Integration of Clinical Variables for the Prediction of Late Distant Recurrence in Patients With Estrogen Receptor-Positive Breast Cancer Treated With 5 Years of Endocrine Therapy: CTS5

Abstract

Purpose Estimating risk of late distant recurrence (DR) is an important goal for managing women with hormone receptor-positive breast cancer after 5 years of endocrine treatment without recurrence. We developed and validated a simple clinicopathologic tool (Clinical Treatment Score post-5 years [CTS5]) to estimate residual risk of DR after 5 years of endocrine treatment. Patients and Methods The ATAC (Arimidex, Tamoxifen, Alone or in Combination) data set (N = 4,735) was used to create a prognostic score for post-5-year risk of DR. Validity of CTS5 (ATAC) was tested in the BIG 1-98 data set (N = 6,711). Time to late DR, 5 years after finishing scheduled endocrine therapy, was the primary end point. Cox regression models estimated the prognostic performance of CTS5 (ATAC). Results CTS5 (ATAC) was significantly prognostic for late DR in the ATAC cohort (hazard ratio, 2.47; 95% CI, 2.24 to 2.73; P < .001) and BIG 1-98 validation cohort (hazard ratio, 2.07; 95% CI, 1.88 to 2.28; P < .001). CTS5 (ATAC) risk stratification defined in the training cohort as low (< 5% DR risk, years 5 to 10), intermediate (5% to 10%), or high (> 10%) identified 43% of the validation cohort as low risk, with an observed DR rate of 3.6% (95% CI, 2.7% to 4.9%) during years 5 to 10. From years 5 to 10, 63% of node-negative patients were low risk, with a DR rate of 3.9% (95% CI, 2.9% to 5.3%), and 24% with one to three positive nodes were low risk, with a DR rate of 1.5% (95% CI, 0.5% to 3.8%). A final CTS5 for future use was derived from pooled data from ATAC and BIG 1-98. Conclusion CTS5 is a simple tool based on information that is readily available to all clinicians. CTS5 was validated as highly prognostic for late DR in the independent BIG 1-98 study. The final CTS5 algorithm identified 42% of women with < 1% per-year risk of DR who could be advised of the limited potential value of extended endocrine therapy.

Trial registration: ClinicalTrials.gov NCT00004205.

Figures

Fig 1.

Predicted distant recurrence (DR) risk in years 5 to 10 since random assignment (start of adjuvant endocrine therapy) for ATAC (Arimidex, Tamoxifen, Alone or Combination) trial (A) overall population and (B) node-negative and node-positive patients. Solid vertical lines indicate cutoff points for risk groups. CTS5, Clinical Treatment Score post–5 years.

Fig 2.

Kaplan-Meier curves and 5- to 10-year distant recurrence (DR) rates since random assignment for the overall population according to trial (solid lines, ATAC [Arimidex, Tamoxifen, Alone or Combination]; dashed lines, BIG [Breast International Group] 1-98).

Fig 3.

Observed versus expected number of events and χ2 values in the BIG (Breast International Group) 1-98 trial according to deciles of Clinical Treatment Score post–5 years (ATAC [Arimidex, Tamoxifen, Alone or Combination]) for (A) node-negative and (B) node-positive patients.

Fig 4.

Predicted 5- to 10-year distant recurrence (DR) risk since random assignment and Clinical Treatment Score post–5 years (CTS5) values for the combined data set. Solid vertical lines indicate cutoff points for risk groups. Arrows indicate the CTS5 and equivalent 5- to 10-year risks of a patient age 54 years with a 12-mm, node-negative, grade 2 tumor. Using the formula CTS5 = 0.438 × nodes + 0.988 × (0.093 × size − 0.001 × size2 + 0.375 × grade + 0.017 × age), her CTS5 score is 2.61 and her 5- to 10-year risk of DR is 3%.

Fig A1.

CONSORT diagram according to trial. ATAC, Arimidex, Tamoxifen, Alone or Combination; BIG, Breast International Group; DR, distant recurrence.

Fig A2.

Observed versus expected number of events and χ2 values in the BIG (Breast International Group) 1-98 trial according to deciles of published Clinical Treatment Scores (CTSO) for (A) node-negative and (B) node-positive patients. p < 0.05 when χ2 > 3.84.