VOLUME
32
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NUMBER
11
䡠
APRIL
10
2014
JOURNAL OF CLINICAL ONCOLOGY
E
D
I
T
O
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I
A
L
The End of the Beginning: Circulating Tumor Cells As a Biomarker in Castration-Resistant Prostate Cancer Terence W. Friedlander and Lawrence Fong, Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, San Francisco, CA See accompanying article on page 1136
Although circulating tumor cells (CTCs) were first observed from patients with metastatic malignancies more than 100 years ago,1 only recently has the clinical and research potential of CTCs become widely recognized. Because CTCs are thought to represent cells that are shed by primary or metastatic tumors, significant interest has focused on examining CTCs as prognostic or predictive biomarkers in several malignancies, including breast and prostate cancer. One could hypothesize that the number of CTCs could be prognostically important by potentially estimating the total-body burden of disease and/or a tumor’s invasiveness. Alternatively, changes in CTC counts might indicate sensitivity or resistance to an anticancer therapy. CTCs could also represent research tools to personalize treatment by serving as a so-called liquid biopsy of an individual’s disease. Quantitation and characterization of CTCs may therefore represent a means to directly inform clinical care but also serve as an investigational platform to elucidate basic mechanisms of tumor biology. The most extensively studied clinical role for CTCs is as a prognostic biomarker; that is, counts at a specific time point are associated with a later discrete clinical end point. In this capacity, CTC counts that are enumerated using the CellSearch platform (Veridex, Raritan, NJ) are the most studied. CellSearch enriches for CTCs with antibodies directed against the epithelial cell adhesion molecule (EpCAM), which is expressed on epithelially derived cells. CTCs are then identified and quantitated on the basis of nuclear staining with 4,6diamidino-2-phenylindole (DAPI), and anticytokeratin and antiCD45 antibodies, which distinguishes CD45⫺ epithelial cells from CD45⫹ leukocytes.2 In clinical trials, CellSearch CTC counts are prognostic for overall survival (OS) in metastatic breast, colon, and prostate cancers.3-5 In prostate cancer, specifically, the Circulating Tumor Cells and the Prediction of Overall Survival in Patients With Androgen Independent Prostate Cancer Entering Onto Chemotherapy (IMMC38) study demonstrated the prognostic value of CellSearch CTCs in 238 men with metastatic castration-resistant disease (mCRPC) starting a new first, second, or third line of chemotherapy.5 In this study, a pretreatment CTC threshold of ⱖ 5 CTCs/7.5 mL of blood distinguished patients into favorable and unfavorable groups, the latter having shorter median OS (11.5 v 21.7 months; hazard ratio, 3.3; P ⬍ .001). In their modeling, the best predictor of survival incorporated baseline high-serum lactate dehydrogenase (LDH) levels with baseline 1104
© 2014 by American Society of Clinical Oncology
CTC counts; the addition of prostate-specific antigen (PSA) did not improve prediction of survival. In patients with unfavorable baseline counts, conversion to a favorable count after the initiation of treatment was also associated with improved survival. Conversely, conversion to unfavorable counts after treatment initiation was associated with worse survival. Perhaps most importantly, CTC counts outperformed PSA in predicting survival at all time points. More recently, the prognostic value of ⱖ 5 CTCs/7.5 mL of blood (with the CellSearch assay) was confirmed in a randomized phase III study of abiraterone acetate, a novel hormonal therapy, in men with mCRPC who were previously treated with docetaxel.6 In this study, CTCs were enumerated at baseline and during the first three cycles. CTC conversion from ⱖ 5 CTCs to ⬍ 5 CTCs, along with changes in serum LDH, was strongly predictive of OS. Similar results were recently observed in a phase III study of docetaxel with or without lenalidomide.7 Building on these findings, in the article that accompanies this editorial, Goldkorn et al8 present an analysis of the impact of baseline and post-treatment CTC counts on OS and disease response in a subset of men with mCRPC who were treated as part of the Southwest Oncology Group (SWOG) trial 0421, a phase III