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Journal of Clinical Oncology, Vol 26, No 8 (March 10), 2008: pp. 1195-1197 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.0474
Measuring Circulating Tumor Cells As a Surrogate End Point for Adjuvant Therapy of Breast Cancer: What Do They Mean and What Should We Do About Them?Virginia Commonwealth University, Medical College of Virginia School of Medicine and the Massey Cancer Center, Richmond, VA The biologic role of dislodged cancer cells that are circulating in the bloodstream and the value of detecting them has long been a subject for speculation.1-3 The fear of inducing such shedding from the primary tumor site was the basis of frequently taught principles of surgical technique.4,5 In this issue of the Journal of Clinical Oncology, Pachmann et al describe a modified assay of breast-cancer–circulating tumor cells (CTC, or circulating epithelial tumor cells [CETC] in their nomenclature), which is sensitive enough to detect tumor cells in the peripheral blood of most postoperative patients with breast cancer who otherwise have no detectable disease.6 Whenever we intend to treat cancer patients with potentially toxic therapies, it would be ideal to know in advance whether tumor burden and our ability to reduce it will produce a clinical benefit. This concept has been investigated extensively in breast cancer with modest success, but few if any absolute predictors of benefit have emerged. Many indicators of prognosis have been described, ranging from "simple" markers such as hormone receptor status, nuclear grade, tumor size, nodal status, and plasminogen activator, to more complex gene expression profiles.7-16 Others have focused on finding microscopic deposits of tumor cells in distant sites or in the circulation.17-21 These markers certainly inform us about the likelihood of recurrence, but most do not indicate the likelihood that treatment will reduce this risk. Some markers are both prognostic and predictive, identifying tumors that are more likely to recur and also those that are more likely to be affected by treatment. The OncotypeDx recurrence score is a good example of such a "mixed" marker, and its potential impact on patient outcomes is now being explored in a large prospective trial.14,22,23 However, most of these markers and profiles really apply to populations of patients; with rare exceptions (such as the absence of hormone receptor expression), none will tell us with any degree of certainty that a particular treatment will be either useful or futile in an individual patient. Even when a patient survives long-term without recurrence, we cannot know whether this represents success of treatment or the initial absence of micrometastases. Being able to predict the response to therapy has been more closely approximated in the neoadjuvant setting, which is one of the main strengths of this approach.24-27 With neoadjuvant treatment, the accuracy of predictive markers can be determined by direct measurement of the treatment's effect on the tumor. Even in this setting, however, profiles that correlate statistically with pathologic complete response (pCR), do not tell us whether an individual patient's tumor will respond in a meaningful way. pCRs occur in only a minority of patients, but most patients experience objective responses and may still benefit clinically even if the tumor does not disappear completely.28 As compared to the ideal of being able to determine ahead of time whether a specific treatment will benefit an individual patient, a surrogate end point would be able to tell us whether a therapy that is being delivered is affecting the true clinical target. In patients with measurable metastatic disease or in the setting of neoadjuvant therapy, the response of tumor that can be palpated or measured on imaging allows us to judge the response to treatment in progress. Even if the primary tumor response is not a perfect surrogate for patient outcomes, it is an excellent predictor of disease-free survival and overall survival. For patients with unmeasurable metastatic disease, the benefit of palliative chemotherapy or hormonal therapy is often determined based on symptoms or serum markers. A well-validated assay of CTC has recently been described, and appears to be a good predictor of outcomes in patients with metastatic breast cancer, when measured either before therapy or at follow-up after treatment.1,20,21 But despite the potential utility of this assay in patients with metastatic disease, its low sensitivity makes it unhelpful in the adjuvant setting. In contrast, by eliminating purification steps that also remove tumor cells, the assay described in this issue by Pachmann et al detected CTCs in 90% of their adjuvant breast cancer patients. It should be kept in mind, of course, that all of the patients selected for this study were candidates for adjuvant chemotherapy based on classical risk factors. Most importantly, the pattern of change in CTC during therapy was highly predictive of patient outcomes. Three patterns of response were detected: 10-fold or more decrease in CTC number, marginal change in CTC, or greater than 10-fold increase in CTC. The last group sometimes demonstrated an increase after an initial decrease in