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Keywords:

  • breast carcinoma;
  • bone metastases;
  • hormonal therapy;
  • chemotherapy;
  • survival

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

The current study was performed to study metastatic breast carcinoma that remains confined to bone.

METHODS

The medical notes of 2514 breast carcinoma patients who were treated in 2 academic units over a 20-year period were screened and patients who fulfilled the following criteria were selected: 1) clinical manifestation and imaging confirmation of bone metastases, and 2) metastatic disease remaining confined to bone for a minimum of 24 months. Available clinical and pathologic data were recorded and analyzed. The objective of the current study was to describe this clinical entity and investigate possible correlations between clinicopathologic parameters and clinical outcome.

RESULTS

A total of 104 patients (4% of the total screened patient population) fulfilled the study criteria. The majority of patients were postmenopausal, with a median age of 58 years; 44 of the patients were found to have metastases at the time of presentation (M1) and 60 patients developed metastases at a median of 38 months (range, 8–160 months) after surgery for the primary tumor. Metastases remained confined to bone for a median of 50 months. Survival after the diagnosis of bony metastases was 72 months and was similar in the 2 groups (66 months vs. 78 months). Of the patients treated, 80% responded to hormonal therapy, and 76.5% responded to chemotherapy. There was no association noted between survival and tumor grade, anatomic distribution, or disease extension.

CONCLUSIONS

Bone-confined metastatic breast carcinoma has an indolent clinical course that alleviates the need for vigorous follow-up and calls into question aggressive therapeutic approaches in these patients. Translational studies are warranted to map the molecular profile, leading to the development of targeted therapies in this group of patients. Cancer 2004. © 2004 American Cancer Society.

The affinity of breast carcinoma for the skeleton is well known. Bone is a common site of the metastatic dissemination of breast carcinoma and the majority of patients have bone metastases when they die.1 Several molecules have been implicated in this metastatic process, but to our knowledge the key mechanism for the development of bone metastases remains a target of investigation.2, 3

Researchers have shown that patients with metastatic spread limited to the skeleton have a relatively prolonged survival and a favorable response to systemic therapy.4 However, whereas breast carcinoma patients whose first metastasis developed in the skeleton have been investigated adequately, to our knowledge, systemic insight into the clinical course and prognosis of, as well as therapy for, breast carcinoma patients in whom metastases remain confined to the skeleton over a prolonged period has been poor to date.5, 6

The current retrospective study was conducted to ascertain the clinical characteristics and define the pathologic features of breast carcinoma occurring in patients who predominantly develop bone metastases and to describe the clinical course of their disease.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The medical files of 2514 patients diagnosed with breast carcinoma who were treated and followed in the Medical Oncology Departments of Ioannina University Hospital and AHEPA University Hospital between 1986–2000 were screened manually and those patients who fulfilled the following criteria were selected: 1) clinical manifestations and imaging confirmation of bone metastases, and 2) metastatic disease remaining confined to bone for a minimum of 24 months.

The selected medical notes were reviewed and the following data were recorded: age and menopausal status at the time of diagnosis, histologic type and grade of the tumor, tumor size, axillary lymph nodes status, estrogen and progesterone receptors, timing of the diagnosis of bone metastases and description of metastatic dissemination, duration of metastatic disease confined to bone, first-line hormonal and/or cytotoxic therapy for metastatic disease and response to treatment, and major skeletal events and survival after the diagnosis of metastases to bone. Major events of bone metastases were defined as spinal cord compression, pathologic fractures, and symptomatic hypercalcemia.

Objective responses were assessed independently by two investigators for confirmation. Because to our knowledge the response evaluation criteria for breast carcinoma-related bone metastases have not been validated to date,7–9 we assessed response to treatment in these patients using five parameters: pain relief, fluctuation of surrogate tumor marker CA 15-3 or serum alkaline phosphatase, and radiologic or scintiscan imaging studies of bone. Complete response was defined as the disappearance of any foci on bone scan or radiologic documentation of the healing of bone lesions occurring simultaneously with normalization of serum CA 15-3 (value < 30 ng/mL) and alkaline phosphatase values. A partial response was defined as a > 50% reduction in the serum CA 15-3 and alkaline phosphatase levels, if applicable, combined with documented improvement of disease-related symptoms (defined as a > 50% reduction in the use of analgesics, along with evidence of reossification of lytic bone lesions and/or improvement noted on bone scan). Patients with stable serum CA 15-3 and/or alkaline phosphatase levels and disease-related symptoms were considered to have stable disease. The appearance of new lesions on imaging studies, a > 30% increase in serum CA 15-3 and/or alkaline phosphatase levels that lasted for > 2 months, or the progression of disease-related symptoms were considered as progressive disease.