study comparing the effectiveness of docetaxel plus atrasentan, an endothelin receptor antagonist, versus docetaxel alone. The study itself failed to meet its coprimary end points of improved OS and progression-free survival with the addition of atrasentan and was halted early for futility. Nevertheless, as part of the study, CTCs were enumerated at baseline and 21 days after the first dose of the study treatment. In contrast to the IMMC-38 study, this study had a uniform cohort of men with chemotherapy-naive CRPC and a longer duration of median follow-up (24 v 16 months). In their analysis, the authors showed that baseline CTC counts were correlated with recognized prognostic markers,9 including PSA, alkaline phosphatase, bone pain, liver disease, and hemoglobin, although relationship with LDH, a widely recognized prognostic marker, was not assessed. Baseline CTC count was associated with subsequent PSA declines and with objective responses. Importantly, median survival for patients with ⬍ 5 CTCs/7.5 mL of blood at baseline was far better than for those with ⱖ 5 CTCs (26 v 13 months), and after adjustment for known prognostic factors, the baseline CTC Journal of Clinical Oncology, Vol 32, No 11 (April 10), 2014: pp 1104-1106
Editorial
count was still strongly associated with survival (hazard ratio, 2.74; P ⬍ .001). Similarly, a rising CTC count after a first dose of the study therapy was independently associated with worse outcomes, likely reflecting inherent chemotherapy resistance. Lastly, the authors used statistical modeling to speculate that in addition to recognized prognostic factors, CTC enumeration has a real, if modest, impact on assessment of prognosis. So what can we learn from this study? The results confirm previous observations that high CTC counts at baseline are a poor prognostic sign; a change from ⬍ 5 to ⱖ 5 CTCs/7.5 mL of blood imparts an extremely poor prognosis and should prompt the clinician to consider alternative therapies; and despite our reliance on PSA, CTC changes are in fact much more valuable in assessing prognosis. The effect (if any) of atrasentan on CTC counts is difficult to discern because the authors do not present a subgroup analysis, but given the agent’s limited clinical activity and the overall association of CTCs with survival, we can assume that this is unlikely to have biased the results. The omission of LDH as a prognostic marker in this study is of concern, given that recently reported data indicate that LDH has a strong independent effect on prognosis and may significantly contribute to the predictive value of CTC counts. Perhaps a more important take-home point relates to the clinical relevance of yet another prognostic biomarker. Although it is true that a clinician could order this test today to predict whether a patient will fare better or worse, the result says nothing about the individual’s likelihood of responding to a different therapy; a patient may be destined to do poorly regardless of treatment. We would argue that a more relevant and immediate clinical application of CTC enumeration would be to predict response to a new line of therapy, or as a surrogate end point for clinical trials. So can we use CTCs to predict response to therapy or to help us decide when to change treatment? Although this is largely unknown in prostate cancer, work is underway in breast cancer using both enumeration and molecular characterization to aid in decision making. Specifically, SWOG S0500 randomly assigns women with locally advanced breast cancer and unfavorable CTC counts after one cycle of adjuvant therapy to continue the same therapy or to change regimens. The Multicenter, Randomized, Phase III Study to Compare Standard Therapy Alone Versus Standard Therapy Plus Lapatinib in Patients With Initially HER2-Negative Metastatic Breast Cancer and HER2Positive Circulating Tumor Cells (DETECT III) explores the benefit of lapatinib in women with HER2-negative metastatic breast cancer but HER2-positive CTCs. Similarly, in the Trastuzumab in HER2Negative Early Breast Cancer As Adjuvant Treatment for Circulating Tumor Cells (TREAT-CTC) study, women with detectable CTCs after neoadjuvant chemotherapy are randomly assigned to trastuzumab or a placebo to see whether vascular endothelial growth factor– directed therapy reduces relapses in women at high risk of recurrence. A challenge in evaluating CTCs as a predictive biomarker is that clinically meaningful results require large studies that are designed around effective therapies, which may be difficult given limited resources and the ever-evolving treatment landscape. Similarly, not all therapies work in the same way, and perhaps specific CTC counts or molecular phenotypes that are predictive for response to one therapy are not relevant for others. Nonetheless, given the clear and immediate potential to aid clinical decision making, studies exploring the predictive value of CTCs should be pursued. www.jco.org
