Prepared by Dr. Pedram Argani, lead pathologist for breast cancer at Johns Hopkins.

The estrogen receptor is present in normal breast epithelium, where it mediates cell proliferation (growth) in response to hormonal changes in the menstrual cycle. Estrogen receptor is present in approximately two-thirds of invasive breast carcinomas, where is presumably mediates hormonally driven tumor growth. In other words, the normal estrogen in the body stimulates the tumor to grow, just as it stimulates the normal breast epithelium to grow. The presence of estrogen receptor in invasive carcinoma is a favorable prognostic factor, since outcome is slightly better regardless of the therapy given. More importantly, the presence of estrogen receptor in invasive carcinoma is an important predictive factor of response to endocrine therapy; specifically, Tamoxifen. In general, estrogen receptor positive tumors respond, estrogen receptor negative tumors do not

Initially, estrogen receptor status was measured using biochemical methods (charcoal binding assay, ligand binding assay). These assays suffer from the fact that they are bulk measurements, and typically include contaminating normal breast tissue in their assessment of the tumor. Currently, immunohistochemistry for the estrogen receptor protein is the standard method of measuring estrogen receptor status in invasive breast carcinoma. Estrogen receptor status by immunohistochemistry has been shown to correlate better with clinical response than the previously used biochemical methods (J Clin Oncol, 1999; 17:1474).

More recent studies have addressed the effect that Tamoxifen therapy has upon prevention of recurrences of ductal carcinoma in situ (DCIS). In the NSABP B24 study, over 1800 patients were randomized to receive either placebo or Tamoxifen in addition to standard lumpectomy and radiation for DCIS. Tamoxifen decreased recurrences of breast cancer by 37 percent with a significant p value of 0.0009. Interestingly, the protective effect was most pronounced upon subsequent invasive breast cancers in the ipsilateral (same) breast and subsequent carcinoma in situ in the contralateral breast. As a result of this study, Tamoxifen has often been recommended for women treated with lumpectomy and radiation therapy for DCIS to prevent subsequent recurrences. However, Tamoxifen does have significant side effects (including increased risk of deep venous thrombosis), and one would not want to expose women to Tamoxifen if they are unlikely to benefit from it.

Since we know that response to Tamoxifen in invasive ductal carcinoma is closely related to the estrogen receptor status of the tumor as determined by immunohistochemistry, the logical question became: does the estrogen receptor status of ductal carcinoma in situ (DCIS) predict response to Tamoxifen?

This question was addressed in a study presented at the most recent San Antonio Breast Cancer Symposium in December, 2002, by Dr. Craig Allred et al. In this study, Dr. Allred was able to determine the estrogen receptor status of approximately one-third of patients in this trial (over 600 patients). Analysis of the data showed that for patients with estrogen receptor positive ductal carcinoma in situ, Tamoxifen therapy was effective; there was an approximately 50% reduction in both ipsilateral and contralateral new breast cancers. In contrast, Tamoxifen was not of significant benefit for patients whose DCIS was negative for the estrogen receptor, in either the ipsolateral or contralateral breast. Dr. Allred emphasizes that it is crucial that the estrogen receptor status of the DCIS be determined accurately, since it appears that non-standardized methods of determining estrogen receptor can lead to false negative results.

These results suggest that the estrogen receptor status of ductal carcinoma in situ, as determined by immunohistochemistry, predicts whether or not Tamoxifen therapy will effectively diminish the chances of recurrences of breast cancer. As a result, many laboratories, including our own, are now testing ductal carcinoma in situ for the estrogen receptor to help guide clinicians and patients in deciding whether or not Tamoxifen is the right choice for them.

References:
The Lancet, 1999; 353: 1993-2000.
Modern Pathology 1998; 11: 155-168
Breast Cancer Res Treat 2002; 76 (11):S36 (abstract 31)

Acknowledgement: Dr. Antonio Wolff, for reviewing this and making helpful suggestions.