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Letters to the Editor

Mammaglobin as Molecular Marker 2. Reinholz MM, NibbeA, Jonart LM, et al. Evaluation of a panel of tumor markers for
molecular detection of circulating cancer cells in women with suspected breast
cancer. Clin Cancer Res 2005 May 15;11:3722 ^ 32.
of Breast Cancer (Micro)Metastases 3. 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 2004
Feb 15;22:691 ^ 8.
To the Editor: In a recent issue of Clinical Cancer Research,
two articles (1,2) addressed the use of PCR to detect micro- In Response: We thank Dr. Span for interest in our article
metastases from breast cancer either in lymph nodes (1) or in (1) and for insightful comments. Although Dr. Span has
peripheral blood (2). Both articles found mammaglobin (mam) correctly pointed out that there is wide range of mammaglobin
to be an excellent marker for this. However, neither article, in (mam) expression levels in primary breast cancers, it still remains
our view, has appropriately considered the effect of the wide the single best marker for the detection of metastatic and
range of expression levels of mam in the primary tumor, and micrometastatic breast cancer (2, 3). The frequency distribution
the association of mam expression with particular tumor analyses in our article confirm that the tissue specificity of mam is
characteristics, on these results. exquisite and there is almost no expression in normal lymph
Mikhitarian et al. (1) diluted the RNA of a metastasis-positive nodes (or peripheral blood; ref. 4). We have recently completed
axillary lymph node with RNA from normal lymph nodes and an interim analysis of a multi-institutional prospective cohort
used microarray analyses to find mam as the gene with highest study (Minimally Invasive Molecular Staging of Breast Cancer)
sensitivity. In addition, TFF1 was found as an additional novel designed to assess the clinical relevance of molecular detection of
marker. However, for this experiment, a positive lymph node
micrometastatic disease in axillary lymph nodes (ALN) of breast
was chosen based on its 5.3  107 – fold overexpression of
cancer patients. In this study, mam was overexpressed in ALN
mam. We have shown that in the primary breast tumor mam
from 79% of patients with pathology-positive ALN and in ALN
levels can vary over 10,000-fold (3). Thus, if Mikhitarian et al.
from 23% of patients with pathology-negative ALN (3).
had chosen a tumor that had a lower level of mam expression,
Although this is higher than any other molecular marker, the
other genes might have been found to have a better detection
heterogeneity of gene expression in primary breast cancer is a
rate. Of note, the broad shoulder in the frequency distribution
good argument for the use of multimarker panels.
in Fig. 1 of their article is in agreement with the wide range of
Although there is evidence that mam expression is higher in
mam expression in primary tumors.
estrogen receptor–positive tumors (5), mam also seems to be an
The authors discuss the fact that TFF1 expression in the
excellent molecular marker for metastatic disease derived from
primary tumor is positively associated with estrogen receptor
estrogen receptor–negative tumors. Results of the Minimally
and progesterone receptor status. We have described a similar,
Invasive Molecular Staging of Breast Cancer study reveal that
strong association of mam with estrogen receptor and
mam is overexpressed in ALN from 80% of patients with
progesterone receptor status. This then may account for the
pathology-positive ALN and estrogen receptor –positive tumors
fact that TFF1 is found as a novel marker by these authors, as
(n = 108) and in ALN from 72% of patients with pathology-
the tumor chosen for this experiment was selected based on its
positive ALN and estrogen receptor–negative tumors (n = 29).
mam overexpression, and as both these markers are correlated
With respect to Dr. Span’s comment regarding tissue
with estrogen receptor status.
selection, we chose an ALN containing metastatic breast
Reinholz et al. (2) used a PCR for mam to detect breast cancer
cancer that highly expressed mam as an internal positive control
cells in peripheral blood samples. Of the patients with breast
for the novel dilutional microarray strategy. Identi-
cancer in this article, a majority (77%) had an estrogen
fication and validation of trefoil factor 1 as a marker for
receptor – positive tumor. This patient selection would favor the
micrometastatic breast cancer provides additional evidence
selection of mam as a sensitive marker for circulating breast
that this strategy can identify novel molecular markers. We
cancer cells, considering the particular association of mam
agree with Dr. Span that selection of an ALN known to over-
expression with just these tumor characteristics (3).
express mam may have affected microarray results. However,
in addition to the study described in the article, we have
Paul N. Span
done dilutional microarray analyses on two pathology-positive
Fred C.G.J. Sweep
ALN that did not overexpress mam with the goal of identifying
Department of Chemical Endocrinology,
novel molecular markers that complement mam in the detection
Radboud University Nijmegen Medical
of micrometastatic breast cancer. Although trefoil factor 1 was
Center, Nijmegen, the Netherlands
again one of the most overexpressed genes in one of the ALN, we
also identified several other potential breast cancer markers.
References Kaidi Mikhitarian
1. Mikhitarian K, Gillanders WE, Almeida JS, et al. An innovative microarray strategy William E. Gillanders
identities informative molecular markers for the detection of micrometastatic breast
cancer. Clin Cancer Res 2005 May 15;11:3697 ^ 704. David J. Cole
Michael Mitas
Department of Surgery, Medical
F 2005 American Association for Cancer Research. University of South Carolina,
doi:10.1158/1078-0432.CCR-05-1378 Charleston, South Carolina