What about using change in CTC counts as a surrogate for survival? If validated, such a surrogate end point could greatly accelerate the development of new cancer treatments. Recently, an algorithm developed from the phase III study of abiraterone incorporating CTC enumeration with LDH levels was shown to fulfill Prentice’s criteria for surrogacy for survival.10 If accepted by regulatory agencies, this finding has the potential to greatly streamline clinical trials, potentially saving precious resources and getting new anticancer agents into the hands of physicians and patients faster than before. Last, much of the clinical development of CTCs to date has focused on their enumeration, which is in truth a simplistic, onedimensional use for CTCs. Additionally, the CellSearch assay only counts epithelial cell adhesion molecule–positive cells and excludes tumor stem cells, CTC clusters, and CTCs with mesenchymal or anaplastic phenotypes, which may have important prognostic and predictive implications.11 To address this, a number of new platforms that isolate CTCs in a marker-independent manner are under active investigation.12-16 Similarly, it should be remembered that CTCs are entirely different from almost all other biomarkers because they represent a sampling of a patient’s tumor. The molecular and genomic profiling of CTCs may therefore identify novel mutations, shed light on mechanisms of resistance to therapy, and aid in the selection of appropriate therapies in real time. Thus, although the analysis by Goldkorn et al8 is not practice changing, it again shows that CTCs can tell us, in a limited way, about prognosis. If we ask the right questions going forward, CTCs may be able to tell us much more. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Lawrence Fong, Dendreon, Bristol-Myers Squibb Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Ashworth TR: A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Med J Australia 14:146-149, 1869 2. Allard WJ, Matera J, Miller MC, et al: Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 10:6897-6904, 2004 3. Cristofanilli M, Budd GT, Ellis MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781-791, 2004 4. Cohen SJ, Punt CJ, Iannotti N, et al: Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 26:3213-3221, 2008 5. de Bono JS, Scher HI, Montgomery RB, et al: Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14:6302-6309, 2008 6. Scher HI, Heller G, Molina A, et al: Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): Planned final analysis
© 2014 by American Society of Clinical Oncology
1105
Editorial
(FA) of COU-AA-301, a randomized, double-blind, placebo-controlled, phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel. J Clin Oncol 29:293s, 2011 (suppl; abstr LBA4517) 7. Vogelzang NJ, Petrylak D, Fizazi K, et al: Analysis of circulating tumor cells (CTCs) in a phase 3 study of docetaxel and prednisone (DP) with or without lenalidomide (LEN) in patients (pts) with castrate-resistant prostate cancer (CRPC): The MAINSAIL trial. Presented at European Cancer Congress 2013, Amsterdam, the Netherlands, September 27 through October 1, 2013 (abstr 23) 8. Goldkorn A, Ely B, Quinn DI, et al: Circulating tumor cell counts are prognostic of overall survival in Southwest Oncology Group trial S0421: A phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer. J Clin Oncol 32:1136-1142, 2014 9. Halabi S, Small EJ, Kantoff PW, et al: Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 21:1232-1237, 2003 10. Scher H, Heller G, Molina A: Evaluation of a composite biomarker panel including circulating tumor cell (CTC) enumeration as a surrogate for survival in metastatic castration-resistant prostate cancer. European Cancer Congress 2013. Amsterdam, the Netherlands, September 27 through October 1, 2013 (abstr 2861)
