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Metabolic Flare: Indicator of Hormone Responsiveness in Advanced Breast Cancer

From the Divisions of Nuclear Medicine and Radiological Sciences, Edward Mallinckrodt Institute of Radiology, Department of Medicine, and Division of Biostatistics, Washington University School of Medicine, St Louis, MO; and Department of Chemistry, University of Illinois, Urbana, IL.

Address reprint requests to Farrokh Dehdashti, MD, Mallinckrodt Institute of Radiology, 510 South Kingshighway Blvd, St Louis, MO 63110; email: dehdashtif{at}mir.wustl.edu

	ABSTRACT

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PURPOSE: The purpose of this study was to investigate whether positron emission tomography (PET) with the glucose analog [¹⁸F]fluorodeoxyglucose (FDG) and the estrogen analog 16 alpha-[¹⁸F]fluoroestradiol-17 beta (FES), performed before and after treatment with tamoxifen, could be used to detect hormone-induced changes in tumor metabolism (metabolic flare) and changes in available levels of estrogen receptor (ER). In addition, we investigated whether these PET findings would predict hormonally responsive breast cancer.

PATIENTS AND METHODS: Forty women with biopsy-proved advanced ER-positive (ER⁺) breast cancer underwent PET with FDG and FES before and 7 to 10 days after initiation of tamoxifen therapy; 70 lesions were evaluated. Tumor FDG and FES uptake were assessed semiquantitatively by the standardized uptake value (SUV) method. The PET results were correlated with response to hormonal therapy.

RESULTS: In the responders, the tumor FDG uptake increased after tamoxifen by 28.4% ± 23.3% (mean ± SD); only five of these patients had evidence of a clinical flare reaction. In nonresponders, there was no significant change in tumor FDG uptake from baseline (mean change, 10.1% ± 16.2%; P = .0002 v responders). Lesions of responders had higher baseline FES uptake (SUV, 4.3 ± 2.4) than those of nonresponders (SUV, 1.8 ± 1.3; P = .0007). All patients had evidence of blockade of the tumor ERs 7 to 10 days after initiation of tamoxifen therapy; however, the degree of ER blockade was greater in the responders (mean percentage decrease, 54.8% ± 14.2%) than in the nonresponders (mean percentage decrease, 19.4% ± 17.3%; P = .0003).

CONCLUSION: The functional status of tumor ERs can be characterized in vivo by PET with FDG and FES. The results of PET are predictive of responsiveness to tamoxifen therapy in patients with advanced ER⁺ breast cancer.

	INTRODUCTION

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APPROXIMATELY 15% of the 182,800 women who will be diagnosed with breast cancer in the United States this year will present with metastatic disease. Another 55,000 women will develop recurrent disease after initial treatment for a localized cancer. Thus, nearly 83,000 women will be candidates for treatment of advanced breast cancer.¹ Most breast cancers are estrogen receptor (ER)-positive (ER⁺) tumors² and therefore potentially hormone responsive. Despite this, chemotherapy often is chosen over hormonal therapy in the initial management of advanced breast cancer, at least in part because many physicians believe that chemotherapy is more likely to produce tumor shrinkage and to produce it more rapidly than hormonal agents. Even in elderly women, who tend to have a more indolent disease process, it has been reported that hormonal therapy is underused.^3,4 In advanced ER⁺ breast cancer, the likelihood of response to hormonal therapy is equivalent to the likelihood of response to chemotherapy.^5,6 A reliable method to predict whether a specific patient is likely to respond to hormonal therapy could lead to wider use of such treatment.

Clinical factors predictive of hormone sensitivity include a long disease-free interval, metastases to nonvisceral sites, high quantitative levels of ER in the tumor, the presence of the progesterone receptor (PR) in the tumor, and the development of a hormone-induced flare reaction.^7-9 Of these, the hormone-induced flare reaction may be the most reliable predictor of response; 75% to 90% of patients who experience a flare reaction demonstrate an objective response when treatment with the same hormone is continued.^10-12