The primary endpoint of the current study was to characterize in detail this particular clinical subgroup of patients with breast carcinoma. The secondary endpoint was to investigate potential correlations between clinicopathologic parameters and response to treatment or disease outcome. Survival was calculated using the Kaplan–Meier method and the comparison of survival curves was performed by the log-rank test. The GraphPad InStat (version 3.05) and Prism version 4 software programs (GraphPad Software, Inc., San Diego, CA) were used for statistical analysis and graphing.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Demographics

All 104 patients with breast carcinoma who were analyzed in the current study met the criteria for bone-confined disease. Patient characteristics are shown in Table 1. The median age of the patients was 58 years (range, 26–79 years) and the median (ECOG) performance status (PS) was 1 (range, 0–2). The majority of patients (90 patients) were postmenopausal at the time of the breast carcinoma diagnosis. The pathologic subtype of the primary tumor was classified as ductal in 79 patients, lobular in 15 patients, and mixed in 10 patients. Fifty tumors were characterized as Elstan and Ellis Grade 1 or Grade 2 and 32 were classified as Grade 3. In 22 cases the histologic grade was not given. With regard to axillary lymph nodes, the lymph nodes were infiltrated (median number of lymph nodes affected was 3; range, 1–55 lymph nodes) in 70 patients, clear in 23 patients, and unknown in 11 patients. Nerve or vessel infiltration was detected in 23 patients.

Table 1. Patient Characteristics
ParameterNo. of patients
  1. Pre: premenopausal; Post: postmenopausal; ER: estrogen receptor; PR: progesterone receptor; +: positive; −: negative.

Screened medical records2514
Cases selected104
Median age (yrs) (range)58 (26–79)
Performance status (range) 1 (0–2)
Menopausal status 
 Pre14
 Post90
Pathology subtype 
 Ductal79
 Lobular15
 Mixed10
Tumor classification 
 T120
 T250
 T3 + T413
 Tx21
Axillary lymph node status 
 N023
 N153
 N217
 Nx11
Diagnosis of bony metastases 
 At presentation44
 At follow-up60
Histologic grade 
 1–250
 332
 Unknown22
Hormonal receptors 
 ER/PR (+)65
 ER/PR (−)19
 Unknown20
Adjuvant therapy 
 Chemotherapy20
 Hormonal therapy29
 Radiotherapy11

In 44 patients (42.3%) bony metastases were diagnosed at the time of presentation whereas in 60 patients (57.7%), the metastases occurred at a median of 38 months after diagnosis (range, 8–160 months). Adjuvant chemotherapy was offered to 20 patients and hormonal therapy was offered to 29 patients. Chest wall irradiation was given to 11 patients.

The median serum CA 15-3 value was 30 ng/mL at the time of diagnosis of bony metastases (range, 9–1040 ng/mL) and was normal in 32 patients. Alkaline phosphatase was found to be abnormally elevated in 25 patients at the time of diagnosis of bony metastases with a median value of 315 ng/dL (range, 128–1070 ng/dL) and in all patients at some time during the follow-up period. Data regarding estrogen receptor and progesterone receptor were known in approximately two-thirds of the patients and were unavailable for a number of patients who had been diagnosed long before (the first patients in this series were diagnosed before 1990). The majority of the tumors (65 patients) had positive estrogen and/or progesterone receptors.

Anatomic Distribution of Skeletal Metastases

The spine was the most common site of metastases (63%), followed by the pelvis, sternum, ribs, scalp, and long bones. At the time of diagnosis, 26 patients (25%) had a single bone metastasis and 78 patients (75%) had multiple bone metastases. Extensive metastatic disease was evident in 6% of patients (Table 2).

Table 2. Distribution of Skeletal Metastases and Major Skeletal Events
Event%
Bone lesions 
 Single25
 Multiple75
Skeletal metastatic sites 
 Spine63
 Pelvis15
 Sternum15
 Ribs20
 Scalp8
 Long bones9
Major events 
 Spinal cord compression7
 Pathologic fractures6

Major Skeletal Events

Thirteen patients (13%) experienced major skeletal events. Spinal cord compression was reported to occur in 7 patients (7%) and 6 patients (6%) had pathologic fractures. Serum calcium was found to be elevated in only five patients. A maximum value of 12 ng/mL (upper limit of normal of 11 ng/mL) was recorded; however, none of the patients affected developed clinically relevant hypercalcemia (Table 2).

Response to Treatment

All patients required palliative radiotherapy at some time during the course of their disease. Anticipatory radiotherapy also was given in a number of patients to prevent major complications.

Systemic hormonal or cytotoxic therapy was the main treatment option in these patients; 53 patients received hormonal therapy and 61 patients received chemotherapy as first-line systemic therapy. Of the 51 patients who received chemotherapy, 34 were offered doxorubicin or mitoxantrone-based chemotherapy and 27 received the cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) combination. An objective response to first-line chemotherapy, as defined earlier, was achieved in 39 patients (76.5%). With regard to first-line hormonal therapy, 49 patients received tamoxifen and 4 were treated with an aromatase inhibitor (letrozole). Thirty-five patients received > 1 hormonal therapy (29 received a second-line hormonal therapy and 6 patients were treated with > 2 hormonal therapies). An objective response to first-line hormonal therapy was observed in 83 patients (80%), whereas 13 patients also responded to second-line hormonal therapy (44%) and 2 patients responded to third-line hormonal therapy. Approximately two-thirds of the patients also received systemic bisphosphonates (Table 3).

