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HER2, HER3, and TROP2 as Therapeutic
Targets in Different Cancers
Access the activity, “Increasing Importance of HER2 and ...
HER2, HER3, and TROP2 as Therapeutic
Targets in Different Cancers
Access the activity, “Increasing Importance of HER2 and ...
HER2 Testing in Breast Cancer
Guidance From ASCO/CAP1
Access the activity, “Increasing Importance of HER2 and HER3 Testing...
HER2 Testing in Breast Cancer
Guidance From ASCO/CAP1
Access the activity, “Increasing Importance of HER2 and HER3 Testing...
HER2 Testing in Breast Cancer
Guidance From ASCO/CAP1
Access the activity, “Increasing Importance of HER2 and HER3 Testing...
HER2 Testing in Breast Cancer
Guidance From ASCO/CAP1
Access the activity, “Increasing Importance of HER2 and HER3 Testing...
HER2 Testing in Gastroesophageal Cancer
Guidance From CAP/ASCP/ASCO1
Access the activity, “Increasing Importance of HER2 a...
HER2 Testing in Gastroesophageal Cancer
Guidance From CAP/ASCP/ASCO1
Access the activity, “Increasing Importance of HER2 a...
HER2 Testing in Gastroesophageal Cancer
Guidance From CAP/ASCP/ASCO1
Access the activity, “Increasing Importance of HER2 a...
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Increasing Importance of HER2 and HER3 Testing in the Context of an Expanding Targeted Therapies Landscape for Breast, Gastrointestinal, Lung, and Other Cancers: Latest Updates and Practical Guidance for Pathologists

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Farnaz Dadmanesh, MD, Laura H. Tang, MD, PhD, Joseph Chao, MD, and Heather L. McArthur, MD, MPH, prepared useful practice aids pertaining to HER2/HER3 testing/treatment in breast, gastrointestinal, lung, and other cancers for this CME/CC activity titled, "Increasing Importance of HER2 and HER3 Testing in the Context of an Expanding Targeted Therapies Landscape for Breast, Gastrointestinal, Lung, and Other Cancers: Latest Updates and Practical Guidance for Pathologists." For the full presentation, complete CME/CC information, and to apply for credit, please visit us at https://bit.ly/2XlnuFi. CME/CC credit will be available until April 2, 2021.

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Increasing Importance of HER2 and HER3 Testing in the Context of an Expanding Targeted Therapies Landscape for Breast, Gastrointestinal, Lung, and Other Cancers: Latest Updates and Practical Guidance for Pathologists

  1. 1. HER2, HER3, and TROP2 as Therapeutic Targets in Different Cancers Access the activity, “Increasing Importance of HER2 and HER3 Testing in the Context of an Expanding Targeted Therapies Landscape for Breast, Gastrointestinal, Lung, and Other Cancers: Latest Updates and Practical Guidance for Pathologists,” at PeerView.com/SMP40 PRACTICE AID HER2 Aberrations: Clinical Role and Frequency Across Tumor Types1,2 • HER2 is an established therapeutic target in breast and gastric cancer • HER2 alterations, including overexpression, amplifications, and other mutations, are found in a variety of other solid tumors as well • A number of novel HER2-targeted therapies are being evaluated in breast, gastrointestinal, lung, and other cancers, indicating that the role and impact of these therapies will continue to expand, along with the need for broader HER2 testing ERBB2 amplifications/mutations and HER2 overexpression have been identified in a range of malignancies Colorectum 5.8 5 2 Pancreas 2 26 1 Ovary 7 27 1 Prostate 5.8–6 10 1 Tumor types HER2 amplification (%) HER2 overexpression (%) HER2 mutation (%) Breast 20 15–20 2 Salivary gland 12–52 17–44 1 Stomach 11–16 20 3 Bladder 8.6 12.4 9 Cervix 0.5~14 21 3 Uterus 4–69 18–80 2 Lung 2–3 2.5 1–3 Biliary tract 5–15 20 2
  2. 2. HER2, HER3, and TROP2 as Therapeutic Targets in Different Cancers Access the activity, “Increasing Importance of HER2 and HER3 Testing in the Context of an Expanding Targeted Therapies Landscape for Breast, Gastrointestinal, Lung, and Other Cancers: Latest Updates and Practical Guidance for Pathologists,” at PeerView.com/SMP40 PRACTICE AID ADC: antibody–drug conjugate; ADCC: antibody-dependent cellular cytotoxicity; EGFR: epidermal growth factor receptor; ERBB2: erb-B2 receptor tyrosine kinase 2; ERK: extracellular signal–regulated kinase; HER2: human epidermal growth factor receptor 2; HER3: human epidermal growth factor receptor 3; JAK: Janus kinase; mAb: monoclonal antibody; MAPK: mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; STAT: signal transducer and activator of transcription; TROP2: trophoblast cell-surface antigen 2. 1. Oh DY, Bang YJ. Nat Rev Clin Oncol. 2020;17:33-48. 2. Hechtman JF, Ross DS. Cancer Cytopathol. 2019;127:428-431. 