Prevalence of Overt Metastases in Locally Advanced Breast Cancer

Clinical Oncology (2008) 20: 340e344 doi:10.1016/j.clon.2008.03.006

Original Article

Prevalence of Overt Metastases in Locally Advanced Breast Cancer H. Al-Husaini*, E. Amir*, B. Fitzgerald*, F. Wrighty, R. Denty, J. Fralicky, M. Clemons* *Princess Margaret Hospital, Toronto, Canada; yToronto Sunnybrook Regional Cancer Centre, Toronto, Canada

ABSTRACT: Aims: Locally advanced breast cancer (LABC) represents a wide spectrum of clinical presentations and poses significant clinical challenges for both patients and their physicians. Before starting neoadjuvant therapy, most patients undergo staging investigations, including a radioisotope bone scan, liver ultrasound and chest X-ray as per our provincial guidelines. The aim of this study was to document the prevalence of metastatic disease using standard baseline radiological staging in patients with LABC. Materials and methods: A retrospective chart review was carried out for LABC patients at two large Canadian centres between 2003 and 2006. Data on tumour characteristics and baseline staging tests were collected. Information on any confirmatory imaging (bone X-ray, computed tomography, magnetic resonance imaging, positron emission tomography) undertaken due to the presence of suspicious baseline tests or due to worrying symptoms was also obtained. The prevalence of metastatic disease after each baseline imaging technique was analysed, as was the frequency of discordance between baseline staging tests and confirmatory imaging where applicable. Results: In total, 144 patients with LABC were assessed. After initial staging investigations, 15 patients (10.4%) were diagnosed as having overt metastatic disease. Confirmatory imaging was carried out on 19 patients (13.2%); five (3.5%) for unexplained symptoms and 14 (9.7%) due to equivocal baseline imaging. These additional investigations isolated a further four subjects with metastatic disease, bringing the overall prevalence of overt metastases to 13.2%. Conclusions: Given that the rate of systemic relapse in patients with LABC is very high, current baseline staging investigations probably underestimate the true incidence of metastases. This study has shown that further confirmatory imaging can be helpful, especially in symptomatic patients, as it seems that negative baseline tests in these patients can be falsely reassuring. Accurate staging of patients with LABC has many advantages and, therefore, further research is needed to define the role of newer imaging modalities. Al-Husaini, H. et al. (2008). Clinical Oncology 20, 340—344 ª 2008 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Imaging, locally advanced breast cancer, metastases, staging

Introduction Breast cancer is the most commonly diagnosed cancer in Canadian women, with 22 500 new cases anticipated in 2007 [1]. Among these cases, locally advanced breast cancer (LABC), despite contributing to around 7% of cases, poses a significant clinical challenge due to the high prevalence of distant disease at first presentation and early disease relapse. LABC consists of a wide spectrum of clinical presentations, including stage IIIA (T0e2, N2, T3, N1e2), stage IIIB (T4, N0e2) and stage IIIC (any T, N3) disease [2]. Since 2003 we have established two dedicated clinics for women with LABC in order to explore potential research questions relating to various patient outcomes. A multidisciplinary approach to managing this group of patients offers the unique opportunity to carry out innovative treatment, translational and basic research. 0936-6555/08/200340þ05 $35.00/0

Traditionally, patients with LABC are treated with neoadjuvant systemic therapy. Neoadjuvant systemic therapy offers the clinical advantage of improving the surgical options, such as the ability to carry out more breastconserving procedures [3], and provides the clinician with an in vivo assessment of the response to chemotherapy. The response to neoadjuvant systemic therapy is a useful predictor of long-term outcome [4] and a pathological complete response is strongly associated with improved disease-free survival and overall survival [5,6]. Evidence shows that a full radiological work-up (radiological imaging of bone, lungs and liver) before any systemic therapy is only beneficial in patients with clinical stage III disease [7]. The Breast Cancer Disease Site Group of the Cancer Care Ontario Practice Guidelines Initiative (CCOPGI) reviewed the evidence for the use of routine chest radiography (CXR), bone scintigraphy and liver

