Purpose: A comprehensive comparison of biomarker expression between patients' primary breast carcinoma (PBC) and their metastatic breast carcinomas (MBC) has not been done. Experimental Design: We did rapid autopsies (postmortem intervals,1-4 hours) on10 consenting patients who died of MBC.We constructed single-patient tissue microarrays from the patients' archived PBC and multiple different MBCs harvested at autopsy, which were immunohistochemically labeled for multiple biomarkers. Methylation of multiple gene promoters was assessed quantitatively on dissected PBC and MBC samples. Results: Extensive heterogeneity was observed between PBC and their paired MBC, as well as among multiple MBC from the same patient. Estrogen and progesterone receptors tended to be uniformly down-regulated in metastases. E-cadherin was down-regulated in a subset of the MBC of one case.Variable overexpression in MBC compared with the PBC was observed for cyclooxygenase-2 (five cases), epidermal growth factor receptor (EGFR; four cases), MET (four cases), and mesothelin (four cases). No case strongly overexpressed HER-2/neu by immunohistochemistry, but eight cases showed variable protein expression ranging from negative to equivocal (2+) in different MBC. In one case, variable low-level HER-2/neu gene amplification was found. EGFR and METoverexpression were restricted to the four basal-type cancers. EGFR protein overexpression did not correlate with EGFR gene amplification. Multigene promoter hypermethylation of RASSF1a, HIN1, cyclin D2,Twist, estrogen receptor a, APC1, and RARb was overall very similar in the PBC and all MBCs in all cases. Conclusions: Therapeutic targets identified in the PBC or even some MBC may not reflect targets present in all metastatic sites.

We obtained 22 sessile serrated adenomas (SSAs) and 19 hyperplastic polyps (HPs) and performed immunolabeling for cytokeratins (CKs) 7 and 20, CDX2, beta-catenin, and p53 to determine the role of these markers in aiding distinction of lesions with neoplastic potential. Patients with SSAs more frequently had a prior or coexistent tubular adenoma (P = .004) that was right-sided (P = .00001) and larger (P = .03). No difference in CK7, CK20, or p53 labeling was found after correction for colonic location. However, CDX2 labeling was significantly lower in SSAs (P = .02) and was predominantly confined to the crypt bases, whereas it was diffusely positive in HPs (P < .001). Surprisingly, aberrant nuclear labeling for beta-catenin was found in 9 (41%) of the SSAs but in none of the HPs (P < .002). We propose that beta-catenin and/or CDX2 immunolabeling may have diagnostic usefulness in the evaluation of serrated polyps. These findings also suggest that Wnt signaling has a role in SSA development.

The BRAF mutation is uniformly distributed in various types of nevi. Its presence in congenital and anogenital nevi points to mechanisms of induction other than sun exposure. Its ubiquitous presence suggests that it poses no significant threat of malignant transformation, raising doubts about its relevance in melanoma development and its suitability as a target of directed therapy in patients with melanoma.

We report a case of a patient with invasive breast carcinoma which demonstrated HER-2 gene amplification on core biopsy, who relapsed while on adjuvant Trastuzumab therapy following her mastectomy and ultimately died 15 months after diagnosis. Surprisingly, analysis of multiple metastases harvested at rapid autopsy demonstrated no evidence of HER-2 gene amplification. Retrospective examination of the carcinoma in the patient’s mastectomy specimen revealed only focal HER-2 amplification within the tumor, localized to the region of the prior core biopsy site. This case highlights several important issues in HER-2 testing of breast cancer, including core biopsy-excision specimen discordance, primary-metastasis discordance, and potential selection for unamplified portions of a heterogeneously-amplified tumors by Trastuzumab.

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