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Identifying Breast Cancer Patients at High Risk for Bone Metastases

From the International Breast Cancer Study Group, Division of Medical Oncology, European Institute of Oncology, Milan, Ospedali Civili, Brescia, and Centro di Riferimento Oncologico Aviano, Aviano, Italy; International Breast Cancer Study Group Statistical Center, Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA; Kantonsspital and Zentrum für Tumordiagnostik und Praevention, St Gallen, International Breast Cancer Study Group Coordinating Center and Institute of Medical Oncology, Inselspital, Bern, and Ospedale Civico, Lugano, Switzerland; Australian Cancer Society, University of Sydney, Sydney, Royal Melbourne Hospital, Victoria, and Australia, New Zealand Trials Group, Waratah, Australia; Institute of Oncology, Ljubljana, Slovenia; Wynberg Hospital, Wynberg, Cape Town, South Africa; Hospital de la Seguridad Social, Madrid, Spain; and Sahlgrenska University/Moelndal’s Hospital, Moelndal, Sweden.

Address reprint requests to Marco Colleoni, MD, International Breast Cancer Study Group, Division of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy; email marco.colleoni{at}ieo.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To identify patient populations at high risk for bone metastases at any time after diagnosis of operable breast cancer, because these patients are potential beneficiaries of treatment with bisphosphonates.

PATIENTS AND METHODS: We evaluated data from 6,792 patients who were randomized in International Breast Cancer Study Group clinical trials between 1978 and 1993. Median follow-up was 10.7 years. A total of 1,275 patients (18.7%) presented with node-negative disease, whereas 3,354 patients (49.4%) had one to three and 2,163 patients (31.9%) had four or more involved axillary lymph nodes. We also assessed the incidence of subsequent bone metastases in the cohort of 1,220 patients who had a first event in local or regional sites or soft tissue alone. Median follow-up for this cohort was 7.7 years from first recurrence.

RESULTS: For the entire population with operable disease, the cumulative incidence of bone metastases at any time was 8.2% at 2 years from randomization and 27.3% at 10 years. The highest cumulative incidences of bone metastases at any time were among patients who had four or more involved axillary nodes at the time of diagnosis (14.9% at 2 years and 40.8% at 10 years) and among patients who had as their first event a local or regional recurrence or a recurrence in soft tissue, without any other overt metastases (21.1% at 2 years from first recurrence and 36.7% at 10 years).

CONCLUSION: Treatments to prevent bone metastases may have a major impact on the course of breast cancer and may be most efficiently studied in populations with several involved axillary nodes at the time of presentation and in populations with local or regional recurrence or recurrence in soft tissue.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
MANY BREAST CANCER patients who are free of overt metastases after initial local and regional treatment eventually die from recurrence of distant disease. Current thinking is that occult micrometastases, present at the time of diagnosis and surgery, are responsible for relapse.^1,2 Overt metastatic breast cancer may affect virtually every organ, and the specific metastatic sites usually determine the type and degree of symptoms. In patients with node-positive breast cancer, bone (either alone or with other foci of relapse) is one of the most frequent sites of overt metastatic involvement.^3,4 Other frequent metastatic sites are the liver, lungs, and pleura, as well as soft tissues including mastectomy scars. Locoregional recurrence of breast cancer occurs in up to one third of patients after primary treatment.^5-8 Breast cancer patients with locoregional recurrence have been found to have 5-year disease-free survival rates of 13% to 37% and overall survival rates of 21% to 50%.^9-15 A 10-year estimated overall survival rate of up to 26% has been reported, indicating that long-term complications of disease are real and should be taken into account.^3,4,10 Adjuvant systemic therapy was found to reduce the risk of recurrence effectively in soft tissue. On the other hand, the incidence of recurrence in bone and viscera was less influenced by adjuvant systemic therapy.¹⁰

