Metal exposure and Ki67 response to neoadjuvant aromatase inhibitor therapy in estrogen receptor-positive (ER+) breast cancer: The NAOMI trial.

Abstract

e12632 Background: Prior studies suggest that exposure to metals, including arsenic, may be elevated in patients with breast cancer. This is particularly relevant in New Hampshire, where higher metal exposure has been attributed to widespread private well use (approximately 46% of households) and granite bedrock. Neoadjuvant endocrine therapy (NET) with the aromatase inhibitor (AI) letrozole is clinically effective in ER+ breast cancer. Through the NAOMI trial, we evaluate whether metal exposure influences clinical outcomes in ER + breast cancer treated with AI and its association with changes in Ki67, a marker of tumor proliferation. Methods: NAOMI is a phase II, single-arm, open-label trial of NET with letrozole in postmenopausal women with stage III ER+ breast cancer. The trial began in 2021 with projected completion in 2029. Participants received letrozole for 4-12 weeks prior to surgical resection. Preoperative urine samples were collected, and urinary metal concentrations were measured. Tumor tissue was obtained at baseline (diagnostic biopsy) and at surgery. Ki67 expression in the tissues were assessed by immunohistochemistry. Linear regression evaluated associations between Ki67 change and urinary metal concentrations along with BMI, tumor size, and age. Urinary metal levels in our patients were compared with NHANES 2017-2018 (US representative) and NH TRACE 2019(regional) reference data. Results: Urine samples were analyzed from 121 patients (93% White). Twenty-seven metals were measured, including speciated arsenic and its metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), as well as cadmium, tin, lead, and uranium. Mean age was 68 years, mean BMI was 31, and mean tumor size was 2 cm. Higher BMI and larger tumor size were significantly associated with greater decreases in Ki67 (BMI: t = −2.5, p = 0.01; tumor size: t = −2.3, p = 0.02). An increase of BMI by 10 led to a decrease of KI67 by 4.3, assuming that the tumor size did not change. A twofold increase in tumor size led to a 2.4 decrease in KI67. Speciated arsenic, MMA, DMA, and other metals showed no significant association with Ki67 change. Median urinary concentrations of arsenic, cadmium, tin, lead, and uranium were 6.0, 0.28, 0.44, 0.39, and 0.009 µg/L, respectively. Between 4-15% of participants exceeded NHANES 95 th percentile values, and 3-15% exceeded NH TRACE 95 th percentile reference values. Conclusions: This study identified BMI and tumor size as the primary predictors of change in Ki67, whereas urinary metal concentrations were not predictive. Urinary metal levels were comparable to national and regional reference populations. Speciated arsenic subtypes related to seafood intake were excluded. Limitations include variability in urinary metal half-lives. Future studies should incorporate blood, nail, and tissue measurements to better characterize metal exposure. Clinical trial information: NCT04568616 .