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In Reply:

Departments of Chemical Endocrinology, Center Nijmegen, Nijmegen, the Netherlands

L.V.A.M. Beex

Medical Oncology, Center Nijmegen, Nijmegen, the Netherlands

J.A. Foekens

Division of Endocrine Oncology, Department of Medical Oncology, Erasmus Medical Center—Daniel den Hoed, Rotterdam, the Netherlands

Although circulating tumor cells were not the subject of our study, we stated in the introduction of our paper¹ that the mammaglobin-negative results of frequent reports on a proportion of primary breast cancers counteract the use of mammaglobin as a marker for circulating tumor cells because shedded tumor cells from mammaglobin-negative tumors will not be detected using mammaglobin specific reverse transcriptase polymerase chain reaction (RT-PCR). Zach and Lutz state that, similar to our study, they found a wide range of mammaglobin expression levels by quantitative RT-PCR in primary breast cancers. In addition, they found 2 of 52 negatives (3.8%), whereas we found 19 of 280 negatives (6.8%) after 40 rounds of amplification. These data are highly comparable. Because they also have data on nested RT-PCR that shows no negatives in their 52 breast tumor samples, they do not share our remark that mammaglobin is less suited as a marker for circulating tumor cells due to the variation in expression.

In our experience, quantitative RT-PCR has a high sensitivity and is able to quantitatively detect approximately 10 molecules per well. Even if no specificity issue is involved, with blood cells spuriously expressing some molecules of mammaglobin and thereby raising the background noise in such an assay, we are not confident that nested RT-PCR could practically be more sensitive than quantitative RT-PCR. We agree with Zach and Lutz that tissue-specificity is the most important factor for a marker for circulating cells—although for mammaglobin some discussion on this is also possible because it has been reported to also be expressed in skin and/or sweat glands.^2,3 However, when used for detection of circulating tumor cells in patients known to have or to have had breast cancer, mammaglobin might very well be tissue specific enough.

In response to the letter of Zach and Lutz, we might discuss our results on the variation of mammaglobin expression levels in primary breast cancer tissues in light of the use of mammaglobin RT-PCR to detect circulating tumor cells, although again, this was not the subject of our paper. With the premise that circulating tumor cells retain the characteristics of the primary tumor they stem from, our results indicate that cells from estrogen receptor (ER) –positive, low-grade breast tumors are more likely to be detected when in circulation. These tumors express the highest number of mammaglobin mRNA molecules per cell. In contrast, ER-negative and high-grade tumors express lower numbers of mammaglobin mRNA molecules per cell, and are more likely to escape detection. The number of totally negative primary breast cancer tissues, whether an existing phenomenon or not, is not important for this statement. Rather, the enormous variation in mammaglobin levels, coupled with its association with certain tumor characteristics, will lead to a divergence in detection probability for particular tumor types. Indeed, by using nested RT-PCR, Zach and Lutz themselves found that patients with ER-positive tumors were more likely to be positive for mammaglobin mRNA in peripheral blood (30%) than patients with ER-negative tumors (16%).⁴ This is in line with the strong correlation between ER status and mammaglobin mRNA levels in the primary tumor we described.¹ Thus, the difference in mammaglobin levels for particular breast tumor types might make this assay highly suitable for detection of dissemination of well-differentiated receptor-positive tumors, and may counteract its use for detecting cells from poorly differentiated, receptor-negative breast cancers.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Span PN, Waanders E, Manders P, et al: Mammaglobin is associated with low-grade, steroid receptor-positive breast tumors from postmenopausal patients, and has independent prognostic value for relapse-free survival time. J Clin Oncol 22:691-698, 2004[Abstract/Free Full Text]

2. Fanger GR, Houghton RL, Retter MW, et al: Detection of mammaglobin in the sera of patients with breast cancer. Tumour Biol 23:212-221, 2002[CrossRef][Medline]

3. Sjodin A, Guo D, Hofer PA, et al: Mammaglobin in normal human sweat glands and human sweat gland tumors. J Invest Dermatol 121:428-429, 2003[CrossRef][Medline]

4. Zach O, Kasparu H, Krieger O, et al: Detection of circulating mammary carcinoma cells in the peripheral blood of breast cancer patients via a nested reverse transcriptase polymerase chain reaction assay for mammaglobin mRNA. J Clin Oncol 17:2015-2019, 1999[Abstract/Free Full Text]

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Related Correspondence

• Mammaglobin Remains a Useful Marker for the Detection of Breast Cancer Cells in Peripheral Blood
  Otto Zach and Dieter Lutz
  JCO 2005 23: 3160 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Span, P.N. Articles by Foekens, J.A. Search for Related Content PubMed Articles by Span, P.N. Articles by Foekens, J.A. Related Articles Related Correspondence Social Bookmarking                            What's this?