Neoadjuvant aromatase inhibitor therapy for ER+ breast cancer: The NAOMI trial.
Authors: Buteau Anne Christine , Tau Steven , Leatheng Chanbormey , Marotti Jonathan D , Miller Todd W. , Chamberlin Mary D. 
Published: June 2024

e12646

Background: Neoadjuvant Endocrine Therapy (NET) is an effective and well tolerated treatment for locally advanced ER+ breast cancer (BC) yet it is underutilized. It can induce comparable clinical response rates to chemotherapy but not pathologic complete response. There is a knowledge gap regarding its effect on residual cancer cells and fatty acid oxidation which is essential for survival of dormant ER+BC cells after estrogen withdrawal in vitro. The NAOMI trial is a study testing the effects of NET with the AI letrozole in early ER+ BC. It aimed to assess the effect of letrozole on residual cancer cells as well as markers of mitochondrial and fatty acid metabolism. Herein we present the results of the molecular and clinical analyses. Methods: NAOMI is a phase II single-arm open-label study with use of letrozole for 4 to 12 weeks prior to surgical resection. Eligible patients were women over 18 years of age, post-menopausal, with stage I-III ER+, HER2- BC. Exclusion criteria included prior ET use or other neoadjuvant options. The primary objective was to assess whether residual cancer cells exhibit upregulation of the fatty acid transporter CPT1A compared to baseline. Secondary objectives included the proportion of subjects who had clinical response and whether residual cancer cells exhibit markers of altered mitochondrial and fatty acid metabolism compared to baseline tumors. Protocol was amended to include adherence rates to adjuvant AI. Results: A total of 77 women have consented to study participation since December 2022 including 57 evaluable patients. Molecular analyses were performed on diagnostic and post-letrozole tumor specimens from the first 33 patients. Immunohistochemistry was done using antibodies against Ki67, CPT1A, FASN, perilipin, CD36, and MT-CO2. CPT1A histoscore between baseline and post letrozole specimens were similar (paired t-test p=0.2636). Markers of altered mitochondrial and fatty acid metabolism including MT-CO2, CD36, FASN, Perilipin were unchanged when comparing pre and post-AI tissues. Post hoc comparisons of changes in Ki67 (marker of biological response to letrozole) vs. changes in metabolic markers were performed. Ki67+ cells were substantially decreased during neoadjuvant letrozole therapy (paired t-test p<0.0001). Linear regression analysis of residual tumor cell proliferation [post-letrozole log2(Ki67+1)] vs. letrozole-induced change in log2(MT-CO2) showed that tumors with more residual cell proliferation had greater levels of MT-CO2 (p=0.0278). Patients enrolled in NAOMI had a rate of adherence to adjuvant ET of 82%, higher than historical averages. Conclusions: NET is associated with a decrease in Ki67+ breast cancer cells however it has minimal impact on fatty acid and mitochondrial metabolism. It is suggested to increase adherence to adjuvant ET. Additional studies are planned to elucidate mechanisms of resistance in those samples that did not show a decrease in Ki67. Clinical trial information: NCT04568616 .