Table 3. Treatment
TreatmentPatients treatedResponse rate (%)
  • CMF: cyclophosphamide, methotrexate, and 5-fluorouracil; LHRH: luteinizing hormone-releasing hormone.

  • a

    Involved sites.

Hormonal first-line therapy 80
 Tamoxifen49 
 Aromatase inhibitors4 
Chemotherapy 76.5
 Doxorubicin or mitoxantrone-based34 
 CMF27 
Hormonal second-line therapy 44
 Megestrol10 
 Aromatase inhibitors12 
 LHRH agonists (triptorelin)7 
Bisphosphonates70 
Radiotherapya104 

Bone-Confined Disease and Survival after the Diagnosis of Bone Metastases

The median duration of bone-confined disease was 50 months. The duration of bone-confined disease was not found to differ significantly between the 2 groups of patients (54 months in the M1 patients vs. 50 months in the M0 patients; P = 0.3)

The median survival of the patients after the diagnosis of bony metastases was 72 months. Again, survival was not found to differ significantly between the 2 groups (66 months in the M1 patients vs. 78 months in the M0 patients; P = 0.7) (Fig. 1). We did not find any difference in survival with regard to histologic tumor type and grade, anatomic distribution, or the number of bone metastases in this highly selected group of patients.

thumbnail image

Figure 1. Survival of patients with bone-confined metastatic breast carcinoma (n = 104) after the diagnosis of skeletal metastases. M1 (dashed line): patients with bony metastases present at the time of diagnosis; M0 (solid line): patients with bony metastases that occurred during follow-up.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In the current study, we investigated the clinical characteristics and the pathologic features of metastatic breast carcinoma that remains confined to bone for a prolonged period. We focused on describing the clinical course of the disease and also attempted to determine any clinicopathologic correlations.

Recent improvements in the available therapeutic options for breast carcinoma patients affected by bone metastases have revitalized the interest of clinical investigators in the study and identification of patients at risk of developing skeletal metastases.10, 11 In this context, the group of breast carcinoma patients who have metastases confined to bone for a prolonged period of time becomes clinically relevant. This specific clinical entity already was identified 20 years ago by Sherry et al.4 Later, Coleman et al., in presenting a single unit experience, found among those breast carcinoma patients whose disease first metastasizes to bone a subgroup of patients with disease confined predominately to the skeleton, and characterized it as bone-only disease. These patients were elderly and had predominantly lobular carcinoma and minimal axillary lymph node involvement at the time of diagnosis. The median survival of these patients with bone–only disease was reported to be 2.1 years.6

In the studies referred to earlier, the recognition and characterization of the clinical course of this special category of patients with breast carcinoma was attempted. However, to our knowledge, the authors did not define a minimal time for the disease to be confined to the skeleton to characterize this as a bone-only metastatic disease. Our objective was not only to report our experience with bone-confined breast carcinoma but also to single out those patients whose metastatic disease remained confined to bone over a prolonged period of time. We used a 2-year period to approximate the median survival reported in previous studies and found that the median time that metastatic disease remained confined to bone was approximately 4 years.

The majority of the patients in the current study were postmenopausal and had limited lymph nodal involvement and positive estrogen and progesterone receptors. The majority of patients demonstrated an impressive response to hormonal therapy as well as first-line chemotherapy. The hormonal sensitivity of this clinical entity also is supported by the fact that, on average, 44% of patients achieved disease control with second-line hormonal therapy. These findings are in keeping with what already has been demonstrated with regard to the indolence of the clinical course and sensitivity to treatment in these patients.12 What is remarkable is that both groups of patients shared an equally long survival after the development of bony metastases of approximately 6 years. To our knowledge, this long survival, even in patients who already had osseous metastases at the time of presentation, is much longer compared with that reported for historic controls.13

The results of the current study provide evidence that metastatic breast carcinoma confined to bone constitutes a special clinical entity characterized by an indolent course, a good response to hormonal therapy as well as systemic chemotherapy, and a better treatment outcome compared with other metastatic entities. The life expectancy in these patients allows clinicians to utilize multiple treatment modalities. The administration of bisphosphonates is recommended with the objective of minimizing skeletal complications and, if possible, improving survival.11 Finally, the indolent course of bone-confined metastatic breast carcinoma, as demonstrated in the current study, mitigates the need for vigorous follow-up strategies for the detection of bone metastases after primary treatment for breast carcinoma and makes aggressive therapeutic approaches questionable. This is supported further by findings that demonstrated that overall survival did not differ significantly between patients who were symptomatic, those who were asymptomatic, and those with elevated tumor markers who had a positive bone scan.14

We suggest that translational research studies are warranted to map the molecular profile of these tumors. This could provide the potential to identify those patients at risk of developing predominately skeletal metastases earlier in the course of the disease, with the intent to consider prophylactic therapeutic intervention, and also could lead to the development of novel, targeted therapies for this group of patients.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES