ASCO/CAP Issue New Guidelines for IHC Hormone Testing in Breast Cancer

The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) jointly released guidelines designed to improve the accuracy and usefulness of immunohistochemical (IHC) testing for estrogen receptor (ER) and progesterone receptor (PgR) status in breast cancer tumors after convening a panel of international experts to study the issue. After reviewing 337 studies in the literature, the panel reported that up to 20% of IHC determinations of ER and PgR status are incorrect. The authors said these false positives or false negatives are due to preanalytic factors, thresholds for positivity, and criteria used to interpret the tests.

When to Test

The panel’s foremost recommendation is that clinicians determine ER and PgR status for all newly diagnosed invasive breast cancers and all recurrent cancers. In patients with multiple tumors, the investigators recommend—at a minimum—testing a specimen from the largest tumor. Noting it has become common to assess newly diagnosed ductal carcinoma in situ (DCIS) for ER and PgR status, the panel said studies demonstrate there is value to doing so. In a recent abstract, the National Surgical Adjuvant Breast and Bowel Project B-24 clinical trial reported that women with ER-positive DCIS who received tamoxifen after lumpectomy and radiation had a 40% to 50% reduction in subsequent breast cancer at 10 years compared with women who received placebo. Absent confirmatory studies, however, the panel leaves the decision on whether to assess the ER status of DCIS to the discretion of the physician and patient.

Standardizing the Laboratory

The guidelines recommend standardizing preanalytic factors, such as tissue handling. After excision, the breast specimen should be immediately fixed, ideally using a volume of fixative 10 times the volume of the tissue. The breast care management team should document both the time the surgeon hands over the tissue and the time it is placed in fixative. The suspect tissue should be transported to the pathology laboratory as soon as possible, and no more than 1 hour should elapse from excision to fixation.

The panel outlines several guidelines laboratory technicians should adhere to for optimal results. They address preanalytic factors, such as how to orient and ink the specimens, what type of fixative to use, and how long to keep the specimen; analytic standardization, including antibody selection and criteria for control samples; and postanalytic standardization for the interpretation and reporting of ER and PgR by IHC. Starting this year, CAP will require laboratories that perform ER and PgR testing to participate in a proficiency testing program as part of the CAP Laboratory Accreditation Program.

receptor positive

receptor uninterpretable

The guidelines describe a test as one in which “at least 1% of tumor cells show positive nuclear staining of any intensity.” A specimen is receptor negative when “<1% of tumor cells show positive nuclear staining of any intensity.” Assays will be identified as if any testing conditions fail to conform to guidelines, controls are not as expected, or “no tumor nuclei are immunoreactive and...internal epithelial elements present in the sample or separately submitted from the same sample lack any nuclear staining.” The pathology report should also list the percentage of tumor cells that stain positively and identify staining intensity as strong, moderate, or weak.

Utility of Test Results

The threshold for a positive test with IHC was lowered because the panel said the literature showed IHC was equal to or better than LBA testing at predicting response to hormonal therapy. “Levels as low as 1% positive-staining carcinoma cells are associated with significant clinical response,” said the authors. With tamoxifen and other endocrine therapies well tolerated and highly effective at reducing mortality, the panel recommends “considering endocrine therapy in patients whose breast tumors show at least 1% ER-positive cells.” For those with <1% ER-positive cells, the panel advises withholding endocrine therapy.

The new guidelines will likely lead some practices to increase their use of endocrine therapy. The panel suggests discussing the pros and cons of endocrine therapy with patients whose IHC testing shows their tumors have low levels of ER, defined as “1% to 10%, weakly positive cells.”

Several studies have identified a relationship between hormone receptor levels and outcomes. According to the authors, patients with higher hormone receptor levels are more likely to have positive outcomes with therapy. While some studies suggest PgR may not have as great a predictive value as ER, the panel notes that “predictive validity for PgR has been demonstrated with as few as 1% of stained tumor nuclei cells in retrospective studies.” Patients with >1% of carcinoma cells exhibiting weakly positive staining for PgR appear to have better disease-free and overall survival, as well as better survival after relapse. In metastatic breast cancer, a 1% staining threshold for PgR was associated with response to first-line endocrine therapy after relapse and 10% and 1% thresholds were associated with response to tamoxifen.

In a press release, panel co-chair Elizabeth Hammond, MD, a pathologist at Intermountain Healthcare and professor of pathology at the University of Utah School of Medicine, said, “All medical professionals involved in cancer care want to do the right thing and offer the most correct and appropriate care to their patients. It is our hope that the ASCO/CAP ER/PgR guidelines will facilitate processes at each health system and institution, so that appropriate measures to ensure accurate predictive biomarker testing (including ER/PgR) are in place and that breast cancer patients receive the highest quality care possible.” ASCO and CAP have made resources available to help clinicians understand these guidelines.