It has been proposed that the apparent transient disease progression associated with the hormone-induced flare reaction is the result of an initial stimulation of tumor growth, which precedes tumor regression, and which is produced by temporary estrogen-like agonist effects induced by increased levels of the hormone.^13,14 Thus, flare may attest not only to the presence of ERs, but also to their capacity to regulate tumor metabolism and to mediate the action of hormonal agents that will control tumor growth. However, clinical flare reaction is of limited use as a predictor of hormone responsiveness, both because it may be impossible to distinguish between a flare and disease progression and because flare reactions are clinically appreciated in less than 5% of patients. It is likely that a flare reaction occurs in many more patients but is not symptomatic.^10-12 Therefore, if a reliable means could be developed to assess the metabolic correlates of hormone-induced tumor flare, this metabolic flare reaction might be detected at higher frequency and might be more readily distinguished from progression; this renders it potentially more useful in the prediction of hormone responsiveness.

Positron emission tomography (PET) is a noninvasive imaging method that is used for in vivo assessment of the function of normal and diseased tissues. PET with the radiolabeled glucose analog [¹⁸F]fluorodeoxyglucose (FDG) has been used extensively in oncologic imaging to exploit the observation that most cancer cells accumulate glucose (and FDG) more avidly than normal cells.¹⁵ FDG-PET has been used in patients with breast cancer for the detection of nodal and distant metastatic disease and for assessment of response to chemotherapy.^16-18 We have used another radiopharmaceutical, the radiolabeled estrogen analog 16 alpha-[¹⁸F]fluoroestradiol-17 beta (FES), to assess the functional status of tumor ERs in women with advanced breast cancer. In our experience, the tumor uptake of FES correlates with ER levels measured in vitro and may be more predictive of response to hormonal therapy than knowledge of the tumor ER status.^19,20

Given that a clinical flare reaction can predict response to hormonal therapy, we hypothesized that this biologic response would occur subclinically in a majority of women who eventually respond to a hormonal agent, and it might be detectable by functional imaging. To test this hypothesis, we used serial PET with both FDG and FES in women with advanced ER⁺ breast cancer, before and after treatment with tamoxifen, to identify the metabolic correlates of this subclinical flare reaction. We predicted that a metabolic flare reaction would be characterized on FDG-PET by an increase in the tumor uptake of this tracer 7 to 10 days after initiation of tamoxifen, because of the known partial estrogen-like stimulatory activity of this antiestrogen, which may be particularly apparent during the initial days of treatment when its levels are still low.^13,14 FES-PET was performed at baseline to determine whether the tumor ERs were functional in vivo. We predicted that after initiation of tamoxifen, a significant decrease in tumor uptake of the estrogen analog would indicate binding of tamoxifen or its metabolites to functional tumor ERs.

The preliminary results from 11 patients with metastatic breast cancer who were included in this study were reported previously.²¹ We report herein the final results of this clinical trial.

	PATIENTS AND METHODS

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Patients
Postmenopausal women with locally advanced, recurrent, or metastatic ER⁺ breast cancer were considered eligible provided that tamoxifen was to be the only systemic agent used to treat their disease. All patients had biopsy-proved ER⁺ tumors confirmed by immunohistochemical staining of the primary breast cancer or a recurrent or metastatic lesion. Patients were required to have assessable or measurable disease. Women who had received chemotherapy in the adjuvant setting or for previous recurrence were considered eligible for study if their disease had recurred more than 6 months after completion of chemotherapy. Participants were required to have Eastern Cooperative Oncology Group performance status of 0 to 2. The study was approved by the institutional review board and the radioactive drug research committee of Washington University School of Medicine. All patients gave written informed consent for study participation.

The pretreatment evaluation included a complete history and physical examination, complete blood count, liver function studies, tumor markers, computed tomography of the chest, abdomen, and pelvis, and skeletal scintigraphy. After the initial assessment and completion of pretherapy PET studies (described below), treatment with tamoxifen 20 mg per day was instituted. Patients were re-examined monthly by the treating medical oncologist, who was blinded to the results of PET imaging. Radiologic imaging was repeated every 2 months to assess response at sites of known disease. Assessment of response to therapy was determined by a single medical oncologist in accordance with standard criteria (see below).