A better description of relapse patterns may improve patient outcome by permitting a better understanding of site-specific risk, which could lead to targeted therapeutic approaches. A strategy for prevention of bone metastases might be implemented using a specific treatment aimed at reducing clinical progression of disease in this site. Recent studies have suggested that using bisphosphonates in addition to systemic antineoplastic therapy might reduce the incidence and number of bone metastases. A total of 302 patients with primary breast cancer and tumor cells in the bone marrow were randomized to receive either clodronate therapy or standard follow-up.¹⁶ A statistically significant reduction of new bone (and also visceral) metastases was observed with the clodronate treatment.¹⁶ A study involving 1,079 patients with metastatic disease demonstrated a clinically relevant reduction in the risk of progression of bony lesions with the use of oral clodronate compared with placebo (relative risk, 0.51; 95% confidence interval, 0.30 to 0.88; P = .012).¹⁷ However, a third study, involving 299 patients, found that administration of oral clodronate did not improve overall outcome and did not have a beneficial effect on the incidence of bone metastases.¹⁸ It is therefore essential to identify a patient population in which there is a high incidence of bone metastases and in which events of interest occur in a short space of time, to allow rapid assessment of the potential benefit of the use of bisphosphonates.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We analyzed data from 6,792 eligible patients with breast cancer who were entered onto International Breast Cancer Study Group (IBCSG; formerly the Ludwig Breast Cancer Study Group) trials I through VII^19-23 between 1978 and 1993 (Table 1).

Clinical, hematologic, and biochemical assessments of each patient were required every 3 months for 2 years, every 6 months until the end of the fifth year, and yearly thereafter until death. All sites of disease recurrence, whether first or subsequent, were recorded in the study databases. In trials I through V, chest x-rays and bone scans were required every 6 months for 2 years and once yearly up to 5 years and were recommended beyond the fifth year only if clinically indicated. In trials VI and VII, chest x-rays and bone scans were required, but further x-rays and scans were obtained only if clinically indicated.

All patient data, including all data regarding disease- and survival-related events, were reviewed and classified by the medical study coordinators (A.G. and M.C.-G.)

Statistical Methods
Cumulative incidence functions for competing causes of recurrence were estimated.²⁴ These functions estimate the actual percentage of patients who will experience the various competing events within the study cohorts as opposed to the overestimated percentages obtained with the Kaplan-Meier method based on the cause-specific hazards.^25,26 Differences between the cumulative incidence functions according to patient subgroups were tested for statistical significance using the procedure of Gray.²⁷ Analyses were conducted to determine whether the risk of recurrence in bone increased according to baseline characteristics and after a first local or regional recurrence or a first distant recurrence in soft tissue. A cumulative incidence function regression model of Fine and Gray²⁸ was used for multiple regression analyses. Covariates included in the model were nodal status, pathologic tumor size, estrogen receptor (ER) status, menopausal status, and age. Likelihood ratio tests were used to obtain the statistical significance of each factor, including all other factors in the model. To determine whether a first local or regional event or a first event in soft tissue increased the risk of subsequent recurrence, we used Cox proportional hazards regression models, including a time-varying covariate for the occurrence of such a first event.²⁹ All P values were two-sided.

Categories of Sites of Recurrence
All first recurring breast cancer events were classified according to their sites, as follows: local recurrences, confined to the ipsilateral chest wall and including mastectomy scars; regional recurrences, including ipsilateral axillary, supraclavicular, and internal mammary lymph node metastases; distant recurrences in soft tissue; bone metastases; and visceral metastases, including all other organ involvement and diffuse intra-abdominal metastases. Other first events, including contralateral breast cancer, non–breast cancer second malignancies, and deaths without malignancies, were also recorded. Any event was considered to be a component of a first event if diagnosed within a 2-month time frame. Time to first event was defined as time from randomization to the occurrence of a first event of any type.

Because special emphasis was being placed on the incidence of recurrence in bone, occurrence of bone metastases with or without recurrence at any other site was classified as the event of interest. All other sites of first recurrence (not bone) and any other event, such as contralateral breast cancer, non–breast cancer second primary tumors, and deaths without recurrence, were considered competing events. The sum of the cumulative incidence of bone metastases plus the cumulative incidence of the other competing events equals the cumulative incidence of recurrence due to any cause.

In addition to evaluations according to site of first recurrence, we calculated cumulative incidence of events in bone at any time (either as first events or as subsequent recurrences). Time to recurrence in bone at any time was defined as the time from randomization to the first or subsequent event in bone, whichever occurred first. Death before recurrence in bone was considered the only competing event in this analysis. Otherwise, patients’ data were censored at the time they were last known to be alive without recurrence in bone.

