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. 2023 Oct 27;102(43):e35798. doi: 10.1097/MD.0000000000035798

Review of the relationship between tumor receptor subtypes and preference for visceral and/or serosal metastasis in breast cancer patients

Pinar Özdemir Akdur a,* , Nazan Çiledağ a
PMCID: PMC10615421  PMID: 37904368

Abstract

In this study, we investigated the molecular phenotype–cancer relationship that may favor the main metastatic tendencies of cancer by comparing the association of receptor subtypes with the presence of metastasis, serosal metastasis, and/or visceral metastases in patients diagnosed with breast cancer. In this study, we retrospectively evaluated 853 patients who were diagnosed with breast cancer and followed up at our hospital between 2017 and 2022. The probability of metastasis in the most common tumor group, the non-special type of invasive carcinoma was significantly higher than that in other tumor groups. We formed our groups according to estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki67 status. In addition, when we compared the receptor groups, no significant difference was found between the receptor groups (Table 1). When the entire breast cancer cohort was considered, the association of serosal metastasis was statistically significantly higher in the ER and/or PR (+) and, HER2 (−) receptor subgroup than in all other receptor groups (P < .006), and the association of visceral metastasis/visceral + serosal metastasis with the ER and/or PR (+) and, HER2 (−) receptor subgroup was significantly higher than that in all other receptor groups (P < .001) (Table 2). In this study, we aimed to investigate the possible relationship between molecular markers of the primary tumor and the preference for serosal and visceral metastases over distant metastases in a large cohort of patients to contribute to the improvement of the diagnosis and treatment of breast cancer, a heterogeneous disease group. To the best of our knowledge, our study is the first to statistically investigate the association between receptor subgroups and visceral, serosal, and serosal + visceral metastases as a group and to reach some conclusions.

Keywords: breast cancer, molecular phenotype, receptor, serosal metastasis, visceral metastasis

1. Introduction

Breast cancer is the most commonly diagnosed malignant tumor in women worldwide and the most common cause of malignancy-related deaths. Breast cancer patients constitute approximately 36% of all oncological patients. The incidence of breast cancer is gradually increasing worldwide, especially in Western countries.[1–3] Since breast cancer is a heterogeneous disease that varies from clinical course to molecular subtypes, it includes a wide spectrum of diseases with different presentations and morphological, biological, and clinical phenotypes. Therefore, the behavior and treatment success of breast cancer vary greatly from person to person, and, as a result, it is possible to encounter very different personalized prognosis processes in breast cancer patients.

Current data suggest that conventional prognostic and predictive classification subheadings fail to reflect the biological and clinical heterogeneity of breast cancer.[4,5] Metastatic disease is the etiological cause of the vast majority of deaths in patients with breast cancer, as in other cancers, and represents the main challenge in tumor oncology. Although therapeutic strategies targeting primary tumors have made significant strides, systemic therapies to prevent metastasis have made little progress. Metastatic disease remains the underlying cause of death in most patients who die from the disease.[6,7] Approximately 12% of patients with breast cancer develop distant metastases, reducing the 5-year survival rate from 90% to 25%.[7,8] Therefore, it is important to identify patients at high risk of tumor metastasis in advance, if possible, to ensure timely intervention.[9–14]

