Comparison of diagnostic sensitivity of [¹⁸F]fluoroestradiol and [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography for breast cancer recurrence in patients with a history of estrogen receptor-positive primary breast cancer

Breast cancer is one of the most frequently diagnosed cancers and is the leading cause of cancer death in women [1]. About 75% of all breast cancer expresses estrogen receptor (ER) at the time of initial diagnosis [2]. The 20-year risk of distant recurrence after adjuvant endocrine therapy for ER-positive breast cancer ranges from 10 to 40% [3]. The diagnosis of recurrence and restaging are important for determining appropriate treatment [4].

Current guidelines on breast cancer recommend that the staging evaluation of women who present with recurrent breast cancer includes standard imaging studies [5, 6]. Positron emission tomography/computed tomography (PET/CT) with [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) would only be used in situations where standard staging studies are equivocal or suspicious [5, 6]. Although clinical studies have indicated high diagnostic accuracy with sensitivities ranging from 81 to 100% and specificities ranging from 52 to 91% and have suggested the superiority of [¹⁸F]FDG PET/CT over standard imaging studies [7‐11], these studies are largely retrospective with heterogeneous cohorts, and there are also methodological issues of concern [7, 10, 11]. The diagnostic accuracy was not separately determined in patients who presented with equivocal or suspicious imaging studies [8, 12‐14]. In addition, both false-negative and false-positive [¹⁸F]FDG PET/CT results [7, 10] are inherent in [¹⁸F]FDG PET/CT [15, 16]. The consensus is that biopsy is more likely to provide useful information [6]. Moreover, the reference standard used in previous studies has ranged from histopathological diagnosis to clinical or radiological follow-up, and misclassification of disease might have led to positive or negative biases. Finally, the positivity threshold of [¹⁸F]FDG PET/CT may differ between studies, depending on how to determine the foci of increased [¹⁸F]FDG uptake are related to benign conditions. Equivocal decisions are therefore likely to be inevitable [8, 9, 11, 12, 17‐19].

The histological and biological characteristics of breast cancer have an important impact on tumor visualization with [¹⁸F]FDG PET/CT [20]. [¹⁸F]FDG uptake correlates with histologic grade and tumor proliferation index [15, 21, 22], and [¹⁸F]FDG uptake is higher in ER-negative tumors [15]. Accordingly, the relatively lower [¹⁸F]FDG uptake in ER-positive breast cancer may affect the diagnostic accuracy. To date, the accuracy of [¹⁸F]FDG PET/CT for the diagnosis of recurrent breast cancer has not been separately reported in patients with ER-positive primary breast cancer.

PET/CT with [¹⁸F]fluoroestradiol ([¹⁸F]FES) provides a unique method to noninvasively assess molecular information on ER expression [23, 24]. The diagnostic sensitivity of [¹⁸F]FES PET/CT for the assessment of ER status in recurrent or metastatic lesions is good overall [25‐31], which indicates a high sensitivity for diagnosing recurrent breast cancer in patients with a history of ER-positive primary breast cancer. Of particular importance is the very high specificity of [¹⁸F]FES PET/CT [25‐31], with no false-positives having been reported in qualitative [¹⁸F]FES studies. Therefore, [¹⁸F]FES PET/CT can be used as an alternative to tissue biopsy and ER assays [31] and may improve clinical decision-making when conventional work-up is inconclusive [32]. To our knowledge, the use of [¹⁸F]FES PET/CT in the diagnosis of recurrent breast cancer in comparison with [¹⁸F]FDG PET/CT has not so far been studied.