CTC numbers. Only one relapse was observed in the first group, while the majority of recurrences were seen in the third group. But is this a truly predictive measure that tells us whether the therapy is working or is it just another prognostic marker? In this small group of patients, especially in the intermediate group, we still cannot say for certain whether the correlation means that failure to detect a fall in CTC indicates a lack of benefit from treatment or just a poor prognosis. It may have been that the "poor responders" would have suffered an even higher rate of recurrence without treatment. Is the rise in CTC enough on which to base stopping a therapy that the authors would argue is not working? Their argument that the CTC changes actually reflect response to therapy is certainly bolstered by their previous work in the neoadjuvant setting, which showed that the pattern of response in CTC predicted the degree of response in the primary breast tumor.29,30 This demonstrates the potential power and usefulness of studies of neoadjuvant therapy, in which the outcomes often predict and explain results in the adjuvant setting. Clearly, this assessment of tumor cells in peripheral blood is easier and more broadly applicable than bone marrow aspirates, and certainly more appropriate for repeated testing. Although this CTC response is not strictly predictive (since it does not tell us the likely results of treatment in advance), it would be useful if it really is indicative of whether treatment in progress is working. A number of potential pitfalls to its utility remain. The most obvious is that it must be reproducible and reliable enough to be used in many institutions or be readily available in central labs. Also, as noted in prior neoadjuvant studies from this group, CTC paradoxically increased during therapy with taxanes even though the primary tumors were shrinking.29 This will become increasingly important as taxanes assume a greater role in adjuvant therapy. Since a rise in CTC at any time during treatment, even after an initial decrease, predicted a poor outcome for patients, when and how often CTC should be assessed needs to be determined and must be practical. Clearly, finding out that a treatment has not been beneficial near the end of that treatment is not particularly useful. Perhaps the most difficult issue to consider is what to do when faced with rising CTC levels during therapy. If validated, we could stop therapy that is not helping the patient. But should we stop chemotherapy altogether or switch to different agents, finish the planned course of therapy and then add more with new agents, or just throw up our hands and admit defeat? While changing drugs might seem the most logical choice, data available to date, mostly from the neoadjuvant setting, do not prove that this is a useful strategy.31-33 A number of important scientific questions remain: Are CTCs detected in the peripheral blood released from existing micrometastases or are they the source of distant metastases after "seeding" organ sites? Are there stem cells capable of "seeding" new tumor sites in the CTC? Could the CTCs be used to assess sensitivity of resistant tumor cells to alternative agents? In order to validate the concept for broad application in the adjuvant setting, the authors suggest including serial CTC assays into large adjuvant trials. However, to determine whether these serial assays really would be useful in altering therapy, a trial would have to be designed that actually includes a change in therapy for some patients based on the CTC results, much as is being done for the OncotypeDx test in the adjuvant setting in the TAILORx trial and in patients with metastatic disease in Southwest Oncology Group SO500. In such a trial, if CTC failed to decrease, patients would be randomized to continue therapy versus stopping the initial drugs and changing agents. If this assay for CTC pans out in confirmatory studies and wins out against competing technologies (such as proteomics or detection of tumor RNA or DNA in serum), then it may serve as a true surrogate end point that can be used to tailor therapy for individual patients. In the future, one can envision a primary assessment of the risk of recurrence with molecular prognostic profiles, followed by assessment of markers that would guide the choice of appropriate agents in those patients deemed to be at sufficient risk. Then, during treatment, CTC's could be serially measured as an indicator of response to therapy. At that point, we will be challenged to figure out what to do with the nonresponding patients; hopefully an arsenal of targeted agents that will destroy chemotherapy-resistant cells will emerge to fill the gap. Obviously, all of this will add additional costs to breast cancer treatment, but it is likely to be less expensive than treating patients uselessly or dealing with early recurrence of disease. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Smerage JB, Hayes DF: The measurement and therapeutic implications of circulating tumour cells in breast cancer. Br J Cancer 94:8-12, 2006[CrossRef][Medline] 2. Tyzzer EE: Factors in the production and growth of tumor metastases. J Med Res 28:309, 1913 3. Ashworth TR: A case of cancer in which cells similar to those in the tumors were seen in the blood after death. Australian Med J 14:146-149, 1869 4. Fisher ER, Turnbull RB Jr: The cytologic demonstration and significance of tumor cells in the mesenteric venous blood in patients with colorectal carcinoma. Surg Gynecol Obstet 100:102-108, 1955[Medline] 5. Turnbull RB Jr, Kyle K, Watson FR, et al: Cancer of the colon: The influence of the no-touch isolation technic on survival rates. Ann Surg 166:420-427, 1967[Medline] 6. Pachmann K, Camara O, Kavallaris A, et al: Monitoring the response of circulating epithelial tumor cells (CETC) to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse J Clin Oncol 26:1208-1215, 2008 7. Fisher ER, Sass R, Fisher B: Pathologic findings from the National Surgical Adjuvant Project for breast cancers. Cancer 53:712-723, 1984[CrossRef][Medline] 8. Tandon AK, Clark GM, Chamness GC, et al: HER-2/neu oncogene protein and prognosis in breast cancer. J Clin Oncol 7:1120-1128, 1989[Abstract] 9. Aaltomaa S, Lipponen P, Eskelinen M, et al: Hormone receptors as prognostic factors in female breast cancer. Ann Med 23:643-648, 1991[Medline] 10. Beenken SW, Urist MM, Zhang YT, et al: Axillary lymph node status, but not tumor size, predicts locoregional recurrence and overall survival after mastectomy for breast cancer. Ann Surg 237:732-738, 2003[CrossRef][Medline] 11. Manders P, Tjan-Heijnen VC, Span PN, et al: Predictive impact of urokinase-type plasminogen activator: Plasminogen activator inhibitor type-1 complex on the efficacy of adjuvant systemic therapy in primary breast cancer. Cancer Res 64:659-664, 2004 12. Manders P, Tjan-Heijnen VC, Span PN, et al: Complex of urokinase-type plasminogen activator with its type 1 inhibitor predicts poor outcome in 576 patients with lymph node-negative breast carcinoma. Cancer 101:486-494, 2004[Medline] 13. Esteva FJ, Hortobagyi GN: Prognostic molecular markers in early breast cancer. Breast Cancer Res 6:109-118, 2004[CrossRef][Medline] 14. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004 15. Fan C, Oh DS, Wessels L, et al: Concordance among gene-expression-based predictors for breast cancer. N Engl J Med 355:560-569, 2006 16. van d Vijver MJ, He YD, van't Veer LJ, et al: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999-2009, 2002 17. Janni W, Rack B, Schindlbeck C, et al: The persistence of isolated tumor cells in bone marrow from patients with breast carcinoma predicts an increased risk for recurrence. Cancer 103:884-891, 2005[CrossRef][Medline] 18. Braun S, Naume B: Circulating and disseminated tumor cells. J Clin Oncol 23:1623-1626, 2005 19. Braun S, Pantel K, Muller 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 342:525-533, 2000 20. Cristofanilli M, Hayes DF, Budd GT, et al: Circulating tumor cells: A novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 23:1420-1430, 2005 21. 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 22. Paik S, Tang G, Shak S, et al: Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24:3726-3734, 2006 23. Sparano JA: TAILORx: Trial assigning individualized options for treatment (Rx). Clin Breast Cancer 7:347-350, 2006[Medline] 24. Ayers M, Symmans WF, Stec J, et al: Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. J Clin Oncol 22:2284-2293, 2004 25. Pusztai L, Symmans FW, Hortobagyi GN: Development of pharmacogenomic markers to select preoperative chemotherapy for breast cancer. Breast Cancer 12:73-85, 2005[CrossRef][Medline] 26. Rouzier R, Perou CM, Symmans WF, et al: Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678-5685, 2005 27. Cleator S, Tsimelzon A, Ashworth A, et al: Gene expression patterns for doxorubicin (Adriamycin) and cyclophosphamide (cytoxan) (AC) response and resistance. Breast Cancer Res Treat 95:229-233, 2006[CrossRef][Medline] 28. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel (Taxotere) to preoperative doxorubicin and cyclophosphamide (AC): Preliminary results from National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-27. J Clin Oncol 21:4165-4174, 2003 29. Camara O, Rengsberger M, Egbe A, et al: The relevance of circulating epithelial tumor cells (CETC) for therapy monitoring during neoadjuvant (primary systemic) chemotherapy in breast cancer. Ann Oncol 18:1484-1492, 2007 30. Pachmann K, Camara O, Kavallaris A, et al: Quantification of the response of circulating epithelial cells to neodadjuvant treatment for breast cancer: A new tool for therapy monitoring. Breast Cancer Res 7:R975–R979, 2005[CrossRef][Medline] 31. Smith IC, Heys SD, Hutcheon AW, et al: Neoadjuvant chemotherapy in breast cancer: Significantly enhanced response with docetaxel. J Clin Oncol 20:1456-1466, 2002 32. von Minckwitz G, Blohmer JU, Raab G, et al: In vivo chemosensitivity-adapted preoperative chemotherapy in patients with early-stage breast cancer: The GEPARTRIO pilot study. Ann Oncol 16:56-63, 2005 33. Thomas E, Holmes FA, Smith TL, et al: The use of alternate, non-cross-resistant adjuvant chemotherapy on the basis of pathologic response to a neoadjuvant doxorubicin-based regimen in women with operable breast cancer: Long-term results from a prospective randomized trial. J Clin Oncol 22:2294-2302, 2004
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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