11. Yu M, Bardia A, Wittner BS, et al: Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339:580584, 2013 12. Alix-Panabie`res C, Brouillet JP, Fabbro M, et al: Characterization and enumeration of cells secreting tumor markers in the peripheral blood of breast cancer patients. J Immunol Methods 299:177-188, 2005 13. Warkiani ME, Guan G, Luan KB, et al: Slanted spiral microfluidics for the ultra-fast, label-free isolation of circulating tumor cells. Lab on a Chip 1:128-137, 2014 14. Zheng S, Lin HK, Lu B, et al: 3D microfilter device for viable circulating tumor cell (CTC) enrichment from blood. Biomed Microdevices 13:203-213, 2011 15. Friedlander TW, Ngo VT, Dong H, et al: Detection and characterization of invasive circulating tumor cells derived from men with metastatic castration resistant prostate cancer (mCRPC). Int J Cancer [epub ahead of print on October 25, 2013] 16. Marrinucci D, Bethel K, Kolatkar A, et al: Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers. Phys Biol 9:016003, 20102
DOI: 10.1200/JCO.2013.54.7307; published online ahead of print at www.jco.org on March 10, 2014
■ ■ ■
Markers in Cancer Diagnostic Development Tutorial 2014 Hosted in conjunction with the Accelerating Anticancer Agent Development and Validation (AAADV) Workshop, the Markers in Cancer Diagnostic Development Tutorial (May 5 and 6, 2014, in Bethesda, MD) will address issues critical to understanding the advances, limitations, and validation of molecular markers. This limited-attendance event will feature didactic presentations and hands-on discussions of real-life challenges. For more information, visit markersincancer.org. Each year, ASCO, in conjunction with our cosponsors, organizes a wide array of high-quality meetings, providing educational and scientific programs to advance your understanding of cancer. Join us for one or more of ASCO’s meetings to interact with oncology experts, network with colleagues, and earn CME credit.
1106
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Editorial
Acknowledgment T.W.F. is supported by Department of Defense Grant No. P0043122 and Prostate Cancer Foundation Grant No. A119352. L.F. is supported by National Institutes of Health Grants No. R01 CA136753 and R01 CA163012, and from the Peter Michael Foundation.
www.jco.org
© 2014 by American Society of Clinical Oncology
32
䡠
NUMBER
11
䡠
APRIL
10
2014
JOURNAL OF CLINICAL ONCOLOGY
E
D
I
T
O
R
I
A
L
The End of the Beginning: Circulating Tumor Cells As a Biomarker in Castration-Resistant Prostate Cancer Terence W. Friedlander and Lawrence Fong, Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, San Francisco, CA See accompanying article on page 1136
Although circulating tumor cells (CTCs) were first observed from patients with metastatic malignancies more than 100 years ago,1 only recently has the clinical and research potential of CTCs become widely recognized. Because CTCs are thought to represent cells that are shed by primary or metastatic tumors, significant interest has focused on examining CTCs as prognostic or predictive biomarkers in several malignancies, including breast and prostate cancer. One could hypothesize that the number of CTCs could be prognostically important by potentially estimating the total-body burden of disease and/or a tumor’s invasiveness. Alternatively, changes in CTC counts might indicate sensitivity or resistance to an anticancer therapy. CTCs could also represent research tools to personalize treatment by serving as a so-called liquid biopsy of an individual’s disease. Quantitation and characterization of CTCs may therefore represent a means to directly inform clinical care but also serve as an investigational platform to elucidate basic mechanisms of tumor biology. The most extensively studied clinical role for CTCs is as a prognostic biomarker; that is, counts at a specific time point are associated with a later discrete clinical end point. In this capacity, CTC counts that are enumerated using the CellSearch platform (Veridex, Raritan, NJ) are the most studied. CellSearch enriches for CTCs with antibodies directed against the epithelial cell adhesion molecule (EpCAM), which is expressed on epithelially derived cells. CTCs are then identified and quantitated on the basis of nuclear staining with 4,6diamidino-2-phenylindole (DAPI), and anticytokeratin and antiCD45 antibodies, which distinguishes CD45⫺ epithelial cells from CD45⫹ leukocytes.2 In clinical trials, CellSearch CTC counts are prognostic for overall