www.aacrjournals.org 7043 Clin Cancer Res 2005;11(19) October 1, 2005


Letters to the Editor

References
1. Mikhitarian K, Gillanders WE, Almeida JS, et al. An innovative microarray strategy
identities informative molecular markers for the detection of micrometastatic breast
cancer. Clin Cancer Res 2005;11:3697 ^ 704.
2. Mitas M, Mikhitarian K,Walters C, et al. Quantitative real-time RT-PCR detection
of breast cancer micrometastasis using a multigene marker panel. Int J Cancer
2001;93:162 ^ 71.
3. Gillanders WE, Mikhitarian K, Hebert R, et al. Molecular detection of micrometa-
static breast cancer in histopathology-negative axillary lymph nodes correlates
with traditional predictors of prognosis: an interim analysis of a prospective multi-
institutional cohort study. Ann Surg 2004;239:828 ^ 37; discussion 837 ^ 40.
4. Baker MK, Mikhitarian K, Osta W, et al. Molecular detection of breast cancer cells
in the peripheral blood of advanced-stage breast cancer patients using multimarker
real-time reverse transcription-polymerase chain reaction and a novel porous barri-
er density gradient centrifugation technology. Clin Cancer Res 2003;9:4865 ^ 71.
5. 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
2004;22:691 ^ 8.

In Response: I am responding to the comment made by


Dr. Span in a Letter to the Editor, received on June 2, 2005. It is
my understanding that Dr. Span had concerns that the patient
population in my study recently published in Clinical Cancer
Research (1) may have had a selection bias. He suggests that
because the majority (77%) of the patients had estrogen
receptor – positive tumors, the patient selection would favor the
selection of mammaglobin as a sensitive marker for circulating
breast cancer cells, considering the particular association of
mammaglobin expression with estrogen receptor – positive
tumor characteristics (2). However, our study was a prospective
study that enrolled women who had an abnormality on
mammography imaging with no prior history of cancer, and
tumor characteristics that were not known at the time of
enrollment. Thus, patients were not excluded from our study
based on their tumor hormone receptor or mammaglobin
status. We appreciate the interesting correlation that exists
between estrogen receptor and mammaglobin expression in
breast tumors observed by Span and coworkers. In general, the
majority of breast cancer patients do have estrogen receptor –
positive tumors and according to Span and others, these tumors
may then express mammaglobin. Overall, our prospective study
design precluded us from having any type of preselection bias
towards tumor hormone receptor and mammaglobin status.

Monica Reinholz, Ph.D.


Assistant Professor
Departments of Experimental Pathology
and Biochemistry and Molecular Biology
Mayo Clinic College of Medicine
Rochester, Minnesota

References
1. Reinholz MM, Nibbe A, Jonart LM, et al. Evaluation of a panel of tumor markers
for molecular detection of circulating cancer cells in women with suspected breast
cancer. Clin Cancer Res 2005;11:3722 ^ 32.
2. Span PN, Waanders E, Manders P, et al. Mammaglobin is associated with low-
grade, steriod receptor-positive breast tumors from postmenopausal patients, and
has independent prognostic value for relapse-free survival time. J Clin Oncol
2004;22:691 ^ 8.

Clin Cancer Res 2005;11(19) October 1, 2005 7044 www.aacrjournals.org

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