Originally published as JCO Early Release 10.1200/JCO.2002.06.157 on July 9 2002

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bunnell, C. A. Articles by Winer, E. P. Search for Related Content PubMed PubMed Citation Articles by Bunnell, C. A. Articles by Winer, E. P. Social Bookmarking                            What's this?

Lumping Versus Splitting: The Splitters Take This Round

Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA

IN THE SEPTEMBER 1, 2002, issue of the Journal of Clinical Oncology, Singletary et al¹ provide an update of the breast cancer staging system from the American Joint Committee on Cancer. The guidelines represent the product of a multidisciplinary Breast Task Force that sought to develop a staging system that would be helpful to clinicians and patients as they make treatment decisions. The task force also wanted to implement a nomenclature that would allow for the tracking of relevant natural history data and the facilitation of clinical trials. Over 200,000 cases of invasive breast cancer and 48,000 cases of noninvasive disease will be diagnosed in the United States in the year 2002 alone.² Perhaps more than any other solid tumor, breast cancer is a remarkably heterogeneous disease. Most experienced clinicians recognize that breast cancer represents a highly variable disease, biologically and clinically, and arguably represents a number of different disease entities. For a staging system to be useful, it must account for these differences, to the extent this is supported by data.

Our current staging system separates patients into subgroups with differing prognoses. To some degree, the current criteria also provide guidance for appropriate treatment. However, the current system is limited in determining both accurate prognoses and optimal treatment. Although recurrence and survival estimates differ among various stages of disease, patients within the same stage may also have very different risks of disease recurrence and mortality. Computer-based risk models have been developed to assist in estimating a woman’s risk of recurrence and death from breast cancer.^3,4 Consider two women with stage II breast cancer. The first has a 2.5-cm tumor that is moderately differentiated, estrogen receptor–positive, and lymph node–negative; using the above-referenced models, her risk of death in the next 10 years is 18% to 25%. The second patient is diagnosed with a 4.5-cm, poorly differentiated, estrogen receptor–negative cancer with 10 positive lymph nodes; her risk of death in the next 10 years is estimated to be 84% to 86%. To make matters more perplexing, a woman with stage III breast cancer with a 6-cm, moderately differentiated, hormone receptor–positive tumor with two positive lymph nodes has a 44% to 63% mortality risk. Furthermore, treatment decisions do not necessarily parallel stage. It is not surprising that many physicians pay relatively little attention to precise staging, and patients are often left confused. This problem arises, in part, because nodal status remains the single most important prognostic characteristic and the present staging system only distinguishes between node-negative and node-positive disease.

With improvements in diagnostic tools and with heightened public awareness of breast cancer, a higher proportion of women are now diagnosed with earlier stage disease.⁵ Although it is widely believed that earlier diagnosis leads to a change in the natural history of the disease, there is controversy surrounding this issue.⁶ The recent decline in breast cancer mortality is well established,⁷ but the relative contribution of various factors to this change is uncertain. The current staging system has not optimized our ability to understand whether the decline in breast cancer mortality is a consequence of early detection, improved treatment, or both. At least two factors complicate the interpretation of the decline in breast cancer mortality. First, it is likely that within each stage, more women are being diagnosed today with "earlier" rather than "later" stage disease (eg, one positive lymph node v eight positive nodes). Second, improved diagnostic capabilities result in stage migration.⁸ With the use of computed tomography and magnetic resonance imaging scans, some women are now classified as having stage IV disease who previously would have been characterized as having early-stage disease. More recently, with the widespread use of sentinel biopsies, it is not uncommon for a woman who was thought to have negative lymph nodes to be categorized as node-positive based on the results of special stains done on a fine section from the sentinel biopsy. The most dramatic example of this stage migration is the woman with ductal carcinoma-in-situ who is reclassified as having stage II breast cancer based on the presence of isolated tumor cells in a sentinel node. Our present staging system is limited in its ability to identify subtle shifts that occur within stage and does not categorize breast cancer in such a manner as to determine whether stage migration actually affects a patient’s prognosis.

The new staging system for breast cancer, which will be adopted by tumor registries in January 2003, represents a significant step forward. The new system is evidence-based, and when adequate evidence was not available, it is based on widely accepted clinical practices. The major changes focus on the categorization of lymph node involvement by breast cancer. Recognizing the importance of the number of involved axillary lymph nodes, the staging criteria have moved beyond the designation of axillary lymph nodes as simply negative or positive. The uncertainty surrounding the prognostic significance of micrometastases led the task force to create a separate designation for patients who only had micrometastatic lymph node involvement and provide a clearer definition of what is meant by micrometastatic disease. The new guidelines also provide a separate designation for patients who have "micro" micrometastatic involvement, defined as isolated tumor cells or clumps of tumor cells measuring less than 0.2 mm. The widespread use of sentinel biopsies has created a striking increase in the number of such cases, and it is critical that we appropriately categorize and track outcome in these patients. In the meantime, however, the panel concluded that these patients should be classified as having node-negative disease. Consistent with current clinical practice, the task force recategorized patients with supraclavicular and infraclavicular disease as having stage III, not stage IV, disease.

