Abstract PD07-01: Z1031B Neoadjuvant Aromatase Inhibitor Trial: A Phase 2 study of Triage to Chemotherapy Based on 2 to 4 week Ki67 level &gt; 10%.
Authors: Ellis MJ , Suman V , McCall L , Luo R , Hoog J , Brink A , Watson M , Ma C , Unzeitig G , Pluard T , Whitworth P , Babiera G , Guenther M , Dayao Z , Leitch M , Ota D , Olson J , Hunt K , Allred C 
Published: August 2014

Abstract
Background: Neoadjuvant aromatase inhibitor (AI) therapy would become a more acceptable alternative to chemotherapy if there was a way to identify AI-resistant cases early for triage to alternate systemic treatment. We therefore conducted a Phase 2 trial of post-menopausal patients with clinical stage 2 or 3 ER+ (Allred Score 6 to 8) breast cancer who were re-biopsied 2 to 4 weeks after initiating neoadjuvant AI therapy. If the tumor Ki67 level was &gt; 10% (AI resistant) the patient was triaged to either chemotherapy or immediate surgery and if &lt; 10% (AI sensitive) the patient completed 16 to 18 weeks of neoadjuvant AI treatment. Co-primary endpoints were: 1) to confirm that the pathological complete response (pCR) rate to standard NCCN chemotherapy in the AI resistant population is in the range of 20% (similar to ER− disease). This required the observation of least 4/35 pCRs; 2) whether patients were willing to accept a recommendation of no chemotherapy when the preoperative endocrine prognostic index score was zero (PEPI-0) (pStage 1 or 2A, Ki67&lt;2.7% and ER+) since, according to the PEPI model, these patients have such a low relapse risk that chemotherapy is unlikely to be of value (Ellis, M JNCI 100:1380–8, 2008). Feasible was defined as &lt;10% PEPI-0 cases receiving adjuvant chemotherapy. Secondary endpoints included a determination of the distribution of intrinsic subtypes in the AI sensitive and resistant groups (using a research use only assay).
Results: 51 patients (21%) had 2 to 4 week Ki67&gt;10%, of these 36 received chemotherapy per protocol (27) anthracycline (A) and taxane (T)-based, 7 T-based, 1 A-only based and 1 other (non-NCCN) regimen but only 2 patients had a pCR (5.5%). 194 patients (79%) had a Ki67 &lt;10%, of these 176 had PEPI score information. 65 had a PEPI-0 (37%), of which 61 (94%) reported a treatment plan that did not include adjuvant chemotherapy. The AI resistant group had a significantly higher frequency of baseline high-risk intrinsic subtypes (LumB: 26, HER2-E: 2 versus LumA: 7) at baseline than the AI sensitive group (LumB: 40, HER2-E: 0 versus LumA: 66) Fishers exact test p = 7.16E−6. Additional molecular data will be presented at the meeting.
Conclusion. A Ki67 value &gt;10% at 2 to 4 weeks strongly enriches for high-risk molecular subtypes (mainly LumB) however standard neoadjuvant chemotherapy did not meet pre-assigned criteria for adequate Phase 2 activity in this group. Novel neoadjuvant approaches for AI resistant-disease defined by high on treatment Ki67 are therefore a high priority. Management of patients with excellent response to neoadjuvant endocrine therapy (PEPI-0) without adjuvant chemotherapy is feasible. The ALTERNATE trial will enroll over 2000 patients to establish a new standard of care for neoadjuvant treatment of ER+ HER2− disease based on these principles.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-01.