2. Material and Methods

2.1. Study population

In this study, we retrospectively evaluated 2500 patients who were diagnosed with breast cancer and followed up at our hospital between 2017 and 2022. Among these patients, we included 853 patients whose complete anamnesis information could be obtained from the hospital record notes and whose radiological computed tomography (CT) follow-ups could be accessed from the hospital picture archiving and communication systems and excluded other patients. In other words, we excluded patients whose anamnesis and radiological imaging were incomplete and whose serosal or visceral metastasis foci were not histopathologically proven. We retrospectively evaluated the remaining 853 patients who had complete clinical information, whose images were available for reevaluation, who were diagnosed with metastasis by imaging methods and subsequently diagnosed with histopathologically proven metastasis, in whom 4 molecular subtypes were studied. We divided this patient group into 4 receptor subgroups and compared them in terms of the possibility of serosal and/or visceral metastasis. While 851 (99.8%) of the patients included in the study were female, only 2 (0.2%) were male. The youngest patient in our case cohort was 22 years old, the oldest was 88 years old, and the mean age of the patients included in the study was 52 years. In the metastatic patient group, the age range was 25 to 86 years, and the mean age of the metastatic patient group was 52 years. When the diagnosis was made, 6% (n = 51) of the patients had metastatic disease, while the rest developed over time.

This study conducted in accordance with the Declaration of Helsinki and was approved by the Hospital Institutional Ethics Committee. Radiographic examinations (chest and abdominal CT and brain magnetic resonance imaging) were performed for all patients to evaluate distant metastasis. Patients with pericardial, pleural, and peritoneal involvement and/or breast cancer metastases on histopathological examination of pleural fluid and ascites fluid samples were included in the serosal metastasis group. However, patients whose cytological examination did not support tumor metastasis or whose results were suspicious were excluded from the serosal metastasis group. Patients with liver, surrenal gland, spleen, kidney, pancreas, and brain metastases were classified as having visceral metastasis. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki67 receptor information was compiled from pathology records, and the status of primary tumor biomarkers, including ER, PR, HER2, and Ki67, were grouped according to routine pathology reports. According to the routine immunohistochemical (IHC) method used in our hospital, IHC staining is performed by taking 4-micron sections from formalin-fixed paraffin-embedded tumor-containing blocks. IHC staining was performed using the BenchMark ULTRA® system (Ventana Medical Systems, Tucson, AZ) is used for IHC staining. Immunohistochemical staining was performed using the antigen retrieval method for ER (SP1), PR (1E2), HER2 (4B5), and Ki67 (30–9). Nuclear staining in >1% of tumor cells was considered positive for ER and PR. A separate scoring system was not used for ER and PR staining, and Ki67 expression was calculated by counting Ki67 nuclear staining-positive cells among 1000 invasive tumor cells. HER 2 status was evaluated immunohistochemically using a 4-grade system (0–3) according to the American Society of Clinical Oncology/College of American Pathologists guidelines. Samples that were 2+ with this method were further analyzed with HER2 ISH (INFORM HER2 dual probe) in the BenchMark ULTRA® system (Ventana) to determine HER2 positivity using the American Society of Clinical Oncology/College of American Pathologists guidelines. In our study, we determined the receptor groups according to the routine ER and PR positivity information obtained from registered reports, defined as 1% or more of tumor cell nuclei, HER2 positivity according to the positive group defined as the result of a 3+ immunohistochemistry score. For Ki67 staining, the percentage of positively stained tumor cells was counted and a cutoff value of 13% for low/high. Patients with unknown ER, PR, HER2, or Ki67 status reported in the tumor registry or medical chart or for whom archival information was not available were excluded. For comparison, we divided breast cancer into 4 subtypes according to hormone receptor and HER2 status, briefly defined as (ER+ and/or PR+, HER2−), (ER−/PR−/HER2+), (ER−/PR−/HER2−) and (ER+ and/or PR+, HER2+) tumor groups. We then compared each receptor subgroup in terms of the association between serosal and/or visceral metastasis.

This study was approved by our Institutional Ethics Committee and was conducted in accordance with the principles of the Declaration of Helsinki. (Decision Date: 23.03.2022; Decision No.: 2022-03/1736) The data that support the findings of this study are available from our hospital, but restrictions apply to the availability of these data, which were used under the license for the current study and so are not publicly available. However, the data are available from the authors upon reasonable request and with permission from our hospital.

