ER/PR testing guidelines: Joint CAP/ASCO recommendations

The College of American Pathologists (CAP) and the American Society of Clinical Oncology (ASCO) issue a joint guideline on April 19, 2010 in an effort to improve the accuracy of immunohistochemistry testing for estrogen (ER) and progesterone receptors (PgR) expression in breast cancer. This is similar to the joint effort the groups made with HER2 testing guideline in 2007.  The guideline is being published in the April 19 issues of ASCO’s Journal of Clinical Oncology (JCO) and the CAP’s Archives of Pathology & Laboratory Medicine in June 2010 but is available in electronic form here.  The ASCO Web page on the guidelines (http://www.asco.org/guidelines/erpr) has links to the unabridged version (yikes!) as well as downloadable slides.

The major recommendation are summarized from the CAP's press release (quoted):

• Testing ER and PgR status on all newly diagnosed invasive breast cancers (primary site and/or metastatic site), and whenever appropriate, repeat testing in patients with a known breast cancer diagnosis who now present with a local or distant recurrence.
• Establishing uniform testing measures that focus on proven, reliable and reproducible assays and procedures.
• Having testing laboratories validate their assays against existing and clinically validated tests. Results should agree at least 90 percent of the time with those of the clinically validated assays for positive receptor status and at least 95 percent for negative receptor status.
• Transporting breast tissue specimens 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 one hour or less. Fixation of the sample in neutral buffered formalin must extend for at least six hours and no longer than 72 hours.
• Performing ER and PgR testing in a CAP-accredited laboratory or in a laboratory that meets the accreditation requirements spelled out in the guideline. The CAP will require that every accredited lab performing testing participate in a mandatory proficiency testing program.
• Considering an ER and PgR test performed by an IHC assay as positive if at least one percent of the tumor in the sample tests positive, which helps predict whether a patient is likely to benefit with endocrine treatment. The panel recognized that it is reasonable for oncologists to discuss the pros and cons of endocrine therapy with patients whose tumors contain low levels of ER by IHC (one percent to ten percent weakly positive cells) and to make an informed decision based on available information.

As with the ASCO/CAP HER2 guidelines, the ER/PR guideline is an excellent state-of-the-art reference.  I welcome the direction it provides for reporting, specifically, for defining a threshold for determining a positive status and, in general, for thoroughly discussing the role of pre-analytic factors in receptor preservation.

Fortunately, my lab has already been reporting most of the elements in the guideline, such as which clone we are using, fixation time, percent of cells positive, staining intensity and Allred score, etc.  BUT 

One troubling recommendation, however, is the mandate that cold ischemia time be documented: "The time of tissue collection (defined as the time that the tissue is handed from the surgical field) and the time the tissue is placed in fixative both must (my emphasis) be recorded on the tissue specimen requisition to document the time to fixation of the specimen."  While I do completely agree with the idea that "cold ischemia time" should be minimized and we need to educate surgeons, radiologists, and OR staff regarding this, to state this categorically in a recommendation with an explicit instruction on how to do it is a mistake.  This creates an unnecessary burden on the pathology department to police the surgeon.  Are we then to reject a specimen as unacceptable for testing whenever this time is not documented?  What if it is documented somewhere else in the medical record (like we document the time the specimen is placed in fixative in our gross description)?  The over-weighted academic composition of the guideline panel really comes through with stuff like this.  It is really a shame that more community pathologist input is not sought for these guideline panels since most breast cancer is diagnosed at the community level.

Another annoying thing is the list of "well-validated" clones for ER and PR listed in Table 3.  The implication is that if your lab is not using one of these clones, then your lab is not in compliance with the guidelines.  Really?  I thought this was the responsibility of the laboratory medical director to validate a new antibody with a clinically validated assay.  For example, I could not approve the validation of the 1A6 clone for PR in my lab using cell lines controls with low, medium and high defined receptor content because of low sensitivity but was able to validate a different clone (which itself was compared with the 1A6 clone by the manufacturer).  Given the authors' disclosures of potential conflicts of interest (yes, I do actually read this stuff!  not that I'm paranoid or anything), I think the panel might have avoided implying in any way that labs must be using these specific clones for testing.

In summary, the guidelines are very welcome indeed and provide support for what many of us are already doing and may also encourage those labs that are unwilling or unable to comply to send-out these tests to another lab.