Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance)

Abstract

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) -positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).

Fig 1.

CONSORT diagram for the ACOSOG Z1031B patients. AI, aromatase inhibitor; Ki67, protein encoded by the MKI67 gene; NAC, neoadjuvant chemotherapy; NET, neoadjuvant endocrine therapy.

Fig 2.

REMARK diagrams for the long-term outcome analysis by Preoperative Endocrine Therapy Prognostic Index (PEPI) score for (A) ACOSOG Z1031A patients, and (B) ACOSOG Z1031B patients. AI, aromatase inhibitor; Ki67, protein encoded by the MKI67 gene; NET, neoadjuvant endocrine therapy.

Fig 3.

Kaplan-Meier analysis by Preoperative Endocrine Prognostic Index (PEPI) = 0 (pathologic stage II or IIA, surgical specimen protein encoded by the MKI67 gene (Ki67) < 2.7%, and estrogen receptor Allred score > 2) versus PEPI > 0 (A) for all patients, (B) for patients who did not receive adjuvant chemotherapy, and (C) for patients in the ACOSOG Z1031A cohort alone. (D) Outcomes for patients according to the 10% Ki67 cut point on ACOSOG Z1031B.

Fig 4.

Gene expression–based analysis of proliferation in 109 patients at baseline and 2-week paired samples (including a small number of patients for whom the data were derived from a 4-week sample) from the ACOSOG Z1031B cohort only (A) REMARK diagram. (B) The effect of aromatase inhibitor (AI) treatment on mRNA levels for estrogen receptor, progesterone receptor, and protein encoded by the MKI67 gene (Ki67) as a heat map showing marked suppression with treatment. The gray and black bars indicate samples associated with Ki67 values above or below 10% and patients who received chemotherapy. The red bar indicates the one patient in this analysis who experienced a pathologic complete response (pCR) to chemotherapy. The lowest bar provides a heat map from the multigene proliferation score (MGPS, cell cycle), also showing marked suppression of treatment, but also identifying patients who have presently high levels of gene expression from cell cycle–related genes that overlap with patients with Ki67 levels of > 10% and received chemotherapy. (C) Box plots comparing the MGPS scores at baseline and 2 weeks in samples associated with 2-week Ki67 < 10% or > 10% showing higher scores at both baseline and at 2 weeks for patients with Ki67 scores > 10% (Wilcoxon signed rank test P ≤ .001 for both comparisons). (D) Correlation between Ki67 values and MGPS values at 2 weeks with the Pearson’s correlation coefficient. MGPS, multigene proliferation; NAC, neoadjuvant chemotherapy.

Fig A1.

Relapse patterns in the two independent training sets used to justify the 10% early on treatment cut point for triage to chemotherapy in Z1031B. (A) is based on data from the IMPACT trial and (B) from data derived from the Preoperative Letrozole (POL) Trial. In both studies, on-treatment Ki67 values of >10% identified in a biopsy taken at 2 weeks (IMPACT) or 4 weeks (POL) are associated with a significantly higher risk of subsequent relapse over time than patients with values of ≤10% at the same time point.