ª 2008 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

PREVALENCE OF OVERT METASTASES IN LABC

ultrasonography in patients with stage I, II and III breast cancer [7]. They reported that fewer than 1% of patients with stage I breast cancer have radiologically detectable metastases, that 2.4% of patients with stage II disease have evidence of bone metastases, and that 2e8% of patients with stage III breast cancer have distant metastases (see Table 1). In addition, the false-positive rate for these investigations ranged from 10 to 66%, and was particularly high in patients with stage I breast cancer. Consequently, guidelines for baseline radiological staging were introduced in 2000 and further updated in 2002. These recommendations apply to women with newly diagnosed breast cancer, who have undergone surgical resection, and have no symptoms, physical signs, or biochemical evidence of metastases. With respect to patients with stage III disease, the rate of detection of metastatic disease using bone scintigraphy, liver ultrasonography and CXR is as little as 8.3, 2 and 1.7%, respectively [7]. Therefore, for these women, a bone scan, CXR and abdominal ultrasound are recommended (see Table 2). These guidelines reflect the increasing risk of a true positive radiological investigation with a more advanced cancer stage. In our programme, before starting neoadjuvant systemic therapy we radiologically stage our patients with bone scintigraphy, CXR and liver ultrasonography as per provincial guidelines [7]. Given the complexities of caring for these patients and the perceived increased risk of overt metastases, it is important to assess whether these guidelines are adequate for the detection of metastatic disease in LABC. This study therefore reviewed the results of radiological staging of our first 144 patients to explore the prevalence of overt metastatic disease after each baseline imaging technique.

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Table 2 e Cancer Care Ontario 2002 guidelines for radiological staging of asymptomatic patients with early breast cancer [7] Recommended staging Stage I

Stage II

Stage III

Bone scan Abdominal ultrasound

No No

Yes Yes

Chest X-ray

No

Yes Only if O4 lymph nodes positive Only if O4 lymph nodes positive

Yes

node involvement, hormonal receptor status, clinical stage), as well as baseline staging tests (bone scintigraphy, liver ultrasonography, CXR) were collected. The current version of the American Joint Committee on Cancer tumourenodeemetastasis staging system was adopted for staging purposes [2]. Data on the number and type of radiological investigations that were carried out and any subsequent confirmatory tests, such as bone radiography, computed tomography, magnetic resonance imaging (MRI) and/or positron emission tomography (PET), were collected. For each staging procedure, the prevalence defined as the number of patients with a diagnosis of metastatic disease after an imaging technique divided by the total number of patients tested was calculated. Furthermore, the rate of discordance between baseline staging investigations and confirmatory tests was assessed. Institutional research ethics board approval was obtained for this study.

Results Materials and Methods A retrospective chart review was carried out on patients referred for neoadjuvant systemic therapy for LABC at two large Canadian centres (Princess Margaret Hospital and the Toronto Sunnybrook Regional Cancer Centre) between 2003 and 2006. The medical oncology records were reviewed and data about both the patient and tumour characteristics (histology, tumour size, tumour grade on core biopsy, lymph Table 1 e Operative stage of disease and incidence of radiologically detected metastases (Cancer Care Ontario Practice Guideline Initiative) [7] Percentage of patients with metastases detected Breast cancer stage I II III False-positive rate

Ultrasound (n ¼ 1625)

Bone scan (n ¼ 5407)

Chest X-ray (n ¼ 3384)

0 0.4 2.0 33e66

0.5 2.4 8.3 10e22

0.1 0.2 1.7 0e23

In total, 144 patients with clinical LABC before neoadjuvant systemic therapy were assessed between 2003 and 2006 (see Table 3). Ninety-five per cent of patients had baseline staging that included CXR, radioisotope bone scan and liver ultrasound. The remaining 5% of patients had initial computed tomography. After the initial staging investigations, 15 patients (10.4%) were diagnosed as having overt metastatic disease. The most common sites of metastasis were bone (8.3%), liver (3.5%) and lung (2.7%) (see Table 4). An initial suspicion raised by unexplained symptoms baseline or by equivocal staging work-up was sometimes confirmed by further independent tests. These included five patients (3.5%) with negative baseline imaging and unexplained symptoms and 14 patients with equivocal baseline tests. Liver ultrasonographic abnormalities were evaluated by computed tomography and/or MRI (1%). Abnormal bone scintigraphy was evaluated by plain film bone radiography and/or computed tomography and/or MRI (7%). CXR abnormalities were evaluated by computed tomography (3%) (see Table 5). There were several discrepancies between baseline staging investigations and confirmatory imaging modalities. Bone scintigraphy detected metastases in eight of 12 patients with skeletal involvement. Computed tomography

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Table 3 e Patient characteristics Variable Median age Gender Female Male Menopausal status Pre Peri Post Missing data Clinical tumour stage Stage IIIA Stage IIIB Stage IIIC Missing data Histological type Invasive ductal carcinoma Invasive lobular carcinoma Other histology Missing data