2.2. Statistical analysis

Statistical analyses were performed using SPSS Version 23.0 (IBM Corp., released in 2015). IBM SPSS Statistics for Windows, Version 23.0 (Armonk, NY) A two-tailed Kolmogorov–Smirnov test was applied to examine whether continuous quantitative variables follow a Gaussian distribution. Patient characteristics, as n (%) or median (minimum–maximum) for categorical and continuous variables, respectively, were compared among treatment groups using chi-square or Mann–Whitney tests, as appropriate. The P significance was set at P < .05.

3. Results

Data from a total of 853 patients were analyzed, comprising 851 (99.8%) females and 2 (00.2%) males with a mean age of 52 years. The patients were divided into 2 groups based on the presence or absence of metastases. There was no statistically significant relationship between the groups except for tumor type in terms of demographics and clinical findings (P > .05). Invasive tumor histological subtypes were divided into 2 main groups: non-special type of invasive carcinoma (NST) and other tumors (tumors with other subtypes of invasive lobular carcinoma, tubular carcinoma, mucinous carcinoma, and papillary carcinoma). We looked for any difference in the incidence of metastasis between these 2 groups and found no statistically significant difference between the 2 groups. When we compared each receptor (ER, PR, HER2, and Ki67) individually without differentiating metastatic localization, there was no statistically significant difference. In addition, when we compared the receptor groups we made: 1st group: ER and/or PR (+), HER2 (−); 2nd group: ER and/or PR (+), HER2 (+); 3rd group: ER (−), PR (−), HER2 (−), and 4th group: ER (−), PR (−), HER2 (+). There was no significant difference between the receptor groups; however, the probability of metastasis in the most common tumor group, NST, was significantly higher than that in other tumor groups (Table 1). In addition, when we examined the receptor subgroups of non-special type of invasive carcinomas, the probability of metastasis in the receptor subgroup with ER and/or PR (+) and HER2 (−) was higher than that in other receptor groups. However, it should be noted that the main percentage of our cohort was NST-type invasive cancers, which may have created a “selective bias” in comparison to other tumor groups. When the entire breast cancer cohort was considered, the association of serosal metastasis was significantly higher in the ER and/or PR (+) and HER2 (−) receptor subgroups than in all other receptor groups (P < .006), and the association of visceral metastasis/visceral + serosal metastasis with the ER and/or PR (+) and HER2 (−) receptor subgroups was significantly higher than that in all other receptor groups (P < .001) (Table 2).

Table 1.

Demographic and clinical data of the study patients.

Group
Total
(N = 853)		 None
(n = 569)		 Metastasis
(n = 284)		 P value
n (%) or median (min–max) n (%) or median (min–max) n (%) or median (min–max)
Age (years) 52 (22–88) 53 (22–88) 52 (25–86) .383
Sex 1.000
Male 2 (0.2) 1 (0.2) 1 (0.4)
Female 851 (99.8) 568 (99.8) 283 (99.6)
Tumoral type <.001
Non-special type of invasive carcinoma 701 (82.2) 449 (78.9) 252 (88.7)
Other 152 (17.8) 120 (21.1) 32 (11.3)
Receptor group .364
ER and/or PR (+), HER2 (−) 453 (53.1) 312 (54.8) 141 (49.6) .153
ER and/or PR (+), HER2 (+) 247 (29) 159 (27.9) 88 (31) .356
ER (−), PR (−), HER2 (−) 86 (10.1) 52 (9.1) 34 (12) .195
ER (−), PR (−), HER2 (+) 67 (7.9) 46 (8.1) 21 (7.4) .827
HER2 .502
Negative 539 (63.2) 364 (64) 175 (61.6)
Positive 314 (36.8) 205 (36) 109 (38.4)
ER .148
Negative 177 (20.8) 110 (19.3) 67 (23.6)
Positive 676 (79.2) 459 (80.7) 217 (76.4)
PR .210
Negative 241 (28.3) 153 (26.9) 88 (31)
Positive 612 (71.7) 416 (73.1) 196 (69)
Ki67 .277
Negative 294 (34.5) 189 (33.2) 105 (37)
Positive 559 (65.5) 380 (66.8) 179 (63)
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Table 2.