Recently, we conducted a prospective cohort study to assess the diagnostic accuracy of [¹⁸F]FES PET/CT for ER status in recurrent lesions in patients with breast cancer [31]. The included participants were a consecutive series of all patients presenting with symptoms and imaging findings of recurrent breast cancer with histological confirmation of recurrent lesions. Most participants underwent [¹⁸F]FDG PET/CT for clinical reasons. The direct comparison of [¹⁸F]FDG and [¹⁸F]FES PET/CT in the same population is robust, as differences in potential modifiers associated with the population, study methods, and technologies can be eliminated. In the current study, we aimed to compare the diagnostic sensitivity of [¹⁸F]FDG and [¹⁸F]FES PET/CT for breast cancer recurrence in patients with ER-positive primary breast cancer who were enrolled in a previous cohort study.

In this study, we showed that [¹⁸F]FES PET/CT had comparable diagnostic sensitivity to [¹⁸F]FDG PET/CT for the diagnosis of recurrent breast cancer when positive [¹⁸F]FDG uptake was used as a threshold. However, [¹⁸F]FES PET/CT had significantly lower sensitivity than [¹⁸F]FDG PET/CT if equivocal [¹⁸F]FDG uptake was included as a positive threshold. When ER-positive recurrent breast cancer was analyzed, there was no significant difference in sensitivity between [¹⁸F]FDG and [¹⁸F]FES PET/CT. One patient with a benign lesion showed true-negative [¹⁸F]FES but false-positive [¹⁸F]FDG uptake. To the best of our knowledge, this is the first study evaluating the diagnostic performance of [¹⁸F]FES and [¹⁸F]FDG PET/CT relative to histological results in patients with ER-positive primary breast cancer.

In this study, we included only ER-positive primary cancer patients in whom [¹⁸F]FES PET/CT would be likely to show high sensitivity. The sensitivity of [¹⁸F]FES PET/CT was comparable to or lower than that of [¹⁸F]FDG, depending on the threshold used. All four patients with ER-negative recurrence showed negative [¹⁸F]FES PET/CT. However, the false-negative [¹⁸F]FES PET/CT results were of relevance, because discordant ER expression between primary and recurrent breast cancer was accurately determined. We also had nine false-negative patients who displayed ER-positive immunohistochemistry but negative [¹⁸F]FES. As seven of the nine [¹⁸F]FES-negative patients showed a positive [¹⁸F]FDG uptake, the false-negative results cannot be explained by the limited spatial resolution of PET/CT, but rather reflect the low ER expression levels in tumor, or inherent differences between ER assays and [¹⁸F]FES uptake [31, 39]. ER-positive but [¹⁸F]FES-negative tumors may represent a functionally endocrine therapy-resistant breast cancer [23, 24]. Further studies are required to clearly characterize those patients with recurrent breast cancer who are ER-positive but [¹⁸F]FES-negative.

An [¹⁸F]FES PET/CT strategy for diagnosing recurrent breast cancer would have false-negative results, which would generally lead to delayed treatment [7]. Therefore, [¹⁸F]FDG PET/CT may be offered for patients who are [¹⁸F]FES-negative. Despite the theoretically lower sensitivity of [¹⁸F]FES PET/CT for breast cancer recurrence, positive [¹⁸F]FES uptake could replace histological diagnosis of recurrent breast cancer and positive ER expression [31] and could lead to a reduction in the number of false-positive diagnoses and biopsies compared with [¹⁸F]FDG PET/CT [40]. [¹⁸F]FES PET/CT would be of additional value in whole-body imaging for tumors expressing ER, to identify the subset of patients with mixed [¹⁸F]FES uptake, as shown in the three patients with heterogeneous uptake [41]. However, an [¹⁸F]FDG PET/CT-first strategy may have lower false-negative results. Nevertheless, positive [¹⁸F]FDG results still require histological confirmation and assessment of ER status, and even negative [¹⁸F]FDG cannot completely exclude the possibility of recurrent breast cancer; therefore, biopsies of possible breast cancer recurrence may still be performed. If collecting a biopsy sample is not feasible or associated with risk, positive [¹⁸F]FES PET/CT results can adequately diagnose ER-positive recurrent breast cancer and represent an alternative to histological assessment. Our results suggest that although [¹⁸F]FES PET/CT may have a slightly lower sensitivity than [¹⁸F]FDG, staging evaluation of women who had ER-positive primary breast cancer and then present with recurrent disease could include [¹⁸F]FES PET/CT. An [¹⁸F]FES PET/CT-first strategy for recurrent cancer may lead to changes in patient management and have an impact on outcomes.

