Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer

Abstract

Background: The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known.

Methods: We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger.

Results: The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%).

Conclusions: Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).

Figure 1.. Effect of Clinical Risk on Prognosis in the Entire Population and Stratified According to Age.

Hazard ratios and 95% confidence intervals (CIs) for a high versus low clinical risk of invasive disease recurrence, second primary cancer, or death and for distant recurrence (a hazard ratio of >1 indicates a higher event rate with high clinical risk) are shown. There were no distant recurrences among 64 patients in the subgroup who had a high clinical risk and a low recurrence score. CIs have not been adjusted for multiple comparisons, and inferences drawn from the intervals may not be reproducible. The size of each square corresponds to the size of the subgroup; the horizontal lines represent the 95% CI.

Figure 2.. Effect of Clinical Risk on Prediction of Chemotherapy Benefit.

Panel A shows the effect of clinical risk on prediction of chemotherapy benefit in 6496 women with a recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy or chemotherapy plus endocrine (chemoendocrine) therapy, and stratified according to age. A total of 4353 women were older than 50 years of age, and 2143 women were 50 years of age or younger. Panel B shows the effect of clinical risk on prediction of chemotherapy benefit in 2143 women who were 50 years of age or younger and had a recurrence score of 11 to 25. Estimated hazard ratios are shown for treatment (endocrine vs. chemoendocrine therapy) and 95% CIs for invasive disease–free survival and distant recurrence (a hazard ratio >1 indicates that chemoendocrine therapy is better). CIs have not been adjusted for multiple comparisons, and inferences drawn from the intervals may not be reproducible. The size of each square corresponds to the size of the subgroup; the horizontal lines represent the 95% CI.

Figure 3.. Effect of Age and Menopausal Status on Chemotherapy Benefit.

Shown is the effect of age and menopausal status on chemotherapy benefit in 4338 women who had a recurrence score of 16 to 25 and were randomly assigned to endocrine therapy or chemoendocrine therapy. Estimated treatment hazard ratios (endocrine vs. chemoendocrine therapy) and 95% CIs for rates of distant recurrence at 9 years are shown (a hazard ratio >1 indicates that chemoendocrine therapy is better). Menopause was defined as an age of 60 years or older; an age of 45 to 59 years with spontaneous cessation of menses for at least 12 months before registration; an age of 45 to 59 years with cessation of menses for less than 12 months before registration and a follicle-stimulating hormone (FSH) level in the postmenopausal range (or >34.4 IU per liter if the institutional range was not available); prior bilateral oophorectomy; or age younger than 60 years with prior hysterectomy without bilateral oophorectomy and an FSH level in the postmenopausal range (or >34.4 IU per liter if the institutional range was not available). CIs have not been adjusted for multiple comparisons, and inferences drawn from the intervals may not be reproducible. The size of each square corresponds to the size of the subgroup; the horizontal lines represent the 95% CI.