Relationship between receptor groups and serosal/visceral metastasis.

Variables Receptor group
ER and/or PR (+), HER2 (−) ER and/or PR (+), HER2 (+) ER (−), PR (−), HER2 (−) ER (−), PR (−), HER2 (+) P value
Non-special type of invasive carcinoma, n (%) 346 (76.4) 226 (91.5) 70 (81.4) 59 (88.1) <.001
Metastasis, n (%) 141 (31.1) 88 (35.6) 34 (39.5) 21 (31.3) <.001
Serosal metastasis 17 (3.8) 9 (3.6) 3 (3.5) 0 (0) .006
Visceral metastasis 70 (15.5) 52 (21.1) 14 (16.3) 17 (25.4) <.001
Serosal + visceral metastasis 54 (11.9) 27 (10.9) 17 (19.8) 4 (6) <.001
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4. Discussion

The classification of breast cancer, which is a heterogeneous disease group in terms of genetic and clinical processes, has evolved over the years and has been discussed using different focal points under various subheadings. Owing to the predominance of molecular-based approaches in the diagnosis and treatment of breast cancer, the classification of breast cancer has been based on a molecular basis, and other molecular markers have been added to the classification over time. The most widely accepted classification of breast cancer is immunohistochemical classification based on the expression of hormone receptors such as estrogen (ER), progesterone (PR), and human epidermal growth factor (HER2). The estrogen receptor (ER) is an important diagnostic parameter and is expressed in approximately 70% to 75% of invasive breast carcinomas, and progesterone receptor (PR) is expressed in more than 50% of ER-positive patients.[15] Human epidermal growth factor receptor 2 (HER2) is expressed in approximately 15% to 25% of breast cancers, and this expression is a guide in the choice of breast cancer treatment. Ki67 antigen is also an important marker that provides information on cell proliferation.[16,17] When we examined the distribution of receptor expression in our patient cohort, 79.2% of the patients were ER (+), 71.7% were PR (+), 36.8% were HER2 (+), and 65.5% of the patient population expressed Ki67. As mentioned in the introduction, the mortality rate of breast cancer has decreased significantly with early diagnosis and treatment. However, distant metastases are uncommon and the median survival time in the presence of advanced breast cancer is 2 to 3 years.[18,19] In most cases, metastatic breast cancer is not uncommon at the time of diagnosis, occurring in only approximately 6% to 7% of cases; however, it is inevitable that approximately 30% of breast cancer patients will develop recurrent or metastatic disease later in life.[20–22] As treatment and, if possible, the prevention of metastases has become the focus of cancer therapy, many theories have been proposed to explain the possible mechanisms of metastasis. Gene expression profiling studies have revealed several findings that may explain organ-specific metastasis. Although gene expression studies have provided useful information for identifying new molecular mediators of organ-specific metastasis, a clear reflection of these data in clinical practice has not yet been fully realized.[23,24] Although the factors that determine the development of breast cancer metastases include the size of the primary tumor, histological grade, lymphovascular invasion, nodal involvement, and receptor status, the relationship between clinicopathological factors and distant recurrence patterns remains unclear.[25] Many studies have analyzed the relationship between breast cancer subtypes and the risk of distant metastasis. The metastatic pattern of breast cancer varies according to the hormone receptor status. The risk of bone metastases is higher in the presence of ER and PR positivity, while the presence of HER2-positive or triple-negative (ER-, PR-, and HER2-negative) receptors increases susceptibility to visceral metastases, including the brain.[10,13] In the same way, there are studies describing the results that HER2-positive cases are more likely to develop liver metastases.[14] There are other studies reporting that liver metastasis is not associated with breast cancer subtypes.[26] Another study suggested that ER-negative patients have more visceral involvement than ER-positive patients.[27] Although these observations are important for deciding on treatment and developing appropriate research strategies, they are not sufficient to elucidate the underlying mechanisms.[27,28]