3. Mishra R et al. Oncol Rev. 2018;12:355. 4. Guerra E et al. Oncogene. 2013;32:1594-1600. 5. Zeng P et al. Sci Rep. 2016;6:33658. Mechanism of Action of Agents Targeting HER21 HER3 and TROP2 as Emerging Therapeutic Targets a. Single-epitope monoclonal antibodies bind HER2 at a single extracellular domain, inhibiting downstream signaling, engaging antibody-dependent cytotoxicity, or inhibiting receptor dimerization b. ADCs also have antitumor effects through these pathways, but they additionally exhibit cytotoxicity by releasing a cytotoxic agent close to HER2-positive tumor cells c. Bispecific antibodies target more than one extracellular region of HER2 d. Small-molecule inhibitors bind the intracellular tyrosine kinase domain HER33 • Crucial heterodimeric partner for other EGFR family members • Potential to regulate EGFR/HER2-mediated resistance • Enhanced expression associated with several cancers, including lung, breast, ovarian, prostate, gastric, bladder, melanoma, colorectal, and squamous cell carcinoma • Implicated in contributing to treatment failure through activation of PI3K/AKT, MAPK/ERK, and JAK/STAT pathways • HER3-targeting investigational therapies: mono and bispecific antibodies targeting HER3 at multiple subdomains; miscellaneous HER3-targeting therapies, including antisense oligonucleotides, HER3-specific peptide vaccines, ligand traps, molecules targeting HER3 pseudokinase activity, pan-HER approaches, HER3 ADCs, and HER3 nanobiologic therapeutic approaches; select examples: U3-1402 (HER3- targeting ADC); and MCLA-128 (HER2–HER3 bispecific antibody) TROP24,5 • Transmembrane glycoprotein overexpressed in many different tumors, including lung, breast, pancreatic, cervical, ovarian, colorectal, and gastric cancers • Membrane bound with an extracellular domain • Effectively internalized with binding antibody • High expression correlates with poor prognosis • Rational therapeutic target; TROP2-targeting investigational therapies: DS-1062, sacituzumab govitecan (IMMU-132), and PF-06664178 Pertuzumab a. Single-Epitope mAbs b. ADCs d. Small-Molecule Inhibitors c. Bispecific Antibodies Dimerization domain Trastuzumab Margetuximab Inhibition of receptor dimerization Targeted delivery of highly cytotoxic agents Direct inhibition of the downstream tyrosine-kinase domain Promotion of receptor internalization and/or degradation Engagement of ADCC Tyrosine-kinase domain Cell membrane Trastuzumab emtansine Trastuzumab deruxtecan Dual targeting of the trastuzumab and pertuzumab binding sites ZW25 Lapatinib Neratinib Tucatinib I II III IV I II III IV Inhibition of PI3-kinase signalling promoting cell-cycle arrest I II III IV
  3. 3. HER2 Testing in Breast Cancer Guidance From ASCO/CAP1 Access the activity, “Increasing Importance of HER2 and HER3 Testing in the Context of an Expanding Targeted Therapies Landscape for Breast, Gastrointestinal, Lung, and Other Cancers: Latest Updates and Practical Guidance for Pathologists,” at PeerView.com/SMP40 PRACTICE AID Summary of HER2 Testing Recommendations Specimens to be tested Optimal algorithm for HER2 testing Topic All newly diagnosed patients with breast cancer must have an HER2 test performed. Patients who then develop metastatic disease must have an HER2 test performed in a metastatic site, if tissue sample is available. Must report HER2 test result as positive for HER2 if: • IHC 3+ based on circumferential membrane staining that is complete, intense • ISH positive based on: – Single-probe average ERBB2 copy number ≥6.0 signals/cell – Dual-probe ERBB2/CEP17 ratio of ≥2.0, with an average ERBB2 copy number ≥4.0 signals/cell – Dual-probe ERBB2/CEP17 ratio of ≥2.0, with an average ERBB2 copy number 4.0 signals/cell – Dual-probe ERBB2/CEP17 ratio of 2.0, with an average ERBB2 copy number ≥6.0 signals/cell Must report HER2 test result as equivocal and order reflex test (same specimen using the alternative test) or new test (new specimen, if available, using same or alternative test) if: • IHC 2+ based on circumferential membrane staining that is incomplete and/or weak to moderate and within 10% of the invasive tumor cells or complete and circumferential membrane staining that is intense and within ≤10% of the invasive tumor cells • ISH equivocal based on: – Single-probe ISH average ERBB2 copy number ≥4.0 and ≤6.0 signals/cell – Dual-probe ERBB2/CEP17 ratio of 2.0 with an average ERBB2 copy number ≥4.0 and ≤6.0 signals/cell Must report HER2 test result as negative if a single test (or both tests) performed shows: • IHC 1+ as defined by incomplete membrane staining that is faint or barely perceptible and within 10% of the invasive tumor cells • IHC 