Abstract P6-03-12: Comprehensive genomic profiling of clinically advanced mucinous carcinoma of the breast
Authors: K Wang, SM Ali, D Khaira, JA Elvin, J-A Vergilio, J Suh, R Yelensky, D Lipson, J Chmielecki, VA Miller, PJ Stephens, JS Ross
Journal: Cancer Research (2016)

Abstract Background: Mucinous carcinoma of the breast (mucBC) is generally associated with a favorable prognosis, but on occasion, may have an aggressive clinical course in which it is commonly refractory to cytotoxic chemotherapy. The low incidence of mucBC (∼2% of breast cancers) precludes the development of consensus based guidelines for management of these relapsed/refractory cases. We performed hybrid-capture based comprehensive genomic profiling (CGP) to identify potential therapy targets not routinely searched for in clinical management of metastatic mucBC. Methods: DNA was extracted from 40 microns of FFPE sections from 22 cases of stage IV mucBC. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of &amp;gt;550X. The results were analyzed for all classes of genomic alterations (GA) including base substitutions, insertions and deletions, select rearrangements, and copy number changes. Clinically relevant genomic alterations (CRGA) were defined as those identifying anti-cancer drugs on the market or in registered clinical trials. Results: The median age of the 22 mucBC patients was 57 years (range 32 to 79 years). Samples were from breast (11), lymph nodes (3), chest wall (2), liver (2), soft tissue (2), bone (1) and pleura (1). Three mucBC were grade 1, 17 were grade 2 and 2 were grade 3. Twenty-one (95%) mucBC were ER+, 19 (86%) were PR+ and 4 (18%) were HER2+ by IHC and/or FISH. There were 129 GA identified on the 22 mucBC (5.9 per tumor) including 51 CRGA with a mean of 2.3 per tumor. Amplifications of FGFR1 and ZNF703 were found in 8 out of 22 cases (36%) on the same amplicon. Other most frequently altered genes were TP53 (32%), CCND1 and FGF3/4/19 often co-amplified together (27%). ERBB2/HER2 alterations were found on 5 cases (23%) including amplifications on all 4 HER2+ cases by IHC and/or FISH, and ERBB2 substitution D769Y on one additional mucBC. CRGA were found on some other 20 genes included PIK3CA (5), BRCA1 (1), TSC2 (1), STK11 (1), AKT3 (1), and ESR1 (1). Conclusions: The subset of relapsed/refractory mucBC presents a management challenge, but comprehensive genomic profiling offers avenues for benefit from targeted therapy. MucBC relative to breast cancer is predominantly ER+, enriched for FGFR1 amplification, 36% vs 11% from TCGA ER+ breast cancer (N=601) with Fisher's test p-value &amp;lt;0.005. Moreover, metastatic mucBC appears more often to have ERBB2/HER2 alterations (23%) than typical mucBC cured by local treatments. Comprehensive genomic profiling uncovers a variety of genomic targets in metastatic mucBC that could facilitate the introduction of targeted therapies for patients with this challenging disease. Citation Format: Wang K, Ali SM, Khaira D, Elvin JA, Vergilio J-A, Suh J, Yelensky R, Lipson D, Chmielecki J, Miller VA, Stephens PJ, Ross JS. Comprehensive genomic profiling of clinically advanced mucinous carcinoma of the breast. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-12.