에서 시행하는 것이 좋겠음.
1.3: 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.
ADC 의 증거가 명확하지 않은 병리 검체에서는 할 수도 있음.
1.4: Recommendation: To determine EGFR and ALK status for initial treatment selection, primary tumors or metastatic lesions are equally suitable for testing.
처음 치료에 있어서 EGFR, ALK 상태를 평가하기 위해서라면 원발 병소나 전이 병소나 상관없음.
1.5: Expert consensus opinion: For patients with multiple, apparently separate, primary lung denocarcinomas, each tumor may be tested but testing of multiple different areas within a single tumor is not necessary.
명백하게 떨어진 원발 ADC가 여러개 있을 때, 각각을 검사해 볼 수는 있음.
하지만, 한 종양의 여러부위에서 검사할 필요는 없음.
Question 2: When Should a Patient Specimen Be Tested for EGFR Mutation or ALK Rearrangement?
언제 검사?
2.1a: 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 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.
진행된 병기(Stage IV)에 해당하는 환자가 진단받은 순간에 EGFR 돌연변이 검사를 해봐야함.
이전에 검사하지 않은 lower stage 환자가 재발하거나 진행하였을 경우.
2.1b: 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.
위에꺼랑 같음.
2.2a: Expert consensus opinion: EGFR testing of tumors at diagnosis from 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.
Stage IV 가 아니더라도 각각의 사정에 맞게 시행하면 됨
2.2b: Expert consensus opinion: ALK testing of tumors at diagnosis from 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.
위에꺼랑 같음.
2.3: Recommendation: Tissue should be prioritized for EGFR and ALK testing.
이 항목은 원문을 찾아봤는데
조직학적 분류를 위해서 추가 검사를 시행하지 말고
바로 치료를 위한 검사를 할 것을 이야기하고 있음.
Question 3: How Rapidly Should Test Results Be Available?
얼마나 결과가 빨리 나와야 하나?
3.1: Expert consensus opinion: EGFR and ALK results should be available within 2 weeks (10 working days) of receiving the specimen in the testing laboratory.
접수된지 2주 이내에는 나와야 함.
3.2: 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 clinical urgency.
2주 이상이 소요되는 검사실에서는 보다 더 빠른 검사 결과를 위한 방안을 갖추고 있어야 함.
3.3: Expert consensus opinion: Laboratory departments should establish processes to ensure that specimens that have a final histopathologic diagnosis are sent to outside molecular pathology laboratories within 3 working days of receiving requests and to intramural molecular pathology laboratories within 24 hours.
별 상관 없는 것 같음. 해석도 잘 못 하겠음.
Section II: How Should EGFR Testing Be Performed?
어떻게 검사해야하나?
Question 4: How Should Specimens Be Processed for EGFR Mutation Testing?
EGFR 검사를 위해서 어떻게 검체를 처리해야 하나?
4.1: Expert consensus opinion: Pathologists should use formalin-fixed, paraffin-embedded (FFPE) specimens or fresh, frozen, or alcohol-fixed specimens for PCR-based EGFR mutation tests. Other tissue treatments (eg, acidic or heavy metal fixatives, or decalcifying solutions) should be avoided in specimens destined for EGFR testing.
탈회 과정을 거친 것이 아닌 이상 왠만하면 PCR 기반의 EGFR 돌연변이 검사를 할 수 있음.
4.2: Expert consensus opinion: Cytologic samples are also suitable for EGFR and ALK testing, with cell blocks being preferred over smear preparations.
cytology 의 경우도 역시 가능함. smear 보다는 cell block 이 좋겠음.
Question 5: What Are the Specimen Requirements for EGFR Testing?
EGFR 검사를 위하여 검체 요구 사항
5.1: Expert consensus opinion: Pathologists should determine the adequacy of specimens for EGFR testing by assessing cancer cell content and DNA quantity and quality.
병리 전문가가 DNA 양, 질 및 cancer cell content 에 대해서 결정 해야함.
5.2: Expert consensus opinion: Each laboratory should establish the minimum proportion and number of cancer cells needed for mutation detection during validation.
검사실은 최소한의 종양 세포 정도에 대하여 기준을 세워두어야 함.
5.3: 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.
직원 교육 잘 해야함.
Question 6: How Should EGFR Testing Be Performed?
어떤 EGFR
6.1: Recommendation: Laboratories may use any validated EGFR testing method with sufficient performance characteristics.
6.2: Expert consensus opinion: Laboratories should use EGFR test methods that are able to detect mutations in specimens with at least 50% cancer cell content, although laboratories are strongly encouraged to use (or have available at an external reference laboratory) more sensitive tests that are able to detect mutations in specimens with as little as 10% cancer cells.