In publications investigating visceral metastases, visceral metastases in breast cancer, as in many other cancer types, are divided into liver, lung, and central nervous system metastases, ascites, and pleural effusion. Non-visceral metastases were divided into bone, skin, and lymph node metastases.[29,30] In our study, we grouped the cases with metastases to one or more of the following organs: liver, lung, spleen, surrenal, pancreas, kidney, and brain under the “visceral metastases group” and the cases with metastases to any serosal surface, including pleural surfaces, pericardium, or peritoneum, under the serosal metastases group. When separating cases with positive serosal metastases, we included those with obvious serosal surface thickening and/or pleural effusion, pericardial effusion, or ascites with cytological results supporting metastasis and excluded cases with negative or doubtful results from the group of cases with serosal involvement.[30]

Although much progress has been made in the medical world in the diagnosis and treatment of metastases of breast cancer to the bone, liver, lung, brain, and other visceral organs, the spread of breast cancer to serosal surfaces such as pleural, pericardial, and peritoneal surfaces is a poorly defined entity. Breast carcinoma is the most common metastatic tumor detected in the pleural effusion samples of women. Pleural metastases usually present as pleural effusions, nodules, or thickening. However, pleural effusion is not always associated with metastasis. However, because pleural metastasis is usually not recognized until effusion occurs, it is difficult to determine its actual incidence. In one study, it was reported that up to 11% of cases presented with pleural effusions, and this rate increased to 36% to 65% in a retrospective evaluation of autopsy series.[31,32]

A retrospective study of a large cohort of patients with a history of invasive breast cancer revealed that 5.34% of the patients developed malignant pleural and/or pericardial fluid as the first clinical sign of distant metastasis.[33] The pericardium is not the preferred site of metastasis in breast cancer, and pericardial metastasis develops in only 19% of cases. Approximately 12 to 25% of breast cancer cases with pericardial metastasis have pericardial effusion. Although cardiac and pericardial metastases are rare, they are more common than primary cardiac tumors and usually have a very poor prognosis. Considering all cardiac metastases, approximately two-thirds of the metastases involve the pericardium, and one-third involve the epicardium or myocardium. Since most cases do not present clinically, they are not diagnosed until autopsy.[34–36]

Involvement of the peritoneal surfaces, which is another serosal involvement of breast cancer, is a rare clinical manifestation that usually occurs during progressive progression or is much less frequently detected at the initial diagnosis. The most common diagnostic finding is diffuse peritoneal thickening and ascites development. The presence of ascites, positive ascites cytology, and recognition of peritoneal lesions on CT scans provide data that can lead to the diagnosis of peritoneal metastases in breast cancer.[37–42]

Although the tendency of breast cancers to spread to serosal surfaces is not as clear as that of visceral metastases, studies based on histopathological subtypes have shown that lobular carcinoma has a higher tendency to spread to the peritoneal surfaces. In another study, although there was no significant difference in the molecular subtype of the primary cancer among the 3 groups, when they examined the probability of pleural metastasis alone or as a concomitant metastasis of lung metastasis, they found a more frequent association with luminal type B. Studies on the genetic phenotyping of serosal metastases in breast cancer are much less common. In a large cohort study, Kennecke et al found that HER2-enriched tumors had the highest incidence of pleural and peritoneal metastases (16.2–16%), followed by luminal B (14.7%) and (12.8%) basal-like tumors.[42–47]

In our study, we defined 4 different receptor subgroups as ER and/or PR (+) and, HER2 (−) in the 1st group; ER and/or PR (+) and, HER2 (+) in the 2nd group; triple negative in the 3rd group; and triple-negative in the 4th group. Group ER and PR (−), HER2 (+) receptor subgroups and comparing the association of serosal, visceral, and serosal + visceral metastases with receptor subgroups, we found the following results: when the whole breast cancer cohort was considered, the association of serosal metastasis was statistically significantly higher in the ER and/or PR (+), HER2 (−) receptor subgroup compared to other receptor groups (P < .006), and, the association of visceral metastasis/visceral + serosal metastasis with ER and/or PR (+) and HER2 (−) receptor subgroups was significantly higher than that in all other receptor groups (P < .001).