We analyzed data from two populations. The first population included all eligible patients who were enrolled onto the trials (6,792 patients). We evaluated data relating to bone as the first site of recurrence, as well as incidence of bone recurrence at any time. The second population included 1,220 patients whose first recurrence was local or regional or in soft tissue (including lymph nodes). Previous analysis of data from the IBCSG database indicated that these sites of recurrence share a similar pattern of subsequent recurrence.³ The cumulative incidence of subsequent recurrence in bone and subsequent competing events was calculated. The time to subsequent recurrence was measured from the time of the first local or regional event or first event in soft tissue. We also analyzed the cumulative incidence of subsequent recurrence in bone at any time after a local or regional event or an event in soft tissue; death without subsequent recurrence in bone was the only competing event.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Included in the analysis were 6,792 eligible patients from IBCSG Trials I through VII. A total of 6,074 patients (89.4%) had total mastectomy and axillary clearance as the primary treatment; 10.6% had lumpectomy and axillary clearance with irradiation of the breast. A total of 1,275 patients (18.7%) had node-negative disease at the time of presentation, 3,354 (49.4%) had one to three positive axillary lymph nodes, and 2,163 (31.9%) had four or more positive lymph nodes. Of the patients with known pathologic tumor size, 55.6% had tumors that were larger than 2 cm. For all trials, ER-positive status was defined as ER levels 10 fmol/mg cytosol protein based on biochemical assay (3,724 patients were considered ER-positive), low ER levels were defined as levels of 1 to 9 fmol/mg (967 patients were considered to have low ER levels), and ER-negative status was defined as ER levels equal to zero (889 patients were considered ER-negative). ER status was unknown in 1,212 patients. A total of 3,700 patients (54.5%) were premenopausal, whereas 3,092 were postmenopausal at the time of study entry. A total of 313 patients (4.6%) were younger than 35 years, 39.0% were 35 to 49, 30.0% were 50 to 59, and 25.6% were 60 years of age.

At a median follow-up of 10.7 years, 54.7% of all patients (3,714 of 6,792) experienced a first event, namely disease recurrence at known sites (n = 3,162), contralateral breast cancer (n = 206), recurrence at an unknown site (n = 8), a non–breast cancer second primary tumor (n = 173), or death without recurrence (n = 165). Overall, bone was a component of first recurrence in 17.1% of patients; viscera, and not along with bone, were components of first recurrence in 11.5%; local or regional sites or soft tissue was a component in 18.0%, and other events were components in 8.1%. Forty-five percent of patients were alive without recurrence.

The site-specific cumulative incidences of bone metastases and other competing events as first recurrences are shown in Fig 1. At 10 years from study entry, the cumulative incidence of bone metastases as components of first recurrences was 17.8%, and the cumulative incidence of competing first events was 38.5%. At 10 years, the total cumulative incidence of recurrence due to any cause as a first event was 56.3% (17.8% + 38.5%).

View larger version (12K): [in this window] [in a new window]   Fig 1. Cumulative incidence of bone metastases and other competing events as first recurrences among 6,792 patients. Time was measured from the date of randomization.

View larger version (19K): [in this window] [in a new window]   Fig 2. Cumulative incidence of bone recurrence at any time, from the time of randomization, among 6,792 patients. (A) Overall results and (B) results according to nodal status (node-negative, n = 1,275; one to three positive nodes, n = 3,354; four positive nodes, n = 2,163) are shown.

View larger version (14K): [in this window] [in a new window]   Fig 3. Cumulative incidence of recurrence in bone as the first subsequent recurrence among the 1,220 patients whose first recurrence was local or regional or in soft tissue or nodes. Time was measured from the date of the first recurrence.

View larger version (13K): [in this window] [in a new window]   Fig 4. Cumulative incidence of bone events at any time, from the date of first recurrence, among the 1,220 patients whose first recurrence was local or regional or in soft tissue or nodes.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

We used cumulative incidence estimates for bone metastases, considering recurrences at other sites, second primary tumors (breast and nonbreast), or death without recurrence as competing events.^25,26 Unlike percentages calculated using the Kaplan-Meier method, such approaches do not lead to overestimation of the percentage of patients developing bone metastases. The cumulative incidence of competing events provides the background against which bone metastases might be observed; for example, a high risk of competing events reduces the chance of observing bone metastases. Thus, presentation of both cumulative incidence of bone metastases and cumulative incidence of competing events is required for a comprehensive evaluation.

