Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics

Abstract

Background: Understanding how tumor response is related to relapse risk would help clinicians make decisions about additional treatment options for patients who have received neoadjuvant endocrine treatment for estrogen receptor-positive (ER+) breast cancer.

Methods: Tumors from 228 postmenopausal women with confirmed ER+ stage 2 and 3 breast cancers in the P024 neoadjuvant endocrine therapy trial, which compared letrozole and tamoxifen for 4 months before surgery, were analyzed for posttreatment ER status, Ki67 proliferation index, histological grade, pathological tumor size, node status, and treatment response. Cox proportional hazards were used to identify factors associated with relapse-free survival (RFS) and breast cancer-specific survival (BCSS) in 158 women. A preoperative endocrine prognostic index (PEPI) for RFS was developed from these data and validated in an independent study of 203 postmenopausal women in the IMPACT trial, which compared treatment with anastrozole, tamoxifen, or the combination 3 months before surgery. Statistical tests were two-sided.

Results: Median follow-up in P024 was 61.2 months. Patients with confirmed baseline ER+ clinical stage 2 and 3 tumors that were downstaged to stage 1 or 0 at surgery had 100% RFS (compared with higher stages, P < .001). Multivariable testing of posttreatment tumor characteristics revealed that pathological tumor size, node status, Ki67 level, and ER status were independently associated with both RFS and BCSS. The PEPI model based on these factors predicted RFS in the IMPACT trial (P = .002).

Conclusions: Breast cancer patients with pathological stage 1 or 0 disease after neoadjuvant endocrine therapy and a low-risk biomarker profile in the surgical specimen (PEPI score 0) have an extremely low risk of relapse and are therefore unlikely to benefit from adjuvant chemotherapy.

Figure 1

Patient populations for univariate and multivariable analysis. The patient populations are described in this diagram to illustrate how the univariable analysis sought to include the largest population possible. The multivariable analysis was performed on a subset of patients among whom all factors in the model were available for comparison. ER = estrogen receptor.

Figure 2

Kaplan–Meier analysis of relapse-free survival (RFS) and breast cancer–specific survival (BCSS) among women whose tumors were established to be estrogen receptor positive (ER+) at baseline by central laboratory analysis. A) RFS for posttreatment pathological stage 1 or 0 (T1N0 or T0N0, green) vs higher stages (red), P < .001; B) RFS for posttreatment pathological node negative (green) vs node positive (red), P < .001; C) RFS for posttreatment clinical responders (green) vs no clinical response (red), P = .002; D) RFS for posttreatment histological grade (Grade I, green, vs Grade II/III, red), P < .001. E) RFS for patients with ER+ tumors posttreatment (green) vs ER negative (−) tumors posttreatment (red), P = .03; F) BCSS for patients with ER+ tumors posttreatment (green) vs ER− tumors posttreatment (red), P = .002; censorship marks are provided as open circles. All P values (two-sided) were calculated using the log-rank test.

Figure 3

Development and validation of the Preoperative Endocrine Prognostic Index (PEPI). A) Relapse-free survival (RFS) for the three PEPI risk groups identified in the P024 model with a log-rank statistic to test the overall trend (P < .001). The green line represents group 1, patients with a PEPI risk score of 0; the red line group 2, a PEPI risk score of 1–3; and the purple line group 3, a PEPI risk score of 4 or more. The three groups have distinct risks of relapse. B) PEPI groups 1, 2, and 3 also have distinct risks of breast cancer death, with similar statistical significance as the RFS data (P < .001). C) The PEPI model was validated in the IMPACT trial for RFS, with a statistically significant association between relapse risk and risk score (P = .002). D) Pathological stage (stage 1 or 0 [green line] vs stage 2 or 3 [red line]) has a distinctly favorable outcome in the IMPACT trial (P = .03). Of 43 patients in the stage 1 or 0 group, only one experienced relapse. This patient's tumor had the highest Ki67 level in the stage 1 or 0 group, and had therefore been correctly assigned to PEPI group 2. E) Top, relationships among risk score, relapse events, and adjuvant chemotherapy administration (Chemo) in patients in the P024 trial. Bottom, heat map summarizing the distribution of the individual components of the risk score. F) Top, relationships among risk score, relapse events, and adjuvant chemotherapy administration (Chemo) in patients in the IMPACT trial. Bottom, heat map summarizing the distribution of the individual components of the risk score. The heat maps indicate the presence of a favorable factor (green) or an adverse factor (red) for large tumor size, node-positive status, or estrogen receptor (ER) negativity. The color coding in the Ki67 line of the heat map indicates Ki67 with a risk point of 0 as green, a risk point of 1 as dark red, and risk point of 2 as red. The bar over the heat map indicates the three risk groups generated by the risk point assignments (green, group 1; red, group 2; and purple, group 3).