PET Imaging
Patients underwent both FES-PET and FDG-PET before and 7 to 10 days after initiation of tamoxifen therapy. Imaging was performed with an ECAT EXACT scanner (Siemens-CTI, Knoxville, TN) that acquires 47 simultaneous slices over an axial extent of 16.2 cm. This tomograph has an intrinsic spatial resolution of 5.5 mm (full width at half maximum). Reconstructed spatial resolution under clinical imaging conditions is approximately 10 mm. A 10- to 15-minute transmission image was performed with a rotating ⁶⁸Ge/⁶⁸Ga rod source before FDG administration and immediately after each emission scan for FES-PET studies.

FDG was prepared on the basis of a published procedure²² with the PETrace FDG MicroLab synthesis module (General Electric Medical Systems, Uppsala, Sweden). FES was prepared by use of a robotic adaptation of previously described methods.²³ FES-PET and FDG-PET studies were performed on 2 separate days. For the FES study, approximately 6 mCi (222 MBq) of FES was administered intravenously. Approximately 90 minutes later, a 30-minute emission scan was obtained for the body region that included the lesion(s) of interest (as determined by physical examination or by reference to correlative imaging studies). Before the FDG-PET study, the patients fasted for at least 4 hours, and the blood glucose concentration was determined immediately before FDG injection to exclude fasting hyperglycemia. There was no significant difference in blood glucose levels measured at the time of the pre- and posttreatment FDG studies. Approximately 10 mCi (370 MBq) of FDG was administered intravenously, and a 60-minute dynamic emission imaging study of the same body region was begun immediately. For the purposes of the current study, the summed data from 30 to 60 minutes postinjection were used for image analysis. Emission images were reconstructed by filtered back projection with use of a Hanning filter (cutoff frequency, 0.6 x Nyquist frequency) and were corrected for attenuation.

Response Criteria
Clinical response was defined by standard criteria and was determined by the treating oncologist at the monthly follow-up visits. A complete response was defined as the disappearance of all clinically detectable disease for at least 4 weeks. A partial response was defined as a decrease of 50% or more in the sum of the products of the biperpendicular dimensions of all measurable lesions that lasted for at least 4 weeks. Stable disease was defined as measurable or assessable disease that decreased by less than 50% or remained unchanged in size. In hormone-sensitive disease, a survival advantage is observed for women who have stable disease for 6 months.^24,25 Accordingly, patients who met this criterion are grouped with those who achieved complete and partial response as "treatment responders." Progression of disease was defined as an increase in tumor dimensions by 25% or more.

For patients with osseous metastases as the sole site of metastatic disease, a complete response was defined as disappearance of all objective and clinical disease, including complete normalization of skeletal scintigrams and radiographs. A partial response was defined as a decrease in pain with evidence of recalcification of known osseous lesions on radiography. Disease progression was defined as worsened disease on scintigrams or radiographs or worsened pain and a decline in performance status. Any response that did not meet the criteria for complete response, partial response, or progression was defined as stable disease.

Hormone Flare Reaction
A clinical flare reaction was considered to have occurred if the patient developed worsened pain or an increase in cutaneous and soft tissue disease after initiation of therapy. A serologic flare was defined as an increase in serum tumor markers, alkaline phosphatase, or calcium. The treating medical oncologist was ultimately responsible for the determination of whether these signs and symptoms were more probably attributable to disease progression or to flare reaction.

Data Analysis
All PET images were evaluated semiquantitatively by analysis of the standardized uptake values (SUVs) of tumor foci. The SUV is the ratio of the decay-corrected activity per unit volume of tissue (nCi/mL) to the administered activity per unit of body weight (nCi/g).²⁶ The absolute initial SUVs as well as both the absolute and percentage changes in SUVs were recorded for both FDG and FES. In patients with multiple lesions, the SUVs of all the lesions observed on PET images were determined and the overall average values for all lesions in a given patient were recorded; these overall average values were used in the comparison of PET findings with clincial response. The absolute pretreatment SUVs for FES and the changes in SUVs for both FES and FDG after treatment were compared in responders and nonresponders with use of the Wilcoxon signed-rank test. To determine the strongest predictor(s) of response, Wilcoxon two-sample tests and univariate logistic regression analyses also were performed with odds ratios computed for each unit increase in baseline SUVs, for each unit increase in absolute changes in SUVs, and for each percentage change in SUVs.²⁷

