Elsevier

Human Pathology

Volume 39, Issue 12, December 2008, Pages 1809-1815
Human Pathology

Original contribution
Bone metastasis is strongly associated with estrogen receptor–positive/progesterone receptor–negative breast carcinomas

https://doi.org/10.1016/j.humpath.2008.05.010Get rights and content

Summary

Bone is one of the most common sites of distant metastasis for breast carcinomas. In this study, our objective is to identify molecular markers and molecular subtypes that may predict patients at higher risk of developing bone metastasis. Immunohistochemical analysis with antibodies against estrogen receptor α, progesterone receptor, androgen receptor, Her2/neu, epidermal growth factor receptor, CK5/6, CK14, CK17, CK8, and CK18 was performed on representative sections of 21 breast carcinomas with bone metastasis and 94 cases without bone metastasis. The expression rates of receptors, subtype distributions (basal versus nonbasal) of 3 molecular classifications (cytokeratin, triple negative, and cytokeratin/triple negative), and 5 subtypes of cytokeratin/triple negative classification were compared between these 2 groups. We found that (1) the breast cancers with bone metastasis were associated with a significant percentage of estrogen receptor–positive/progesterone receptor–negative tumors compared with tumors without bone metastasis (38% versus 6%, P < .0001). (2) There was significant difference on estrogen receptor expression between high grade and non–high grade in tumors with or without bone metastasis (P = .0084 and 1.0000, respectively). (3) The breast cancers with bone metastasis were more likely to be estrogen receptor positive (85%) and androgen receptor positive (95%) compared with those without bone metastasis (59% and 74%, respectively, both P < .05). (4) There was no significant difference between tumors with or without bone metastasis in subtype distribution (basal versus nonbasal) among all 3 molecular classifications. (5) Luminal B carcinomas of cytokeratin/triple negative classification tended to be associated with bone metastasis but not to a statistically significant extent. In conclusion, bone metastasis is strongly associated with estrogen receptor–positive/progesterone receptor–negative tumors. Significant difference in estrogen receptor expression between high-grade and non–high-grade tumors with bone metastasis suggests that different panels of molecular markers should be used to predict bone metastasis in these 2 groups of tumors.

Introduction

Breast carcinoma is the most common malignancy in women. At least 80% of patients who develop metastatic breast cancer will, at some point during their disease, develop bone metastasis [1]. Bone represents the first site of metastasis in more than 50% of patients who fail systemically [2]. The complications associated with bone metastases—such as intractable bone pain, decreased mobility, neurologic compromise, and pathologic fractures—have significant impacts on affected patients [3]. Studies have suggested that prophylactic strategies might delay or even prevent these complications [4]. Thus, the ability to accurately predict the probability of bony metastasis and identify subsets of patients at increased risk for this complication might have significant clinical relevance for breast cancer patients in terms of adequate surveillance, subsequent prophylaxis, and early treatment to prolong survival and maintain a better quality of life [5].

Clinicopathologic factors associated with bone metastasis of breast cancers have been described; the most consistent features include lower histologic grade, estrogen receptor (ER) positivity, and lymph node staging [6], [7], [8]. It has also been suggested that factors such as S-phase fraction less than 5% [7], expression of parathyroid hormone-related peptide [9], bone sialoprotein [10], and calcium-sensing receptor [11], lack of squamoid differentiation and involucrin expression [12], strand growth pattern, and presence of fibrotic foci in invasive ductal carcinoma [13] are also associated with bone metastasis. In addition, Smid et al [14] have recently identified a 69-gene panel that is relevant to bone metastasis, and many of the genes seem to be involved in the fibroblast growth factor receptor signaling pathway.

After the identification of several distinct molecular subtypes of breast carcinomas by gene expression profiling [15], [16], [17], several immunohistochemical (IHC)-based molecular classifications have been described in the literature. Cytokeratin (CK) classification divides breast cancer into basal (basal CKs—CK5, CK14, or CK17 positive) and luminal subtypes (basal CKs negative, luminal CKs—CK8 and CK18 positive), with basal subtype associated with high-grade (HG) tumors [18] and poor prognosis [19], [20]. The triple negative (TN) classification, with basal subtype defined as lack of the expression for ER, progesterone receptor (PR), and Her2/neu (HER2), is commonly used among clinical oncologists because of its lack of target therapy [21]. It is more likely to occur in patients younger then 40 years and demonstrates a more aggressive clinical course regardless of the tumor stage at diagnosis [22]. In addition, these tumors appear to be more sensitive to anthracyclin-based neoadjuvant chemotherapy [23]. CK/TN classification, based on the expression of both CK markers and receptors, seems to be the best surrogate and most closely resemble the molecular classification derived from gene expression profiling with basal subtype demonstrating CK5/6 and/or epidermal growth factor receptor (EGFR) expression, whereas lacking expression of ER and HER2 [24], [25]. Furthermore, the basal-like and HER2-overexpressing subtypes seem more likely to have metastatic recurrence in lung and brain [26], [27]. These IHC surrogates for molecular subtypes of breast carcinoma demonstrated similar prognostic significance compared with expression profiling and may even be predictive for the patterns of distant metastatic recurrences.

The objective of this study is to identify molecular markers and molecular subtypes that may help to identify a subgroup of tumors with an increased propensity for skeletal dissemination.

Section snippets

Materials and methods

Twenty-one cases of breast carcinomas with bone metastasis and 94 cases without bone metastasis were retrieved from the files of the Pathology Department at Strong Memorial Hospital (Rochester, NY, USA). Using standard nuclear grading criteria [28], the tumors from both groups were divided into HG and non-HG (NHG) subgroups. IHC staining was performed with various antibodies (Table 1) on one representative section of formalin-fixed paraffin-embedded tissue from each case (Fig. 1). Pretreatments

Clinical features of breast carcinomas with and without bone metastasis

The mean age was 50 years for primary cancers and 57 for bone metastasis with a range between breast primary and bone metastasis of 0 to 30 years and a mean of 9 years. The patients with bone metastasis included 17 cases of invasive ductal carcinoma (81%) and 4 cases of invasive lobular carcinoma (19%). Fourteen cases (67%) were NHG tumors, and 7 cases (33%) were HG tumors. Also, the tumors with bone metastasis seemed to be associated with tumors with larger size and lymph node metastasis, as

Discussion

Our data demonstrated that although there was no significant difference with PR status alone between tumors with and without bone metastasis, ER-positive/PR-negative tumors were significantly higher in tumors with bone metastasis, suggesting that ER-positive/PR-negative phenotype may represent a distinct subgroup of breast carcinoma. Rakha et al [29] recently demonstrated that ER-positive/PR-negative tumors were more frequently seen in elderly postmenopausal women and in grade 2 ductal

Acknowledgment

The authors thank Dr Steven Hajdu for encouragement and critical suggestions and Marjorie Goldman for assistance with the manuscript.

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