Abstract P5-05-03: Adipocyte associated methionine domain containing (AAMDC): A nuclear envelope protein with predictive and prognostic potential in luminal breast cancer
Authors: Weerasena Indunil , Spalding Lisa , Dessauvagie Benjamin F , Golden Emily , Woodward Eleanor , Blancafort Pilar , Redfern Andrew 
Published: March 2022

Abstract
Background Estrogen receptor (ER) positive breast cancers (BCs) are less likely to relapse than other types, due to a lower propensity to disseminate and to sensitivity to anti-estrogen drugs in the adjuvant setting. However, combined analysis of DNA mutation and mRNA expression profiles in BC identifies a number of Integrative Clusters (IntClus), one of which, IntClus2, is characterized by ER positivity but high relpase and mortality. A hallmark of IntClus2 tumours is an amplification of chromosome 11, at the center of which lies the gene for the protein AAMDC. Pre-clinical research shows this protein to drive proliferation, migration, colony formation, switching between glucose and lipid metabolism, folate metabolism and anti-estrogen resistance. We postulated that resultant clinical behaviours could include; high relapse and mortality, anti-estrogen resistance, an interaction with the protective effect on relapse from statins and sensitivity to fluorouracil (FU)-based therapies. Methods The retrospective study cohort comprised 1766 ER positive early BC patients treated 1994-2014. Patient and tumour demographic, statin prescription and treatment data were collated. Primary tumour tissue was available with AAMDC expression data on 419 patients. On noting nuclear (N), cytoplasmic (C) and nuclear envelope (NE) expression, separate intensity scores were attributed to each localization. Intensity score cut-points were based on providing statistically useable sub-group sizes for comparison. Results No significant correlations between BC biology and patterns of AAMDC expression were seen. Cytoplasmic AAMDC weakly linked to some aggressive features, including high grade, luminal B sub-type and progesterone receptor negativity, although less lymph node spread. In contrast, nuclear AAMDC associated with some less aggressive features, being less in high grade and luminal B cancers. Nuclear envelope AAMDC was rarer in the HER2 positive sub-type without other correlates. A trend to higher distant relapse was seen for NE +ive BCs (20 v 14%, p=0.09). Overall mortality was statistically higher for NE expression (54 v 44% mortality, p=0.04) and cytoplasmic expression (56 v 47% mortality, p=0.04) and a trend to lower mortality for nuclear expression (46 v 54%, p=0.06). Looking at combinatorial expression, BC deaths were significantly lower in the nuclear +ive/NE -ive phenotype (4.7%) than the nuclear -ive/NE -ive (19.5%, p=0.013), nuclear -ive/NE +ive (17.6%, p=0.017) or nuclear +ive/NE +ive phenotypes (19.3%, p=0.011).Considering the effects of statins on early BC outcome, overall our patients on statins had notably lower BC return rates (HR 0.31, p=0.004). Considering interactions with AAMDC, in high-risk NE +ive cancers statin protection was high (HR for relapse 0.33, p=0.032), compared to no protection in already low risk NE -ive tumours (HR 0.90, p=0.41). The hypothesis that AAMDC confers sensitivity to FU-based agents was confirmed with a correlation observed for longer responses to FU-based chemotherapy for increasing NE AAMDC expression (R=0.334), whereas no link was seen for other agents or other AAMDC expression sub-locations. The mean times on FU-based therapy for low, moderate and high NE expression were 2.0, 5.7 and 12.2 months respectively (p=0.02). This work indicates that AAMDC expression can BC affect outcome, identifying nuclear envelope located AAMDC as both associating with higher mortality and correlating with superior protection from statins as well as response to FU-based chemotherapies. This could guide metastatic chemotherapy selection for affected patients, implies NE positive BCs might preferentially benefit from adjuvant statins and suggests that AAMDC and NE-associated AAMDC partners may be future therapeutic targets.
Citation Format: Indunil Weerasena, Lisa Spalding, Benjamin F Dessauvagie, Emily Golden, Eleanor Woodward, Pilar Blancafort, Andrew Redfern. Adipocyte associated methionine domain containing (AAMDC): A nuclear envelope protein with predictive and prognostic potential in luminal breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-05-03.