The Oncologist, Vol. 12, No. 5, 505-509, May 2007; doi:10.1634/theoncologist.12-5-505
© 2007 AlphaMed Press
An Interpretation of the EBCTCG Data
Jerry P. Lewis
Departments of Medicine and Pathology, School of Medicine, University of California, Davis, California, USA
Key Words. Breast Cancer • Adjuvant therapy • Carryover benefit
Correspondence: Jerry P. Lewis, M.D., 1198 Muirfield Drive, West Chester, Pennsylvania 19382, USA. Telephone: 610-793-3665; e-mail: jerrymarguerite{at}comcast.net
Received June 16, 2006;
accepted for publication December 5, 2006.
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ABSTRACT
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Published data and figures from the Early Breast Cancer Clinical Trialists' Collaborative Group are explored and interpreted as supporting a concept that the prime impact of adjuvant hormonal and polychemotherapy therapy is on soon-to-emerge tumors, with the timing of benefit accrual being mostly limited to the time of drug administration. Nevertheless, once benefit in reducing recurrence occurs, the benefit is maintained for years. Depending on how this is viewed, there may or may not be a carryover effect of these therapies in the setting of adjuvant breast cancer.
Disclosure of potential conflicts of interest is found at the end of this article.
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INTRODUCTION
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The possibility of adjuvant breast cancer therapy having a carryover benefit was raised by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) in their 1998 publication wherein they state: "One potential difficulty for such trials is the possible carry-over benefit of adjuvant tamoxifen, whereby 5 years of adjuvant tamoxifen produces a substantial protective effect not only while it is being taken but also during the next 5 years" [1]. The meaning of this statement is open to interpretation. Does a carry over benefit mean added benefit over time once the agent is discontinued or does it merely imply that the benefit gained during therapy will not be lost? If the former is true, then all adjuvant agents should be studied for this added benefit; if the latter is true, such is not required. These issues are explored using recent data from the large meta-analyses published by the EBCTCG [2, 3]. The timing and duration of benefit for tamoxifen, polychemotherapy, mastectomy, and ipsilateral breast radiation are examined.
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IN WOMEN WITH EARLY BREAST CANCER SELECTED FOR 5 YEARS OF ADJUVANT TAMOXIFEN, DOES HORMONAL THERAPY ACT SELECTIVELY ON AN AGE SUBSET OF UNRECOGNIZED TUMORS AND DOES THE BENEFIT INCREASE AFTER TAMOXIFEN THERAPY IS WITHDRAWN?
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These issues may be addressed by examining recurrence curves over time in women with hormone receptor–positive or unknown early breast cancer (EBC) enrolled in clinical trials and randomized to placebo or 5 years of tamoxifen [2]. Five years of tamoxifen treatment in these women reduced recurrences by 11.4% at 5 years, 13.6% at 10 years, and 11.8% at 15 years (Fig. 1A). Thus, only about 12% of women given 5 years of tamoxifen benefit, with the majority of benefit accruing during the first 5 years. There was no added benefit beyond 6 years. In order to focus on this issue further, the tamoxifen curve is raised 11.8% (overall benefit at 15 years, 11.8%) so that the 15-year data points overlap (Fig. 1B). This can be simply done using a transparency of the first figure (Fig. 1A) and sliding it over the original figure until the 15-year data points converge, in essence deleting women who benefited from tamoxifen from the treatment arm. From this exercise, it is clear that the benefit from tamoxifen accrues over 6 years, with most occurring during the first 5 years of drug administration. Once the benefit is gained it is not lost, but persists through year 15; there is no tendency for the benefit to increase from year 6 through year 15. In other words, there is no added carryover effect of tamoxifen, if one means by this that the benefit from the drug gets better following drug withdrawal. This also means that, at year 7 post–primary treatment, the likelihood of women who had received 5 years of tamoxifen experiencing a recurrence or a new breast cancer is similar to that of women who have not received tamoxifen and at 7 years were clinically free of disease. Supporting this are breast cancer mortality curves published by these same authors (data not shown), which show that annual deaths were similar between women randomized to either adjuvant tamoxifen or placebo and to either adjuvant polychemotherapy or no polychemotherapy 10 years after primary therapy [2].
