Clinical and Genomic Risk for Late Breast Cancer Recurrence and Survival

Abstract

Background: The 21-gene recurrence score (RS) assay (Oncotype DX) is used to guide adjuvant chemotherapy use for patients with hormone receptor-positive, HER2 (human epidermal growth factor receptor 2)-negative, axillary node-negative breast cancer. Its role, however, in providing prognostic information for late distant recurrence when added to clinicopathologic prognostic factors is unknown.

Methods: A patient-specific meta-analysis including 10,004 women enrolled in three trials was updated using extended follow-up data from TAILORx, integrating the RS with histologic grade, tumor size, and age at surgery for the RSClin tool. Cox models integrating clinicopathologic factors and the RS were compared by using likelihood ratio (LR) tests. External validation of prognosis for distant recurrence in years 0 to 10 and 5 to 10 was performed in an independent cohort of 1098 women in a real-world registry.

Results: RSClin provided significantly more prognostic information than either the clinicopathologic factors (ΔLR chi-square, 86.2; P<0.001) or RS alone (ΔLR chi-square, 131.0; P<0.001). The model was prognostic in an independent cohort for distant recurrence by 10 years after diagnosis (standardized hazard ratio, 1.56; 95% confidence interval, 1.25 to 1.94), was associated with late distant recurrence risk between 5 and 10 years after diagnosis (standardized hazard ratio, 1.78; 95% confidence interval, 1.25 to 2.55), and approximated the observed 10-year distant recurrence risk (Lin concordance, 0.87) and 5- to 10-year distant recurrence risk (Lin concordance, 0.92).

Conclusions: The 21-gene RS is prognostic for distant recurrence and overall survival in early breast cancer. A model integrating the 21-gene RS and clinicopathologic factors improved estimates of distant recurrence risk compared with either used individually and stratified late distant recurrence risk. (Funded by the National Cancer Institute, National Institutes of Health [U10CA180820, U10CA180794, UG1CA189859, U10CA180868, and U10CA180822] and others.).

Figure 1.

Kaplan–Meier Estimates for Clinical End Points for the Four Study Groups in the TAILORx Trial Using an Intention-to-Treat Analysis. Study groups are as follows: patients with a recurrence score (RS) of 0 to 10 and assigned to receive endocrine therapy (ET) alone (group A), an RS of 11 to 25 and randomly assigned to receive ET alone (group B), an RS of 11 to 25 and randomly assigned to receive chemotherapy plus ET (chemo+ET; group C), and an RS of 26 to 100 assigned to receive chemo+ET (group D). Disease-free survival probability (Panel A), distant recurrence-free probability (Panel B), recurrence-free probability (Panel C), and survival probability (Panel D) are shown.

Figure 2.

Effect of RS and Clinical Risk on Clinical End Points and Chemotherapy Benefit for Patients ≤50 Years. Twelve-year Kaplan–Meier estimates for invasive disease–free survival and freedom from recurrence at a distant site for patients 50 years of age or younger with a recurrence score (RS) of 11 to 25 randomly assigned to receive chemoendocrine therapy or endocrine therapy alone stratified according to RS (Panel A) or 12-year freedom from recurrence at a distant site stratified according to RS (11 to 15, 16 to 20, and 21 to 25) and clinical risk category (high vs. low) (Panel B). No multiplicity adjustments for exploratory end points were defined. Therefore, only point estimates and 95% confidence intervals are provided. Estimates have not been adjusted for multiple comparisons and should not be used to infer definitive treatment effects.

Figure 3.

RSClin Estimates. Estimates using RSClin (a combination of the recurrence score and clinical features of the breast cancer at the time of diagnosis) of distant recurrence risk in years 5 to 10 for patients who received adjuvant endocrine therapy alone conditional on surviving 5 years without distant recurrence. Typical clinical scenarios are provided stratified according to grade (low, intermediate, or high) in a 55-year-old patient with a 1.5-cm tumor (Panel A), tumor size (1.0, 2.0, or 3.0 cm) in a 55-year-old patient with an intermediate-grade tumor (Panel B), and age (40, 55, or 70 years) in a patient with a 1.5-cm intermediate-grade tumor (Panel C). No multiplicity adjustments for exploratory end points were defined. Therefore, only point estimates and 95% confidence intervals are provided. Estimates have not been adjusted for multiple comparisons and should not be used to infer definitive treatment effects.

Figure 4.

RSClin External Validation. External validation of RSClin (a combination of the recurrence score and clinical features of the breast cancer at the time of diagnosis) in the real-world Clalit Health Registry including 1098 patients with estrogen receptor–positive, HER2 (human epidermal growth factor receptor 2)-negative, axillary node–negative breast cancer who had a 21-gene recurrence score (RS) assay performed as a component of standard care. This included the RSClin model used at diagnosis (Panel A) and for patients treated with endocrine therapy alone without distant recurrence (DR) at 5 years (Panel B). No multiplicity adjustments for exploratory end points were defined. Therefore, only point estimates and 95% confidence intervals are provided. Estimates have not been adjusted for multiple comparisons and should not be used to infer definitive treatment effects.