	RESULTS

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Patient Characteristics
Forty-eight women were enrolled onto the study between January 1995 and April 1999. Eight patients were excluded: two were too ill to complete the PET imaging protocol; one received chemotherapy before response to tamoxifen could be assessed; in three patients, the tumor was found to be too small to be reliably assessed by PET after baseline FDG imaging, so the remainder of the protocol was not performed; and in two patients, the PET images were inadequate because of patient motion or poorly controlled diabetes mellitus. The demographic characteristics of the 40 assessable patients are summarized in Table 1. Their median age was 58 years (range, 36 to 82 years). Twenty-one patients (52%) had metastatic disease and 19 had either locally advanced primary cancers or recurrent disease of the chest wall. As required by the protocol, the tumors were ER⁺ in all 40 patients; the tumors in 32 patients were also PR-positive (PR⁺). The receptor status was determined for the original primary tumor or index recurrent or metastatic lesion in 34 patients; in the remaining six patients, the receptor status of metastatic or recurrent lesions was assumed to be the same as that of the original primary tumor. Thirty-one patients (78%) were treatment naive, five had developed recurrent disease after adjuvant chemotherapy, and four had received chemotherapy as treatment for advanced disease. None had received prior hormonal therapy.

View larger version (12K): [in this window] [in a new window]   Fig 1. (A) The baseline tumor uptake of FES; (B) the percentage increase in tumor uptake for FDG after 7 to 10 days of tamoxifen treatment in patients who responded and who did not respond to treatment.

When an increase in tumor FDG uptake of 10% or greater was arbitrarily selected as the cutoff criterion for defining metabolic flare, the positive-predictive value for response to hormonal therapy was 91% (20 of 22 such patients responded). The negative-predictive value for a change in tumor FDG uptake of less than 10% was 94% (17 of 18 such patients failed to respond). The positive- and negative-predictive values for baseline FES uptake (using an arbitrarily selected cutoff SUV of 2.0 for defining functional ERs) were 79% (19 of 24 such patients responded) and 88% (14 of 16 such patients failed to respond), respectively.

By use of univariate logistic regression analysis, response to tamoxifen was predicted by all FES uptake measurements (baseline uptake and both the absolute and percentage change) and by the change in FDG uptake (both absolute and percentage change). With use of the baseline FES uptake, the odds ratio (95% confidence interval) for response is 2.35 (1.34 to 4.10; P = .0029). The odds ratio for response with use of the absolute change in FDG uptake was 2.02 (1.07 to 3.8; P = .03), and with use of the percentage change in FDG uptake it was 1.14 (1.04 to 1.24; P = .003).

In a multivariate logistic regression analysis, the combination of baseline FES uptake and the percentage change in FDG uptake predicted a hormonal response with odds ratios of 3.4 (1.08 to 10.59) for baseline FES uptake and 1.13 (1.04 to 1.23) for percentage change in FDG uptake. Overall, P = .011 for the model.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Hormonal therapies are consistently underused in the management of breast cancer, although the majority of patients have ER⁺ disease.^3,4 The presence of ER alone predicts clinical benefit in 55% to 60% of patients. If both ER and PR are present, the likelihood of benefit increases only slightly, to 60% to 70%.^7-9 The presence of a hormone receptor does not indicate that the receptor is functional and essential to the growth of the cancer cell, of course, nor does it imply that interference with receptor function will result in tumor-cell kill. None of the available serologies, prognostic factors, or radiologic studies can accurately predict for clinical benefit from hormonal therapy.

Hormone flare reactions seem to be more predictive of hormone responsiveness than the results of receptor assays, because flare indicates that the receptors are both present and functional. The flare reaction typically occurs in postmenopausal women with ER⁺ breast cancer and osseous metastases. Within 7 to 10 days of initiation of hormonal therapy, patients develop increased pain at metastatic sites, often accompanied by increased serum calcium, alkaline phosphatase, or tumor markers.^10-13 Serial skeletal scintigraphy may show increased activity at sites of known metastasis or may identify areas not appreciated on pretreatment scintigrams.¹¹ Although this clinical presentation often is indistinguishable from disease progression, true hormone-induced flare reactions herald subsequent response to treatment in 75% to 90% of patients.^10-13 Nevertheless, clinical flare is of limited use in the prediction of response because it is uncommon (observed in less than 5% of patients), although it may occur at a subclinical level in more patients.