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Figure 1. Recurrence curves for breast cancer patients allocated to tamoxifen or no tamoxifen. (A): 15-year probability of breast cancer recurrence among 10,386 women with estrogen receptor (ER)-positive disease (20% status unknown), 30% with node-positive disease, allocated to 5 years of tamoxifen or no tamoxifen. Error bars are ±1 standard error (SE). (B): Modified from (A) by deleting patients who benefited from 5 years of tamoxifen. Note the tamoxifen curve has been moved up 11.8%, as discussed in the body of the paper. In this case, the curves become superimposable at year 5 and remain so through year 15.
From Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 2005;365:1687–1717, with permission from Elsevier.
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IN WOMEN WITH EBC TREATED WITH ADJUVANT POLYCHEMOTHERAPY DOES POLYCHEMOTHERAPY ACT SELECTIVELY ON AN AGE SUBSET OF UNRECOGNIZED TUMORS AND DOES THE BENEFIT INCREASE AFTER THE TREATMENT IS WITHDRAWN?
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Data from the EBCTCG addressing these issues are shown in Figure 2A and Figure 3A [2]. Polychemotherapy is given over a rather short period of time of <1 year, and the data shown demonstrate its benefit within the first year or so of being administered (Figs. 2B and 3B). Thus, like tamoxifen, polychemotherapy impacts soon-to-emerge tumors and has no demonstrable effect on tumors slowly developing that are destined to emerge in later years. Among women with breast cancer <50 years of age at diagnosis, the benefit for polychemotherapy at 5 years is 12.5%, at 10 years is 12.4%, and at 15 years is 12.4%. These numbers are similar at each time point.
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Figure 2. Recurrence curves for breast cancer patients <50 years of age allocated to polychemotherapy or no chemotherapy. (A): 15-year probability of breast cancer recurrence among women with early breast cancer <50 years of age at study entry allocated to polychemotherapy or no polychemotherapy. (B): Modified from (A) by deleting patients who benefited from polychemotherapy. Note the polychemotherapy curve has been moved up 12.3%, as discussed. The major benefit of polychemotherapy occurs during the first year, with less benefit during years 2 and 3. For years 3–15, the curves are superimposable.
Abbreviation: SE, standard error.
From Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 2005;365:1687–1717, with permission from Elsevier.
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Figure 3. Recurrence curves for breast cancer patients  50 years of age allocated to polychemotherapy or no polychemotherapy. (A): 15-year probability of breast cancer recurrence among women with early breast cancer 50 years of age at study entry allocated to polychemotherapy or no polychemotherapy. Permission granted by Elsevier as in Figure 1A. (B): modified from 3A by deleting patients who benefited from polychemotherapy. Note the polychemotherapy curve has been moved up 4.1%, as discussed. The major benefit of polychemotherapy occurs during the first year. For years 1–15, the curves are superimposable.
From Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 2005;365:1687–1717, with permission from Elsevier.
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Among women aged 50–69 at the time of diagnosis, the benefit for polychemotherapy at 5 years is 6%, at 10 years is 4.7%, and at 15 years is 4.2%. There is no evidence of an added carryover benefit of polychemotherapy because the data do not improve over time. But like the tamoxifen story, to a great extent, once a benefit has been established, that benefit is carried forward into later years. This is true for women <50 years of age at diagnosis, who benefit the most, and for older women, who benefit less from polychemotherapy.
