NEW GUIDELINESS FOR HORMONE RECEPTOR TESTING IN BREAST CANCER

April 23, 2010 — The College of American Pathologists (CAP) and the American Society of Clinical Oncology (ASCO) have developed a joint guideline aimed at improving the accuracy of immunohistochemical estrogen-receptor (ER) and progesterone-receptor (PgR) testing in breast cancer. The guideline has been published online April 19 in both the Journal of Clinical Oncology and the Archives of Pathology & Laboratory Medicine.

ER is the paradigm tumor marker for managing breast cancer patients, and its clinical significance has made the assessment of ER status of primary invasive breast cancer mandatory. However, the guideline authors note that the accuracy of the testing method used determines the appropriate application of treatment, and for the past 3 decades, several methods with various biochemical principles, analytic sensitivity, and analytic precision have been used.

The expert panel convened to write the guideline found that up to 20% of current immunohistochemical determinations of ER and PgR testing worldwide could be inaccurate. The majority of these issues occurred because of variations in preanalytic variables, thresholds for positivity, and interpretation criteria.

"There is clearly a need to accurately identify breast cancer subtypes as ER- and/or PgR-positive to help us identify those patients most likely to benefit from endocrine therapy and minimize the risk of potentially denying effective and life-saving therapy to patients incorrectly labeled as having ER- or PgR-negative invasive disease," said Antonio C. Wolff, MD, FACP, cochair of the ASCO/CAP Hormone Receptor Testing in Breast Cancer Panel and associate professor of oncology at the Johns Hopkins Kimmel Comprehensive Cancer Center in Baltimore, Maryland, in a release.

The international panel of experts, convened by ASCO and CAP — in partnership with Cancer Care Ontario, in Toronto — conducted a systematic review and evaluation of the literature on hormone-receptor testing published since 1990.

The overall purpose was to develop recommendations for optimal immunohistochemical testing performance to improve the accuracy and utility of ER and PgR as prognostic and predictive markers. In all, 337 studies met the inclusion criteria.

Summary of Recommendations

The guideline recommends testing ER and PgR status for all newly diagnosed invasive breast cancers (including primary and/or metastatic sites) and, when appropriate, repeating the test in patients with a known breast cancer diagnosis who present with a local or distant recurrence.

Also recommended is the establishment of uniform testing measures that focus on proven, reliable, and reproducible assays and procedures.

Laboratories conducting testing are advised to validate their assays against existing and clinically validated tests. Results should agree with those of the clinically validated assays at least 90% of the time for positive receptor status and at least 95% of the time for negative receptor status.

It is recommended that breast tissue specimens be transported from the operating room to the pathology laboratory as soon as they are available for gross assessment. The time from tumor removal to initiation of fixation should be kept to 1 hour or less. The sample must be fixed in neutral buffered formalin for at least 6 hours and no longer than 72 hours.

The guideline notes that ER and PgR tests should be conducted in a CAP-accredited laboratory or in a laboratory that meets the accreditation requirements spelled out in the guideline. CAP requires that every accredited lab performing testing participate in a mandatory proficiency testing program.

An ER and PgR test performed by an immunohistochemical assay should be considered positive if at least 1% of the tumor in the sample tests positive, which helps predict whether a patient is likely to benefit from endocrine treatment.

The panel also recognized that it is reasonable for oncologists to discuss the pros and cons of endocrine therapy with patients whose tumors contain immunohistochemical-identified low levels of ER and to make an informed decision on the basis of available information.

Optimal Algorithm and Testing Conditions

Recommended optimal algorithms for testing are:

* that ER or PgR is positive if 1% of more of tumor cell nuclei are immunoreactive
* that ER or PgR is negative if less than 1% of tumor cell nuclei are immunoreactive in the presence of evidence that the sample can express ER or PgR (i.e., positive intrinsic controls are seen)
* that ER or PgR results are uninterpretable if no tumor nuclei are immunoreactive and if internal epithelial elements present in the sample, or separately submitted from the same sample, lack any nuclear staining.

Recommended optimal testing conditions are:

* that large, preferably multiple core biopsies of tumor for testing are preferred if they are representative of the tumor (grade and type) at resection
* that interpretation follows guideline recommendations
* that accession slip and report must include guideline-detailed elements.

Attention to Simple Measures

"Increased attention to simple measures, such as the handling of tissue specimens from the moment they are taken from the patient to when they reach the pathologist, the uniform fixation of specimens, the standardization and validation of lab assays, rigorous reporting procedures, and greater access to treatment interventions, have the potential to significantly improve breast cancer outcomes around the world," said Elizabeth Hammond, MD, cochair of the ASCO/CAP Hormone Receptor Testing in Breast Cancer Panel, pathologist at Intermountain Healthcare, and professor of pathology at the University of Utah School of Medicine in Salt Lake City, in a statement.

The guideline authors note that ASCO and CAP will work to coordinate these recommendations with those of other organizations, including the National Comprehensive Cancer Network, the American College of Surgeons Commission on Cancer, the American Joint Committee on Cancer, and patient advocacy organizations.

J Clin Oncol. Published online April 19, 2010. Abstract
Arch Pathol Lab Med. 2010;134(6):E1-E16. Abstract