Circulating Tumor Cells in Metastatic Breast Cancer — Toward Individualized Treatment?
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《新英格兰医药杂志》
When Steven Paget published his theory of "seed and soil" in 1889,1 the idea of hematogenous tumor-cell dissemination was born. More than a century later, with the use of molecular tools, new clinical findings have resulted in explanations of hither-to unexplainable phenomena, such as that donor-derived cancer in recipient organ allografts2 and viable single tumor cells in secondary organs were both the descendants of a known primary tumor3 and the potential precursors of subsequent metastasis.4 Now, as shown by Cristofanilli et al.5 in this issue of the Journal, a laboratory assay of circulating tumor cells enables us to predict a response to treatment.
As a major finding of their study, the opportunity to predict a response as early as three to four weeks after initiation of treatment reflects an important step toward decisions about individualized treatment for patients with metastatic disease. It goes without saying that we would be more than glad to have tools that would enable us to tailor treatment decisions to patients without measurable metastatic disease and, even better, to patients starting adjuvant therapy. Although Cristofanilli et al. were able to show that their assay is also applicable to patients without measurable disease, there is no evidence of its clinical usefulness in the adjuvant setting.
Interesting options, however, are on the horizon. The presence of disseminated tumor cells that were detected in the bone marrow of patients with stage I, stage II, or stage III breast cancer is an independent prognostic factor for a poor outcome.4 Although a blood test that was designed specifically for these patients would be highly desirable, preliminary unpublished data suggest that, in contrast to bone marrow findings in patients with early-stage breast cancer, circulating tumor cells in the peripheral blood are not prognostically useful. One likely explanation for the difference in importance between circulating tumor cells and disseminated tumor cells in advanced disease or metastatic disease is the magnitude of the tumor load. Metastatic lesions are prone to support a pool of circulating tumor cells, whereas unifocal tumors and small primary tumors shed far fewer tumor cells into the circulation.
Surprisingly, circulating tumor cells have not been studied as markers for monitoring individual residual tumor load. Consequently, we are not aware of data with which to compare the present findings. Moreover, the semiautomated device used in sample preparation and in the analysis described by Cristofanilli et al. was used first only in a study setting. By comparison, looking back a few decades, serum tumor markers such as CA 15-3 come to mind. Measurements of CA 15-3 predict a response to treatment in 78 percent of patients with metastatic breast cancer, but only 88 percent of serum samples from patients with benign breast disease have values below threshold.6 The assay presented by Cristofanilli et al. may outperform measurements of serum CA 15-3, but, unfortunately, no data were included by the authors to prove this assumption.
This lack of data gives rise to the question of whether there are other ways to predict a response to treatment. The massive accumulation of data in gene-expression studies may be diagnostic overkill, since the relatively minimalistic approach of a two-gene expression ratio was sufficient to predict the clinical outcome as well as the response in patients with breast cancer who were treated with tamoxifen.7 Other seemingly causal links to tumor progression that might be used instead of arrays for the best prediction of likelihood are tumor-specific epigenetic changes, such as hypermethylation, which has been investigated by Muller et al.8 Both these studies were retrospective analyses that were based on a specified biologic rationale and await prospective confirmation.
From the clinician's point of view, it is beneficial to outline briefly our current understanding and clinical practice in order to acknowledge new opportunities for stratifying and monitoring patients with metastatic disease, as indicated by Cristofanilli et al. Metastatic lesions are usually measured and counted with the use of radiography, sonography, or scintigraphy. Measurement of circulating tumor cells predicts a response to treatment much more quickly than our usual clinical practice, which in the best of circumstances permits a treatment evaluation after two to three months (i.e., depending on the availability of imaging resources). The assay provides for the first time a means of evaluating patients without measurable disease — that is, those who are still excluded from clinical trials of new treatment approaches and their potential benefits.
Beyond these considerations, our treatment decisions with regard to the use of targeted or specific therapies, such as trastuzumab or the aromatase inhibitors, are based on the view that metastatic cells are linear descendants of primary tumor cells and have conserved biologic features. However, a hallmark of breast cancer is its genetic instability. Therefore, this view is challenged by the often completely different growth characteristics of tumor cells and their susceptibility to treatment. This difference becomes obvious if, for example, we compare settings with measurable disease (e.g., primary and metastatic tumor cells during neoadjuvant treatment as compared with first-line treatment in metastatic disease) and assess the subsequent course of the disease. It appears that, despite the advent of targeted therapies, we are careless about the expression of targets, the elimination of target cells, and, as a direct consequence of targeted therapy on a heterogeneous cell population, the clonal expansion of cells that do not express the target.
What lessons can we learn from the study by Cristofanilli et al.? First, their assay permits the prediction of progression-free survival and overall survival; these findings were significant and robust in all subgroups, with the exception of patients receiving hormone therapy. The limited number of these patients (31 percent of the total study group) and the length of time required to show the effects of hormone therapy are possible explanations of the failure of the assay to reach statistical significance in this subgroup.
