Approximately one in four women suspected of distant recurrence on [18F]FDG-PET/CT were diagnosed with MBC by biopsy in a daily clinical setting. The posterior probability of a positive [18F]FDG-PET/CT for any metastatic cancer was 85%; however, examinations of the false-positive findings were performed in one of six. Incidental malignant findings other than MBC were suspected by [18F]FDG-PET/CT in every five women, and further examinations revealed other cancer diseases in approximately one-fifth of them. Sensitivity, specificity, and AUC-ROC of [18F]FDG-PET/CT were 1.00, 0.88, and 0.98, respectively.
Clinical benefits of [18F]FDG-PET/CT in women suspected of recurrent breast cancer are reflected by the prior- and posterior probabilities of being diagnosed with metastatic cancer. However, the clinical drawbacks are the high false-positive rate that implies a risk for referral for supplemental examinations of which the patient could have been spared. For the latter, downplaying the harmfulness of such findings, e.g., in the colon or lungs, and carefully weighing the communication to the patient seems of great importance. Hesitancy to invasive procedures and watchful waiting should be considered instead of not referring to [18F]FDG-PET/CT.
In total, 18 other cancers were detected by [18F]FDG-PET/CT. In nine patients, the origin of the detected metastases was suggested to be breast cancer, and [18F]FDG-PET/CT suggested synchronous cancer in the remaining 9 of 225 patients (4%). This number corresponds well with the 3.88% of incidental findings in a population of high-risk primary breast cancer in the same institution and time [10]. Other studies on different cancers have also found between 1–8% of additional malignancies at [18F]FDG-PET/CT [9, 15–18].
Colon and the thyroid gland were the most common lesions with [18F]FDG-uptake that needed further examination. None of the patients (0 of 12) in this cohort were diagnosed with colorectal cancer, but one out of 12 patients (8.3%) with focal [18F]FDG-uptake in the thyroid gland was diagnosed with thyroid cancer. Our findings are based on small numbers but correspond well with the approximately 8% malignancy rates found in other studies of focal [18F]FDG-uptake in the thyroid gland [19, 20].
This study confirms the high diagnostic accuracy of [18F]FDG-PET/CT in examining suspected recurrent breast cancer reported in previous studies [4, 21]. We found distant metastases in 52 of 225 (23.1%) women with clinically suspected recurrent breast cancer referred for [18F]FDG-PET/CT, which is in line with an earlier study in our institution [4] with 22 of 100 (22.0%) diagnosed with distant metastases. The sensitivity of 1.00 was equal to that in the earlier study, but we found a slightly lower specificity of 0.88 (0.82–0.92) compared with 0.91 (0.83–0.96) earlier. The higher rate of false-positive findings was related to the diagnosis of other malignancies in nine patients where metastatic lesions detected on [18F]FDG-PET/CT were considered to be from breast cancer. Further, another seven patients had suspected metastatic lesions with inconclusive biopsy results and no progression of lesions during follow-up, and hence they were considered false-positive.
Patients had [18F]FDG-PET/CT performed with diagnostic contrast-enhanced CT, which exposes them to a radiation dose of 12–16 mSv. The excess radiation dose for women in this study was restricted compared with the traditional examination program of CE-CT and bone scintigraphy, with a combined radiation dose of approximately 14 mSv.
A major strength in this study is the prospective design of daily clinical practice with confirmatory biopsies for patients diagnosed with MBC. Further, the overall clinical impact of the false-positive rate and accuracy was evaluated. The study was registered at ClinicalTrials.gov with an enrolment of patients with high-risk primary breast cancer. This population has been described elsewhere as the clinical impact of [18F]FDG-PET/CT differs between patients with high-risk primary breast cancer and patients suspected of recurrent breast cancer [10]. Another strength is that we managed to reproduce and validate the diagnostic accuracy of an earlier study [4]. Reproducibility and transparency are key parts of the scientific path and crucial for implementing research results in clinical guidelines [22–25]. Despite excellent sensitivity and high specificity, [18F]FDG-PET/CT remains to be implemented in clinical guidelines as the diagnostic modality for recurrent breast cancer.
Limitations include the single-center validation design and lack of comparison of [18F]FDG-PET/CT with CE-CT and bone scintigraphy. However, we consider the existing evidence substantial supporting the use of [18F]FDG-PET/CT to be superior in diagnosing distant metastases compared with CE-CT and bone scintigraphy [4–6].
[18F]FDG-PET/CT has already been implemented as a stand-alone examination in suspected recurrent breast cancer in our institution. Although we acknowledge the impact of supplemental examinations and the shortage of [18F]FDG-PET/CT scanners in other countries, we wish to encourage [18F]FDG-PET/CT to be implemented in clinical guidelines for diagnosing recurrent breast cancer.
Clinical follow-up after early-stage breast cancer comprises mammography, and no recommendations exist on whole-body examinations, particularly not for high-risk patients. However, these recommendations arose from a former time with less advanced image techniques and less efficacious treatments for MBC [7]. Since patients in this study had very widespread disease with more than five metastatic lesions, a perspective for future studies could be to explore the impact of [18F]FDG-PET/CT as follow-up after high-risk early-stage breast cancer, i.e., patients treated for locally advanced breast cancer, extensive lymph node involvement in the axilla, triple-negative, and HER2 positive breast cancer. Such studies should be designed to address the false-positive rates and cost-benefit analyses as well. [18F]FDG-PET/CT has high sensitivity and could be the modality to detect oligometastatic disease, which could translate into potential patient benefit.