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Year : 2019  |  Volume : 15  |  Issue : 5  |  Page : 971-975

Bone metastases incidence and its correlation with hormonal and human epidermal growth factor receptor 2 neu receptors in breast cancer

Department of Radiotherapy, Gandhi Medical College, Bhopal, Madhya Pradesh, India

Date of Web Publication4-Oct-2019

Correspondence Address:
Veenita Yogi
Department of Radiotherapy, Gandhi Medical College, Sultania Road, Bhopal - 462 001, Madhya Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_235_18

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 > Abstract 

Aim: In this paper, we present a prospective observational study, which determines the incidence of bone metastases and its correlation with hormonal receptors (estrogen receptor [ER]/progesterone receptor [PR]) and human epidermal growth factor receptor 2 (HER2) in breast cancer.
Materials and Methods: From October of 2015 to July 2017, 262 patients were eligible for the study, of which 98 patients presented/developed bone metastases. ER/PR and HER2 receptor status were determined, and bone scintigraphy with a technetium-99 m was carried out on each patient during the study.
Results: The incidence rate of bone metastases as found in this study was 25.25%, and the mean and median age at diagnosis were 47.23 and 46, respectively (age range = 28–80). Bone metastases were more prevalent in ER-positive tumors (P = 0.043), tumors with lymph node positivity (P = 0.002), and lower grade tumors (P = 0.002), whereas visceral metastases were more common with ER-tumors (P = 0.005), tumors with higher grade (P = 0.012), and tumors with lymph node positivity (P = 0.034). In this study cohort, the spine and pelvis were the most commonly involved subsites of bone metastases (P < 0.001).
Conclusion: This study demonstrates that the metastatic patterns in breast cancer strongly correlate with various breast cancer subtypes, mainly designated by ER, PR, and HER2. Hormone receptor-positive tumors show a predilection for bones as the first site of relapse compared to hormone-receptor-negative tumors which have a proclivity to develop as visceral metastases.

Keywords: Bone metastases, breast cancer, estrogen receptor, human epidermal growth factor receptor 2, spine and pelvis, visceral metastases

How to cite this article:
Pareek A, Singh O P, Yogi V, Ghori H U, Tiwari V, Redhu P. Bone metastases incidence and its correlation with hormonal and human epidermal growth factor receptor 2 neu receptors in breast cancer. J Can Res Ther 2019;15:971-5

How to cite this URL:
Pareek A, Singh O P, Yogi V, Ghori H U, Tiwari V, Redhu P. Bone metastases incidence and its correlation with hormonal and human epidermal growth factor receptor 2 neu receptors in breast cancer. J Can Res Ther [serial online] 2019 [cited 2020 Jul 7];15:971-5. Available from: http://www.cancerjournal.net/text.asp?2019/15/5/971/268447

 > Introduction Top

Breast cancer is the most frequently diagnosed form of cancer and is the world's leading cause of female death. It accounts for 23% of all the global cancer cases and 14% of all the global cancer deaths.[1] It accounts for 27% of all cancer cases in women.[2],[3]

According to a recent analysis performed by National cancer registry program, India, breast cancer has replaced cervical cancer as the most common form of cancer in women in India. In the city of Bhopal, breast cancer is the leading form of cancer in females and accounts for 31.2% among all cancer cases. Its crude rate and age-adjusted rate per 100,000 population is 28.2 and 33.1, respectively.[4]

Metastatic breast cancer is defined as a tumor spreading beyond the confines of the breast chest wall and the ipsilateral regional lymph nodes. Bones are the most common site of metastatic recurrence in breast cancer and the first site of metastases in >50% of the patients who fail systematically.[5] The hormone receptor status is strongly related to the metastatic pattern. Hormone-receptor-positive (estrogen receptor [ER] and progesterone receptor [PR]) tumors are more likely to spread to bones as their primary site of metastases and have better survival outcomes; when compared to the hormone receptor-negative or human epidermal growth factor receptor 2 (HER2) neu positive tumors which tend to develop as visceral metastasis.[6]

Moreover, the number of studies based on the correlation of metastatic pattern and hormonal receptors in breast cancer from India are quite sparse. The objectives of this study are to determine the incidence of bone metastases and the correlation between hormonal receptors and fundamental clinicopathologic findings with bone metastases.