survival (OS) in metastatic breast, colon, and prostate cancers.3-5 In prostate cancer, specifically, the Circulating Tumor Cells and the Prediction of Overall Survival in Patients With Androgen Independent Prostate Cancer Entering Onto Chemotherapy (IMMC38) study demonstrated the prognostic value of CellSearch CTCs in 238 men with metastatic castration-resistant disease (mCRPC) starting a new first, second, or third line of chemotherapy.5 In this study, a pretreatment CTC threshold of ⱖ 5 CTCs/7.5 mL of blood distinguished patients into favorable and unfavorable groups, the latter having shorter median OS (11.5 v 21.7 months; hazard ratio, 3.3; P ⬍ .001). In their modeling, the best predictor of survival incorporated baseline high-serum lactate dehydrogenase (LDH) levels with baseline 1104
© 2014 by American Society of Clinical Oncology
CTC counts; the addition of prostate-specific antigen (PSA) did not improve prediction of survival. In patients with unfavorable baseline counts, conversion to a favorable count after the initiation of treatment was also associated with improved survival. Conversely, conversion to unfavorable counts after treatment initiation was associated with worse survival. Perhaps most importantly, CTC counts outperformed PSA in predicting survival at all time points. More recently, the prognostic value of ⱖ 5 CTCs/7.5 mL of blood (with the CellSearch assay) was confirmed in a randomized phase III study of abiraterone acetate, a novel hormonal therapy, in men with mCRPC who were previously treated with docetaxel.6 In this study, CTCs were enumerated at baseline and during the first three cycles. CTC conversion from ⱖ 5 CTCs to ⬍ 5 CTCs, along with changes in serum LDH, was strongly predictive of OS. Similar results were recently observed in a phase III study of docetaxel with or without lenalidomide.7 Building on these findings, in the article that accompanies this editorial, Goldkorn et al8 present an analysis of the impact of baseline and post-treatment CTC counts on OS and disease response in a subset of men with mCRPC who were treated as part of the Southwest Oncology Group (SWOG) trial 0421, a phase III study comparing the effectiveness of docetaxel plus atrasentan, an endothelin receptor antagonist, versus docetaxel alone. The study itself failed to meet its coprimary end points of improved OS and progression-free survival with the addition of atrasentan and was halted early for futility. Nevertheless, as part of the study, CTCs were enumerated at baseline and 21 days after the first dose of the study treatment. In contrast to the IMMC-38 study, this study had a uniform cohort of men with chemotherapy-naive CRPC and a longer duration of median follow-up (24 v 16 months). In their analysis, the authors showed that baseline CTC counts were correlated with recognized prognostic markers,9 including PSA, alkaline phosphatase, bone pain, liver disease, and hemoglobin, although relationship with LDH, a widely recognized prognostic marker, was not assessed. Baseline CTC count was associated with subsequent PSA declines and with objective responses. Importantly, median survival for patients with ⬍ 5 CTCs/7.5 mL of blood at baseline was far better than for those with ⱖ 5 CTCs (26 v 13 months), and after adjustment for known prognostic factors, the baseline CTC Journal of Clinical Oncology, Vol 32, No 11 (April 10), 2014: pp 1104-1106
Editorial
count was still strongly associated with survival (hazard ratio, 2.74; P ⬍ .001). Similarly, a rising CTC count after a first dose of the study therapy was independently associated with worse outcomes, likely reflecting inherent chemotherapy resistance. Lastly, the authors used statistical modeling to speculate that in addition to recognized prognostic factors, CTC enumeration has a real, if modest, impact on assessment of prognosis. So what can we learn from this study? The results confirm previous observations that high CTC counts at baseline are a poor prognostic sign; a change from ⬍ 5 to ⱖ 5 CTCs/7.5 mL of blood imparts an extremely poor prognosis and should prompt the clinician to consider alternative therapies; and despite our reliance on PSA, CTC changes are in fact much more valuable in assessing prognosis. The effect (if any) of atrasentan on CTC counts is difficult to discern because the authors do not present a subgroup analysis, but given the agent’s limited clinical activity and the overall