United States and Canadian Academy of Pathology Annual Meeting

Filename: 451006

Author for Correspondence: Pedram Argani, M.D.
Department/Institution: Pathology and Oncology, Johns Hopkins Medical Institutions
Address: 401 N. Broadway, Weinberg Building, Room 2242
City/State/Zip/Country: Baltimore, Maryland, 21231-2410, U.S.A.
Phone: 410 614-2428
E-mail: pargani@jhmi.edu

Presenting Author: Julie M. Wu
Phone: 410 955-3980
E-mail: juliemwu@gmail.com

Abstract Categories: 3. Breast

Presentation format: Poster Only

Award: Stowell-Orbison Award, Surgical Award, and Autopsy Award

Is the first author of this abstract a pathologist-in-training? Yes


Title: HETEROGENEITY OF BREAST CANCER METASTASES: A RAPID AUTOPSY STUDY USING MATCHED PRIMARY-METASTASES TISSUE MICROARRAYS (TMAs)

JM Wu1, M Halushka1, D Molavi1, J Fetting1, NE Davidson1, AM De Marzo1, MJ Fackler1, S Sukumar1 and P Argani1.
1Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.

Background: Heterogeneity of biomarker expression among a patients primary breast carcinoma (PBC) and their metastatic breast carcinomas (MBCs), as well as among different MBCs from different sites in the same patient, has not been well studied.

Design: We performed eight rapid autopsies (post-mortem intervals, 1-4 hours) on patients who died of MBC. Paraffin tissue blocks from the patients archived PBC and multiple different MBCs were used to construct single patient TMAs. Eight TMA slides containing PBCs and in total 515 spots derived from 108 MBC sites were immunohistochemically labeled for the following: estrogen receptor (ER), progesterone receptor (PR), Her-2/neu, E-cadherin, Fascin, EGFR, C-Met, Cox-2, and Mesothelin. Methylation of the RASSF1a, HIN1, Cyclin D2, Twist, and RAR gene promoters was assessed quantitatively on dissected PBC and MBC samples.

Result: Extensive heterogeneity was observed between PBC and their paired MBC, as well as among multiple MBC from the same patient. The patterns observed are summarized into three categories: 1. Markers Downregulated Uniformly in All Metastases of a Case: ER, PR. Three cases were ER-PR- and two cases were ER+PR+ in the PBC and all MBC. However, one ER+PR+ PBC was ER-PR- in all its MBC, one ER+PR- PBC was ER-PR- in all its MBC, and one ER+PR+ PBC was ER+PR- in all its MBC. 2. Markers Consistently Expressed between Primary and Metastasis. Fascin, implicated in the lung metastasis gene expression signature of PBC (Nature 2005;436: 518-524), was overexpressed in the PBC and all MBC in 1 of 8 cases. Interestingly, this was the only case with bulky lung metastasis. Promoter hypermethylation of RASS F1A, RAR, Cyclin D2, Twist, and RAR was very similar in the PBC and all MBC in all 7 evaluable cases. 3. Markers Variably Expressed among Metastases. E-cadherin was variably downregulated in the MBC of one case; the E-cadherin positive invasive ductal PBC gave rise to both E-cadherin positive ductal MBC and E-cadherin negative MBC with lobular morphology. Variable overexpression in MBC compared to the PBC was observed for Cox-2 (5 cases), EGFR (4 cases), C-met (2 cases), and Mesothelin (1 case). No case strongly overexpressed Her-2/neu, but 3 cases showed variable expression ranging from negative to weakly positive (2+) in different MBC.

Conclusion: Therapeutic targets identified in the PBC or even some MBC may not reflect targets present in all metastatic sites.

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