The concept of flare reaction used to predict a response to hormonal therapy is not new. Many years ago, surgeons administered stilbestrol 10 mg daily for 3 days to women with inoperable breast cancer and osseous metastases, to determine whether adrenalectomy or oophorectomy should be performed. Patients who experienced a 50% or greater increase in 24-hour urinary calcium excretion or who developed increased bone pain were considered candidates for a surgical ablative procedure.²⁸ Although the scintigraphic flare phenomenon was first described in 1972,²⁹ its reliability as an indicator of response to hormonal therapy has not been studied widely.¹¹ Furthermore, predictive use of scintigraphic flare has several important limitations. Skeletal scintigraphy is of value only in the 50% to 60% of patients with osseous lesions as a component of the metastatic process. It is further compromised by its lack of specificity; apparent worsening on skeletal scintigraphy can be observed with both flare reaction and disease progression. Neither the treating clinician nor the radiologist can accurately distinguish between the two. Thus, for hormone-induced flare to be useful in the prediction of hormone responsiveness, an objective method is needed to identify hormone-induced flare in all patients in whom it occurs, whether they are symptomatic or not. This method also should accurately distinguish between flare reaction and progression of disease at all sites of metastatic disease. Our results suggest that PET may fulfill these objectives.

Our findings support our hypothesis that tumor receptor levels and hormone-induced metabolic flare reactions can be assessed by imaging in vivo with FES-PET and FDG-PET. The most important single predictors of response to tamoxifen were the baseline FES uptake (P = .0007) and the change in FDG uptake after tamoxifen (P = .0002). Our results further indicate that metabolic flare reactions occur in most patients who respond to tamoxifen, although concomitant clinical flare reactions are recognized infrequently. The treating oncologist suspected a clinical flare reaction in six of our patients (16%). Of these, a pattern of metabolic flare was documented by FDG-PET in the five responders and was not observed in the patient who experienced disease progression. In comparison, metabolic flare detected by PET (cutoff increase in tumor FDG uptake, 10%) had positive- and negative-predictive values for response to tamoxifen of 91% and 94%, respectively. The corresponding positive- and negative-predictive values for the baseline FES uptake (cutoff SUV, 2.0) were 79% and 88%, respectively. Furthermore, serial PET with FES and FDG before and after initiation of tamoxifen therapy can accurately predict subsequent response within 10 days after therapy begins, in contrast to the several weeks often required to make this assessment on the basis of clinical symptoms or objective evaluation of assessable or measurable disease.

Accessibility to PET imaging has increased as the technology has gained acceptance in the management of different disease processes. Currently, there are more than 160 PET facilities in the United States. FDG is the most commonly used radiopharmaceutical for PET, and it is now commercially available in most areas of the United States. Therefore, at minimum, the FDG-PET component of our method to assess the change in tumor FDG uptake after starting tamoxifen therapy, which was the best single predictor of response, could be applied to patients treated in the community setting. Physicians who treat advanced ER⁺ breast cancer may be more comfortable with hormonal therapies, if they could quickly and accurately identify the flare reaction and distinguish between it and progression of disease, as we propose can be achieve by use of PET. The potential impact of such a strategy on the patient’s quality of life is obvious.

The present study included only patients who received tamoxifen as the initial treatment for their advanced disease. Many women who present with metastatic disease already have been treated with tamoxifen in the adjuvant setting. In such patients, an aromatase inhibitor is used as second-line hormonal therapy. On the basis of the results of the current study, we are exploring the use of serial PET imaging to predict response to second- and third-line hormonal therapy. We think that the information provided by PET will allow for optimal selection of the most appropriate systemic therapy in individual patients with advanced breast cancer.

	ACKNOWLEDGMENTS

 
Supported by grant no. CA48286 from the National Institutes of Health, and in part by grant no. CA25836 from the National Institutes of Health and grant nos. DE-FG02 to 84ER60218 from the Department of Energy.

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Submitted October 31, 2000; accepted February 23, 2001.

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