association of CTCs with survival, we can assume that this is unlikely to have biased the results. The omission of LDH as a prognostic marker in this study is of concern, given that recently reported data indicate that LDH has a strong independent effect on prognosis and may significantly contribute to the predictive value of CTC counts. Perhaps a more important take-home point relates to the clinical relevance of yet another prognostic biomarker. Although it is true that a clinician could order this test today to predict whether a patient will fare better or worse, the result says nothing about the individual’s likelihood of responding to a different therapy; a patient may be destined to do poorly regardless of treatment. We would argue that a more relevant and immediate clinical application of CTC enumeration would be to predict response to a new line of therapy, or as a surrogate end point for clinical trials. So can we use CTCs to predict response to therapy or to help us decide when to change treatment? Although this is largely unknown in prostate cancer, work is underway in breast cancer using both enumeration and molecular characterization to aid in decision making. Specifically, SWOG S0500 randomly assigns women with locally advanced breast cancer and unfavorable CTC counts after one cycle of adjuvant therapy to continue the same therapy or to change regimens. The Multicenter, Randomized, Phase III Study to Compare Standard Therapy Alone Versus Standard Therapy Plus Lapatinib in Patients With Initially HER2-Negative Metastatic Breast Cancer and HER2Positive Circulating Tumor Cells (DETECT III) explores the benefit of lapatinib in women with HER2-negative metastatic breast cancer but HER2-positive CTCs. Similarly, in the Trastuzumab in HER2Negative Early Breast Cancer As Adjuvant Treatment for Circulating Tumor Cells (TREAT-CTC) study, women with detectable CTCs after neoadjuvant chemotherapy are randomly assigned to trastuzumab or a placebo to see whether vascular endothelial growth factor– directed therapy reduces relapses in women at high risk of recurrence. A challenge in evaluating CTCs as a predictive biomarker is that clinically meaningful results require large studies that are designed around effective therapies, which may be difficult given limited resources and the ever-evolving treatment landscape. Similarly, not all therapies work in the same way, and perhaps specific CTC counts or molecular phenotypes that are predictive for response to one therapy are not relevant for others. Nonetheless, given the clear and immediate potential to aid clinical decision making, studies exploring the predictive value of CTCs should be pursued. www.jco.org
What about using change in CTC counts as a surrogate for survival? If validated, such a surrogate end point could greatly accelerate the development of new cancer treatments. Recently, an algorithm developed from the phase III study of abiraterone incorporating CTC enumeration with LDH levels was shown to fulfill Prentice’s criteria for surrogacy for survival.10 If accepted by regulatory agencies, this finding has the potential to greatly streamline clinical trials, potentially saving precious resources and getting new anticancer agents into the hands of physicians and patients faster than before. Last, much of the clinical development of CTCs to date has focused on their enumeration, which is in truth a simplistic, onedimensional use for CTCs. Additionally, the CellSearch assay only counts epithelial cell adhesion molecule–positive cells and excludes tumor stem cells, CTC clusters, and CTCs with mesenchymal or anaplastic phenotypes, which may have important prognostic and predictive implications.11 To address this, a number of new platforms that isolate CTCs in a marker-independent manner are under active investigation.12-16 Similarly, it should be remembered that CTCs are entirely different from almost all other biomarkers because they represent a sampling of a patient’s tumor. The molecular and genomic profiling of CTCs may therefore identify novel mutations, shed light on mechanisms of resistance to therapy, and aid in the selection of appropriate therapies in real time. Thus, although the analysis by Goldkorn et al8 is not practice changing, it again shows that CTCs can tell us, in a limited way, about prognosis. If we ask the right questions going forward, CTCs may be able to tell us much more. