Solitary Bone Metastasis and Oligometastatic Bone Disease in Breast Cancer: Are They Two Different Entities?

In this study, we planned to investigate the clinical course of breast cancer patients with oligometastatic bone disease (OMBD). The patients were grouped according to the characteristics and the sites of metastases. Group I included 928 patients without metastasis. Group II, OMBD group, icluded 68 patients. Group III, widespread metastasis group, consisted of 185 patients with multiple bone metastases and/or solid organ metastases. The mean overall survival of the groups were 16.7 ± 0.3 years in Group 1, and 7.8 ± 0.8 and 5.9 ± 0.4 years in Group 2 and 3, respectively (p<0,001 for the comparison of all three groups together; p <0.001 for Group 1 vs 2 & 3) and (p=0.037 for Group 2 vs. Group 3). In the subgroup survival analysis of patients in Group 2 (OMBD), the mean and median survival were 5.5 ± 0.8 and 4.0±0.8 years versus 9.2 ± 0.98 and 9.0 ±1.05 years in more than one bone metastasis and SBM patients, respectively (p = 0.019). As a result; OMBD seems to be a different disease than breast cancer with isolated bone metastases. The high risk of developing OMBD especially following locoregional recurrences increases the importance of locoregional therapy in large T and N stage tumors.


Introduction
Breast carcinoma is a tumor with osteotropic potential and the most common cause of carcinoma-related deaths in women [1,2]. Indeed, nearly 70% of the patients dying of breast cancer have evidence of metastatic bone disease at autopsy [3]. The models for predicting the effect of variables on breast cancer mortality have estimated a median of 19 percent reduction attributable to adjuvant therapy alone [4].
Besides, in a recently updated study, the addition of targeted therapies to a chemotherapeutic agent have improved median overall survival (OS) up to 56.5 months in patients with HER2-positive metastatic breast cancer [5]. The survival outcomes of stage IV breast cancer patients vary according to metastatic site and those with bone metastasis have the best survival [6]. In this context, oligometastatic breast cancer (OMBC) generally refers a special group of patients with less than ve metastatic deposits in a single organ and is considering potentially curable stage IV disease [7]. However, the de nition of OMBC in the literature varies according to the number and location of metastasis [8]. It is still uncertain whether OMBC corresponds to an intermediate stage between a localized disease and a widespread disease or a genetically unique entity rather than a transition point from primary tumor to metastasis [9].
In this study, with inspiration from the current literature and our previous publication about clinicopathologic features of single bone metastasis in breast cancer [10], we planned to investigate the clinical course of breast cancer patients with oligometastatic bone disease (OMBD). We evaluated demographic features of patients, histopathologic features with intrinsic subtypes of tumors and treatment-related factors on "survival outcomes" among non-metastatic group (Group I), OMBD group (Group II), and widespread metastatic group included patients with solid organ metastases with or without bone metastasis (Group III). (Fig. 1) Also, we aimed to determine the common characteristics of the patients with solitary (only one) and oligo (more than 1 but less than or equal 5) bone metastasis in OMBD group by evaluating them in terms of clinico-pathological factors and survival outcomes. For this purpose, a sub-group analysis was conducted to compare two strata of the OMBD grup (group II), comparing solitary bone metastatic patients (group IIa) with oligo bone metastatic patients (group IIb).

