Hormone Receptor and c-ERBB2 Status in Distant Metastatic and Locally Recurrent Breast Cancer: Pathologic Correlations and Clinical Significance

Anatomic Pathology / Receptor Status in Recurrent Breast Cancer Hormone Receptor and c-ERBB2 Status in Distant Metastatic and Locally Recurrent Breast Cancer Pathologic Correlations and Clinical Significance Pushpalatha K.A. Idirisinghe, MBBS,1* Aye Aye Thike, MMedSc,1* Poh Yian Cheok, BSc,1 Gary Man-Kit Tse, FRCPC,2 Philip Chi-Wai Lui, FRCPA,2 Stephanie Fook-Chong, MSc,3 Nan Soon Wong, MRCP (UK),4 and Puay Hoon Tan, FRCPA1 Key Words: Breast cancer; Discordance; Hormone receptors; c-ERBB2; Metastases; Local recurrence DOI: 10.1309/AJCPJ57FLLJRXKPV Abstract Estrogen receptor (ER), progesterone receptor (PR), and c-ERBB2 (HER2/neu) are therapeutically and prognostically important markers in the management of breast carcinoma. They are not always analyzed in distant metastatic and locally recurrent breast cancers. We compared immunohistochemical expression in a series of primary breast carcinomas with their distant metastases (n = 72) and local recurrences (n = 45) and analyzed the impact of any changes on survival. Discordance rates between primary and metastatic and between primary and locally recurrent lesions, respectively, were 18% (13/72) and 13% (6/45) for ER, 42% (30/72) and 33% (15/45) for PR, and 7% (5/72) and 2% (1/45) for c-ERBB2. There was statistically significant discordance between primary and metastatic PR status (P = .017; κ = 0.201). Among locally recurrent tumors, 15 (33%) of 45 revealed discordance for PR (P = .006; κ = 0.366). We observed a trend for shorter survival among women with ER– metastatic and locally recurrent tumors regardless of the primary tumor ER status. Our findings suggest a benefit for routine evaluation of ER, PR, and c-ERBB2 status in distant metastatic and locally recurrent breast cancer for therapeutic and prognostic purposes. 416 Am J Clin Pathol 2010;133:416-429 Downloaded 416 from https://academic.oup.com/ajcp/article-abstract/133/3/416/1766073 DOI: 10.1309/AJCPJ57FLLJRXKPV by guest on 29 April 2018 Estrogen receptor (ER), progesterone receptor (PR), and c-ERBB2 (HER2/neu) are therapeutically and prognostically important markers in the management of breast carcinoma. About 60% to 70% of breast carcinomas express ER protein, and these tumors are associated with better prognosis.1 Detecting ER expression in a tumor depends on physiologic and technical factors, including menopausal status, endocrine therapy, tumor sampling and intratumoral heterogeneity, tissue fixation, method of examination (biochemical, immunohistochemical), and type of antibody used.2-4 ER status is important in predicting the response to adjuvant tamoxifen (hormonal) therapy. Desombre and Jensen5 demonstrated a decrease in the ER content as a tumor progresses. PR is a surrogate marker of functional ER because PR is an estrogen-regulated gene. More than half of ER+ tumors express PR. Hence, simultaneous analysis of ER and PR gives more information regarding likely hormonal response.6 Some studies have reported the presence of PR as a better predictive marker of response to hormone therapy than quantitative ER.7,8 Of breast carcinomas, 55% express both ER and PR, whereas 22% do not express either ER or PR. In addition, 20% of tumors are ER+ and PR–, and 3% are ER– and PR+.8,9 Humanized epidermal growth factor receptor 2 (c-ERBB2) is a proto-oncogene, located on chromosome 17, encoding a 185-kDa transmembrane tyrosine kinase receptor for an unknown growth factor. The c-ERBB2 oncogene is altered by gene amplification, causing protein overexpression in a wide variety of human epithelial malignancies. Such alterations activate signaling systems that promote cell growth, angiogenesis, and cancer metastases.10-13 The © American Society for Clinical Pathology Anatomic Pathology / Original Article oncogene c-ERBB2 is amplified and/or overexpressed in approximately 25% of breast cancers and is associated with aggressive disease as shown by an association with shorter disease-free survival (DFS) and overall survival (OS) of women,14 although more recent studies have indicated a lower rate of c-ERBB2 overexpression, about 18%.15 Carcinomas that overexpress c-ERBB2 respond to treatment with humanized anti–c-ERBB2 monoclonal antibody (trastuzumab) and are associated with resistance to hormonal therapy.16 Binding of trastuzumab to c-ERBB2 blocks growth stimulating intracellular signaling and decreases the cellular repair capacity after chemotherapy, possibly also improving apoptosis.16 Administration of trastuzumab with chemotherapeutic agents has been shown to produce longer DFS and OS, with 25% to 50% of c-ERBB2+ patients with metastatic breast cancer responding favorably to trastuzumab. Treatment failure could be a result of heterogeneity in expression of c-ERBB2 in the primary tumor and its metastases.16 Several studies have investigated expression of hormonal receptors of primary breast carcinomas and their metastases, mainly comparing ER and PR status of the primary tumor with regional nodal metastases. Some authors have lumped local recurrences and distant metastases together as 1 group. Distant metastases, however, may not be biologically equivalent to local recurrences or regional axillary lymph node metastases, potentially behaving as clonal outgrowths with genetic modifications that may not be detectable in the primary tumors.2 Data referring to distant metastases are scant, with studies comparing primary and distant metastases using small numbers of patients. Studies specifically relating receptor status of primary tumors with local recurrences are also few. Mobbs et al17 demonstrated 19% discordance of ER and 33% discordance of PR between primary and secondary tumors with no intervening treatment. With intervening chemotherapy and/or irradiation, overall discordance in hormone receptor status was 24%.17 Hormone receptor status between primary and secondary tumors may be altered whether the secondary tumor is locally recurrent or metastatic. Studies using immunohistochemistry,18-21 fluorescence in situ hybridization (FISH), or both22-25 have reported a high level of consistency, although not absolute, in c-ERBB2 status in primary tumors, locoregional recurrences, and distant metastases. Santinelli et al18 reported 13.3% discordance of c-ERBB2 in local recurrences compared with the primary tumor. In this study, we compared ER, PR, and c-ERBB2 status in series of primary breast carcinomas with their local recurrences and distant metastases. In addition, we analyzed the impact of changes of hormonal and c-ERBB2 status on survival. Materials and Methods Files of the Department of Pathology, Singapore General Hospital, Singapore, were searched for cases of primary breast carcinoma with subsequent histologically proven local recurrences and distant metastases during the period from 1991 to 2007. The study cohort included 72 distant metastatic and 45 locally recurrent lesions. Local recurrence was defined as tumor recurring in the ipsilateral breast in pati (...truncated)