Second, a cautionary note is warranted with respect to uncritical, immediate adoption of this assay for routine use and is in agreement with the authors' own opinion, as outlined in their careful discussion of the results. We still need to know, for example, whether any change in the treatment based on the number of circulating tumor cells alone will translate into a benefit in progression-free survival. The current findings clearly encourage such studies. Nevertheless, the already noticeable improvements are in themselves sufficient to allow us to speculate that this assay will soon realize its potential to change the standard of care for patients with metastatic breast cancer.
Third, it is but a short step to envisioning the influence these data might have on diagnostic processes and treatment stratification in the adjuvant setting for patients with no measurable disease. At present, our treatment decisions are based on lymph-node metastasis, tumor size, tumor grade, the patient's age, and estrogen-receptor expression. In our experience, however, comprehensive cancer centers diagnose breast cancer on the basis of a mean tumor size of close to 1 cm, with lymph-node metastasis in less than 30 percent of cases and hormone-receptor expression in almost 80 percent. Consequently, there is not much room for decisions about individualized treatment, especially if we follow international consensus recommendations for the adjuvant treatment of early breast cancer. With regard to decisions on adjuvant treatment, the importance of the role of bone marrow micrometastasis in patients with early breast cancer, as we and others have previously reported,4,9 may be similar to that of the role of circulating tumor cells in patients with metastatic breast cancer.
Taken together, the article by Cristofanilli et al. and the studies it is likely to stimulate in the near future may substantially affect our current understanding of breast cancer and of the standards and practice of decisions about treatment not only in palliative care but also in adjuvant care for patients with this disease.
Source Information
From the Department of Gynecology and Obstetrics and the Breast Health Center, Innsbruck Medical University, Innsbruck, Austria.
References
Paget S. Distribution of secondary growths in cancer of the breast. Lancet 1889;1:571-573.
Loh E, Couch FJ, Hendricksen C, et al. Development of donor-derived prostate cancer in a recipient following orthotopic heart transplantation. JAMA 1997;277:133-137.
Klein CA, Schmidt-Kittler O, Schardt JA, Pantel K, Speicher MR, Riethmüller G. Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells. Proc Natl Acad Sci U S A 1999;96:4494-4499.
Braun S, Pantel K, Müller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000;342:525-533.
Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004;351:781-791.
Stieber P, Molina R, Chan DW, et al. Clinical evaluation of the Elecsys CA 15-3 test in breast cancer patients. Clin Lab 2003;49:15-24.
Ma XJ, Wang Z, Ryan PD, et al. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 2004;5:607-616.
Muller HM, Widschwendter A, Fiegl H, et al. DNA methylation in serum of breast cancer patients: an independent prognostic marker. Cancer Res 2003;63:7641-7645.
Braun S, Vogl FD, Janni W, Marth C, Schlimok G, Pantel K. Evaluation of bone marrow in breast cancer patients: prediction of clinical outcome and response to therapy. Breast 2003;12:397-404.(Stephan Braun, M.D., and )
As a major finding of their study, the opportunity to predict a response as early as three to four weeks after initiation of treatment reflects an important step toward decisions about individualized treatment for patients with metastatic disease. It goes without saying that we would be more than glad to have tools that would enable us to tailor treatment decisions to patients without measurable metastatic disease and, even better, to patients starting adjuvant therapy. Although Cristofanilli et al. were able to show that their assay is also applicable to patients without measurable disease, there is no evidence of its clinical usefulness in the adjuvant setting.
Interesting options, however, are on the horizon. The presence of disseminated tumor cells that were detected in the bone marrow of patients with stage I, stage II, or stage III breast cancer is an independent prognostic factor for a poor outcome.4 Although a blood test that was designed specifically for these patients would be highly desirable, preliminary unpublished data suggest that, in contrast to bone marrow findings in patients with early-stage breast cancer, circulating tumor cells in the peripheral blood are not prognostically useful. One likely explanation for the difference in importance between circulating tumor cells and disseminated tumor cells in advanced disease or metastatic disease is the magnitude of the tumor load. Metastatic lesions are prone to support a pool of circulating tumor cells, whereas unifocal tumors and small primary tumors shed far fewer tumor cells into the circulation.
Surprisingly, circulating tumor cells have not been studied as markers for monitoring individual residual tumor load. Consequently, we are not aware of data with which to compare the present findings. Moreover, the semiautomated device used in sample preparation and in the analysis described by Cristofanilli et al. was used first only in a study setting. By comparison, looking back a few decades, serum tumor markers such as CA 15-3 come to mind. Measurements of CA 15-3 predict a response to treatment in 78 percent of patients with metastatic breast cancer, but only 88 percent of serum samples from patients with benign breast disease have values below threshold.6 The assay presented by Cristofanilli et al. may outperform measurements of serum CA 15-3, but, unfortunately, no data were included by the authors to prove this assumption.
This lack of data gives rise to the question of whether there are other ways to predict a response to treatment. The massive accumulation of data in gene-expression studies may be diagnostic overkill, since the relatively minimalistic approach of a two-gene expression ratio was sufficient to predict the clinical outcome as well as the response in patients with breast cancer who were treated with tamoxifen.7 Other seemingly causal links to tumor progression that might be used instead of arrays for the best prediction of likelihood are tumor-specific epigenetic changes, such as hypermethylation, which has been investigated by Muller et al.8 Both these studies were retrospective analyses that were based on a specified biologic rationale and await prospective confirmation.