Diagnostic accuracy studies are at risk of bias due to shortcomings in their design and conduct, and the results may not be applicable to other patient populations [42]. We retrospectively reviewed our database of a prospective cohort who underwent [¹⁸F]FES PET/CT for the assessment of ER status in recurrent lesions, and included consecutive patients who were typical of those presenting for first breast cancer recurrence. However, our patient inclusion and exclusion criteria may have resulted in potential risks and limited applicability. We enrolled only those patients who had histological confirmation and who underwent [¹⁸F]FES PET/CT for restaging to guide optimal therapy. The diagnostic sensitivity may be higher if lesions are large enough for a tissue biopsy to be attained. In addition, PET/CT studies might have not been performed in situations where standard staging studies are equivocal or suspicious, as recommended by the guidelines. Nevertheless, we believe that the primary purpose of this study, which was to compare sensitivity between [¹⁸F]FDG and [¹⁸F]FES PET/CT, is unlikely to be influenced by our patient selection. We excluded only one patient who had no [¹⁸F]FDG PET/CT. In most patients, the [¹⁸F]FDG studies were performed for clinical reasons. There are no other potential risks of bias or applicability regarding the quality of the diagnostic sensitivity data [43]. Furthermore, the qualitative [¹⁸F]FES positivity threshold could be precisely determined, as suggested by a very low P level for the differences in SUV results between the dichotomous qualitative [¹⁸F]FES categories.

There are several limitations to this study. First, we enrolled only one patient with a benign inflammatory lesion. It was not possible to directly demonstrate a high specificity of [¹⁸F]FES PET/CT compared with [¹⁸F]FDG PET/CT; however, the main concern was how the sensitivity of [¹⁸F]FES differs from that of [¹⁸F]FDG in patients with ER-positive primary breast cancer. A comparison of the specificity of [¹⁸F]FES and [¹⁸F]FDG PET/CT can be inferred from previous studies. Second, we did not include asymptomatic patients with elevated tumor markers. Our results may not be applicable to the specific setting of rising tumor markers. Third, this study may have verification bias in which the positive results of [¹⁸F]FDG PET/CT in 13 patients could affect the biopsy decision leading to a high sensitivity estimate. Nonetheless, the sensitivity of [¹⁸F]FES PET/CT was comparable to that of [¹⁸F]FDG PET/CT when positive interpretation was defined as positive for the presence of recurrent breast cancer. Finally, we did not assess the diagnostic value of [¹⁸F]FDG and [¹⁸F]FES PET/CT in addition to or instead of standard imaging tests. [¹⁸F]FES PET/CT can be performed as an initial test in the setting of recurrent disease when standard imaging studies are equivocal or suspicious.

The sensitivity of [¹⁸F]FES PET/CT in patients who had ER-positive breast cancer and presented with recurrent disease was comparable to or lower than that of ¹⁸F-FDG, depending on the threshold used. Although we were not able to directly demonstrate a high specificity in this study, the well-established high specificity indicates that positive [¹⁸F]FES PET/CT results can adequately diagnose ER-positive recurrent breast cancer. [¹⁸F]FES PET/CT would be of additional value in whole-body imaging of tumor ER expression, to identify additional patients with recurrence with mixed [¹⁸F]FES uptake. We conclude that the restaging of women who have ER-positive primary breast cancer and present with recurrent disease may include [¹⁸F]FES PET/CT. Large-scale prospective intervention studies are needed to investigate the potential utility of [¹⁸F]FES PET/CT as a replacement for, rather than an addition to, standard imaging studies, and to determine the impact of [¹⁸F]FES PET/CT on patient outcomes.