- The College of American Pathologists (CAP) and the American Society of Clinical Oncology (ASCO) convened an expert panel to consider new evidence or emerging data that might prompt changes to clinical practices that were established with the 2010 ASCO/CAP Guideline Recommendations for Immunohistochemical (IHC) Testing of Estrogen and Progesterone Receptors (ER/PgR) in Breast Cancer.
- A well-performed ER/PgR assay identifies which patients could benefit from to endocrine therapy as treatment after a diagnosis of breast cancer. Additionally, hormone receptor status can be valuable more broadly for tumor classification and other factors that inform treatment.
- Globally, more than 1 million women are being diagnosed annually with breast cancer and receptor testing conducted on these biopsies typically discern that approximately 8 in 10 of these women have ER positive breast cancer.
- The new guidance reaffirms many of the 2010 recommendations, including that patients with breast cancers having 1–100% ER expression be considered ER positive for the purpose of endocrine therapy decisions. However, new reporting recommendations are made for cases with 1–10% ER expression to acknowledge the more limited data on endocrine responsiveness in this group and overlapping features with ER negative cancers.
- The update also has a new recommendation for labs to establish a specific standard operating procedure to ensure the validity of low positive (1–10%) or negative (0 or <1%) interpretations and results. Correlation of ER staining with the histologic features (as well as attention to other standard quality control measures) is also recommended and unusual/discordant results worked up.
- The utility of PgR testing continues to be largely prognostic in the ER-positive population, but testing using similar principles to ER testing is still recommended for invasive cancers.
- Additionally, the updated draft now recommends ER testing for patients diagnosed with ductal carcinoma in situ, but PgR testing is optional.
Recommendation 1.1. Optimal algorithm for ER/PgR testing
- Samples with 1-100% of tumor nuclei positive for ER or PgR are interpreted as positive. For reporting of ER (not PgR), if 1-10% of tumor cell nuclei are immunoreactive the sample should be reported as ER Low Positive with a recommended comment (see Figure 1 and Table 2). A sample is considered negative for ER or PgR if <1% or 0%of tumor cell nuclei are immunoreactive. A sample may be deemed uninterpretable for ER or PgR if the sample is inadequate (insufficient cancer or severe artifacts present, as determined at the discretion of the pathologist), external and internal controls (if present) do not stain appropriately or if pre-analytical variables have interfered with the assay’s accuracy (see Figures 1-4). Clinicians should be aware of and 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. (Strong Recommendation; EB-H)
Recommendation 1.2. Optimal testing conditions (no change)
- 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. (Strong Recommendation; EB-H)
Recommendation 1.3. Optimal tissue handling requirements (no change)
- Time from tissue acquisition to fixation should be as short as possible. Samples for ER and PgR testing are fixed in 10% neutral buffered formalin (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, using unstained slides cut more than 6 weeks before analysis is not recommended. 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. (Strong Recommendation; EB-H)
Recommendation 1.4. Optimal internal validation procedures (change anticipated)
- This topic is deferred to 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. (Strong Recommendation; EB-H)
Recommendation 1.5. Optimal internal QA procedures
- Ongoing quality control and equipment maintenance are required. Initial and ongoing laboratory personnel training and competency assessment should be performed. Standardized operating procedures 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. Revalidation is needed whenever there is a significant change to the test system. Ongoing competency assessment and education of pathologists is required. (Strong Recommendation; EB-H)
Recommendation 1.6. Optimal external proficiency assessment
- The laboratory performing ER and PgR testing must participate in external proficiency testing or alternative performance assessment as required by its accrediting organization. (Strong Recommendation; EB-H)
Recommendation 1.7. Optimal laboratory accreditation
- On-site inspection every other year should be undertaken with annual requirement for self-inspection. (Moderate Recommendation; IC-I)
- Laboratories should include ongoing quality control using standard operating procedures for test evaluation prior to scoring (readout) and interpretation of any case as defined in the checklist in Figure 1.(Strong Recommendation; IC-H)
- 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 (see Table 1 as an aid in this process). (Strong Recommendation; IC-H)
- Laboratories should establish and follow a standard operating procedure (SOP) stating the steps the lab takes to confirm or adjudicate ER results for cases with weak stain intensity or ≤10% of cells staining (see Figure 1 for an example SOP). (Strong Recommendation; IC-H)
- The status of internal controls should be reported for cases with 0-10% staining. For cases with these results without internal controls present and with positive external controls, an additional report comment is recommended (see Table 2). (Strong Recommendation; IC-H)
- 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. (Strong Recommendation; EB-H)
- 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. PgR testing is considered optional. (Moderate Recommendation; EB-I)
Table 1. Invasive Breast Cancer Histopathologic Concordance with Estrogen Receptor Staining
|HIGHLY UNUSUAL ER NEGATIVE RESULTS||HIGHLY UNUSUAL ER POSITIVE RESULTS|
Table 2. Additional Recommended Reporting Comments for Specific Scenarios
|Result:||Additional recommended comment:|
|1-10% cells staining:||The cancer in this sample has a low level (1-10%) of ER expression by IHC. There are limited data on the overall benefit of endocrine therapies for patients with low level (1-10%) ER expression, but they currently suggest possible benefit, so patients are considered eligible for endocrine treatment. There are data that suggest invasive cancers with these results are heterogeneous in both behavior and biology and often have gene expression profiles more similar to ER negative cancers.|
|No internal controls and ER is 0-10%:||No internal controls are present, but external controls are appropriately positive. If needed, testing another specimen that contains internal controls may be warranted for confirmation of ER status.|