종양 세포의 비율이 50% 이상이 있을 때 돌연변이 여부를 확인할 수 있는 검사를 시행하여야 함.
가능하다면 10% 이상이 있을 경우에도 찾을 수 있는 예민한 검사 방법을 확보하길 바람.
6.3: Expert consensus opinion: Clinical EGFR mutation testing should be able to detect all individual mutations that have been reported with a frequency of at least 1% of EGFR-mutated lung adenocarcinomas.
1% 정도의 빈도로 보도되는 돌연 변이정도는 찾을 수 있어야 함.
6.4: Recommendation: Immunohistochemistry for total EGFR is not recommended for selection of EGFR TKI therapy.
EGFR IHC 는 더이상 추천되지 않음.
6.5: Recommendation: EGFR copy number analysis (ie, FISH or CISH) is not recommended for selection of EGFR TKI therapy.
EGFR FISH나 CISH 등 copy number analysis 는 추천되지 않음.
Question 7: What Is the Role of KRAS Analysis in Selecting Patients for Targeted Therapy With EGFR TKIs?
KRAS는 어떻게 바라볼 것인가?
7.1: Recommendation: KRAS mutation testing is not recommended as a sole determinant of EGFR TKI therapy.
KRAS 단독 검사는 추천하지 않음.
Question 8: What Additional Testing Considerations Are Important in the Setting of Secondary or Acquired EGFR TKI Resistance?
EGFR TKI 저항성이 있을때.
8.1: Recommendation: If a laboratory performs testing on specimens from patients with acquired resistance to EGFR kinase inhibitors, such tests should be able to detect the secondary EGFR T790M mutation in as few as 5% of cells.
이러한 목적으로 바탕으로 검사를 시행할 것이라면
T970M 이 5% 이상에서 관찰될 경우 이를 검출할 수 있을 정도로 예민한 검사를 사용하여야 한다.
Section III: How Should ALK Testing Be Performed?
ALK는 어떻게?
Question 9: What methods should be used for ALK testing?
9.1: Recommendation: Laboratories should use an ALK FISH assay using dual-labeled break-apart probes for selecting patients for ALK TKI therapy; ALK immunohistochemistry, if carefully validated, may be considered as a screening methodology to select specimens for ALK FISH testing.
BA probe를 사용한 ALK FISH 를 사용하여야 한다.
잘 세팅된 경우라면 ALK IHC 를 선별 검사 목적으로 이용할 수 있다.
9.2: Recommendation: RT-PCR is not recommended as an alternative to FISH for selecting patients for ALK inhibitor therapy.
RT-PCR은 환자군 선택에 있어서 FISH 대안으로 추천되지 않음.
9.3: 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.
병리 전문의가 ALK FISH 과정에 참여할 것
9.4: 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.
직원 교육에 관한 내용
9.5: Expert consensus opinion: Testing for secondary mutations in ALK associated with acquired resistance to ALK inhibitors is not currently required for clinical management.
ALK 저항성과 관련된 돌연변이 검사는 아직 추천되지 않음.
Section IV: Should Other Genes Be Routinely Tested in Lung Adenocarcinoma?
ADC에서 딴 유전자도 검사해야하나?
Question 10: Are Other Molecular Markers Suitable for Testing in Lung Cancer?
10.1a: Recommendation: Testing for EGFR should be prioritized over other molecular markers in lung adenocarcinoma.
일단 EGFR 부터
10.1b: Suggestion: After EGFR testing, testing for ALK should be prioritized over other proposed molecular markers in lung adenocarcinoma, for which published evidence is insufficient to support testing guideline development at the present time.
EGFR 검사 다음엔 ALK 를 할 것. 나머지는 아직 때가 아님.
Section V: How Should Molecular Testing of Lung Adenocarcinomas Be Implemented and Operationalized?
Question 11: Must All Adenocarcinomas Be Tested for Both EGFR and ALK?
ADC는 죄다 검사해야하나?
11.1: 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.
전반적인 효율성을 고려한 알고리즘은 있어야 함.
Question 12: How Should EGFR and ALK Results Be Reported?
12.1: 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.
알아듣기 쉽게 보고서가 쓰여야 함.
Question 13: How Should EGFR and ALK Testing Be Validated?
13.1: Expert consensus opinion: EGFR and ALK testing validation should follow the same guidelines as for other molecular diagnostics and FISH tests.
일반적인 수준의 검증이 필요함.
Question 14: How Should Quality Assurance Be Maintained?
14.1: 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. In particular, laboratories performing EGFR and ALK testing for TKI therapy should enroll in proficiency testing, if available.
최소한 옆 동네 수준 정도는 되어야 함.
