Hunt, Kelly K.

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.

Abstract Background: The Preoperative Endocrine Prognostic Index (PEPI) scores the independent prognostic effects of tumor pathologic staging and expression levels of ER and the “proliferation” marker Ki67 in the surgical sample to predict long term outcomes after completion of neoadjuvant endocrine treatment (Ellis et al JNCI 100:1380, 2008). A limitation of the PEPI is that the prognostic information becomes available only after 4 months of treatment. We therefore evaluated the value of an early assessment of the Ki67 level in a tumor biopsy sample taken two to four weeks after initiating treatment in two neoadjuvant endocrine therapy trials for the purposes of the early identification of non- respondersMethods: A Ki67 cut point of greater than 10% for poor outcome in ER+ breast cancer was derived by comparing the PAM50 intrinsic subtype profile using a qRT-PCR assay with Ki67 data in a 700+ sample data set. A baseline level of 10% or less correlated most closely with a PAM50-based definition of LumA breast cancer and above 10% LumB breast cancer. We subsequently applied the 10% cut point to the baseline and early on-treatment Ki67 data in two trials, POL (Olson et al JACS 208:906, 2009) and IMPACT (Smith et al JCO: 23, 5108, 2005).Results: At baseline the dichotomized Ki67 definition was not significantly predictive for surgical Ki67 level, PEPI score or RFS in this modest size sample set. In contrast, in a result that emphasizes the enhaced prognostic properties of the on-treatment Ki67 approach, the one month POL sample Ki67 values (62 patients) predicted a higher level of Ki67 in the surgical samples at four months after treatment initiation (P=.01), a poorer PEPI score (P=0.01), a smaller number of patients in the PEPI risk point zero group (P=0.08) and worse relapse free survival (P=0.003). The IMPACT data (153 patients) confirmed that a two week Ki67 >10% predicted higher Ki67 in the surgical specimen (P=0.001), a poorer PEPI score (P=0.001), smaller numbers of patients in the PEPI 0 risk point group (P= 0.004) and worse relapse free survival (P=0.008).Ki67 and OutcomePOL 4W Ki67% PEPI 0RFS (events)10%>1/19 (5%)5/21 (23%)10%≤10/36 (28%)1/41 (2.4%)P ValueP=0.08 (Fisher)P=0.003 (log rank)IMPACT 2W Ki67% PEPI 0RFS (events)10%>0/32 (0%)9/35 (26%)10%≤21/101 (21%)13/118 (11%)P ValueP=0.004 (Fisher)P=0.008 (log rank) Conclusions: A tumor Ki67 assessment taken a short time (2 to 4 week window) after the initiation of neoadjuvant AI identifies patients with poor outcome ER+ disease. Amendment 6 of the neoadjuvant endocrine therapy protocol ACOSOG Z1031 will triage patients with an “on treatment” Ki67 value above 10% to chemotherapy in order to assess the pathological response rate to cytotoxic therapy in this important tumor subset.Supported by R01 CA095614, Avon PFP award 3P50 CA68438-07S2, U01 CA114722, ACOSOG U10 CA 76001, Breakthrough Cancer UK and AstraZenica (IMPACT trial). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 78.