0 as defined by no staining observed or membrane staining that is incomplete and is faint or barely perceptible and within ≤10% of the invasive tumor cells • ISH negative based on: – Single-probe average ERBB2 copy number 4.0 signals/cell – Dual-probe ERBB2/CEP17 ratio of 2.0 with an average ERBB2 copy number of 4.0 signals/cell Recommendations Must report HER2 test result as indeterminate if technical issues prevent one or both tests (IHC and ISH) from being reported as positive, negative, or equivocal. Conditions may include: • Inadequate specimen handling • Artifacts (crush or edge artifacts) that make interpretation difficult • Analytic testing failure Another specimen should be requested for testing to determine HER2 status The reason for indeterminate testing should be noted in a comment in the report
  4. 4. HER2 Testing in Breast Cancer Guidance From ASCO/CAP1 Access the activity, “Increasing Importance of HER2 and HER3 Testing in the Context of an Expanding Targeted Therapies Landscape for Breast, Gastrointestinal, Lung, and Other Cancers: Latest Updates and Practical Guidance for Pathologists,” at PeerView.com/SMP40 PRACTICE AID Summary of HER2 Testing Recommendations (Cont’d) Optimal algorithm for HER2 testing Topic 1. The revised definition of IHC 2+ (equivocal) is invasive breast cancer with weak to moderate complete membrane staining observed in 10% of tumor cells 2. On the basis of some criteria (including a tumor grade 3), if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may be ordered on the excision specimen 3. If a case has an ERBB2/CEP17 ratio of ≥2.0 but the average ERBB2 signals/cell is 4.0, a definitive diagnosis will be rendered based on additional workup. If not already assessed by the institution or laboratory performing the ISH test, IHC testing for HER2 should be performed using sections from the same tissue sample used for ISH, and the slides from both ISH and IHC should be reviewed together to guide the selection of areas to score by ISH (local practice considerations will dictate the best procedure to accomplish this concomitant assessment): • If the IHC result is 3+, diagnosis is HER2 positive • If the IHC result is 2+, recount ISH by having an additional observer, blinded to previous ISH results; count at least 20 cells that include the area of invasive cancer with IHC 2+ staining: – If reviewing the count by the additional observer changes the result into another ISH category, the result should be adjudicated per internal procedures to define the final category – If the count remains an average of 4.0 ERBB2 signals/cell and the ERBB2/CEP17 ratio is ≥2.0, diagnosis is HER2 negative with a comment 4. If a case has an average of ≥6.0 ERBB2 signals/cell with an ERBB2/CEP17 ratio of 2.0, formerly diagnosed as ISH positive for HER2, a definitive diagnosis will be rendered based on additional workup. If not already assessed by the institution or laboratory performing the ISH test, IHC testing for HER2 should be performed using sections from the same tissue sample used for ISH, and the slides from both ISH and IHC should be reviewed together to guide the selection of areas to score by ISH (local practice considerations will dictate the best procedure to accomplish this concomitant review): • If the IHC result is 3+, diagnosis is HER2 positive • If the IHC result is 2+, recount ISH by having an additional observer, blinded to previous ISH results; count at least 20 cells that include the area of invasive cancer with IHC 2+ staining: – If reviewing the count by the additional observer changes the result into another ISH category, the result should be adjudicated per internal procedures to define the final category – If the ERBB2/CEP17 ratio remains 2.0 with ≥6.0 ERBB2 signals/cell, diagnosis is HER2 positive • If the IHC result is 0 or 1+, diagnosis is HER2 negative with a comment 5. If the case has an average ERBB2 signals/tumor cell of ≥4.0 and 6.0 and the ERBB2/CEP17 ratio is 2.0, formerly diagnosed as ISH equivocal for HER2, a definitive diagnosis will be rendered based on additional workup. If not already assessed by the institution or laboratory performing the ISH test, IHC testing for HER2 should be performed using sections from the same tissue sample used for ISH, and the slides from both ISH and IHC should be reviewed together to guide the selection of areas to score by ISH (local practice considerations will dictate the best procedure to accomplish this concomitant review): • If the IHC result is 3+, diagnosis is HER2 positive • If the IHC result is 2+, recount ISH by having an additional observer, blinded to previous ISH results; count at least 20 cells that include the area of invasive cancer with IHC 2+ staining: – If reviewing the count by the additional observer changes the result into another ISH category, the result should be adjudicated per internal procedures to define the final category – If the count remains an average of ≥4.0 and 6.0 ERBB2 signals/cell with an ERBB2/CEP17 ratio of 2.0, diagnosis is HER2 negative with a comment • If the IHC result is 0 or 1+, diagnosis is HER2 negative with a comment 2018 Focused Update Recommendations
