Background: Androgen receptor (AR) expression has emerged as a potential prognostic and predictive marker in patients with triple negative breast cancer (TNBC). We conducted a retrospective analysis to evaluate pathologic complete response (pCR) rates, disease-free survival (DFS) and overall survival (OS) in patients with AR positive and AR negative TNBC treated with neoadjuvant chemotherapy. Methods: 107 patients with TNBC subtype, treated with neoadjuvant chemotherapy between June 2006 and March 2016 were evaluated for AR expression. Androgen receptors were evaluated by immunohistochemical staining (clone AR441, Dilution 1:50, Dako-Agilent, Santa Clara, CA) using whole tissue sections from archived paraffin-embedded formalin-fixed (FFPE) blocks. AR positive was defined as ≥10% nuclear stained cells. Correlation of AR expression was examined with age, BMI, race, menopausal status, tumor grade, tumor size, and lymph node involvement, and response and outcomes. Univariate and multivariate analyses were performed to determine an association with AR expression and pathologic response and survival outcomes. Results: Fifty-eight patients with available tumor specimens were stained, with twenty (34.5%) being AR-positive and thirty-eight (65.5%) being AR negative. Median age was 49 years and median follow up was 5.7 years. All patients received anthracycline based neoadjuvant chemotherapy with 13 patients (23%) receiving an additional platinum chemotherapy. BRCA mutation positivity was 7% for the entire group. No differences in age, menopausal status, BMI, race, tumor size and lymph node involvement were observed between the two groups. However, there was a statistically significant difference in tumor grade between the two groups (p=0.008). Overall pCR rate was 28% with no difference between the two groups (30% vs 26%, p=0.56). There was no statistically significant difference in median DFS (5.9 years vs 5.2 years ( p =0.94) and median OS (6.2 years vs 5.4 years, p =0.98) between the AR positive and AR negative groups. Conclusions: Our study did not find an association of AR status and the pathologic responses or survival outcomes in patients with TNBC treated with neoadjuvant chemotherapy. Further studies exploring the prognostic and predictive role of AR in patients with TNBC are warranted.
Rationale: Obesity induces resistance to Omega-3 (ω-3) FA anticarcinogenesis effect. Obesity associated excessive fatty acid intracellular concentration results in excess triglycerides stored as intracellular lipid droplets, saturated acyl-co-A transport of FA to triglycerides resulting in excess substrate for cyclooxygenase metabolism with increased formation of PGE2 and other inflammatory eicosanoids. Methods: Five weeks old male F344 rats were randomized equally into two diet groups. One cohort fed a western diet of ω-6 fatty acids (EPA:ω6 ratio of 0) and other fed an ω-3 fatty acid supplemented diet (EPA:ω6 ratio of 0.4). One half from each diet group were further treated with azoxymethane/dextran sulfate sodium (AOM/DSS) and then euthanized at 21 weeks after the carcinogen induction. Snap frozen colon tissue were assayed for Prostaglandins and fatty acids. OCT fixed colonic tissue stained with oil red O (ORO) to detect lipid droplets which were quantified using Aperio image analysis. From the second set, rat colons were opened longitudinally and fixed in 10% Formalin. Tumors were identified and enumerated using stereomicroscope to get tumor count, incidence and volume. These tissue were subjected to hematoxylin & eosin staining for histological evaluation of colonic tumors. Results: The ω-3 FA diet significantly increased the percent of eicosapentaenoic acid (EPA) in total fatty acids in both untreated and AOM/DSS-treated rats. EPA in the colonic tissue was increased with ω-3 diet as compared to ω-6 from 1.4±0.8 to 2.6±1.0* in untreated rats and from 1.3±1.3 to 3.3±1.7* in AOM/DSS-treated rats (*p<0.005). PGE2 increased with AOM/DSS treatment. The ω-3 diet decreased PGE2 in colonic mucosa of untreated rats from 132±64 in ω-6 to 78±17 in ω-3 and 150±74 in ω-6 to 92±43 in ω-3 with AOM/DSS treatment. Most tumors were found in the distal colon (DC) with ω-3 diet significantly reducing the number of tumors (p value=0.0011). The ω-3 diet significantly reduced colonic adenoma volume and multiplicity. When tumors were stratified by size and location, there was a significant effect of diet in the DC, with ω-3 diet reducing the number of tumors in the 1-3mm range (p value=0.0018), 3-5mm (p value=0.0041) and >5mm (p value=0.0055). ω-3 also reduced the number of 3-5mm size tumors in the cecum (p value=0.0377). On preliminary quantification of lipid droplets, there was a reduction in the positive pixels divided by the total pixels of ORO stained colonic tissue of ω-3 rats (0.004 ±0.01 as compared to 0.013±0.07 in ω-6 rats; p value=0.0121) Conclusions: Dietary ω-3 supplementation that increases the EPA:AA ratio in colonic tissue phospholipids reduces excess intracellular FA concentrations reflected by a reduction in size and number of lipid droplets. Lipid droplet number and size may be useful as a biomarker for effective reduction of obesity associated inflammation and carcinogenesis risk. Citation Format: Muhammad N. Aslam, Nithya Sridhar, Maheen Nadeem, Becky R. Simon, Jianwei Ren, Ananda Sen, James Varani, William L. Smith, Zora Djuric, Dean E. Brenner. Intracellular lipid droplet quantity as a biomarker for obesity associated resistance to omega-3 fatty acid colon cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5256. doi:10.1158/1538-7445.AM2017-5256
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