Materials And Methods
This retrospective cohort study was performed at the Izmir Bozyaka Health Practice and Research Center, University of Health Sciences Turkey and has been prepared for publication following the approval of the ethics committee on May 6, 2020. The study included patients with breast cancer operated between 2000 and 2020 at the Department of General Surgery. Those, who were between the ages of 23-92 years, have completed adjuvant therapy, had regular database and follow-ups, and followed up for at least 6 months were included.
There were a total of 1181 patients (1175 women, 6 men) in our series. The patients were grouped according to the characteristics and the sites of metastases. Group I included 928 patients without metastasis. Group II, OMBD group, icluded 68 patients. Group III, widespread metastasis group, consisted of 185 patients with multiple (more than six) bone metastases and/or solid organ metastases.
Between 2000 to 2015, we performed whole-body bone scintigraphy (B-scan) and/or magnetic resonance imaging (MRI) to determine bone metastases. After 2015, bone metastases were detected by B-scan and/or computed tomography and con rmed by 18-uorodeoxyglucose (FDG) whole-body positron emission tomography (PET)/CT method in all cases.
Beside radiological diagnoses, histopathological diagnoses of bone metastases were available in only 5 of 68 cases. Of these, two patients underwent bone biopsy, and three patients had had total excision of metastatic bone fragments of the pathological fractures.
The groups were compared in terms of demography, treatments applied, histopathological features and TNM stages of the American Joint Committee on Cancer (AJCC). In demographic factors, body mass index (BMI), smoking, family history, menopausal status, co-morbidity, hormone use were investigated.
The history of hormone use described oral contraceptive (OC) drugs for pre-menopausal and estrogenprogesterone combinations in postmenopausal patients. Hormone replacement therapy (HRT) refers to regular hormone therapy taken at any time, up to the diagnosis of breast cancer. Co-morbidity in patients refers to hypertensive atherosclerotic heart disease, chronic obstructive pulmonary disease, congestive heart failure, cerebrovascular disease and autoimmune diseases. Treatment factors included the type of breast surgery (mastectomy-M, breast-conserving surgery-BCS), axillary intervention (axillary lymph node dissection-ALND, sentinel lymph-node biopsy-SLNB), neoadjuvant-CT (NACT), radiotherapy (RT) and hormone therapy (HT). Histopathological features and staging explain tumor localization, histological and nuclear grade, mitotic activity, perinodal involvement, receptor status, cerb2, e-cadherin, p53, Ki67, lymph-vessel invasion, molecular classi cation (luminal A-B, triple negative, HER2(+), TNM staging and local recurrence.
Molecular subtypes of breast cancer are de ned as follows: Luminal A: Hormone-receptor positive (HR + / estrogen-receptor and / or progesterone-receptor positive), HER2 negative, low Ki-67 levels and nuclear grade (Grade I).
Luminal B: HR + and HER2 positive or HR + with high Ki-67 levels but HER2 negative. Nuclear grade is moderate or high (Grade II-III).
Triple-negative / basal-like: HR negative and HER2 negative. Nuclear grade is moderate or high (Grade II-III).

STATISTICS
In univariate analyzes, the patients in three groups were compared using the chi-square test for categorical variables and the Student-t test for continuous variables. Two separate logistic regression models were developed using backward likelihood ratio method with variables found signi cant in univariate analyzes, one exploring independent fators associated with isolated and/or oligo-bone metastasis (group II), and the other predicting independent risk factors of multiple bone metastases and/or solid organ metastases (group III), both compared to the non-metastatic group (group I). Odds ratios (OR) and 95% con dence intervals (CI) were calculated for each possible determinant adjusted for other variables in the model. Survival times and survival curves were calculated and plotted using Kaplan-Meier analysis. Also, single bone metastatic patients were compared with more than one bone metastatic patients in terms of survival outcomes with chi-square, Student's T and Mann-Whitney U tests.
A p-value less than 0.05 was considered signi cant.

Results
There was no signi cant difference in the history and demographic parameters except for tumor markers (Table 1). CEA and CA 15 − 3 values were statistically signi cantly different between the groups. The surgical treatment applied is presented comparatively in Table 2. Breast conserving surgery (BCS) was performed more frequently in patients in Group 1 (44.5%) than in group 2 (13.2%) and 3 (11.9%) (p < 0.001). Mastectomy was performed mostly on patients with OBMD. The proportion of patients who underwent SLNB was 36.6% in group 1, 13.2% in group 2 and 9.2% in group 3 (p < 0.001). ALND was applied mostly to patients with oligo-bone metastasis (Group 2) and SLNB to non-metastatic patients (Group 1). After ALND, the number of metastatic lymph nodes was 0 (0-44) in group 1, 6.0 (0-32) in group 2, and 4 (0-51) in group 3 (p < 0.001).
The protocol and e cacy of adjuvant and neoadjuvant treatment on the groups are shown in Table 3. Neoadjuvant chemotherapy (NACT) was applied mostly to patients in Group 3 (p = 0.003). The percentage of patients who received hormonotherapy after the operation was 79.8% in group 1, 68.2% in group 2 and 55.8% in group 3 (p < 0.001).
The histopathological features of the tumor are compared in Table 4. The percentage of mixed-type tumor histology was 5.4% in group 1 and 3 and, 17.6 % in group 2. ILC and mixed type tumors were more common in patients with oligo-bone metastasis (p < 0.001).
The percentage of progesterone receptor positivity was highest in Group 1 (60%) (p = 0.003). The median value of Ki67 was 25 % in group 3 and was signi cantly higher compared to other groups (p < 0.001). The rate of lymphoid and blood vessel invasion was similar in Groups 2 and 3, and was signi cantly higher compared to Group 1 (p < 0.001).
In molecular classi cation; Luminal-A subtype was most common in non-metastatic patients (p = 0.003) with a rate of 37.2%, whereas the incidence of Luminal-B subtype was similar in all three groups.
The staging of T (tumor size), N (nodal involvement) and cancer (TNM) were statistically different between the groups (p < 0.001) ( Table 5). T1-T2 tumor and N0-N1 lymph node were most common in nonmetastatic patients (group 1), while T3-T4 tumor was most common in patients with oligo-bone metastases (group 2). < 0,001 All demographic, treatment-speci c, histopathological and molecular variables which have statistical signi cance in univariate analysis were re-evaluated in multivariate logistic regression analysis.
The parameters that were statistically signi cantly different between the patients in Group 1 and 3, were evaluated in the multiple regression analysis. (Table 6). Those with a negative impact on Group 1 patients were as follows:  Multivariate logistic regression analysis of demographic, therapeutic and histopathological parameters between Group 1 & 2 is shown in Table 7. For the patients in Group 1; the risk of OMBD increased 7.7 and 5.4 times in patients with T3 and T4 tumors, and 2.7 times in those with perinodal invasion of the primary tumor. Also, every 1 unit rise of CEA value increased the risk of OMBD by 1.08 times. The most remarkable nding was the 68.3-fold increased risk of transition from nonmetastatic state to OMBD in patients who developed locoregional recurrence. In our series, we have 39 patients with single bone metastasis (SBM) and 29 patients with more than one bone metastasis. When these two strata of the OMBD group were compared, with the analysis being limited to the total number of patients (n: 68), no signi cant difference was found between them in terms of demographic, treatment-speci c, histopathological and molecular variables.