Table 5 e Baseline staging work-up findings and the results of subsequent confirmatory tests Number (%) 51 years (range 27e91 years)

Bone scan A: staging confirmed

143 (99) 1 (1) 62 11 69 2

(43) (8) (48) (1)

52 73 12 7

(36) (51) (8) (5)

124 10 4 6

(86) (7) (3) (4)

Histological grade Grade 1 Grade 2 Grade 3 Missing data

10 65 46 23

(7) (45) (32) (16)

Hormonal receptor status ERþ/PRþ ERþ/PRe ERe/PRe Missing data

63 29 47 5

(44) (20) (33) (3)

B: downstaging C: upstaging

Chest X-ray A: staging confirmed B: downstaging C: upstaging Liver ultrasonography Downstaging

3 2 1

Confirmatory test

1 1 1 1 2

MRI MRI, bone plain film X-ray Computed tomography, MRI, bone plain film X-ray Computed tomography, MRI, bone plain film X-ray PET, bone plain film X-ray Computed tomography Computed tomography MRI Computed tomography, MRI

1 1 2 1

Computed tomography Computed tomography Computed tomography MRI

1

Computed tomography

MRI, magnetic resonance imaging; PET, positron emission tomography.

or MRI was carried out in patients with symptomatic lower back pain despite a negative bone scan in order to rule out spinal cord compression or vertebral metastases. Four of these patients were found to have evidence of bone metastases. Conversely, a single patient with a positive bone scan showed no evidence of metastatic bone disease after computed tomography. Lung metastases were detected in four patients. The use of thoracic computed tomography or MRI showed that three patients with a normal CXR did in fact have pulmonary involvement, whereas a single patient with a suspicious CXR showed no Table 4 e Prevalence of metastatic disease after radiological staging for locally advanced breast cancer patients

Bone metastasis Liver metastasis Lung metastasis Mediastinal lymphadenopathy

Number of patients

1

ER, oestrogen receptor; PR, progesterone receptor.

Site of metastasis

Baseline work-up

Number (%) 12 5 4 2

(8.3) (3.5) (2.7) (1.4)

evidence of lung involvement on computed tomography. Liver ultrasonography detected liver metastases in four patients, whereas computed tomography detected liver involvement in one patient in whom a liver ultrasound was not carried out. Liver ultrasonography was generally concordant with other imaging modalities with only a single patient with an equivocal liver lesion being shown to have no evidence of metastatic spread on computed tomography. Two patients went on to have a PET scan, which confirmed similar findings to bone scintigraphy and computed tomography, with bone and internal mammary lymph node metastases, respectively. In total, the use of secondary or confirmatory imaging isolated a further four patients as having distant or metastatic spread, increasing the overall prevalence to 13.2%.

Discussion The role of baseline radiological investigations for overt metastases in patients with early breast cancer is contentious, with many patients undergoing inappropriate radiological examination. Studies have shown that the prevalence of detectable metastatic disease in asymptomatic patients is low. However, rates of distant spread do increase from stage I to stage III disease [8], underscoring the problems of current radiological techniques in asymptomatic patients. Given the importance of significant false-positive radiological imaging, it is entirely appropriate that staging guidelines exist.

PREVALENCE OF OVERT METASTASES IN LABC

We have previously evaluated strategies to improve physician adherence to our provincial guidelines. These strategies resulted in a significant reduction in the proportion of patients with clinical stage I disease undergoing staging investigations. In clinical stage II there was no difference in the percentage of patients undergoing these investigations, whereas in stage III disease there was a trend towards all patients receiving staging tests, although this trend was not statistically significant [9]. The results of the current study show that the prevalence of metastatic disease in LABC was 13.2%, with the most common sites of metastases being bone (8.3%), liver (3.5%) and lung (2.7%). These figures are consistent with other published studies [7]. This supports the continued need for full routine staging tests for patients with LABC as compared with those women with earlier stage disease. In our study, the use of plain CXR, bone scintigraphy and liver ultrasonography (as per our provincial guidelines) isolated only 15 patients (10.4%) with metastatic disease at diagnosis. Based on equivocal baseline imaging or the presence of unexplained symptoms in the setting of negative baseline investigations, a cohort of patients (13.2%) went on to have further confirmatory imaging. The use of such confirmatory modalities isolated a further four patients (2.8%) with metastatic disease. This raises the question of whether negative baseline investigations are sufficient to accurately stage patients with unexplained symptoms. Data from this study seem to imply that in symptomatic patients, negative baseline investigations can be falsely reassuring. The ability to accurately stage patients has many benefits. First, clinicians will be better able to advise patients on their prognosis. Second, appropriate palliative measures could be introduced at an earlier opportunity. Finally, clinicians will be better able to individualise treatment to their patients. For instance, patients who are truly locally advanced can be offered more aggressive chemotherapy with curative intent as the potential longterm benefits far outweigh any short-term toxicities or quality-of-life disruption in these cases. Conversely, in those who present with metastatic disease, a more balanced, quality-of-life-oriented approach can be utilised. It is important to stress that the authors of this study would not support the blanket withdrawal of locoregional management in patients with metastatic disease. It is, however, considered beneficial for the accurate staging of disease to be known when decisions regarding adjuvant systemic therapy are made. Evidence shows that LABC is associated with a very high rate of relapse and eventual death. Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) programme shows that the 5-year relative survival rate for women with stage III breast cancer is 55%, with a median survival of just 6.4 years [10]. However, these numbers are misleading, as LABC is a heterogeneous disease and, as such, prognosis varies significantly. For instance, the SEER data have shown that women with inflammatory breast cancer, a subgroup of LABC, have a much worse prognosis, with a median survival of just 2.9 years [10].

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This discordance between initial staging investigations and long-term outcome queries the accuracy of the current modalities of staging. It is possible that these investigations underestimate the true incidence of metastases. It also questions whether other investigational modalities would be more accurate at detecting systemic spread. For instance, there is some evidence for the benefit of thoracic computed tomography in inflammatory breast cancer [11]. It is highly probable that a proportion of patients with LABC have detectable metastatic disease at diagnosis. Such distant spread may well be detectable by high-resolution imaging technologies such as computed tomography, MRI or PET. Clearly, not all patients with LABC who are destined to relapse will have detectable metastases at baseline and in such a population it is hoped that the characterisation of disseminated tumour cells and circulating tumour cells will shed new light on the complex process underlying early tumour cell dissemination and metastatic progression. However, at present the use of disseminated and circulating tumour cells is limited to prognostic information and thus far there have been no validated data on their use in the context of tumour staging. Nevertheless, further research on such tumour cells may help to identify novel targets for biological therapies aimed at preventing metastatic relapse, as well as to provide the ability to monitor the efficacy of these therapies [12]. This study did have limitations. First, it was retrospective and as such the completeness of the data collected will be questioned. However, accurate and complete data extraction at our institutions is possible, as all radiology results are computerised. Second, our study was limited to the types of investigation outlined in the CCOPGI, and as such the use of computed tomography or PET was not formally assessed. At present, the role of these modalities is not included in published guidelines. However, there are limited reports that PET may be a more sensitive method of detecting metastases, particularly in locally advanced disease [13]. However, the role of PET still needs to be confirmed in randomised controlled studies. In conclusion, this study supports the current evidence that about one in 10 women with LABC present with distant spread detectable by baseline imaging investigations. However, the high prevalence of systemic relapse in patients with LABC suggests that the currently used investigations may underestimate this figure. Data from this study have shown that the use of higher resolution imaging techniques can isolate further patients with overt metastases in a cohort of patients with unexplained symptoms. These data allow for a hypothesis to be generated stating that a significant number of symptomatic patients with negative baseline staging will probably be upstaged by higher resolution imaging. It is possible that a proportion of asymptomatic patients may also have overt metastatic disease, although the ability to answer this question is outside the scope of the current study. Therefore, investigational modalities such as computed tomography, MRI or PET need to be compared in controlled studies to assess whether they are better able to accurately stage patients with LABC.

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Given the relatively small number of women with LABC, these patients are traditionally an understudied population and there is only limited scope for the collection of prospective, long-term data. Four cancer centres in Ontario have formed a provincial consortium involving experts in this field. The goal of this consortium is to influence the direction of innovative practice and to merge prospective data. A provincial study assessing investigational modalities and whether they are better able to accurately stage this group of patients is currently in development. At the core of this study is the hypothesis that more detailed staging investigations may show a higher prevalence of overt metastatic disease in patients with LABC. This ability to more accurately stage patients with LABC may allow for a greater consistency between staging and the long-term outcome of this disease group. It will only be thorough this type of multicentre collaboration that it will be possible to assess whether alternative staging strategies are needed for patients with LABC. Author for correspondence: M. Clemons, Princess Margaret Hospital (Suite 5-205), 610 University Avenue, Toronto, ON M5G 2M9, Canada. Tel: þ1-416-946-4534; Fax: þ1-416-946-2983; E-mail: [email protected] Received 22 October 2007; received in revised form 6 March 2008; accepted 10 March 2008

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