Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer

Abstract

Context: Breast cancer estrogen-receptor (ER) status is useful in predicting benefit from endocrine therapy. It may also help predict which patients benefit from advances in adjuvant chemotherapy.

Objective: To compare differences in benefits from adjuvant chemotherapy achieved by patients with ER-negative vs ER-positive tumors.

Design, setting, and patients: Trial data from the Cancer and Leukemia Group B and US Breast Cancer Intergroup analyzed; patient outcomes by ER status compared using hazards over time and multivariate models. Randomized trials comparing (1): 3 regimens of cyclophosphamide, doxorubicin, and fluorouracil (January 1985 to April 1991); (2) 3 doses of doxorubicin concurrent with cyclophosphamide, with or without subsequent paclitaxel (May 1994 to April 1997); (3) sequential doxorubicin, paclitaxel, and cyclophosphamide with concurrent doxorubicin and cyclophosphamide followed by paclitaxel, and also 3-week vs 2-week cycles (September 1997 to March 1999). A total of 6644 node-positive breast cancer patients received adjuvant treatment.

Main outcome measures: Disease-free and overall survival.

Results: For ER-negative tumors, chemotherapy improvements reduced the relative risk of recurrence by 21%, 25%, and 23% in the 3 studies, respectively, and 55% comparing the lowest dose in the first study with biweekly cycles in the third study. Corresponding relative risk reductions for ER-positive tumors treated with tamoxifen were 9%, 12%, and 8% in the 3 studies, and 26% overall. The overall mortality rate reductions associated with chemotherapy improvements were 55% and 23% among ER-negative and ER-positive patients, respectively. All individual ER-negative comparisons and no ER-positive comparisons were statistically significant. Absolute benefits due to chemotherapy were greater for patients with ER-negative compared with ER-positive tumors: 22.8% more ER-negative patients survived to 5 years disease-free if receiving chemotherapy vs 7.0% for ER-positive patients; corresponding improvements for overall survival were 16.7% vs 4.0%.

Conclusion: Among patients with node-positive tumors, ER-negative breast cancer, biweekly doxorubicin/cyclophosphamide plus paclitaxel lowers the rate of recurrence and death by more than 50% in comparison with low-dose cyclophosphamide, doxorubicin, and fluorouracil as used in the first study.

Figure 1. Treatment Regimens in the Three Studies of Chemotherapy for Node-Positive Breast Cancer.

C denotes cyclophosphamide, A doxorubicin, F fluorouracil, and P paclitaxel. Study 8541 had three treatment arms, with doses of C, A and F in proportion to the dose of doxorubicin that is shown (in milligrams per square meter of body surface area). Study 9344 had a 3 by 2 factorial design, with randomization to one of 3 doses of A with a second randomization to 4 cycles of paclitaxel or not. Study 9741 had a 2 by 2 factorial design, with patients being randomized to biweekly vs triweekly schedules and separately to concurrent AC followed by P vs sequential A followed by P then C.

Figure 2. Kaplan-Meier Curves for Disease-free Survival According to ER Status in the Three Studies.

Cumulative at-risk sample sizes over time are shown in each panel. The initial sample sizes were approximately equally divided among the groups in question. The dose effect of doxorubicin in study 9344 and the comparison of sequential or concurrent therapy in study 9741 are not shown; neither factor was associated with disease-free survival in unadjusted or adjusted analyses, nor were there significant differences within ER subgroups.

Figure 2. Kaplan-Meier Curves for Disease-free Survival According to ER Status in the Three Studies.

Cumulative at-risk sample sizes over time are shown in each panel. The initial sample sizes were approximately equally divided among the groups in question. The dose effect of doxorubicin in study 9344 and the comparison of sequential or concurrent therapy in study 9741 are not shown; neither factor was associated with disease-free survival in unadjusted or adjusted analyses, nor were there significant differences within ER subgroups.

Figure 3. Empirical Risk of Recurrence or Death over Time According to ER Status.

Risk was calculated as the number of events during the year divided by the number of patients at risk for experiencing the event at the beginning of the year. Cumulative at-risk sample sizes over time are shown in the respective panels of Figure 2. In the rightmost parts of the curves the samples were relatively small, and the standard errors (not shown) were correspondingly large. Not all patients have reached the later follow-up times. In addition, patients with earlier recurrences have been eliminated from the at-risk group.

Figure 3. Empirical Risk of Recurrence or Death over Time According to ER Status.

Risk was calculated as the number of events during the year divided by the number of patients at risk for experiencing the event at the beginning of the year. Cumulative at-risk sample sizes over time are shown in the respective panels of Figure 2. In the rightmost parts of the curves the samples were relatively small, and the standard errors (not shown) were correspondingly large. Not all patients have reached the later follow-up times. In addition, patients with earlier recurrences have been eliminated from the at-risk group.

Figure 4. Empirical Risk of Recurrence or Death over Time for ER-Positive Patients in Study 8541.

Panel A shows the risks for patients not receiving tamoxifen (initial n=552), and Panel B shows the risks for patients receiving tamoxifen (same as Panel B of Figure 3) (initial n=472).

Figure 5. Disease-free and Overall Survival for Patients in Study 8541: Actual Patients in Lowdose CAF vs Modeled as though Receiving Biweekly Doxorubicin, Cyclophosphamide and Paclitaxel as in Study 9741.

Patients have mean tumor size, number of positive lymph nodes and menopausal status as in the low-dose arm of Study 8541. The “Modeled q2wk in Study 9741” curves do not apply to the patients in Study 9741 but instead for patients having the characteristics of the low-dose arm of Study 8541. Both panels A (DFS) and C (OS) show an average reduction in hazard of 55 percent for ER-negative disease while panels B (DFS) and D (OS) show average reductions of 26 and 23 percent for ER-positive disease receiving tamoxifen (see Table 2). The proportional hazards model assumption is that average reduction in hazard applies over the entire 20-year period. The p-values shown are from multivariate models for given ER status. The ER status by chemotherapy interaction p-value for DFS is 0.02 and for OS is 0.05.