5. Conclusion

The main reason underlying most breast cancer treatment failures, which are a heterogeneous disease group and should be considered a systemic disease in terms of the treatment process, is the breast cancer diagnosis and treatment modeling that targets the primary tumor but is still incomplete in the treatment of metastasis. As breast cancer is a heterogeneous group of diseases, each with a different clinicobiological behavior and various molecular and genetic subtypes, the traditional histopathological classification of breast cancer offers only limited prognostic value in terms of guiding treatment. In the treatment of breast cancer, genetic molecular phenotyping, and elucidation of association relationships based on these phenotypes will open the door to new classifications that predict disease aggressiveness and add value to prognostic data. Thus, owing to these molecular signatures, it is possible to achieve more successful treatment results with new receptor-targeted therapies and personalized therapeutic options.

With the increasing use of high-throughput molecular techniques, a large amount of new data continues to emerge, which could lead to the identification of new therapeutic targets and allow for more precise classification systems and prognosis predictions that could accurately predict the response to treatment. However, in order to contribute to the treatment process and prognosis prediction of tumors, it is becoming increasingly important to carry out studies that will reveal the relationships between the molecular phenotypes we can reach and the behavioral analysis of tumors, such as the way the disease occurs and the tendency to choose the site of metastasis. To the best of our knowledge, this is the first study to statistically investigate the association of receptor subgroups with visceral, serosal, and serosal + visceral metastases and to reach some conclusions. We hope that through multicenter studies based on such experience transfers, personalized treatment strategies for breast cancer that increase survival rates, manage the long-term sequelae of the treatment process, and contribute to quality of life will evolve in a much shorter time and be reflected in daily practice. Furthermore, based on our own experience, we would like to emphasize that radiologists working in oncological radiology departments or oncology hospitals should prepare their reports with attention to molecular subtypes and even encourage necessary histopathological sampling.

6. Limitations

Although the number of participants was not low, the fact that almost 2/3 of the participants had to be eliminated because of gaps in the archive records caused by incomplete and incorrect data constituted the main limitation of our study.

Author contributions

Conceptualization: Pinar Özdemir Akdur.

Data curation: Pinar Özdemir Akdur.

Formal analysis: Pinar Özdemir Akdur.

Funding acquisition: Pinar Özdemir Akdur.

Investigation: Pinar Özdemir Akdur.

Methodology: Pinar Özdemir Akdur, Nazan Çiledağ.

Project administration: Pinar Özdemir Akdur, Nazan Çiledağ.

Resources: Pinar Özdemir Akdur.

Software: Pinar Özdemir Akdur.

Supervision: Pinar Özdemir Akdur.

Validation: Pinar Özdemir Akdur.

Visualization: Pinar Özdemir Akdur.

Writing – original draft: Pinar Özdemir Akdur.

Writing – review & editing: Pinar Özdemir Akdur, Nazan Çiledağ.

Abbreviations:

CT
computed tomography
ER
estrogen receptor
HER2
human epidermal growth factor receptor 2
IHC
immunohistochemical
NST
non-special type of invasive carcinoma
PR
progesterone receptor

This study was reviewed and approved by the institutional review board and ethical committee.

The authors have no conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

How to cite this article: Özdemir Akdur P, Çiledağ N. Review of the relationship between tumor receptor subtypes and preference for visceral and/or serosal metastasis in breast cancer patients. Medicine 2023;102:43(e35798).

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