  5. 5. HER2 Testing in Breast Cancer Guidance From ASCO/CAP1 Access the activity, “Increasing Importance of HER2 and HER3 Testing in the Context of an Expanding Targeted Therapies Landscape for Breast, Gastrointestinal, Lung, and Other Cancers: Latest Updates and Practical Guidance for Pathologists,” at PeerView.com/SMP40 PRACTICE AID Summary of HER2 Testing Recommendations (Cont’d) Topic ISH rejection criteria • Test is rejected and repeated if: – Controls are not as expected – Observer cannot find and count at least two areas of invasive tumor – 25% of signals are unscorable due to weak signals – 10% of signals occur over cytoplasm – Nuclear resolution is poor – Autofluorescence is strong • Report HER2 test result as indeterminate as per parameters described Reporting requirements for all assay types • Report must include guideline-detailed elements except for changes to reporting requirements and algorithms defined in this table • Test is rejected and repeated or tested by FISH if: – Controls are not as expected – Artifacts involve most of the sample – Sample has strong membrane staining of normal breast ducts (internal controls) IHC rejection criteria IHC interpretation criteria • Should interpret IHC test using a threshold of 10% of tumor cells that must show homogenous, dark circumferential (chicken wire) pattern to call result 3+, HER2 positive Recommendations Optimal tissue handling requirements • Time from tissue acquisition to fixation should be as short as possible; samples for HER2 testing are fixed in 10% neutral buffered formalin for 6-72 h; cytology specimens must be fixed in formalin • Samples should be sliced at 5- to 10-mm intervals after appropriate gross inspection and margin designation and placed in a sufficient volume of neutral buffered formalin • Any exceptions to this process must be included in the report • The pathologist should scan the entire ISH slide before counting at least 20 cells or use IHC to define the areas of potential ERBB2 amplification • If there is a second population of contiguous cells with increased ERBB2 signals/cell and this cell population consists of 10% of tumor cells on the slide (defined by image analysis or visual estimation of the ISH or IHC slide), a separate counting of at least 20 nonoverlapping cells must also be performed within this cell population and reported • For brightfield ISH, counting requires comparison between patterns in normal breast and tumor cells because artifactual patterns may be seen that are difficult to interpret; if the tumor cell pattern is neither normal nor clearly amplified, the test should be submitted for expert opinion ISH interpretation Acceptable (IHC and ISH) tests • Should preferentially use an FDA-approved IHC, brightfield ISH, or FISH assay
  6. 6. HER2 Testing in Breast Cancer Guidance From ASCO/CAP1 Access the activity, “Increasing Importance of HER2 and HER3 Testing in the Context of an Expanding Targeted Therapies Landscape for Breast, Gastrointestinal, Lung, and Other Cancers: Latest Updates and Practical Guidance for Pathologists,” at PeerView.com/SMP40 PRACTICE AID ASCO: American Society of Clinical Oncology; CAP: College of American Pathologists; CEP17: chromosome enumeration probe 17; ER: estrogen receptor; ERBB2: erb-B2 receptor tyrosine kinase 2; FISH: fluorescence in situ hybridization; HER2: human epidermal growth factor receptor 2; IHC: immunohistochemistry; ISH: in situ hybridization; LDT: laboratory-developed test; MSI: microsatellite instability; NGS: next-generation sequencing; PgR: progesterone receptor; TMB: tumor mutational burden. 1. Wolff AC et al. Arch Pathol Lab Med. 2018;142:1364-1382. 2. Hechtman JF, Ross DS. Cancer Cytopathol. 