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Originally published as JCO Early Release 10.1200/JCO.2005.01.910 on April 18 2005 © 2005 American Society of Clinical Oncology.
Contralateral Breast Cancer: Where Does It All Begin?Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Department of Health and Human Services, Bethesda, MD Contralateral breast cancer (CBC) is the most common second primary cancer in patients diagnosed with breast cancer.1 Patients with a history of breast cancer have an increased risk of developing a second primary breast cancer (PBC), with an annual risk of 0.5% to 1% or a cumulative lifetime risk of 2% to 15%.2 Because breast cancer is the most commonly diagnosed cancer in women in the United States,3 prevention of CBC is a significant clinical issue. Before this can be accomplished, a more precise characterization and definition of CBC must be attained. Diagnostic criteria for CBC have been described,4,5 but it may be difficult to differentiate between metastasis and a new primary because of a lack of universally accepted criteria. In this issue, Arpino et al6 conclude that the hormone receptor status of the PBC does not predict the hormone receptor status of a subsequent CBC in the absence of prior adjuvant therapy. This is in contrast to other studies showing that the receptor status between the PBC and the CBC is concordant.7,8 In the current study, 193 pairs of PBC and CBC with estrogen receptor (ER) and/or progesterone receptor (PgR) assays performed in central laboratories were identified. Among patients receiving no adjuvant therapy, 88% who had an ER-positive PBC and 75% who had an ER-negative PBC developed an ER-positive CBC (P = .11). Patients treated with tamoxifen whose PBCs were ER positive were equally likely to develop an ER-positive or ER-negative CBC, which is consistent with the results from the National Surgical Adjuvant Breast and Bowel Project P-1 prevention study.9 Differences among study populations may have led to disparate results from previous studies. In the current study, the median age of diagnosis of the PBC was 62 years, with a CBC developing at a median interval of 3 years. This compares to a median age of 47 years in a National Surgical Adjuvant Breast and Bowel Project study evaluating the ER status in PBC and CBC. In situ lesions (2%) made up a minority of the tumors in the patients in the study by Arpino et al6 because they were not routinely sent for hormone receptor assays. ER status was determined using a ligand-binding assay in the current study. It is known that a false-negative ER result can be obtained with this assay because of receptor occupancy with tamoxifen.10 Because the median interval to CBC diagnosis was 3 years, it is probable that many of these patients were being treated with tamoxifen. Determining ER status by immunohistochemistry might have led to a more accurate measurement of ER status.11 The ER-positive rate (75% to 88%) in the CBC group of the current study is similar to the ER-positive rate (75.1%) of primary breast tumors seen in the general population from the Surveillance, Epidemiology, and End Results data.12 This high rate of ER-positive CBC in the absence of adjuvant therapy supports the hypothesis that the CBCs seen in the current study may be sporadic cancers unrelated to the PBC. Determination of the origin of the breast cancer cells and regulation of ER expression are central to understanding CBC. Since its initial proposal, the multistep process has been well accepted as the route by which tumors arise.13 Breast cancers likely emerge from inherited or acquired mutations in stem or early progenitor cells.14 Mammary stem cells have only recently been isolated by identifying tumorigenic cells based on cell-surface marker expression.15 These stem cells represent important targets for mutations because they are slow-dividing, long-lived cells that may be exposed to various damaging agents over time, leading to a series of alterations that ultimately leads to carcinoma. For the cancer to metastasize, certain features must be present. Early observations by Paget16 resulted in the seed and soil theory, in which metastases develop only when particular cells with metastatic ability are present in the appropriate host microenvironment. If applied to CBC, this theory could support the notion that CBC may represent a metastatic lesion that has developed in the primed contralateral breast where the necessary homeostatic factors are present. However, is it really important to make the distinction of a new primary or metastases? Absolutely! The answer to this question has both prognostic and predictive importance. If considered a new primary tumor, local regional therapy will be followed by systemic therapy as deemed necessary. However, if considered metastatic, systemic treatment alone in the form of hormonal or cytotoxic chemotherapy may be considered. It has long been debated whether ER-positive and ER-negative tumors either originate from distinctly different cells or represent a continuum. Gene expression profiling has suggested ER-positive and ER-negative tumors are distinct tumor types.17 Different molecular phenotypes have been reported for the ER-positive/luminal-like and ER-negative basal tumors.17 Recently, a model has been developed proposing that ER-positive and