 > Materials and Methods Top

The conducted study is a single-institute prospective observational study. After obtaining informed consent and prior ethical clearance, 388 patients diagnosed with breast cancer between October 2015 and July 2017 are included in the study. Out of the 388 HPR proven cases of breast carcinoma, 262 patients were eligible for the study, 98 of whom presented/developed bone metastases, and 41 patients developed visceral metastases. All of the patients' age, habitat, religion, tumor histology, tumor grade, lymph node status, and TNM staging were thoroughly recorded. ER/PR status were determined using immunohistochemistry (IHC); nuclear staining in <1% cells were considered as negative and staining in 1%–10% of the tumor cells was considered as focally positive and staining in >10% of cells was considered as positive for ER and PR. HER2 status was also determined using IHC and equivocal positive results were confirmed using fluorescent in situ hybridization. On the basis of ER and HER2 neu, status patients were divided into four groups, ER-positive HER-negative, ER-positive HER-positive, ER-negative HER-positive, ER-negative HER-negative.

Metastatic breast cancer is defined as a tumor spreading beyond the confines of the breast, chest wall, and ipsilateral regional lymph nodes. Metastatic sites were classified as bone and visceral (lung, liver, and brain).

Patients were thoroughly investigated for the presence of metastases at the time of presentation. Bone scintigraphy with a technetium-99m was performed on each patient during the study; these were first performed at the time of presentation and then for a second time after the completion of chemotherapy, an additional follow-up was carried out every 6 months. If there persisted any indication pertaining to bone-related issues such as increased bone pain, raised alkaline phosphatase levels, or bony tenderness on physical examination, bone scans were done. When patients developed metastases to one organ site, it was assessed if this was the first metastatic site or not. Subsites of bone metastases were also recorded in the patients who developed bone metastases.

Statistical methods

All the data were analyzed using the SPSS version 20 software, IBM, New York, USA. The descriptive statistical analysis was carried out in the present study. Results on continuous measurements are presented on mean standard deviation (minimum–maximum), and results on categorical measurements are presented in a numbered (percentage) manner. The significance is assessed at 5% level of significance. Chi-square/Fisher's exact test was used to find the significance of the study parameters on a categorical scale between two or more groups. Student's t-test and ANOVA were used to compare the mean of all quantitative variables. The null hypothesis of discrepant results was declined when the value of P ≤ 0.05.

 > Results Top

The demographic data of this study cohort are summarized in [Table 1]. On completion of the study, we found that mean and the median age at diagnosis were 47.23 and 46, respectively (age range = 28–80). One hundred and fifty-two out of the 262 patients belonged to an urban area (P = 0.035). There was a statistically significant difference in the religious practices of the patients with 213 out of the 262 patients (P = 0.026) practicing Hinduism.
Table 1: Demographic data of the patients

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The distribution of metastatic disease in the patients is displayed in [Table 2]. In the study, bone metastases were the most commonly observed metastases. A total of 98 (37.4%) patients' first site of presentation of metastatic disease was that of the bone, of which, 92 patients had no evidence of bone metastases at the time of presentation. The incidence rate of bone metastases as found in our study was 25.25%. During the study cohort, 41 patients' first site of presentation of metastatic disease was that as visceral metastases. The correlation between metastatic presentation and tumor characteristics of the study cohort (n = 262) is shown in [Table 3].
Table 2: Sites of the first presentation of metastatic breast carcinoma

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Table 3: Tumor characteristics of the study population

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There was a statistically significant relationship between tumor histology and bone metastases as the first site of metastatic presentation. Bone metastases were significantly more likely to be associated with patients having intraductal tumor histology rather than a lobular type of tumor (P = 0.005). Patients with bone metastases as the first site of recurrence were more likely to have a lower histological grade (P = 0.002). Bone metastases were also more common with patients who had lymph node positivity (P = 0.002). A significant association was observed between hormone receptor (ER) positivity and development of bone metastases as the first site of metastatic presentation as compared to that of visceral metastases (P = 0.043).

