New Serum Markers: More Data Needed

This practical review on the use of serum markers and circulating tumor cells (CTCs) focuses on the role of these assays in the management of patients with breast cancer and contains important information and perspectives for the practicing oncologist. The varying roles of these markers in early-stage and advanced disease are presented, and the implications in management are quite different in each setting.

Paradoxically, the bulk of the data, and hence recommendations regarding clinical utility of serum markers are in the metastatic setting, where therapy has a more modest effect on survival. In the early-stage setting, the authors, along with other expert panels, agree that while tumor markers and CTC levels can sometimes be elevated both at diagnosis and at follow-up (and in several studies have correlated with a higher risk of recurrence),[1,2] there is no role for the routine use of these markers in decision-making at the present time. This is in part due to the false-positive rates, but also due to the fact that cutpoints for decision-making have not been established.

As has been the case for multigene assays, large bodies of data that correlate specific scores of these indices to outcome, and more importantly, predict the magnitude of benefit from specific adjuvant therapies, could in the future be very useful in decision-making. In fact, this is the setting in which curability and survival can be impacted to the greatest degree with specific adjuvant regimens, and individualization of therapy would have the largest role. Others have called for the use of circulating tumor cells to be incorporated into current staging, given the fact that pooled analyses now firmly show a relationship to outcome and could further refine our ability to choose which patients would derive the greatest benefit from adjuvant chemobiologic therapy.[3,4]

Complicated Pathways

The development and progression of metastases involves multiple genes and complicated biologic pathways such that one specific protein assay may not be sufficiently prognostic of a patient’s outcome.[5] It is also important to distinguish between assays that measure a static characteristic such as tumor burden and one that measures a dynamic parameter such as tumor growth rate and may therefore project disease trajectory over time. Of course, these two factors are related, as tumor burden does predict survival. Several older parameters such as disease-free interval and primary tumor characteristics such as grade and hormone-receptor status also can correlate with both burden and outcome.

The authors provide a useful summary of the relationship of tumor markers including carcinoembryonic antigen (CEA), CA 15-3, and CA 27.29 to both burden and outcome, rightfully suggesting that these can serve as adjuncts to imaging and clinical assessment, especially when the latter two are ambiguous. This concept is concordant with the most recent guidelines from the American Society of Clinical Oncology (ASCO). However, it does not address the counterargument that a rising serum marker in isolation without accompanying progression by imaging, physical examination, or symptoms should not constitute a reason to change therapy.

The compromise between these two principles is to use serum markers to help determine the frequency of scans and overall medical follow-up and to integrate these results with the overall clinical picture in order to make appropriate treatment decisions. The as yet unproven expectation underlying this approach is that this will delay deterioration in quality of life, or even extend survival because proper intervention would precede a rapid decline that might make the patient ineligible for further therapy.

Clear Evidence Lacking

Circulating tumor cell analysis represents a composite phenotype of metastatic potential that probably includes tumor egress from the primary site, ability to survive for some period of time in the circulation (presumably related to the capacity to establish clinically relevant metastases), and other measures of aggressiveness and refractoriness to therapy that explain its relationship to survival.[6] The standardization and commercialization of this technique and confirmatory studies supporting its prognostic and predictive ability are important steps forward, but clear evidence of the independence of this assay compared to other measures of tumor burden is lacking.

The authors point to data whereby CTC number retains its prognostic ability over and above serum tumor markers and scans.[7,8] The key question as to whether CTC assays can provide a more timely readout of the effectiveness of therapy to the point that an early change improves patient outcome is the subject of a cooperative group study (SWOG-S0500) cited by the authors.[9] CTC analysis is also an important research tool that can shed further light on tumor evolution in real time and important phenomena such as genetic drift and the mediators of drug resistance and site-specific metastases. In fact, there is evidence from CTC analysis that a shift from HER2-negative primaries to HER2-positive metastases may occur, and further confirmation of this could have significant implications for therapy.[10]

Newer markers and their cooperation in cancer behavior can also be discovered and eventually applied in the clinic.[11] However, the use of CTC enumeration for practical patient management remains controversial, and like other clinical indices that might help choose between options such as single vs combination chemotherapy, this assay should be used only when a clear decision will be made on its basis.

Conclusions

In summary, tumor markers and circulating tumor cells are clearly related to patient outcome both in early and advanced-stage breast cancer, as summarized nicely by the authors of this review. While both physicians and patients may derive some level of comfort from the ordering of these assays for surveillance, or at the time of recurrence, no prospective data have shown that decisions based on these assays can improve patient outcomes. Trials to confirm the utility of an assay are extremely difficult to perform once the assay is commercially available, but such trials are underway, and these assays are increasingly being adopted into correlative studies of novel agents. This provides some optimism that tailored therapy on the basis of these and other markers will continue to move forward.

References:

References

1. Pachmann K, Camara O, Kavallaris A, et al: Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse. J Clin Oncol 26:1208-1215, 2008.

2. Ignatiadis M, Kallergi G, Ntoulia M, et al: Prognostic value of the molecular detection of circulating tumor cells using a multimarker reverse transcription-PCR assay for cytokeratin 19, mammaglobin A, and HER2 in early breast cancer. Clin Cancer Res 14:2593-2600, 2008.

3. Braun S, Vogl FD, Naume B, et al: A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793-802, 2005.

4. Pantel K, Brakenhoff RH, Brandt B: Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8:329-340, 2008.

5. Nguyen DX, Massagué J: Genetic determinants of cancer metastasis. Nat Rev Genet 8:341-352, 2007.

6. 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.

7. Budd GT, Cristofanilli M, Ellis MJ, et al: Circulating tumor cells versus imaging-predicting overall survival in metastatic breast cancer. Clin Cancer Res 12:6403-6409, 2006.

8. Beveridge R: Circulating tumor cells in the management of metastatic breast cancer patients Community Oncology 4:79-82, 2007.

9. Phase III randomized study of treatment decision making based on levels of circulating tumor cells in women with metastatic breast cancer undergoing chemotherapy (SWOG-S0500). Available at

www.cancer.gov

. Accessed May 19, 2008.

10. Meng S, Tripathy D, Shete S, et al: HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci USA 101:9393-9398, 2004.

11. Meng S, Tripathy D, Shete S, et al: uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues. Proc Natl Acad Sci USA 103:17361-17365, 2006.