Biomarker Testing: ER, PR and Her2
Written by: Ashley Cimino-Mathews MD and Gang Zheng MD PhD
One important aspect of the role of Pathology in the evaluation of breast cancer is biomarker testing, specifically the accurate assessment of the estrogen receptor (ER), progesterone receptor (PR), and Her2 status of a patient's breast cancer. Biomarkers can be prognostic, predictive, or both. Prognostic biomarkers are independent measures of prognosis such that the presence or absence of the biomarker is associated with a patient's overall clinical outcome (i.e., risk of recurrence and mortality). Predictive biomarkers, in contrast, predict whether or not a patient will respond to a given therapy.
The expression of the hormone receptors ER and PR in a patient's breast cancer is an example of a weak prognostic but strong predictive biomarker. If a patient's tumor expresses ER and/or PR, as seen in approximately 70% of invasive breast cancers, we can predict that this patient will likely benefit from endocrine therapy such as tamoxifen. The overexpression of the oncogene Her2 in a patient's breast cancer, as seen in approximately 15-20% of invasive breast cancers, is an example of both a prognostic and predictive biomarker. Her2 expression is associated with a diminished prognosis (e.g., higher risk of recurrence), however, it also predicts that a patient will more likely benefit from anthracycline and taxane-based chemotherapies and directed therapies that target Her2 (trastuzamab), but not to endocrine-based therapies.
Many factors influence the accuracy of detection of ER, PR, and Her2 in the laboratory. These include pre-analytical factors (including prompt fixation of appropriate duration), analytic factors (including utilization of validated procedures with ongoing proficiency testing), and post-analytic factors (including appropriate reporting). Importantly, the results of these tests alone are the key determinants of what treatment is selected. The goal is to provide the right treatment to the right patient. The role of the pathologist is to accurately assess these biomarkers, which as indicated above is quite challenging and involved. The role of the oncologist is to treat the patient with one of several standardized therapies (endocrine therapy for ER/PR positive carcinomas, Trastuzumab for Her-2 positive carcinomas).
A Summary of the Key Points of Biomarker Testing:
- All primary invasive breast carcinomas should be tested for ER/PR/Her-2. Since ER/PR/Her2 status will change in a small percentage of breast recurrences, these markers should generally be reevaluated in recurrences/metastases.
- Endocrine therapy is highly effective and relatively non-toxic. One would never want to deny a patient the potential benefits of endocrine therapy. Pathologists have known for over ten years that as little as 1% labeling of invasive carcinoma nuclei predicts clinical benefit from endocrine therapy (Harvey et al. JCO 1999;17: 1474-1481), so pathologists should carefully examine these stains so as not to miss potentially significant focal labeling.
- PR labeling adds predictive information to ER labeling and, therefore, both are assessed.
- Her2 status is initially assessed by immunohistochemistry (measuring protein overexpression). Cases which are equivocal for protein overexpression are assessed by Fluorescence in Situ Hybridization (FISH), which assesses Her2 DNA amplification.