On conducting a subanalysis, it was observed that 41 patients who developed visceral metastases as the first site of metastatic presentation. Patients with visceral metastases were more likely to be associated with intraductal histology (P = 0.021), higher tumor grade (P = 0.012), lymph node positivity at the time of presentation (P = 0.034), and hormone receptor (ER) negativity (P = 0.005).

There was no significant association observed between the stages at the time of presentation and development of bone and visceral metastases. Subsites of bone metastases development are displayed in [Table 4] and [Figure 1]. The spine was the most commonly involved subsite (P ≤ 0.001) followed by the pelvis.
Table 4: Subsites of the bone metastases

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Figure 1: Subsites of the bone metastases

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 > Discussion Top

Breast cancer is a disparate disease, with a tendency to most commonly metastasize to bone.[7] The median age of the development of breast cancer worldwide is a decade later than the median age in this study.[8] Breast cancer is mainly subclassified as ER, PR, and HER2 neu status and these are strongly related to the pattern of metastases, regarding site-specific relapse, early/late metastasis, survival outcomes, and prognosis. The most common site for breast cancer metastases are bones followed by the lung, liver, lymph nodes, chest wall, and brain.[9] Metastatic recurrence is the leading cause of mortality in breast cancer patients. Up to 13.6% of all breast cancer patients who are diagnosed between Stages I and III, will eventually develop bone metastases.[10] Metastases regarding the breasts are a complex process, it comprises tumor intravasation, circulation, extravasation, proliferation, and angiogenesis in the suitable microenvironment. It was first described in 1889 by Stephen Paget as the “seed and soil” hypothesis.[11] It has been revealed that there may be a possibility that bone marrow serves as a reservoir for metastatic breast cancer cells.[12] Breast cancer with bone only metastasis confers a better prognosis as compared to metastases to visceral sites.[13] The classification of breast cancer on the basis of molecular subtypes was first reported by Perou et al.[14] In the current study, we explored the occurrence of site-specific metastases with hormonal and in relation with hormonal and HER2 neu receptors and various clinicopathologic variables in breast cancer.

Clinical observation along with previous studies divulged the difference between ER-positive and ER-negative tumors.[15] Studies have confirmed the impact of the first site of metastases on the prognosis of breast cancer patients.[16],[17],[18] ER-positive tumors show preference to develop bone metastases as their first site of relapse as compared to ER-negative or HER2-positive tumors.[19],[20] In accordance with the previous literature, our data clearly state the close relationship between ER-positive tumors and tendency to develop bone metastases.[17] Factors indicating favorable prognosis were related with the development of bone metastases.[21]

This study significantly corroborated with the published literature showing the proneness of ER-negative and HER2-positive tumors to develop visceral metastases. There is a significant correlation between well differentiated or low-grade tumors and development of bone metastases depicted by this study too.[22] We did not find any significant correlation between the stages of presentation and development site-specific metastases. The spine is the most frequently involved subside of bone metastases as also portrayed in this study.[23]

 > Conclusion Top

This study demonstrates that metastatic pattern in breast cancer strongly correlates to breast cancer subtypes, which are designated as ER and HER2. Bone metastases are more likely to be associated with patients who have intraductal histology, lower tumor grade, and lymph node positivity. Hormone receptor-positive tumors show a predilection for bone as the first site of relapse, as compared to that of hormone-receptor-negative tumors which had a proclivity to develop visceral metastases.

It had been observed that patients with bone metastases receive a far better prognosis and have a better overall survival rate, compared to patients with visceral metastases. Hence, it is important to observe if the patient has any high-risk factors that lead to the development of bone metastases. In the investigation armamentarium, bone scan holds an important portfolio in the patients with a susceptible receptor profile, as it can prognosticate patients and hence cohort them into a watchful waiting group.


We would like to thank Dr. Varsha Mandloi and Dr. Haridas P. Mani for their unwavering support during the study. We would also like to thank all the patients and their caregivers for providing consent and giving their full support for this research work.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

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Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature 2000;406:747-52.  Back to cited text no. 14
Andry G, Suciu S, Vico P, Faverly D, Andry-t'Hooft M, Verhest A, et al. Locoregional recurrences after 649 modified radical mastectomies: Incidence and significance. Eur J Surg Oncol 1989;15:476-85.  Back to cited text no. 15
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  [Table 1], [Table 2], [Table 3], [Table 4]


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