Recent Changes in Physicians' Interpretation of Estrogen Receptor (ER) Assay Results: Adjuvant Endocrine Therapy in Patients with low, but Detectable ER
Jennifer Motley, MD

In the last few years, a number of factors have caused physicians to re-evaluate the use of adjuvant hormonal therapy based on estrogen and progesterone receptor assay results.

• A report by Harvey et al in May 1999 (1) evaluated the benefits of adjuvant endocrine therapy (mainly tamoxifen) based on immunohistochemical (IHC) assays for ER and PR. This retrospective study —based on the San Antonio Breast Cancer tissue bank —compared IHC to traditional ligand binding results in a series of 1982 patients with close clinical follow-up. IHC proved to be a better predictor of response to endocrine therapy, and patients with as few as 1% cells staining weakly for ER on IHC derived benefit from endocrine therapy.
  
  
• A number of prominent clinical trials, including two key studies from the NSABP (2,3), have reported benefits of tamoxifen in high-risk women and for patients with ductal carcinoma in situ, and many such patients have being treated. This has increased awareness of the chemopreventive effects of tamoxifen on contralateral breast cancer in patients with invasive disease, who are at a risk of similar magnitude to patients in the NSABP prevention trial (4). The reduction in rate of second breast cancers in women receiving adjuvant tamoxifen has not yet been clearly correlated with the estrogen receptor assay result of the first cancer.
  
  
• The final statement (5) of the November 2000 NIH Consensus Conference on Adjuvant Therapy of Breast Cancer notes:

  The decision whether to recommend adjuvant hormonal therapy should be based on the presence of hormone receptors, as assessed by immunohistochemical staining of breast cancer tissue. If the available tissue is insufficient to determine hormone receptor status, it should be considered as being positive, particularly in postmenopausal women. The small subset of women whose tumors lack estrogen receptor protein but contain progesterone receptor also appear to benefit from hormonal therapy...Adjuvant hormonal therapy should be recommended to women whose breast tumors contain hormone receptor protein, regardless of age, menopausal status, involvement of axillary lymph nodes or tumor size. While the likelihood of benefit correlates with the amount of hormone receptor protein in tumor cells, patients with any extent of hormone receptor in their tumor cells may still benefit from hormonal therapy. Such treatment has led to substantial reductions in the likelihood of tumor recurrence, second primary breast cancer and death persisting for at least 15 years of follow-up.

• At a presentation during the December 2000 San Antonio Breast Cancer Symposium, pathologist Craig Allred, MD, verbalized his concerns on quality control in receptor assay technology:

  "Estrogen receptor and progesterone receptor assays are simply the most important biomarkers in breast cancer today. Their assessment is essential in deciding how to treat all patients with breast cancer. However, the overall quality of the data that we're getting from immunohistochemistry (IHC) today is, in fact, not as good as what we got from the ligand binding assay (LBA). That doesn't mean that it can't be, but right now I believe that it's not... It's impossible to be very precise about what the magnitude of this inaccuracy is, but I believe that we are misdiagnosing at least five percent of patients that we see. If you extrapolate that number to the 200,000 newly diagnosed patients in the United States alone, that's 10,000 patients. That's a lot, and in fact, I believe it's more on the order of 10 or 15 percent."

To assess how this changing environment has affected clinical practice, a random series of telephone surveys was conducted in June 1999 of 100 oncologists and 100 surgeons in the United States. A second random survey was conducted in June 2000 of a different random sample of 100 oncologists and 100 surgeons. Theoretical breast cancer case scenarios were presented, and the physicians were asked how they would manage such patients. The results show a marked change in prescribing attitude during this time period with a significantly greater fraction of physicians indicating they would recommend adjuvant therapy with tamoxifen in women with both receptor-positive cancers and tumors with low but detectable estrogen receptors. (Figure 2) While physicians seem to be more proactive about utilizing endocrine therapy in women with tumors with low, but detectable, estrogen receptor assays, a number of recent reports from the pathology literature suggests problems in performing and reporting these assays including the following:

Rhodes A, Bharat J, Balaton A, Barnes D, Anderson E, Bobrow L, Miller K Study of Interlaboratory Reliability and Reproducibility of Estrogen and Progesterone Receptor Assays in Europe. Am J Clin Path Jan 2001; 15(1). Full text version of this article: http://www.ajcp.com/rhodes0101ar.html#12

• This study analyzed the specificity, sensitivity and reproducibility of IHC assay for estrogen receptors (ER) and progesterone receptors (PR) from 105 laboratories (66 of which had full participation) over a two-year period.

• Receptor-positive status was defined as 10% or greater of invasive tumor nuclei staining by IHC.
  
  
• Only 36% of the 66 labs that participated in all eight of the assessment runs obtained reliable IHC assay results.
  
  
• Inadequate microwave antigen retrieval time was found to be the major contributing factor in the unreliable assays. While a majority of the labs that were producing consistently reliable results were using pressure cookers instead of microwaves, it was found that when microwave-heating times were increased, IHC reliability scores improved significantly.

Rhodes A, Jasani B, Barnes DM, Bobrow LG, Miller KD Reliability of Immunohistochemical Demonstration of Oestrogen Receptors in Routine Practice: Interlaboratory Variance in the Sensitivity of Detection and Evaluation of Scoring Systems. J Clin Pathol 2000; 53: 125-130.

• This study was designed to determine the rate of false negatives in IHC detection of estrogen receptors.
  
  
• Histological sections of breast cancers with low, medium and high estrogen receptor expression were sent to 200 labs for evaluation.
  
  
• Only 37% of laboratories detected the low estrogen-expressing tumors. About 80% of the labs were able to correctly detect the medium- and high-expressing estrogen receptor cancers.
  
  
• Analyses of the data showed that using a 1% or greater cut-off value for determining receptor-positive status would significantly increase the number of labs detecting all levels of ER expression (high, medium and low).
  
  
• This study was not able to identify specific variables predominantly responsible for the differences in IHC sensitivity between the labs.

The two studies discussed above point out the wide range of interlaboratory variability in results and suggest that external quality assessment of the variables involved in IHC assays could help standardize procedures and increase reliability. Noting that close to one tenth of estrogen receptor-positive patients have only 1-10% of estrogen receptor-positive staining nuclei, and the second study proposes a 1% or greater staining threshold for calling a cancer ER positive. A lower threshold may help to "compensate for the slightly differing levels for IHC sensitivity observed between laboratories."

While surgeons and medical oncologists are being more proactive about utilizing adjuvant tamoxifen in breast cancer patients with detectable but low levels of estrogen receptor protein, pathology laboratories may be providing misleading information that may result in undertreatment of patients.

1. Harvey et al. Estrogen receptor status by immunohistochemistry (IHC) is superior to the ligand-binding assay (LBA) for predicting response to adjuvant endocrine therapy in breast cancer. Journal of Clinical Oncology 1999;17:1471-1481.

2. Fisher B et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998 Sep 16;90(18):1371-1388

3. Fisher, B et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999 Jun 12;353(9169):1993-2000

4. Mamounas EP et al. Primary breast cancer as a risk factor for subsequent contralateral breast cancer: NSABP experience from nine randomized adjuvant trials. Breast Can Res Treat 1999, Abstract 15.

5. Final NIH 2000 Consensus Statement on Adjuvant Therapy of Breast Cancer: http://odp.od.nih.gov/consensus/cons/114/114_statement.htm

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