Discussion
In our previous study, we analyzed demographic, epidemiological, histopathological and intrinsic tumor subtype differences between 863 breast cancer (BC) patients without metastasis and 47 BC patients with single bone metastasis (SBM) ≥ 6 months after their rst diagnosis. Among established risk factors, we studied twenty-nine variables and found that the risk of developing SBM was approximately 4.8 and 2.8 times higher in BC patients with TNM Stage III tumors and with mixed type (invasive ductal carcinoma + invasive lobular carcinoma) histology [10]. Following this study and again in our own patient series; we aimed to evaluate the patients without metastases and those with OMBD according to demographic, epidemiological, histopathological and intrinsic tumor subtypes. Thus, we planned to identify the common characteristics of patients with SBM and OMBD and to reveal whether OMBD is a different entity or a more aggressive form originating from isolated bone disease (SBM). Although ILC & mixed type tumors were found to be signi cantly higher in patients with OMBD (17.6% vs. 5.4%, p < 0.001) compared to other groups in univariate analysis, this feature lost its signi cance in multivariate regression analysis. In the present study study, the most important risk factors for the development of OMBD in the non-metastatic patient group were: T3-T4 tumor, perinodal tumor invasion, and particularly the postoperative locoregional recurrence. When we compare these results with our previous study [10]; the common feature in our patients with single bone metastasis and OMBD is the development of both following advanced stage tumors (Stage IIIA & B).
In 1995, Hellman and colleagues rst described oligometastasis and suggested that at this stage the cancer has not yet reached its full metastatic potential and is restricted to certain regions [9]. In other words; the concept of oligometastatic disease implies that few metastases, usually under ve, may be present before tumor cells reach diffuse metastatic potential [11]. In this context, breast cancer patients with oligometastasis have so long been considered to have a disease with favorable course which should be treated with curative intent [12].
Herein, we examined the clinical course of oligometastatic patients in our large series of patients and compare the results with the literature. Our de nition of OMBC is the presence of solitary or less than ve detectable lesions limited to single organ amenable to local treatment with curative intent. Breast cancer patients with bone-only metastasis have pretty good prognosis with an average survival of 24-65 months after metastasis is detected [13][14][15]. In our study, the mean overall survival was 7.8 ± 0.8 years in the patient group with oligo-bone metastasis.
In our previous study on patients with isolated (single) bone metastases, the mean and median survival times were 9.9 and 7.0 years, respectively [10]. In the present study, the mean and median overall survival of patients with > 1 bone metastasisi was 5.5 ± 0.8 and 4 years and is signi cantly lower than those with SBM (9,2 ± 0,98 and 9 years) (p = 0,019 . Indeed, in a study of fty patients with extracranial oligometastatic breast cancer, those with single metastasis were highly bene ted from systemic chemotherapy and surgical resection and gained survival advantage with statistical signi cance [17].
Our study has several limitations. First of all, it is a single institute series. Although 43 prognostic and confounding factors were analyzed in depth in our study, the small number of patients with OMBD did not enable us to reveal the distinctive biological characteristics of these cases. With our own data, we were able to show that single bone metastatic disease and OMBD are not similar entities. However; we could not identify any molecular marker that would show whether a transition period existed between them.

Conclusion
As a result; OMBD seems to be a different disease than breast cancer with isolated bone metastases. The high risk of developing OMBD especially following locoregional recurrences increases the importance of locoregional therapy in large T and N stage tumors.
Larger case groups are needed to clarify whether these two subgroups, including patients with single and oligo-bone metastases, have different determinants.  The Overall Survival of Groups 1, 2 & 3.