Abstract Introduction Male breast cancer (MBC) is rare, comprising ∼1% of all breast cancers. While clinically characterized as being similar to postmenopausal ER+ BC, MBC has been much less characterized molecularly than female BC. Methods 60 male (ages 37-84) and 5000 female (ages 27-98) breast cancer samples were evaluated for common gene mutations (Sanger or Illumina TruSeq), protein expression (immunohistochemistry), microarray, and/or amplification/rearrangement (CISH or FISH). The samples were analyzed for patterns within the MBC cohort and similarities/differences compared to the female (FBC) subtypes (TNBC, non-TNBC, HER2+, and ER+) evaluated at Caris Life Sciences. Results Within the MBC cohort, approximately 23% were negative for ER, PR, and HER2 (TNBC); of those 18% were also negative for AR; 72% were ER+; 51% were both ER+ and PR+. The incidence of high ER and PR protein expression was greater (72% vs. 56%, 54% vs. 40%) but incidence of HER2 overexpression (IHC, 3+) and amplification (FISH, HER2/CEP17 ratio higher than 2) was lower (8.8% vs. 11%, 5% vs. 14.9%) when compared to FBC overall. The rate of EGFR amplification (measured as ≥ 4 copies in 40% or more tumor cells by FISH) was not different from FBC (15%), while the percentage of MBC pts with AR protein expression (70%) was most similar to ER, PR positive FBC patients. Other biomarkers: the rate of ERCC1 overexpression was lower in MBC when compared to FBC (36% vs. 49), the rate of PTEN loss was lower (36% vs. 61%), and the rates of MGMT, TLE3, and RRM1 overexpression were higher (73% vs. 64%, 70% vs. 53%, and 47% vs. 30%, respectively). In the 14 MBC cases evaluated by NGS, no PTEN gene mutations were identified, although PIK3CA gene mutations were seen at a similar rate (41%) as in the >50yo ER+ FBC (37%), and TP53 gene mutations (21%) were seen slightly less frequently than in the >50yo ER+ FBC (27%). Comparison of the TN MBC to the ER+ MBC cohort identified differences in the mTOR pathway (PTEN loss of 13% vs. 28% and PIK3CA mutation rate of 13% vs. 50%, respectively), in P53 mutation rates (33% vs. 0%), and in AR protein expression (33% vs. 82% overexpression), TLE3 (14% vs. 83% overexpression), and ERCC1 (100% vs. 77% low). Conclusions The gene mutation, amplification, and protein expression profiles in MBC patients, including HER2 protein expression/amplification, AR and TLE3 protein expression and PIK3CA gene mutation, may inform standard and investigational therapeutic options for this rare cancer population. Citation Format: Sherri Z Millis, Joanne Xiu, Zoran Gatalica, Joyce O'Shaughnessy. Multiplatform molecular profiling of BC reveals significant differences in actionable targets from matched female breast carcinomas [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-17.