Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031

Abstract

Purpose: Preoperative aromatase inhibitor (AI) treatment promotes breast-conserving surgery (BCS) for estrogen receptor (ER)-positive breast cancer. To study this treatment option, responses to three AIs were compared in a randomized phase II neoadjuvant trial designed to select agents for phase III investigations.

Patients and methods: Three hundred seventy-seven postmenopausal women with clinical stage II to III ER-positive (Allred score 6-8) breast cancer were randomly assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary end point was clinical response. Secondary end points included BCS, Ki67 proliferation marker changes, the Preoperative Endocrine Prognostic Index (PEPI), and PAM50-based intrinsic subtype analysis.

Results: On the basis of clinical response rates, letrozole and anastrozole were selected for further investigation; however, no other differences in surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for mastectomy-only patients at presentation was 51%. PAM50 analysis identified AI-unresponsive nonluminal subtypes (human epidermal growth factor receptor 2 enriched or basal-like) in 3.3% of patients. Clinical response and surgical outcomes were similar in luminal A (LumA) versus luminal B tumors; however, a PEPI of 0 (best prognostic group) was highest in the LumA subset (27.1% v 10.7%; P = .004).

Conclusion: Neoadjuvant AI treatment markedly improved surgical outcomes. Ki67 and PEPI data demonstrated that the three agents tested are biologically equivalent and therefore likely to have similar adjuvant activities. LumA tumors were more likely to have favorable biomarker characteristics after treatment; however, occasional paradoxical increases in Ki67 (12% of tumors with > 5% increase after therapy) suggest treatment-resistant cells, present in some LumA tumors, can be detected by post-treatment profiling.

Fig 1.

CONSORT diagram. AI, aromatase inhibitor; PEPI, Preoperative Endocrine Prognostic Index.

Fig 2.

Distribution of biomarkers by treatment assignments and intrinsic subtypes. (A) Geometric mean percentage suppression of Ki67 from baseline by treatment arm to graphically summarize the overall treatment effect on each arm (Data Supplement). There was no significant difference in Ki67 suppression between treatment arms (Kruskal-Wallis P = .45, adjusted for three-way comparison). (B) Box plots of baseline and surgery Ki67 values in luminal A (LumA), luminal B (LumB), and human epidermal growth factor receptor 2 (HER2) –enriched breast cancer subtypes (P values listed in Table 3). (C) Box plots of baseline and surgery estrogen receptor Allred values in LumA, LumB, and HER2-enriched breast cancer subtypes (P values listed in Table 3). (D, E, F) Arrow plots showing individual paired Ki67 values in (D) LumA, (E) LumB, and (F) HER2-enriched breast cancer subtypes. Red arrows highlight patients with paradoxical increase in Ki67 values.

Fig A1.

Hierarchical clustering of Z1031 patients, with 40 subtype controls used for data normalization. Subtype assignments are marked red for basal, pink for human epidermal growth factor receptor 2 enriched, dark blue for luminal B, light blue for luminal A, and green for normal-like.