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Lawrence Fong, Dendreon, Bristol-Myers Squibb Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Ashworth TR: A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Med J Australia 14:146-149, 1869 2. Allard WJ, Matera J, Miller MC, et al: Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 10:6897-6904, 2004 3. Cristofanilli M, Budd GT, Ellis MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781-791, 2004 4. Cohen SJ, Punt CJ, Iannotti N, et al: Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 26:3213-3221, 2008 5. de Bono JS, Scher HI, Montgomery RB, et al: Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14:6302-6309, 2008 6. Scher HI, Heller G, Molina A, et al: Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): Planned final analysis
© 2014 by American Society of Clinical Oncology
1105
Editorial
(FA) of COU-AA-301, a randomized, double-blind, placebo-controlled, phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel. J Clin Oncol 29:293s, 2011 (suppl; abstr LBA4517) 7. Vogelzang NJ, Petrylak D, Fizazi K, et al: Analysis of circulating tumor cells (CTCs) in a phase 3 study of docetaxel and prednisone (DP) with or without lenalidomide (LEN) in patients (pts) with castrate-resistant prostate cancer (CRPC): The MAINSAIL trial. Presented at European Cancer Congress 2013, Amsterdam, the Netherlands, September 27 through October 1, 2013 (abstr 23) 8. Goldkorn A, Ely B, Quinn DI, et al: Circulating tumor cell counts are prognostic of overall survival in Southwest Oncology Group trial S0421: A phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer. J Clin Oncol 32:1136-1142, 2014 9. Halabi S, Small EJ, Kantoff PW, et al: Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 21:1232-1237, 2003 10. Scher H, Heller G, Molina A: Evaluation of a composite biomarker panel including circulating tumor cell (CTC) enumeration as a surrogate for survival in metastatic castration-resistant prostate cancer. European Cancer Congress 2013. Amsterdam, the Netherlands, September 27 through October 1, 2013 (abstr 2861)
11. Yu M, Bardia A, Wittner BS, et al: Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339:580584, 2013 12. Alix-Panabie`res C, Brouillet JP, Fabbro M, et al: Characterization and enumeration of cells secreting tumor markers in the peripheral blood of breast cancer patients. J Immunol Methods 299:177-188, 2005 13. Warkiani ME, Guan G, Luan KB, et al: Slanted spiral microfluidics for the ultra-fast, label-free isolation of circulating tumor cells. Lab on a Chip 1:128-137, 2014 14. Zheng S, Lin HK, Lu B, et al: 3D microfilter device for viable circulating tumor cell (CTC) enrichment from blood. Biomed Microdevices 13:203-213, 2011 15. Friedlander TW, Ngo VT, Dong H, et al: Detection and characterization of invasive circulating tumor cells derived from men with metastatic castration resistant prostate cancer (mCRPC). Int J Cancer [epub ahead of print on October 25, 2013] 16. Marrinucci D, Bethel K, Kolatkar A, et al: Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers. Phys Biol 9:016003, 20102
DOI: 10.1200/JCO.2013.54.7307; published online ahead of print at www.jco.org on March 10, 2014
■ ■ ■
Markers in Cancer Diagnostic Development Tutorial 2014 Hosted in conjunction with the Accelerating Anticancer Agent Development and Validation (AAADV) Workshop, the Markers in Cancer Diagnostic Development Tutorial (May 5 and 6, 2014, in Bethesda, MD) will address issues critical to understanding the advances, limitations, and validation of molecular markers. This limited-attendance event will feature didactic presentations and hands-on discussions of real-life challenges. For more information, visit markersincancer.org. Each year, ASCO, in conjunction with our cosponsors, organizes a wide array of high-quality meetings, providing educational and scientific programs to advance your understanding of cancer. Join us for one or more of ASCO’s meetings to interact with oncology experts, network with colleagues, and earn CME credit.
1106
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Editorial
Acknowledgment T.W.F. is supported by Department of Defense Grant No. P0043122 and Prostate Cancer Foundation Grant No. A119352. L.F. is supported by National Institutes of Health Grants No. R01 CA136753 and R01 CA163012, and from the Peter Michael Foundation.
www.jco.org
© 2014 by American Society of Clinical Oncology
