Advances in the treatment of primary breast cancer include the use of chemotherapy, tamoxifen and, more recently, aromatase inhibitors for patients with ER-positive tumors, as well as trastuzumab for those with HER2-positive disease.15–18
Breast cancer is heterogeneous, with differences among subtypes in treatment responses and outcomes. Patients with ER-positive tumors who receive adjuvant hormonal therapy have better disease-free and overall survival than do those with ER-negative tumors, particularly during the first five years after diagnosis. Our results indicate that advances in chemotherapy have lessened the survival differences between ER-positive patients who receive hormonal therapy and ER-negative patients, with the latter group deriving much greater benefit from modern improvements in chemotherapy regimens.
Since early and overall event rates are higher for patients with ER-negative tumor status than for those with ER-positive status, relative reductions in these rates due to improvements in chemotherapy translate into even greater absolute benefits for patients with ER-negative tumors. The absolute improvement in five-year disease-free survival was 22.8 percent for ER-negative patients, as compared with 7.0 percent for ER-positive patients, and the difference for overall survival was also pronounced: an improvement of 16.7 percent for ER-negative patients versus 4.0 percent for ER-positive patients ( and ).
The risks of recurrence and death vary over time, as shown in , and so do the reductions in risk that are attributable to improved chemotherapy. The high risk of an event in the first two to three years after treatment for ER-negative patients coincides with the period of time when the benefit of the more effective chemotherapy regimens is manifest. For example, the reduction in risk with high-dose CAF as compared with low-dose CAF was 55 percent in the first year and 30 percent in the second year. There was little or no advantage of high-dose CAF for ER-negative patients after three years. However, the benefit was durable in that there was no sign of a rebound in risk in the high-dose group in later years, a finding reflected as well by the persistent separation in the corresponding survival curves in .
The benefit of chemotherapy in women with ER-positive tumors is far less dramatic, possibly because the benefits of improved adjuvant chemotherapy are due mostly, if not entirely, to a reduction in the risk of recurrence in the first few years after treatment. In this early period, the risk of recurrence is so small in ER-positive patients who are treated with tamoxifen, and presumably other hormonal therapies, that any additional risk reduction due to chemotherapy would be very difficult to detect statistically. Moreover, based on data from the preoperative setting, there is reason to believe that many ER-positive tumors are intrinsically less responsive to short courses of chemotherapy than ER-negative tumors. Despite the lack of a statistically significant benefit from improved chemotherapy regimens in ER-positive patients, some of these patients almost certainly derive an added benefit from such regimens. Identifying such patients is complex. In study 8541, HER2/neu overexpression or amplification identified patients who derived a benefit from high-dose CAF (600, 60, and 600 mg per square meter, respectively, per cycle), which is now the standard CAF regimen.19,20
This benefit was independent of ER status (results not shown). Subgroup analyses according to HER2 status from studies 9344 and 9741 are pending. Although the findings will be of interest, they will have to be interpreted in light of recent data demonstrating a benefit of adjuvant and neoadjuvant trastuzumab therapy in patients with HER2-positive tumors.15–18,21–24
Of interest, recent studies have documented the benefits of chemotherapy in subsets of tamoxifen-treated patients who have hormone-responsive tumors,25,26
but they have also suggested that patients with ER-positive tumors who are not in these subsets derive little or no benefit from adjuvant chemotherapy.
No method of assessing ER status is perfect, and some tumors labeled ER-positive may actually be ER-negative.27
In the same vein, an obvious question is whether the benefits of chemotherapy depend on the degree of ER positivity. Unfortunately, quantitative ER measurements were not routinely collected in our studies.
As illustrates, the risk of recurrence in both ER groups was between 2 percent and 4 percent per year after approximately three to five years and did not appear to be influenced by treatment. This level of risk is similar to that for women with node-negative disease. Moreover, the risk of recurrence decreased dramatically after about year 3, irrespective of the number of positive nodes and tumor size (data not shown). Tumors that have not recurred are those that are less aggressive or are sensitive to therapy: in effect, nonrecurrence trumps baseline clinical characteristics.
The long-term hazards were slightly higher in the ER-positive group than in those with ER-negative disease (). Possible explanations for this finding are the development of resistance to initial hormonal therapy, differences in the underlying biology of the disease, or both.28
The Oxford Overview1
suggested a possible role of age in any interaction between ER status and benefits of early polychemotherapy regimens, although the subset sample sizes were small. Our study also suffers from a sample size limitation. However, we addressed this interaction and found little evidence that age plays a role. If anything, in our studies the interaction between ER status and chemotherapy benefits is stronger in younger women. In particular, for women younger than 50 who had ER-positive tumors treated with tamoxifen there was no suggestion of a benefit for the accumulation of more intensive and extensive chemotherapies over the three studies.
Our analysis has several limitations. One is that patients admitted to our clinical trials may not be typical of patients generally. (Although there is evidence from models of breast cancer that adjuvant therapy benefits observed in clinical trials applies as well to the general U.S. population.29
) We combined the results of three trials with a total of 13 treatment regimens. The trials were randomized separately, and each patient was eligible to receive only a subgroup of the 13 regimens. Each trial was confounded with any covariates that were temporally related, limiting the ability to draw definitive conclusions based on cross-study analyses. For example, the use of screening mammography increased over the course of these studies. There is a well-understood stage shift for cancers detected on screening, but such cancers are also associated with an improved prognosis, even after accounting for known prognostic factors.30,31
We accounted for known patient and tumor characteristics using multivariate analyses, but we did not have information about how the patients’ cancers were detected.
Another limitation is that tamoxifen therapy was not randomly assigned in the studies we considered. In studies 9344 and 9741, almost all ER-positive patients received tamoxifen, and we compared ER-positive patients who received tamoxifen with ER-negative patients. In a separate analysis of study 8541, the benefit of more intensive chemotherapy was similar in ER-positive patients not
treated with tamoxifen and in ER-negative patients. There may have been a bias in the assignment of tamoxifen in study 8541; however, with the exception of menopausal status, the most important determinant of tamoxifen use was time, with much greater use after the announcement of the Oxford Overview results in 1988.32
Multiple comparisons are a concern in any subgroup analysis: examining enough subgroups will identify spurious treatment correlations, with the effects tending to be stronger with greater numbers of subgroups examined.33,34
Subgroup analyses based on hypotheses established from previous trials are less problematic. In our study, the three trials independently show the same effect. Viewing one study as hypothesis-generating leaves the other two as confirmatory. The fact that the specific chemotherapy question differed across the three trials is an important consideration but may not be relevant. Our analysis suggests that the biologic subtype of breast cancer is the most important predictor of the benefits of an improved chemotherapy regimen, regardless of the specific regimen.
Our study has two substantive clinical implications. First, although patients with ER-positive breast tumors may reasonably opt for chemotherapy, they should recognize that the benefits are not great as compared with those for patients with ER-negative disease. The benefits of intensive and extensive chemotherapy for unselected patients who have ER-positive disease treated with tamoxifen are modest at best. Whether such patients should opt for chemotherapy will depend on their attitudes toward the associated negative sequelae. In the years ahead, it is likely that we will have better predictors that will allow clinicians to determine which patients with ER-positive disease truly benefit from the addition of chemotherapy.25,26
Second, with advances in chemotherapy, patients with ER-negative tumors have had sequentially improved outcomes, and their prognoses now approach those of optimally treated patients with ER-positive disease. For patients with ER-negative disease, the overall disease-free survival and overall survival benefits of modern intensive and extensive chemotherapy considered in our study are substantial.