ER-negative tumors arise from separate subpopulations of stem and progenitor cells.18 On the basis of this model, three different subtypes of breast cancer could occur based on the cell of origin. The authors of this model conclude that differing breast cancer phenotypes result from a combination of the cell of origin and particular mutations. However, there is also evidence supporting the emergence of ER-negative cancers from ER-positive precursors. A lower frequency of ER-positivity is seen as tumors increase in size, implying that ER expression is blocked as tumors grow.11,19 Furthermore, a certain percentage of patients with ER-positive tumors develop ER-negative metastases.20 Thus, the true origins of ER-positive and ER-negative tumors have yet to be elucidated. At this time, it is still unclear how initial tumor ER expression develops and later correlates with a subsequent CBC. One of the fundamental goals for assessment of ER in any breast tumor is treatment selection. Tamoxifen improves survival of women with ER-positive breast cancers but does not improve survival of women with ER-negative tumors.21 Also, the risk of CBC is reduced by 45% after 5 years of tamoxifen therapy,21 and incidence of invasive cancer decreased by 49% with primary tamoxifen chemoprevention.9 A majority of the patients in the current report, in the absence of adjuvant therapy, were diagnosed with an ER-positive CBC regardless of the hormone receptor status of the PBC. Given these conclusions, should we consider prescribing tamoxifen to all patients with a diagnosis of PBC, regardless of receptor status, as a chemopreventive agent for CBC? This is a provocative question, which cannot be answered by our current limited knowledge of the biology of these contralateral cancers. It is unlikely that the question of whether tamoxifen is beneficial for patients with an ER-negative PBC will ever be answered in a prospective clinical trial because of the low event rate requiring a large number of study patients. In addition, the increased risk of thromboembolic disease and endometrial cancer associated with tamoxifen would need to be considered. At the current time, we would not recommend tamoxifen for ER-negative primary tumors given the insufficient data supporting any benefit in such a situation. Studies with microarray analysis have provided insight into the understanding that distinct molecular profiles exist that can be useful in classifying tumors and predicting outcome.17,22 A recent report suggests that genetic analysis using DNA from paraffin-embedded tissue in combination with statistical tools can more accurately classify dual-site cancers.23 In the future, molecular profiling or other laboratory based studies in combination with histopathologic analysis will delineate the true origin of CBCs as either new primary cancers or recurrences. This differentiation has implications for the development of drug resistance and subsequent systemic treatment of the CBC. These critical investigations will be essential for the understanding of the etiology of breast cancer. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. 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3. Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5-26, 2003 4. Robbins GF, Berg JW: Bilateral primary breast cancer: A prospective clinicopathological study. Cancer 17:1501-1527, 1964[CrossRef][Medline] 5. Lewison EF, Neto AS: Bilateral breast cancer at the Johns Hopkins Hospital: A discussion of the dilemma of contralateral breast cancer. Cancer 28:1297-1301, 1971[Medline]
6. Arpino G, Weiss HL, Clark GM, et al: Hormone receptor status of a contralateral breast cancer is independent of the receptor status of the first primary in patients not receiving adjuvant tamoxifen. J Clin Oncol 23:4687-4694, 2005
7. Swain SM, Wilson JW, Mamounas EP, et al: Estrogen receptor status of primary breast cancer is predictive of estrogen receptor status of contralateral breast cancer. J Natl Cancer Inst 96:516-523, 2004 8. McCaskill-Stevens W: Hormone receptor concordance and predictors of contralateral breast cancer in Surveillance, Epidemiology, and End Results (SEER) population-based registries, Frontiers in Cancer Prevention Research, Seattle, WA, October 16-20, 2004
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15. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983-3988, 2003 16. Paget S: The distribution of secondary growths in cancer of the breast. Lancet 1:571-573, 1889 17. Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumours. Nature 406:747-752, 2000[CrossRef][Medline] 18. Dontu G, El-Ashry D, Wicha MS: Breast cancer, stem/progenitor cells and the estrogen receptor. Trends Endocrinol Metab 15:193-197, 2004[CrossRef][Medline] 19. Clark GM, Osborne CK, McGuire WL: Correlations between estrogen receptor, progesterone receptor, and patient characteristics in human breast cancer. J Clin Oncol 2:1102-1109, 1984[Abstract] 20. Kuukasjarvi T, Kononen J, Helin H, et al: Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 14:2584-2589, 1996[Abstract] 21. Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998[CrossRef][Medline] 22. van't Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530-536, 2002[CrossRef][Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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