Abstract PO4-04-09: Incidence, prevalence, risk factors, and impact of fatty liver disease in metastatic HR+/HER2− breast cancer patients treated with Endocrine Therapy and CDK 4/6 Inhibitor
Authors: Gimenez Diego Malon , Valiente Consolacion Molto , Prasla Shopnil , Cuthbert Danielle , Mittal Abhenil , Tamimi Faris , Iorio Massimo Di , Li Meredith , Pathak Neha , Amir Eitan , Jhaveri Kartik , Nadler Michelle 
Published: May 2024

Abstract
Background: In patients with early-stage breast cancer (BC), non-alcoholic fatty liver disease (NAFLD) is associated with increased recurrence, cardiovascular events, and non-cancer death. Endocrine therapy increases the risk of NAFLD. The impact of cyclin-dependent kinases 4/6 inhibitors (CDKi) combined with endocrine therapy on NAFLD and prognostic association in metastatic breast canceris unknown. Here, we characterize the incidence, prevalence, risk factors, and treatment outcomes of NAFLD in women with metastatic HR+/HER2- BC.
Methods: We conducted a retrospective cohort study of patients with advanced HR+/HER2- BC receiving first line endocrine and CDKi at Princess Margaret Cancer Centre, Toronto, Canada between January 2018 – June 2022. Patients were excluded if they had liver disease, prior chemotherapy, or no access to CT scans. Demographic, treatment, toxicity, and survival data were extracted. Liver Attenuation Index (LAI) on contrast-enhanced portal venous phase CT scan was utilized.NAFLD was defined as LAI &gt;25 HU. Univariable binary-logistic regression analysis wasused to assess independent predictive factors of NAFLD. Statistical significance was defined as p&lt; 0.05. Quantitative significance was defined by the Burnand criteria. Time to treatment failure (TTF) was assessed using Cox proportional hazards modeling.
Results: Of approximately 90 eligible patients, 40 are included in this analysis. Baseline demographics included median age 61 years, 72% post-menopausal, 58% de-novo metastatic disease, and 27% visceral disease. Of 40 patients, 28 (70%) had NAFLD at anytime (12 at baseline and 16 incident). Associations with NAFLD are shown in Table 1. Presence of NAFLD was associated quantitatively but not statistically with age &gt; 65 (OR 2.6), post-menopausal status (OR 2.6), and inversely associated with prior chemotherapy (OR 0.27) and visceral disease (OR 0.38). Lack of NAFLD at any time was significantly associated with worse TTF (mean TTF 497 versus 1228 days, HR=4.28, 95% CI: 1.89-9.68, p&lt; 0.001). Patients without NAFLD at baseline also had a worse TTF (mean 903 vs 1186 days) compared to those with it at baseline, but this difference was not statistically significance (HR=1.93, 95%CI: 0.77-4.83, p= 0.163). No significant differences were found in grade 3/4 adverse events. Patients who have presented NAFLD at any time received an average of 1.36 subsequent lines of therapy compared to 2.08 in those without.
Discussion & Conclusion: This analysis demonstrated an association between presence of NAFLD and longer TTF. This may reflect reverse causation whereby longer exposure to ET and CDKi increases the observation of NAFLD or that these are distinct populations with different molecular pathways leading to differences in response to treatment and prognosis. It is noteworthy that the median time to develop NAFLD in the incident group was 339 days, and the group that never developed NAFLD was on treatment longer than this. Overexpression of CDK 4/6 pathway, could increase sensitivity and duration to treatment with CDKi but produce adverse metabolic changes of increased lipid synthesis, as described in pre-clinical models. If this hypothesis is confirmed, synergistically addressing these metabolic changes with physical exercise, dietary, or pharmacological interventions may improve these patients’ fitness for subsequent lines of therapy.
Table 1
Citation Format: Diego Malon Gimenez, Consolacion Molto Valiente, Shopnil Prasla, Danielle Cuthbert, Abhenil Mittal, Faris Tamimi, Massimo Di Iorio, Meredith Li, Neha Pathak, Eitan Amir, Kartik Jhaveri, Michelle Nadler. Incidence, prevalence, risk factors, and impact of fatty liver disease in metastatic HR+/HER2− breast cancer patients treated with Endocrine Therapy and CDK 4/6 Inhibitor [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-09.