2019;127:428-431. Summary of HER2 Testing Recommendations (Cont’d) Topic Optimal tissue sectioning requirements • Sections should ideally not be used for HER2 testing if cut 6 weeks earlier; this may vary with primary fixation or storage conditions Optimal external proficiency assessment • Participation in and successful completion of external proficiency testing program with at least two testing events (mailings) a year • Satisfactory performance requires at least 90% correct responses on graded challenges for either test • Unsatisfactory performance will require laboratory to respond according to accreditation agency program requirements • See text below, under optimal laboratory accreditation Optimal monitoring of test concordance between methods Optimal internal quality assurance procedures • Should review and document external and internal controls with each test and each batch of tests • Ongoing quality control and equipment maintenance • Initial and ongoing laboratory personnel training and competency assessment • Use of standardized operating procedures, including routine use of control materials • Revalidation of procedure if changed • Ongoing competency assessment and documentation of the actions taken as a part of the laboratory record Recommendations Optimal laboratory accreditation • Onsite inspection every other year with annual requirement for self-inspection • Reviews laboratory validation, procedures, QA results and processes, results, and reports • Unsatisfactory performance results in suspension of laboratory testing for HER2 for that method • Validation of test must be performed before test is offered Optimal internal validation procedure Optimal initial test validation • Laboratories performing these tests should be following all accreditation requirements, one of which is initial testing validation. The laboratory should ensure that initial validation conforms to the published 2010 ASCO/CAP recommendations for IHC testing of ER and PgR guideline validation requirements with 20 negative and 20 positive for FDA-approved assays and 40 negative and 40 positive for LDTs. This requirement does not apply to assays that were previously validated in conformance with the 2007 ASCO/CAP HER2 testing guideline, and those who routinely participate in external proficiency testing for HER2 tests, such as the program offered by CAP. • Laboratories are responsible for ensuring the reliability and accuracy of their testing results by compliance with accreditation and proficiency testing requirements for HER2 testing assays. Specific concordance requirements are not required. NGS2 can also be used for HER2 testing of surgical specimens or cell blocks and has recently been shown to work well with cytologic supernatant; NGS also provides additional information: ERBB2 copy number, mutations, TMB, and MSI status
  7. 7. HER2 Testing in Gastroesophageal Cancer Guidance From CAP/ASCP/ASCO1 Access the activity, “Increasing Importance of HER2 and HER3 Testing in the Context of an Expanding Targeted Therapies Landscape for Breast, Gastrointestinal, Lung, and Other Cancers: Latest Updates and Practical Guidance for Pathologists,” at PeerView.com/SMP40 PRACTICE AID GEA and potential candidate for HER2-targeted therapy HER2-targeted therapy should not be initiated until HER2 positivity is confirmed Biopsy or resection specimen from primary or metastatic sites should be used Alternative: FNA specimens (cell blocks) may be used Request HER2 test Equivocal or negative result Inadequate specimen tested No positive results Positive results Initiate HER2-targeted therapy; no further HER2 testing is required Retest additional available tissue; if there is no available tissue, additional tumor tissue may be obtained for retesting NGS2 enables assessment of ERBB2 copy number and mutations simultaneously, along with other molecular events such as TMB and MSI status; can be performed on both surgical specimens or cell blocks and has recently been shown to work with cytologic supernatant
  8. 8. HER2 Testing in Gastroesophageal Cancer Guidance From CAP/ASCP/ASCO1 Access the activity, “Increasing Importance of HER2 and HER3 Testing in the Context of an Expanding Targeted Therapies Landscape for Breast, Gastrointestinal, Lung, and Other Cancers: Latest Updates and Practical Guidance for Pathologists,” at PeerView.com/SMP40 PRACTICE AID Perform HER2 Test using IHC IHC 2+ Equivocal IHC 1+ Negative IHC 3+ Positive Perform ISH Testing IHC 0 Negative Surgical specimen Strong, complete basolateral or lateral membranous reactivity in ≥10% of tumor cells Biopsy specimen Tumor cell clustera with strong, complete basolateral or lateral membranous activity irrespective of percentage of tumor cells stained Surgical specimen Weak to moderate, complete basolateral or lateral membranous reactivity in ≥10% of tumor cells Biopsy specimen Tumor cell clustera with weak/ moderate, complete basolateral or lateral membranous activity irrespective of percentage of tumor cells stained Surgical specimen Faint/barely perceptible membranous reactivity in ≥10% of tumor cells; cells reactive only in part of their membrane Biopsy specimen Tumor cell clustera with faint/ barely membranous activity irrespective of percentage of tumor cells stained Surgical specimen No reactivity or membranous reactivity in 10% of tumor cells Biopsy specimen No reactivity in any tumor cells No further ISH testing is required No further ISH testing is required Tissue sample from patient diagnosed with GEA