The task force took another major step forward. By subcategorizing the method of detection of node positivity (sentinel biopsy v standard dissection; hematoxylin and eosin v immunohistochemistry v reverse transcriptase polymerase chain reaction), they recognized the potential importance and possible confounding influence of the methodology used in making a diagnosis. Unless this information is included in the staging criteria, we will be limited in our ability to determine whether the method of detection actually makes a difference in predicting outcomes. Whether or not these particular distinctions are important, incorporating the method of detection represents a new paradigm in cancer staging.

There is no question that the new staging guidelines will be more work for many of us. Tumor registrars will have to learn a new system, and undoubtedly there will be many queries of pathologists and treating clinicians. The new system is complex, and it will take some time to become accustomed to the nomenclature. The training time and additional hours to record all of the details required by the new system will result in some incremental expense. In our view, the effort and cost are likely to be worthwhile. In the short term, the new system may be beneficial to clinicians and their patients by better risk categorization and by acknowledging the uncertainty that exists in some situations. Perhaps the new staging criteria will provide physicians with the reassurance that treatment recommendations should not necessarily be altered based on the finding of a clump of "brown cells." Ultimately, the new staging guidelines are an investment in the future. By better defining subgroups, we will have the tools to characterize the natural history of breast cancer to a degree never before possible.

Stage is the integration of time and biology. A woman with locally advanced breast cancer may have had a very slow-growing tumor for many years or a much more aggressive cancer that rapidly enlarged. Improvements in the treatment of breast cancer will largely depend on advances in our understanding of breast cancer biology and our ability to apply that knowledge in the clinic. Certain biologic differences—tumor grade, HER-2/neu, and hormone receptor status—have been well described. The task force considered the possibility of including selected features, such as tumor grade, in defining stage. The task force concluded, based on their own discussions and recent deliberations from the American Joint Committee on Cancer,⁹ that there is insufficient data to include these factors at this time. In the years ahead, improved knowledge of the biology of breast cancer may allow for better definition of prognosis and a greater understanding of the heterogeneity of the disease. At that time, optimal staging will need to move beyond a definition of the anatomic findings, such as tumor size and lymph node involvement. The revised guidelines do not take us to a new biologic era, but they are a step in the right direction.

For several decades, there has been debate about whether breast cancer clinicians and researchers should lump or split. With the new criteria, the splitters have taken this round. The stage is set for a time when we better understand the heterogeneity of breast cancer and use this information in making treatment decisions.

NOTES

This editorial was published ahead of print at www.jco.org.

REFERENCES

1. Singletary S, Allred C, Ashley P, et al: Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20: 3628-3636, 2002[Abstract/Free Full Text]

2. Jemal A, Thomas A, Taylor M, et al: Cancer statistics, 2002. CA Cancer J Clin 52: 23-45, 2002[Abstract/Free Full Text]

3. Ravdin PM, Siminoff LA, Davis GJ, et al: Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 19: 980-991, 2001[Abstract/Free Full Text]

4. Loprinzi C, Thome S: Understanding the utility of adjuvant systemic therapy for primary breast cancer. J Clin Oncol 19: 972-979, 2001[Abstract/Free Full Text]

5. Ries L, Eisner M, Kosary C, et al: SEER Cancer Statistics Review, 1973-1999. Bethesda, MD, National Cancer Institute, 2002

6. Olsen O, Gotzsche PC: Cochrane review on screening for breast cancer with mammography. Lancet 358: 1340-1342, 2001[CrossRef][Medline]

7. Peto R, Boreham J, Clarke M, et al: UK and USA breast cancer deaths down 25% in year 2000 at ages 20-69 years. Lancet 355: 1822, 2000[Medline]

8. Feinstein AR, Sosin DM, Wells CK: The Will Rogers phenomenon: Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 312: 1604-1608, 1985[Abstract]

9. Yarbro JW, Page DL, Fielding LP, et al: American Joint Committee on Cancer prognostic factors consensus conference. Cancer 86: 2436-2446, 1999[CrossRef][Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				W. A. Woodward, E. A. Strom, S. L. Tucker, M. D. McNeese, G. H. Perkins, N. R. Schechter, S. E. Singletary, R. L. Theriault, G. N. Hortobagyi, K. K. Hunt, et al. Changes in the 2003 American Joint Committee on Cancer Staging for Breast Cancer Dramatically Affect Stage-Specific Survival J. Clin. Oncol., September 1, 2003; 21(17): 3244 - 3248. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bunnell, C. A. Articles by Winer, E. P. Search for Related Content PubMed PubMed Citation Articles by Bunnell, C. A. Articles by Winer, E. P. Social Bookmarking                            What's this?