From the clinician's point of view, it is beneficial to outline briefly our current understanding and clinical practice in order to acknowledge new opportunities for stratifying and monitoring patients with metastatic disease, as indicated by Cristofanilli et al. Metastatic lesions are usually measured and counted with the use of radiography, sonography, or scintigraphy. Measurement of circulating tumor cells predicts a response to treatment much more quickly than our usual clinical practice, which in the best of circumstances permits a treatment evaluation after two to three months (i.e., depending on the availability of imaging resources). The assay provides for the first time a means of evaluating patients without measurable disease — that is, those who are still excluded from clinical trials of new treatment approaches and their potential benefits.
Beyond these considerations, our treatment decisions with regard to the use of targeted or specific therapies, such as trastuzumab or the aromatase inhibitors, are based on the view that metastatic cells are linear descendants of primary tumor cells and have conserved biologic features. However, a hallmark of breast cancer is its genetic instability. Therefore, this view is challenged by the often completely different growth characteristics of tumor cells and their susceptibility to treatment. This difference becomes obvious if, for example, we compare settings with measurable disease (e.g., primary and metastatic tumor cells during neoadjuvant treatment as compared with first-line treatment in metastatic disease) and assess the subsequent course of the disease. It appears that, despite the advent of targeted therapies, we are careless about the expression of targets, the elimination of target cells, and, as a direct consequence of targeted therapy on a heterogeneous cell population, the clonal expansion of cells that do not express the target.
What lessons can we learn from the study by Cristofanilli et al.? First, their assay permits the prediction of progression-free survival and overall survival; these findings were significant and robust in all subgroups, with the exception of patients receiving hormone therapy. The limited number of these patients (31 percent of the total study group) and the length of time required to show the effects of hormone therapy are possible explanations of the failure of the assay to reach statistical significance in this subgroup.
Second, a cautionary note is warranted with respect to uncritical, immediate adoption of this assay for routine use and is in agreement with the authors' own opinion, as outlined in their careful discussion of the results. We still need to know, for example, whether any change in the treatment based on the number of circulating tumor cells alone will translate into a benefit in progression-free survival. The current findings clearly encourage such studies. Nevertheless, the already noticeable improvements are in themselves sufficient to allow us to speculate that this assay will soon realize its potential to change the standard of care for patients with metastatic breast cancer.
Third, it is but a short step to envisioning the influence these data might have on diagnostic processes and treatment stratification in the adjuvant setting for patients with no measurable disease. At present, our treatment decisions are based on lymph-node metastasis, tumor size, tumor grade, the patient's age, and estrogen-receptor expression. In our experience, however, comprehensive cancer centers diagnose breast cancer on the basis of a mean tumor size of close to 1 cm, with lymph-node metastasis in less than 30 percent of cases and hormone-receptor expression in almost 80 percent. Consequently, there is not much room for decisions about individualized treatment, especially if we follow international consensus recommendations for the adjuvant treatment of early breast cancer. With regard to decisions on adjuvant treatment, the importance of the role of bone marrow micrometastasis in patients with early breast cancer, as we and others have previously reported,4,9 may be similar to that of the role of circulating tumor cells in patients with metastatic breast cancer.
Taken together, the article by Cristofanilli et al. and the studies it is likely to stimulate in the near future may substantially affect our current understanding of breast cancer and of the standards and practice of decisions about treatment not only in palliative care but also in adjuvant care for patients with this disease.
Source Information
From the Department of Gynecology and Obstetrics and the Breast Health Center, Innsbruck Medical University, Innsbruck, Austria.
References
Paget S. Distribution of secondary growths in cancer of the breast. Lancet 1889;1:571-573.
Loh E, Couch FJ, Hendricksen C, et al. Development of donor-derived prostate cancer in a recipient following orthotopic heart transplantation. JAMA 1997;277:133-137.
Klein CA, Schmidt-Kittler O, Schardt JA, Pantel K, Speicher MR, Riethmüller G. Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells. Proc Natl Acad Sci U S A 1999;96:4494-4499.
Braun S, Pantel K, Müller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000;342:525-533.
Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004;351:781-791.
Stieber P, Molina R, Chan DW, et al. Clinical evaluation of the Elecsys CA 15-3 test in breast cancer patients. Clin Lab 2003;49:15-24.
Ma XJ, Wang Z, Ryan PD, et al. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 2004;5:607-616.
Muller HM, Widschwendter A, Fiegl H, et al. DNA methylation in serum of breast cancer patients: an independent prognostic marker. Cancer Res 2003;63:7641-7645.
Braun S, Vogl FD, Janni W, Marth C, Schlimok G, Pantel K. Evaluation of bone marrow in breast cancer patients: prediction of clinical outcome and response to therapy. Breast 2003;12:397-404.(Stephan Braun, M.D., and )