  9. 9. HER2 Testing in Gastroesophageal Cancer Guidance From CAP/ASCP/ASCO1 Access the activity, “Increasing Importance of HER2 and HER3 Testing in the Context of an Expanding Targeted Therapies Landscape for Breast, Gastrointestinal, Lung, and Other Cancers: Latest Updates and Practical Guidance for Pathologists,” at PeerView.com/SMP40 PRACTICE AID a Tumor cell cluster is defined as a cluster of 5 or more tumor cells. Additional recommendations: Pathologists should ensure that biopsy or resection specimens used for HER2 testing are rapidly placed in fixative, ideally within 1 h (cold ischemic time) and are fixed in 10% neutral buffered formalin for 6-72 h. Routine histology processing and HER2 testing should be performed according to analytically validated protocols. Pathologists should identify areas of invasive adenocarcinoma and also mark areas with the strongest intensity of HER2 expression by IHC in the GEA specimen for subsequent scoring when ISH is required. ASCO: American Society of Clinical Oncology; ASCP: American Society for Clinical Pathology; CAP: College of American Pathologists; ERBB2: erb-B2 receptor tyrosine kinase 2; FNA: fine needle aspiration; GEA: gastroesophageal adenocarcinoma; HER2: human epithelial growth factor receptor 2; IHC: immunohistochemistry; ISH: in situ hybridization; MSI: microsatellite instability; NGS: next-generation sequencing; TMB: tumor mutational burden. 1. Bartley AN et al. Am J Clin Pathol. 2016;146:647-669. 2. Hechtman JF, Ross DS. Cancer Cytopathol. 2019;127:428-431. Summary of HER2 Testing Recommendations Strength of Recommendation Strong recommendation • In patients with GEA who are potential candidates for HER2-targeted therapy, the treating clinician should request HER2 testing on tumor tissue Strong recommendation • Laboratories must incorporate GEA HER2 testing methods into their overall laboratory quality improvement program, establishing appropriate quality improvement monitors as needed to ensure consistent performance in all steps of the testing and reporting process; in particular, laboratories performing GEA HER2 testing must participate in a formal proficiency testing program, if available, or an alternative proficiency assurance activity • Laboratories should report HER2 testing results in GEA specimens in accordance with the CAP “Template for Reporting Results of HER2 (ERBB2) Biomarker Testing of Specimens From Patients With Adenocarcinoma of the Stomach or Esophagogastric Junction” Strong recommendation Strong recommendation • Pathologists should identify areas of invasive adenocarcinoma and also mark areas with the strongest intensity of HER2 expression by IHC in GEA specimens for subsequent ISH scoring when required Recommendations No recommendation • There is insufficient evidence to recommend for or against genomic testing in patients with GEA at this time Strong recommendation • When GEA HER2 status is being evaluated, laboratories/pathologists should perform/order IHC testing first, followed by ISH when IHC result is 2+ (equivocal); positive (3+) or negative (0 or 1+) HER2 IHC results do not require further ISH testing • Pathologists should select the tissue block with the areas of lowest grade tumor morphology in biopsy and resection specimens; more than 1 tissue block may be selected if different morphologic patterns are present Recommendation • Pathologists should use the Ruschoff/Hofmann method in scoring HER2 IHC and ISH results for GEAStrong recommendation Strong recommendation • Laboratories/pathologists must specify the antibodies and probes used for the test and ensure that assays are appropriately validated for HER2 IHC and ISH on GEA specimens Recommendation • Treating clinicians should offer combination chemotherapy and HER2-targeted therapy as the initial treatment for appropriate patients with HER2-positive tumors who have metastatic or recurrent GEA Recommendation • Treating clinicians or a pathologist should request HER2 testing on tumor tissue in the biopsy or resection specimens (primary or metastasis), preferably before the initiation of trastuzumab therapy if such specimens are available and adequate; HER2 testing on FNA specimens (cell blocks) is an acceptable alternative

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