Version May 2024
| 2010 Recommendation | Updated recommendation |
| Clinical question 1: What are the optimum QA, specimen handling, positive threshold, scoring system, and reporting for determining potential benefit from endocrine therapy? | |
| Optimal algorithm for ER/PR testing | Optimal algorithm for ER/PR testing |
| Positive for ER or PR if finding that ≥1% of tumor cell nuclei are immunoreactive. | Samples with 1 to 100% of tumor nuclei positive for ER or PR are interpreted as positive. |
| Negative for ER or PR if finding that <1% of tumor cell nuclei are immunoreactive in the presence of evidence that the sample can express ER or PR (positive intrinsic controls are seen). | For reporting of ER (not PR), if 1 to 10% of tumor cell nuclei are immunoreactive, the sample should be reported as ER low positive with a recommended comment. |
| Uninterpretable for ER or PR if finding that no tumor nuclei are immunoreactive and that internal epithelial elements present in the sample or separately submitted from the same sample lack any nuclear staining. | A sample is considered negative for ER or PR if <1% or 0% of tumor cell nuclei are immunoreactive. |
| A sample may be deemed uninterpretable for ER or PR if the sample is inadequate (insufficient cancer or severe artifacts present, as determined at the discretion of the pathologist), if external and internal controls (if present) do not stain appropriately, or if preanalytic variables have interfered with the assay’s accuracy. | |
| Clinicians should be aware of and be able to discuss with patients the limited data on ER-low positive cases and issues with test results that are close to a positive threshold. | |
| Optimal testing conditions | Optimal testing conditions (no changes) |
| Large (preferably multiple) core biopsies of tumor are preferred for testing if they are representative of the tumor (grade and type) at resection. | Large (preferably multiple) core biopsies of tumor are preferred for testing if they are representative of the tumor (grade and type) at resection. |
| Accession slip and report must include guideline-detailed elements. | Accession slip and report must include guideline-detailed elements. |
| Optimal tissue handling requirements | Optimal tissue handling requirements (no changes) |
| Time from tissue acquisition to fixation should be as short as possible. Samples for ER and PR testing are fixed in 10% NBF for 6 to 72 hours. Samples should be sliced at 5-mm intervals after appropriate gross inspection and margins designation and placed in sufficient volume of NBF to allow adequate tissue penetration. If tumor comes from remote location, it should be bisected through the tumor on removal and sent to the laboratory immersed in a sufficient volume of NBF. Cold ischemia time, fixative type, and time the sample was placed in NBF must be recorded. | Time from tissue acquisition to fixation should be as short as possible. Samples for ER and PR testing are fixed in 10% NBF for 6 to 72 hours. Samples should be sliced at 5-mm intervals after appropriate gross inspection and margins designation and placed in sufficient volume of NBF to allow adequate tissue penetration. If tumor comes from remote location, it should be bisected through the tumor on removal and sent to the laboratory immersed in a sufficient volume of NBF. Cold ischemia time, fixative type, and time the sample was placed in NBF must be recorded. |
| As in the ASCO/CAP HER2 guideline, use of slides cut more than 6 weeks before analysis is not recommended. | As in the ASCO/CAP HER2 guideline, use of unstained slides cut more than 6 weeks before analysis is not recommended. |
| The time tissue is removed from patient, time tissue is placed in fixative, duration of fixation, and fixative type must be recorded and noted on accession slip or in report. | The time tissue is removed from patient, time tissue is placed in fixative, duration of fixation, and fixative type must be recorded and noted on accession slip or in report. |
| Optimal internal validation procedures | Optimal internal validation procedures |
| Internal validation must be done before test is offered; refer to separate article on testing validation.[1] | This topic is deferred to the forthcoming CAP guideline update, principles of analytic validation of IHC assays, once available. There should be initial test validation/verification prior to reporting any clinical samples. Prior to that, previously recommended principles apply.[1,2] |
| Validation must be done using a clinically validated ER or PR test method. | |
| Revalidation should be done whenever there is a significant change to the test system, such as a change in the primary antibody clone or introduction of new antigen retrieval or detection systems. | |
| Optimal internal QA procedures | Optimal internal QA procedures |
| Ongoing quality control and equipment maintenance. | Ongoing quality control and equipment maintenance are required. |
| Initial and ongoing laboratory personnel training and competency assessment. | Initial and ongoing laboratory personnel training and competency assessment should be performed. |
| Use of SOPs, including routine use of external control materials with each batch of testing and routine evaluation of internal normal epithelial elements or the inclusion of normal breast sections on each tested slide, wherever possible. | SOPs should be used that include routine use of external control materials with each batch of testing and routine evaluation of internal normal epithelial elements or the inclusion of normal breast sections (or other appropriate control) on each tested slide, wherever possible. External controls should include negative and positive samples as well as samples with lower percentages of ER expression (such as tonsil). On-slide controls are recommended. |
| Regular, ongoing assay reassessment should be done at least semiannually;[1,2] revalidation is needed whenever there is a significant change to the test system. | Regular, ongoing assay reassessment should be done at least semiannually.[1] Revalidation is needed whenever there is a significant change to the test system.[2] |
| Ongoing competency assessment and education of pathologists. | Ongoing competency assessment and education of pathologists is required. |
| Optimal external proficiency assessment | Optimal external proficiency assessment |
| Mandatory participation in external proficiency testing program with at least two testing events (mailings) per year. | The laboratory performing ER and PR testing must participate in external proficiency testing or alternative performance assessment as required by its accrediting organization. |
| Satisfactory performance requires at least 90% correct responses on graded challenges for either test. | |
| Optimal laboratory accreditation | Optimal laboratory accreditation |
| On-site inspection every other year with annual requirement for self-inspection. | On-site inspection every other year should be undertaken with annual requirement for self-inspection. |
| Clinical question 2: What additional strategies can promote optimal performance, interpretation, and reporting of IHC assays, particularly in cases with low ER expression? | |
| No specific recommendations were specified in 2010 for low ER expression cases. | Laboratories should include ongoing quality control using SOPs for test evaluation prior to scoring (readout) and interpretation of any case (refer to UpToDate algorithm on scoring of IHC for ER in BC). |
| Interpretation of any ER result should include evaluation of the concordance with the histologic findings of each case. Clinicians should also be aware of when results are highly unusual/discordant and work with pathologists to attempt to resolve or explain atypical reported findings (refer to UpToDate table on invasive breast cancer histopathologic concordance with ER staining). | |
| Laboratories should establish and follow an SOP stating the steps the laboratory takes to confirm or adjudicate ER results for cases with weak stain intensity or ≤10% of cells staining. | |
| The status of internal controls should be reported for cases with 0 to 10% staining. For cases with these results without internal controls present and with positive external controls, an additional report comment is recommended. | |
| Clinical question 3: Are other ER expression assays acceptable for identifying patients likely to benefit from endocrine therapy? | |
| No assays other than IHC are recommended as testing platforms. | Validated IHC is the recommended standard test for predicting benefit from endocrine therapy. No other assay types are recommended as the primary screening test for this purpose. |
| Clinical question 4: Should DCIS be routinely tested for hormone receptors? | |
| ER and PR testing of DCIS is optional (no formal recommendation made to test or not test). | ER testing in cases of newly diagnosed DCIS (without associated invasion) is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer; PR testing is considered optional. |
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