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DISCUSSION
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The EBCTCG figures and data can be used to help understand where, when, and for how long our adjuvant drug therapies work [2, 3]. For tamoxifen as well as for polychemotherapy, these adjuvant therapies appear to work on soon-to-emerge clinically unrecognized tumors during the period of drug exposure, and the benefit gained lasts at least for 15 years. There is little to support these therapies having an increased beneficial effect after the drugs have been withdrawn.
Contrary to the above interpretation for adjuvant drug therapy, recently the EBCTCG has published data on (a) local recurrence following mastectomy versus lumpectomy and (b) local recurrence following conservative surgery followed by ipsilateral breast radiation versus conservative surgery alone [3]. The benefit of the more aggressive treatments is substantial and in the range of 20%. This benefit begins with the onset of the intervention and accrues over a period of 10 years. These interventions therefore appear to impact tumors at various stages of development from very new foci of malignant cells up through larger and soon-to-emerge lesions. These interventions therefore can be considered as having a true added carryover benefit.
Figure 4 depicts the growth of breast cancer from its earliest development until clinical recognition and through advanced disease. It is acknowledged that an evolving tumor most likely does not grow in a strictly exponential fashion, but for the sake of discussion this matters little. Basically, the tumor exists for years prior to being detected. In the example shown, it has been growing for about 7.5 years, representing approximately three fourths of its total growth assuming no medical intervention. Because both tamoxifen and polychemotherapy demonstrate a benefit during the first year of adjuvant therapy and there is essentially no added benefit following treatment withdrawal, the major impact of these therapies is focused on to soon-to-emerge clinically unrecognized tumors. If there was added benefit after the drugs were discontinued, there would be an added carryover effect, meaning most likely that the intervention affected earlier developing tumors destined to be clinically recognized in subsequent years as well as those likely to emerge during therapy. On the other hand, total mastectomy (as one might expect) and ipsilateral breast radiation appear to exert effects on local developing tumors regardless of stage of maturity.
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Figure 4. Breast cancer growth from a single cell to clinically recognized disease. Complete mastectomy or whole breast radiation impacts the tumor population regardless of size. Tamoxifen and polychemotherapy appear to impact clinically unrecognized late tumor growth within a year or two of becoming clinically recognized disease.
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In a similar fashion, the same appears to be true for trastuzumab, wherein 1 year of treatment in the adjuvant setting of human epidermal growth factor 2/neu–positive tumors yields some benefit, but after treatment withdrawal at 1 year, there is striking benefit for the trastuzumab-treated patient, with a difference in recurrence between the treatment and placebo arms of about 11.7% at year 3 and >18% at year 4 [4]. Trastuzumab therefore does have a significant added carryover benefit and thus appears to have a favorable impact on earlier developing tumors as opposed to tamoxifen or polychemotherapy.
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CONCLUSIONS
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A review of two recent EBCTCG publications supports the concept that adjuvant tamoxifen and polychemotherapy have their greatest impact on soon-to-emerge unrecognized tumors, with little influence on earlier developing tumors. The benefits achieved by these therapies primarily occur during the period of drug administration. Little to no added benefit can be detected after drugs are withdrawn. Nevertheless, the benefit achieved persists through 15 years. The only carryover effect of these agents is that benefit once gained is not lost even out to 15 years. The benefit does not appear to increase, however, once the therapies are discontinued.
Insights from these clinical trials add to our understanding of the nature of EBC and its response to adjuvant therapy. This Commentary may suggest new avenues to be explored that might improve our management of EBC and women at high risk for developing invasive breast cancer who are considering tamoxifen intervention.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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J.P.L. was a medical director in oncology with Zeneca and AstraZeneca from 1994 to 2005.
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REFERENCES
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- Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 1998;351:1451–1467.[CrossRef][Medline]
- Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;365:1687–1717.[CrossRef][Medline]
- Clarke M, Collins R, Darby S et al. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for breast cancer on local recurrence and 15-year survival: An overview of randomised trials. Lancet 2005;366:2087–2106.[Medline]
- Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–1684.[Abstract/Free Full Text]
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Abstract
Introduction