Considering patients in the adjuvant treatment setting, we found the incidence of bone metastases to be highest among those presenting with four or more positive nodes. Other authors recently presented a higher incidence of first recurrence in bone among patients with node-positive disease.^30-32 The National Surgical Adjuvant Breast and Bowel Project concluded, on the basis of an analysis of 14,614 patients, that node-positive patients have a higher 5-year incidence of bone metastases than do patients with node-negative disease.³² Results of this study have been reported only in abstract form, and a detailed analysis by number of axillary nodes involved was not presented, nor was the cumulative incidence within specific time frames. Furthermore, only the incidence of bone metastases as first metastases could be assessed. In our study, among patients with four or more axillary lymph nodes involved, the cumulative incidence of bone metastases as first metastases was 12.2% 2 years after randomization and 26.8% at 10 years. With regard to bone metastases at any time as a possible end point for future evaluations of bisphosphonates, the cumulative incidence was 14.9% at 2 years and 40.8% at 10 years. Bone metastases also occur during follow-up in patients with high-risk node-negative disease, but the relatively limited number of skeletal metastases in this population (202 of 1,275 patients had recurrence in bone) did not allow further definition of predisposing features for such event.

Patients with larger primary tumors had a higher risk of both bone metastases and competing events. The initial site of recurrence differed according to ER content in the primary tumors. In fact, although patients with ER-negative tumors or tumors with low ER levels had a higher early incidence of bone metastases than did patients with ER-positive tumors, ER-positive primary tumors were ultimately predictive of a higher long-term incidence of recurrence in bone. This might be due primarily to a better control of disease with endocrine treatments among patients with ER-positive tumors (as indicated by a lower risk of competing events), leaving them at higher risk for later recurrence in the form of slow-growing tumors.

Although the incidence of bone metastases did not differ according to menopausal status, there was a suggestion that younger patients (< 35 years of age) were at higher risk. Multiple regression analyses showed that nodal status, tumor size, ER status, and young age predicted statistically significant differences in the incidence of bone metastases. Other histologic factors, such as tumors growing in a strand growth pattern or with fibrotic focus³³ or tumors without either squamous features or diffuse involucrin expression,³⁴ might also become useful for predicting a high risk of bone metastases. On the basis of routinely available features, however, it can be said that patients with four or more nodes are at high risk of developing a bone metastasis either as a first recurrence or at any time.

The most relevant observation concerning the patterns of distant metastases was the high incidence of subsequent bone involvement among patients with first recurrence in local sites or in soft tissue or nodes. In these patients, we found a high incidence of subsequent recurrence in bone within 2 years of the first recurrence (21.1%) and a 10-year cumulative incidence of 36.7% with regard to skeletal involvement at any time (Table 5). There was no significant difference between premenopausal and postmenopausal patients in terms of rates of bone metastases, nor was there any significant difference between any other baseline features that would indicate a different pattern of recurrence.

Bisphosphonates might reduce the release of growth factors from microfoci of bone destruction, thereby reducing bone absorption and decreasing stimuli of micrometastatic breast cancer.^35,36 This therapeutic pathway, which should be distinguished from the effect on osteolytic lesions, is likely to influence tumor growth and progression more efficiently with early rather than delayed use of these compounds.^37,38 The effect of bisphosphonates is thus hypothesized to be additive to the effect of other antineoplastic drugs used in the adjuvant treatment setting. The combination of bisphosphonates and other systemic treatments might be used to redefine an adjuvant strategy.³⁹ In addition, a specific site-related effect might be achieved with bisphosphonates, because adherence of tumor cells to the bone is reduced if bisphosphonates are absorbed by the bone matrix.^40-42

Thus, in this study, two patient populations were found to have a high incidence of bone metastases at any time: patients with four or more involved axillary lymph nodes and patients who had a first recurrence in local, regional, or distant soft tissue sites. The second patient population had a steep cumulative incidence curve within the first 2 years, making this population particularly suitable for rapid evaluation of the effectiveness of treatment with bisphosphonates. It might be important, therefore, to study the effects of bisphosphonates within both subpopulations, to take advantage of the different patterns of subsequent events and because few clinical research trials are conducted in women like those in the latter group.

	ACKNOWLEDGMENTS

 
We thank the patients, physicians, nurses, and data managers who participate in the International Breast Cancer Study Group trials. We acknowledge Mary Isley for her special contributions as chief data manager for the group and Robert J. Gray, PhD, for his help with statistical analysis of the cumulative incidence estimates.

	NOTES

 
Initial support was provided by the Ludwig Institute for Cancer Research, the Cancer League of Ticino, and the Swiss Cancer League. Continuing support for central coordination, data management, and statistics is being provided by the Swedish Cancer League, Australian Cancer Society, Australian New Zealand Breast Cancer Trials Group (National Health and Medical Research Council grants no. 880513 and 910420), Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research, American-Italian Cancer Foundation (AICF 101-98 and 101-99), and National Cancer Institute (grant no. CA-75362).

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Submitted November 4, 1999; accepted June 21, 2000.

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